The Food and Drug Administration's policy in administering the new-drug, antibiotic, and other regulatory provisions of the Federal Food, Drug, and Cosmetic Act regarding fixed combination dosage form prescription drugs for humans is as follows:

(a) Two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug. Special cases of this general rule are where a component is added:

(1) To enhance the safety or effectiveness of the principal active component; and

(2) To minimize the potential for abuse of the principal active component.

(b) If a combination drug presently the subject of an approved new-drug application has not been recognized as effective by the Commissioner of Food and Drugs based on his evaluation of the appropriate National Academy of Sciences-National Research Council panel report, or if substantial evidence of effectiveness has not otherwise been presented for it, then formulation, labeling, or dosage changes may be proposed and any resulting formulation may meet the appropriate criteria listed in paragraph (a) of this section.

(c) A fixed-combination prescription drug for humans that has been determined to be effective for labeled indications by the Food and Drug Administration, based on evaluation of the NAS-NRC report on the combination, is considered to be in compliance with the requirements of this section.

The use of chlorofluorocarbons in human drugs as propellants in self-pressurized containers is generally prohibited except as provided by § 2.125 of this chapter.

As used in this part:

(a) The term act means the Federal Food, Drug, and Cosmetic Act, as amended (secs. 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

(b) Department means the Department of Health and Human Services.

(c) Secretary means the Secretary of Health and Human Services.

(d) Commissioner means the Commissioner of Food and Drugs.

(e) The term person includes individuals, partnerships, corporations, and associations.

(f) The definitions and interpretations of terms contained in section 201 of the act shall be applicable to such terms when used in the regulations in this part.

(g) New drug substance means any substance that when used in the manufacture, processing, or packing of a drug, causes that drug to be a new drug, but does not include intermediates used in the synthesis of such substance.

(h) The newness of a drug may arise by reason (among other reasons) of:

(1) The newness for drug use of any substance which composes such drug, in whole or in part, whether it be an active substance or a menstruum, excipient, carrier, coating, or other component.

(2) The newness for a drug use of a combination of two or more substances, none of which is a new drug.

(3) The newness for drug use of the proportion of a substance in a combination, even though such combination containing such substance in other proportion is not a new drug.

(4) The newness of use of such drug in diagnosing, curing, mitigating, treating, or preventing a disease, or to affect a structure or function of the body, even though such drug is not a new drug when used in another disease or to affect another structure or function of the body.

(5) The newness of a dosage, or method or duration of administration or application, or other condition of use prescribed, recommended, or suggested in the labeling of such drug, even though such drug when used in other dosage, or other method or duration of administration or application, or different condition, is not a new drug.

(i) [Reserved]

(j) The term sponsor means the person or agency who assumes responsibility for an investigation of a new drug, including responsibility for compliance with applicable provisions of the act and regulations. The “sponsor” may be an individual, partnership, corporation, or Government agency and may be a manufacturer, scientific institution, or an investigator regularly and lawfully engaged in the investigation of new drugs.

(k) The phrase related drug(s) includes other brands, potencies, dosage forms, salts, and esters of the same drug moiety, including articles prepared or manufactured by other manufacturers: and any other drug containing a component so related by chemical structure or known pharmacological properties that, in the opinion of experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, it is prudent to assume or ascertain the liability of similar side effects and contraindications.

(l) Special packaging as defined in section 2(4) of the Poison Prevention Packaging Act of 1970 means packaging that is designed or constructed to be significantly difficult for children under 5 years of age to open or obtain a toxic or harmful amount of the substance contained therein within a reasonable time and not difficult for normal adults to use properly, but does not mean packaging which all such children cannot open or obtain a toxic or harmful amount within a reasonable time.

(m) [Reserved]

(n) The term radioactive drug means any substance defined as a drug in section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act which exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons and includes any nonradioactive reagent kit or nuclide generator which is intended to be used in the preparation of any such substance but does not include drugs such as carbon-containing compounds or potassium-containing salts which contain trace quantities of naturally occurring radionuclides. The term “radioactive drug” includes a “radioactive biological product” as defined in § 600.3(ee) of this chapter.

(a) If a drug has an approved license under section 351 of the Public Health Service Act (42 U.S.C. 262 et seq.) or under the animal virus, serum, and toxin law of March 4, 1913 (21 U.S.C. 151 et seq.), it is not required to have an approved application under section 505 of the act.

(b) To obtain marketing approval for radioactive biological products for human use, as defined in § 600.3(ee) of this chapter, manufacturers must comply with the provisions of § 601.2(a) of this chapter.

(a) The Food and Drug Administration's conclusions on the effectiveness of drugs are currently being published in the Federal Register as Drug Efficacy Study Implementation (DESI) Notices and as Notices of Opportunity for Hearing. The specific products listed in these notices include only those that were introduced into the market through the new drug procedures from 1938-62 and were submitted for review by the National Academy of Sciences-National Research Council (NAS-NRC), Drug Efficacy Study Group. Many products which are identical to, related to, or similar to the products listed in these notices have been marketed under different names or by different firms during this same period or since 1962 without going through the new drug procedures or the Academy review. Even though these products are not listed in the notices, they are covered by the new drug applications reviewed and thus are subject to these notices. All persons with an interest in a product that is identical, related, or similar to a drug listed in a drug efficacy notice or a notice of opportunity for a hearing will be given the same opportunity as the applicant to submit data and information, to request a hearing, and to participate in any hearing. It is not feasible for the Food and Drug Administration to list all products which are covered by an NDA and thus subject to each notice. However, it is essential that the findings and conclusions that a drug product is a “new drug” or that there is a lack of evidence to show that a drug product is safe or effective be applied to all identical, related, and similar drug products to which they are reasonably applicable. Any product not in compliance with an applicable drug efficacy notice is in violation of section 505 (new drugs) and/or section 502 (misbranding) of the act.

(b)(1) An identical, related, or similar drug includes other brands, potencies, dosage forms, salts, and esters of the same drug moiety as well as of any drug moiety related in chemical structure or known pharmacological properties.

(2) Where experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs would conclude that the findings and conclusions, stated in a drug efficacy notice or notice of opportunity for hearing, that a drug product is a “new drug” or that there is a lack of evidence to show that a drug product is safe or effective are applicable to an identical, related, or similar drug product, such product is affected by the notice. A combination drug product containing a drug that is identical, related, or similar to a drug named in a notice may also be subject to the findings and conclusions in a notice that a drug product is a “new drug” or that there is a lack of evidence to show that a drug product is safe or effective.

(3) Any person may request an opinion on the applicability of such a notice to a specific product by writing to the Food and Drug Administration at the address shown in paragraph (e) of this section.

(c) Manufacturers and distributors of drugs should review their products as drug efficacy notices are published and assure that identical, related, or similar products comply with all applicable provisions of the notices.

(d) The published notices and summary lists of the conclusions are of particular interest to drug purchasing agents. These agents should take particular care to assure that the same purchasing policy applies to drug products that are identical, related, or similar to those named in the drug efficacy notices. The Food and Drug Administration applies the same regulatory policy to all such products. In many instances a determination can readily be made as to the applicability of a drug efficacy notice by an individual who is knowledgeable about drugs and their indications for use. Where the relationships are more subtle and not readily recognized, the purchasing agent may request an opinion by writing to the Food and Drug Administration at the address shown in paragraph (e) of this section.

(e) Interested parties may submit to the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Compliance, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, the names of drug products, and of their manufacturers or distributors, that should be the subject of the same purchasing and regulatory policies as those reviewed by the Drug Efficacy Study Group. Appropriate action, including referral to purchasing officials of various government agencies, will be taken.

(f) This regulation does not apply to OTC drugs identical, similar, or related to a drug in the Drug Efficacy Study unless there has been or is notification in the Federal Register that a drug will not be subject to an OTC panel review pursuant to §§ 330.10, 330.11, and 330.5 of this chapter.

(a) Over the years since 1938 the Food and Drug Administration has given informal advice to inquirers as to the new drug status of preparations. These drugs have sometimes been identified only by general statements of composition. Generally, such informal opinions were incorporated in letters that did not explicitly relate all of the necessary conditions and qualifications such as the quantitative formula for the drug and the conditions under which it was prescribed, recommended, or suggested. This has contributed to misunderstanding and misinterpretation of such opinions.

(b) These informal opinions that an article is “not a new drug” or “no longer a new drug” require reexamination under the Kefauver-Harris Act (Public Law 87-781; 76 Stat. 788-89). In particular, when approval of a new drug application is withdrawn under provisions of section 505(e) of the Federal Food, Drug, and Cosmetic Act, a drug generally recognized as safe may become a “new drug” within the meaning of section 201(p) of said act as amended by the Kefauver-Harris Act on October 10, 1962. This is of special importance by reason of proposed actions to withdraw approval of new drug applications for lack of substantial evidence of effectiveness as a result of reports of the National Academy of Sciences - National Research Council on its review of drug effectiveness; for example, see the notice published in the Federal Register of January 23, 1968 (33 FR 818), regarding rutin, quercetin, et al.

(c) Any marketed drug is a “new drug” if any labeling change made after October 9, 1962, recommends or suggests new conditions of use under which the drug is not generally recognized as safe and effective by qualified experts. Undisclosed or unreported side effects as well as the emergence of new knowledge presenting questions with respect to the safety or effectiveness of a drug may result in its becoming a “new drug” even though it was previously considered “not a new drug.” Any previously given informal advice that an article is “not a new drug” does not apply to such an article if it has been changed in formulation, manufacture control, or labeling in a way that may significantly affect the safety of the drug.

(d) For these reasons, all opinions previously given by the Food and Drug Administration to the effect that an article is “not a new drug” or is “no longer a new drug” are hereby revoked. This does not mean that all articles that were the subjects of such prior opinions will be regarded as new drugs. The prior opinions will be replaced by opinions of the Food and Drug Administration that are qualified and current on when an article is “not a new drug,” as set forth in this subchapter.

(a) The Food and Drug Administration is aware of the need in the practice of medicine for the ingredients of a new drug to be available for tests of hypersensitivity to such ingredients and therefore will not object to the shipment of a new drug substance, as defined in § 310.3(g), for such purpose if all of the following conditions are met:

(1) The shipment is made as a result of a specific request made to the manufacturer or distributor by a practitioner licensed by law to administer such drugs, and the use of such drugs for patch testing is not promoted by the manufacturer or distributor.

(2) The new drug substance requested is an ingredient in a marketed new drug and is not one that is an ingredient solely in a new drug that is legally available only under the investigational drug provisions of this part.

(3) The label bears the following prominently placed statements in lieu of adequate directions for use and in addition to complying with the other labeling provisions of the act:

(i) “Rx only”; and

(ii) “For use only in patch testing”.

(4) The quantity shipped is limited to an amount reasonable for the purpose of patch testing in the normal course of the practice of medicine and is used solely for such patch testing.

(5) The new drug substance is manufactured by the same procedures and meets the same specifications as the component used in the finished dosage form.

(6) The manufacturer or distributor maintains records of all shipments for this purpose for a period of 2 years after shipment and will make them available to the Food and Drug Administration on request.

(b) When the requested new drug substance is intended for investigational use in humans or the substance is legally available only under the investigational drug provisions of part 312 of this chapter, the submission of an “Investigational New Drug Application” (IND) is required. The Food and Drug Administration will offer assistance to any practitioner wishing to submit an Investigational New Drug Application.

(c) This section does not apply to drugs or their components that are subject to the licensing requirements of the Public Health Service Act of 1944, as amended. (See subchapter F - Biologics, of this chapter.)

(a) Duration of prescription requirement. Any drug limited to prescription use under section 503(b)(1)(B) of the act remains so limited until it is exempted as provided in paragraph (b) or (e) of this section.

(b) Prescription-exemption procedure for drugs limited by a new drug application. Any drug limited to prescription use under section 503(b)(1)(B) of the act shall be exempted from prescription-dispensing requirements when the Commissioner finds such requirements are not necessary for the protection of the public health by reason of the drug's toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, and he finds that the drug is safe and effective for use in self-medication as directed in proposed labeling. A proposal to exempt a drug from the prescription-dispensing requirements of section 503(b)(1)(B) of the act may be initiated by the Commissioner or by any interested person. Any interested person may file a petition seeking such exemption, which petition may be pursuant to part 10 of this chapter, or in the form of a supplement to an approved new drug application.

(c) New drug status of drugs exempted from the prescription requirement. A drug exempted from the prescription requirement under the provisions of paragraph (b) of this section is a “new drug” within the meaning of section 201(p) of the act until it has been used to a material extent and for a material time under such conditions except as provided in paragraph (e) of this section.

(d) Prescription legend not allowed on exempted drugs. The use of the prescription caution statement quoted in section 503(b) (4) of the act, in the labeling of a drug exempted under the provisions of this section, constitutes misbranding. Any other statement or suggestion in the labeling of a drug exempted under this section, that such drug is limited to prescription use, may constitute misbranding.

(e) Prescription-exemption procedure of OTC drug review. A drug limited to prescription use under section 503(b)(1)(B) of the act may also be exempted from prescription-dispensing requirements by the procedure set forth in § 330.13 of this chapter.

(a) The prescription-dispensing requirements of section503(b)(1)(B) of the Federal Food, Drug, and Cosmetic Act are not necessary for the protection of the public health with respect to the following drugs subject to new drug applications:

(1) N-Acetyl-p-aminophenol (acetaminophen, p-hydroxy-acetanilid) preparations meeting all the following conditions:

(i) The N-acetyl-p-aminophenol is prepared, with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The N-acetyl-p-aminophenol and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505 (b) of the act is approved for it.

(iv) The preparation contains not more than 0.325 gram (5 grains) of N-acetyl-p-aminophenol per dosage unit, or if it is in liquid form not more than 100 milligrams of N-acetyl-p-aminophenol per milliliter.

(v) The preparation is labeled with adequate directions for use in minor conditions as a simple analgesic.

(vi) The dosages of N-acetyl-p-aminophenol recommended or suggested in the labeling do not exceed: For adults, 0.65 gram (10 grains) per dose or 2.6 grams (40 grains) per 24-hour period: for children 6 to 12 years of age, one-half of the maximum adult dose or dosage; for children 3 to 6 years of age, one-fifth of the maximum adult dose or dosage.

(vii) The labeling bears, in juxtaposition with the dosage recommendations, a clear warning statement against administration of the drug to children under 3 years of age and against use of the drug for more than 10 days, unless such uses are directed by a physician.

(viii) If the article is offered for use in arthritis or rheumatism, the labeling prominently bears a statement that the beneficial effects claimed are limited to the temporary relief of minor aches and pains of arthritis and rheumatism and, in juxtaposition with directions for use in such conditions, a conspicuous warning statement, such as “Caution: If pain persists for more than 10 days, or redness is present, or in conditions affecting children under 12 years of age, consult a physician immediately”.

(2) Sodium gentisate (sodium-2, 5-dihydroxybenzoate) preparations meeting all the following conditions:

(i) The sodium gentisate is prepared, with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The sodium gentisate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 0.5 gram (7.7 grains) of anhydrous sodium gentisate per dosage unit.

(v) The preparation is labeled with adequate directions for use in minor conditions as a simple analgesic.

(vi) The dosages of sodium gentisate recommended or suggested in the labeling do not exceed: For adults, 0.5 gram (7.7 grains) per dose of 2.0 grams (31 grains) per 24-hour period; for children 6 to 12 years of age, one-half of the maximum adult dose or dosage.

(vii) The labeling bears, in juxtaposition with the dosage recommendations, a clear warning statement against administration of the drug to children under 6 years of age and against use of the drug for a prolonged period, except as such uses may be directed by a physician.

(3) Isoamylhydrocupreine and zolamine hydrochloride (N, N-dimethyl-N′-2-thiazolyl-N′-p-methoxybenzyl-ethyl- enediamine hydrochloride) preparations meeting all the following conditions:

(i) The isoamylhydrocupreine and zolamine hydrochloride are prepared in dosage form suitable for self-medication as rectal suppositories or as an ointment and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The isoamylhydrocupreine, zola-amine hydrochloride, and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 0.25 percent of isoamylhydrocupreine and 1.0 percent of zolamine hydrochloride.

(v) If the preparation is in suppository form, it contains not more than 5.0 milligrams of isoamylhydrocupreine and not more than 20.0 milligrams of zolamine hydrochloride per suppository.

(vi) The preparation is labeled with adequate directions for use in the temporary relief of local pain and itching associated with hemorrhoids.

(vii) The directions provide for the use of not more than two suppositories or two applications of ointment in a 24-hour period.

(viii) The labeling bears, in juxtaposition with the dosage recommendations, a clear warning statement against use of the preparation in case of rectal bleeding, as this may indicate serious disease.

(4) Phenyltoloxamine dihydrogen citrate (N,N-dimethyl-(a-phenyl-O-toloxy) ethylamine dihydrogen citrate), preparations meeting all the following conditions:

(i) The phenyltoloxamine dihydrogen citrate is prepared, with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The phenyltoloxamine dihydrogen citrate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 88 milligrams of phenyltoloxamine dihydrogen citrate (equivalent to 50 milligrams of phenyltoloxamine) per dosage unit.

(v) The preparation is labeled with adequate directions for use in the temporary relief of the symptoms of hay fever and/or the symptoms of other minor conditions in which it is indicated.

(vi) The dosages recommended or suggested in the labeling do not exceed: For adults, 88 milligrams of phenyltoloxamine dihydrogen citrate (equivalent to 50 milligrams of phenyltoloxamine) per dose or 264 milligrams of phenyltoloxamine dihydrogen citrate (equivalent to 150 milligrams of phenyltoloxamine) per 24-hour period; for children 6 to 12 years of age, one-half of the maximum adult dose or dosage.

(vii) The labeling bears, in juxtaposition with the dosage recommendations:

(a) Clear warning statements against administration of the drug to children under 6 years of age, except as directed by a physician, and against driving a car or operating machinery while using the drug, since it may cause drowsiness.

(b) If the article is offered for temporary relief of the symptoms of colds, a statement that continued administration for such use should not exceed 3 days, except as directed by a physician.

(5)-(7) [Reserved]

(8) Dicyclomine hydrochloride (1-cyclohexylhexahydrobenzoic acid. β-diethylaminoethyl ester hydrochloride; diethylaminocarbethoxy-bicyclohexyl hydrochloride) preparations meeting all the following conditions:

(i) The dicyclomine hydrochloride is prepared with suitable antacid and other components, in tablet or other dosage form for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The dicyclomine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 5 milligrams of dicyclomine hydrochloride per dosage unit, or if it is in liquid form not more than 0.5 milligram of dicyclomine hydrochloride per milliliter.

(v) The preparation is labeled with adequate directions for use only by adults and children over 12 years of age, in the temporary relief of gastric hyperacidity.

(vi) The dosages recommended or suggested in the directions for use do not exceed 10 milligrams of dicyclomine hydrochloride per dose or 30 milligrams in a 24-hour period.

(vii) The labeling bears, in juxtaposition with the dosage recommendations, clear warning statements against:

(a) Exceeding the recommended dosage.

(b) Prolonged use, except as directed by a physician, since persistent or recurring symptoms may indicate a serious disease requiring medical attention.

(c) Administration to children under 12 years of age except as directed by a physician.

(9)-(10) [Reserved]

(11) Hexadenol (a mixture of tetracosanes and their oxidation products) preparations meeting all the following conditions:

(i) The hexadenol is prepared and packaged, with or without other drugs, solvents, and propellants, in a form suitable for self-medication by external application to the skin as a spray, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The hexadenol and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 5 percent by weight of hexadenol.

(v) The preparation is labeled with adequate directions for use by external application in the treatment of minor burns and minor skin irritations.

(vi) The labeling bears, in juxtaposition with the directions for use, clear warning statements against:

(a) Use on serious burns or skin conditions or prolonged use, except as directed by a physician.

(b) Spraying the preparation in the vicinity of eyes, mouth, nose, or ears.

(12) Sulfur dioxide preparations meeting all the following conditions:

(i) The sulfur dioxide is prepared with or without other drugs, in an aqueous solution packaged in a hermetic container suitable for use in self-medication by external application to the skin, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The sulfur dioxide and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 5 grams of sulfur dioxide per 100 milliliters of solution.

(v) The preparation is labeled with adequate directions for use by external application to the smooth skin in the prevention or treatment of minor conditions in which it is indicated.

(vi) The directions for use recommend or suggest not more than two applications a day for not more than 1 week, except as directed by a physician.

(13)-(15) [Reserved]

(16) Tuaminoheptane sulfate (2-aminoheptane sulfate) preparations meeting all the following conditions:

(i) The tuaminoheptane sulfate is prepared, with or without other drugs, in an aqueous vehicle suitable for administration in self-medication as nose drops, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The preparation is packaged with a style of container or assembly suited to self-medication by the recommended route of administration, and delivering not more than 0.1 milliliter of the preparation per drop.

(iii) The tuaminoheptane sulfate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iv) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(v) The tuaminoheptane sulfate content of the preparation does not exceed 10 milligrams per milliliter.

(vi) The preparation is labeled with adequate directions for use in the temporary relief of nasal congestion.

(vii) The dosages recommended or suggested in the directions for use do not exceed the equivalent: For adults, 5 drops of a 1 percent solution per nostril per dose, and 5 doses in a 24-hour period; for children 1 to 6 years of age, 3 drops of a 1 percent solution per nostril per dose, and 5 doses in a 24-hour period; for infants under 1 year of age, 2 drops of a 1 percent solution per nostril per dose, and 5 doses in a 24-hour period.

(viii) The labeling bears, in juxtaposition with the dosage recommendations:

(a) Clear warning statements against use of more than 5 doses daily, and against use longer than 4 days unless directed by a physician.

(b) A clear warning statement to the effect that frequent use may cause nervousness or sleeplessness, and that individuals with high blood pressure, heart disease, diabetes, or thyroid disease should not use the preparation unless directed by a physician.

(17) [Reserved]

(18) Vibesate (a mixture of copolymers of hydroxy-vinyl chlorideacetate, sebacic acid, and modified maleic rosin ester) preparations meeting all the following conditions.

(i) The vibesate is prepared and packaged, with or without other drugs, solvents, and propellants, in a form suitable for self-medication by external application to the skin as a spray, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The vibesate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 13 percent by weight of vibesate.

(v) The preparation is labeled with adequate directions for use by external application as a dressing for minor burns, minor cuts, or other minor skin irritations.

(vi) The labeling bears in juxtaposition with the directions for use clear warning statements against:

(a) Use on serious burns and on infected, deep, and puncture wounds unless directed by a physician.

(b) Spraying the preparation near the eyes or other mucous membranes.

(c) Inhaling the preparation.

(d) Use near open flames.

(e) Puncturing the container or throwing the container into fire.

(19) Pramoxine hydrochloride (4-N-butoxyphenyl γ-morpholinopropyl ether hydrochloride) preparations meeting all the following conditions:

(i) The pramoxine hydrochloride is prepared, with or without other drugs, in a dosage form suitable for use in self-medication by external application to the skin, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The pramoxine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 1.0 percent of pramoxine hydrochloride.

(v) The preparation is labeled with adequate directions for use by external application to the skin for the temporary relief of pain or itching due to minor burns and sunburn, nonpoisonous insect bites, and minor skin irritations.

(vi) The directions for use recommend or suggest not more than four applications of the preparation per day, unless directed by a physician.

(vii) The labeling bears, in juxtaposition with the directions for use, clear warning statements against:

(a) Prolonged use.

(b) Application to large areas of the body.

(c) Continued use if redness, irritation, swelling, or pain persists or increases, unless directed by a physician.

(d) Use in the eyes or nose.

(20) [Reserved]

(21) Pamabrom (2-amino-2-methylpropanol-1-8-bromotheophyllinate) preparations meeting all the following conditions:

(i) The pamabrom is prepared with appropriate amounts of a suitable analgesic and with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The pamabrom and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 50 milligrams of pamabrom per dosage unit.

(v) The preparation is labeled with adequate directions for use in the temporary relief of the minor pains and discomforts that may occur a few days before and during the menstrual period.

(vi) The dosages recommended or suggested in the labeling do not exceed 50 milligrams of pamabrom per dose or 200 milligrams per 24-hour period.

(22) Diphemanil methylsulfate (4-diphenylmethylene-1,1-dimethyl-piperidinium methylsulfate) preparations meeting all the following conditions:

(i) The diphemanil methylsulfate is prepared, with or without other drugs, in a dosage form suitable for use in self-medication by external application to the skin, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The diphemanil methylsulfate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 2.0 percent of diphemanil methylsulfate.

(v) The preparation is labeled with adequate directions for use by external application to the skin for the relief of symptoms of mild poison ivy, oak, and sumac and other minor irritations and itching of the skin.

(vi) The directions for use recommend or suggest not more than four applications of the preparation per day, unless directed by a physician.

(vii) The labeling bears, in juxtaposition with the directions for use, a clear warning statement, such as: “Caution: If redness, irritation, swelling, or pain persists or increases, discontinue use and consult physician.”

(23) Dyclonine hydrochloride (4-butoxy-3-piperidinopropiophenone hydrochloride; 4-n-butoxy-β-piperidonopropiophenone hydrochloride) preparations meeting all the following conditions:

(i) The dyclonine hydrochloride is prepared, with or without other drugs, in a dosage form suitable for use as a cream or ointment in self-medication by external application to the skin, or rectally, and contains no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The dyclonine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 1.0 percent of dyclonine hydrochloride.

(v) The preparation is labeled with adequate directions for use:

(a) By external application to the skin for the temporary relief of pain and itching in sunburn, nonpoisonous insect bites, minor burns, cuts, abrasions, and other minor skin irritations.

(b) [Reserved]

(c) In the prevention or treatment of other minor conditions in which it is indicated.

(vi) The labeling bears, in juxtaposition with the directions for use, clear warning statements against:

(a) Continued use if redness, irritation, swelling, or pain persists or increases, unless directed by a physician.

(b) Use in case of rectal bleeding, as this may indicate serious disease.

(c) Use in the eyes.

(d) Prolonged use.

(e) Application to large areas of the body.

(f) Use for deep or puncture wounds or serious burns.

(24) Chlorothen citrate (chloromethapyrilene citrate; N,N-dimethyl-N′-(2-pyridyl)-N′-(5-chloro-2-thenyl) ethylenediamine citrate) preparations meeting all the following conditions:

(i) The chlorothen citrate is prepared, with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The chlorothen citrate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 25 milligrams of chlorothen citrate per dosage unit.

(v) The preparation is labeled with adequate directions for use in the temporary relief of the symptoms of hay fever and/or the symptoms of other minor conditions in which it is indicated.

(vi) The dosages recommended or suggested in the labeling do not exceed: For adults, 25 milligrams of chlorothen citrate per dose or 150 milligrams of chlorothen citrate per 24-hour period; for children 6 to 12 years of age, one-half of the maximum adult dose or dosage.

(vii) The labeling bears, in juxtaposition with the dosage recommendations:

(a) Clear warning statements against administration of the drug to children under 6 years of age or exceeding the recommended dosage, unless directed by a physician, and against driving a car or operating machinery while using the drug, since it may cause drowsiness.

(b) If the article is offered for the temporary relief of symptoms of colds, a statement that continued administration for such use should not exceed 3 days, unless directed by a physician.

(25) [Reserved]

(26) Methoxyphenamine hydrochloride (β-(o-methoxyphenyl)-isopropyl-methylamine hydrochloride; 1-(o-methoxyphenyl)- 2-methylamino-propane hydrochloride) preparations meeting all the following conditions:

(i) The methoxyphenamine hydrochloride is prepared with appropriate amounts of a suitable antitussive, with or without other drugs, in a dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The methoxyphenamine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 3.5 milligrams of methoxyphenamine hydrochloride per milliliter.

(v) The preparation is labeled with adequate directions for use in the temporary relief of cough due to minor conditions in which it is indicated.

(vi) The dosages recommended or suggested in the labeling do not exceed: For adults, 35 milligrams of methoxyphenamine hydrochloride per dose or 140 milligrams of methoxyphenamine hydrochloride per 24-hour period; for children 6 to 12 years of age, one-half of the maximum adult dose or dosage.

(vii) The label bears a conspicuous warning to keep the drug out of the reach of children, and the labeling bears, in juxtaposition with the dosage recommendations:

(a) A clear warning statement against administration of the drug to children under 6 years of age, unless directed by a physician.

(b) A clear warning statement to the effect that frequent or prolonged use may cause nervousness, restlessness, or drowsiness, and that individuals with high blood pressure, heart disease, diabetes, or thyroid disease should not use the preparation unless directed by a physician.

(c) A clear warning statement against use of the drug in the presence of high fever or if cough persists, since persistent cough as well as high fever may indicate the presence of a serious condition.

(27) Biphenamine hydrochloride (β-diethylaminoethyl-3-phenyl-2-hydroxybenzoate hydrochloride) preparations meeting all the following conditions:

(i) The biphenamine hydrochloride is prepared in a form suitable for use as a shampoo and contains no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.

(ii) The biphenamine hydrochloride meets its professed standards of identity, strength, quality, and purity.

(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.

(iv) The preparation contains not more than 1 percent of biphenamine hydrochloride.

(v) The preparation is labeled with adequate directions for use for the temporary relief of itching and scaling due to dandruff.

(vi) The label bears a conspicuous warning to keep the drug out of the reach of children.

(28) Tyloxapol (an alkylarylpolyether alcohol) and benzalkonium chloride ophthalmic preparations meeting all the following conditions:

(i) The tyloxapol and benzalkonium chloride are prepared, with other appropriate ingredients which are not drugs limited to prescription sale under the provisions of section 503(b)(1) of the act, as a sterile, isotonic aqueous solution suitable for use in self-medication on eye prostheses.

(ii) The preparation is so packaged as to volume and type of container as to afford adequate protection and be suitable for self-medication with a minimum risk of contamination of the solution during use. Any dispensing unit is sterile and so packaged as to maintain sterility until the package is opened.

(iii) The tyloxapol, benzalkonium chloride, and other ingredients used to prepare the isotonic aqueous solution meet their professed standards of identity, strength, quality, and purity.

(iv) An application pursuant to section 505(b) of the act is approved for the drug.

(v) The preparation contains 0.25 percent of tyloxapol and 0.02 percent of benzalkonium chloride.

(vi) The label bears a conspicuous warning to keep the drug out of the reach of children and the labeling bears, in juxtaposition with the dosage recommendations, a clear warning that if irritation occurs, persists, or increases, use of the drug should be discontinued and a physician consulted. The labeling includes a statement that the dropper or other dispensing tip should not touch any surface, since this may contaminate the solution.

(29) [Reserved]

(b) [Reserved]

(a) A new drug may not be approved for marketing unless it has been shown to be safe and effective for its intended use(s). After approval, the applicant is required to establish and maintain records and make reports related to clinical experience or other data or information necessary to make or facilitate a determination of whether there are or may be grounds under section 505(e) of the act for suspending or withdrawing approval of the application. Some drugs, because of the nature of the condition for which they are intended, must be used for long periods of time - even a lifetime. To acquire necessary data for determining the safety and effectiveness of long-term use of such drugs, extensive animal and clinical tests are required as a condition of approval. Nonetheless, the therapeutic or prophylactic usefulness of such drugs may make it inadvisable in the public interest to delay the availability of the drugs for widespread clinical use pending completion of such long-term studies. In such cases, the Food and Drug Administration may approve the new drug application on condition that the necessary long-term studies will be conducted and the results recorded and reported in an organized fashion. The procedures required by paragraph (b) of this section will be followed in order to list such a drug in § 310.304.

(b) A proposal to require additional or continued studies with a drug for which a new drug application has been approved may be made by the Commissioner on his own initiative or on the petition of any interested person, pursuant to part 10 of this chapter. Prior to issuance of such a proposal, the applicant will be provided an opportunity for a conference with representatives of the Food and Drug Administration. When appropriate, investigators or other individuals may be invited to participate in the conference. All requirements for special studies, records, and reports will be published in § 310.304.

(a) Scope. FDA is requiring manufacturers, packers, and distributors of marketed prescription drug products that are not the subject of an approved new drug or abbreviated new drug application to establish and maintain records and make reports to FDA of all serious, unexpected adverse drug experiences associated with the use of their drug products. Any person subject to the reporting requirements of paragraph (c) of this section must also develop written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences to FDA.

(b) Definitions. The following definitions of terms apply to this section:

Adverse drug experience. Any adverse event associated with the use of a drug in humans, whether or not considered drug related, including the following: An adverse event occurring in the course of the use of a drug product in professional practice; an adverse event occurring from drug overdose whether accidental or intentional; an adverse event occurring from drug abuse; an adverse event occurring from drug withdrawal; and any failure of expected pharmacological action.

Disability. A substantial disruption of a person's ability to conduct normal life functions.

Individual case safety report (ICSR). A description of an adverse drug experience related to an individual patient or subject.

ICSR attachments. Documents related to the adverse drug experience described in an ICSR, such as medical records, hospital discharge summaries, or other documentation.

Life-threatening adverse drug experience. Any adverse drug experience that places the patient, in the view of the initial reporter, at immediate risk of death from the adverse drug experience as it occurred, i.e., it does not include an adverse drug experience that, had it occurred in a more severe form, might have caused death.

Serious adverse drug experience. Any adverse drug experience occurring at any dose that results in any of the following outcomes: Death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.

Unexpected adverse drug experience. Any adverse drug experience that is not listed in the current labeling for the drug product. This includes events that may be symptomatically and pathophysiologically related to an event listed in the labeling, but differ from the event because of greater severity or specificity. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the labeling only listed cerebral vascular accidents. “Unexpected,” as used in this definition, refers to an adverse drug experience that has not been previously observed (i.e., included in the labeling) rather than from the perspective of such experience not being anticipated from the pharmacological properties of the pharmaceutical product.

(c) Reporting requirements. Each person identified in paragraph (c)(1)(i) of this section must submit to FDA adverse drug experience information as described in this section. Except as provided in paragraph (e)(2) of this section, 15-day “Alert reports” and followup reports, including ICSRs and any ICSR attachments, must be submitted to the Agency in electronic format as described in paragraph (e)(1) of this section.

(1) Postmarketing 15-day “Alert reports”. (i) Any person whose name appears on the label of a marketed prescription drug product as its manufacturer, packer, or distributor must report to FDA each adverse drug experience received or otherwise obtained that is both serious and unexpected as soon as possible, but no later than 15 calendar days from initial receipt of the information by the person whose name appears on the label. Each report must be accompanied by the current content of labeling in electronic format as an ICSR attachment unless it is already on file at FDA.

(ii) A person identified in paragraph (c)(1)(i) of this section is not required to submit a 15-day “Alert report” for an adverse drug experience obtained from a postmarketing study (whether or not conducted under an investigational new drug application) unless the applicant concludes that there is a reasonable possibility that the drug caused the adverse experience.

(2) Postmarketing 15-day “Alert reports” - followup. Each person identified in paragraph (c)(1)(i) of this section must promptly investigate all serious, unexpected adverse drug experiences that are the subject of these postmarketing 15-day Alert reports and must submit followup reports within 15 calendar days of receipt of new information or as requested by FDA. If additional information is not obtainable, records should be maintained of the unsuccessful steps taken to seek additional information.

(3) Submission of reports. To avoid unnecessary duplication in the submission of, and followup to, reports required in this section, a packer's or distributor's obligations may be met by submission of all reports of serious adverse drug experiences to the manufacturer of the drug product. If a packer or distributor elects to submit these adverse drug experience reports to the manufacturer rather than to FDA, it must submit, by any appropriate means, each report to the manufacturer within 5 calendar days of its receipt by the packer or distributor, and the manufacturer must then comply with the requirements of this section even if its name does not appear on the label of the drug product. Under this circumstance, the packer or distributor must maintain a record of this action which must include:

(i) A copy of each adverse drug experience report;

(ii) The date the report was received by the packer or distributor;

(iii) The date the report was submitted to the manufacturer; and

(iv) The name and address of the manufacturer.

(4) [Reserved]

(5) A person identified in paragraph (c)(1)(i) of this section is not required to resubmit to FDA adverse drug experience reports forwarded to that person by FDA; however, the person must submit all followup information on such reports to FDA.

(d) Information reported on ICSRs. ICSRs include the following information:

(1) Patient information.

(i) Patient identification code;

(ii) Patient age at the time of adverse drug experience, or date of birth;

(iii) Patient gender; and

(iv) Patient weight.

(2) Adverse drug experience.

(i) Outcome attributed to adverse drug experience;

(ii) Date of adverse drug experience;

(iii) Date of ICSR submission;

(iv) Description of adverse drug experience (including a concise medical narrative);

(v) Adverse drug experience term(s);

(vi) Description of relevant tests, including dates and laboratory data; and

(vii) Other relevant patient history, including preexisting medical conditions.

(3) Suspect medical product(s).

(i) Name;

(ii) Dose, frequency, and route of administration used;

(iii) Therapy dates;

(iv) Diagnosis for use (indication);

(v) Whether the product is a combination product as defined in § 3.2(e) of this chapter;

(vi) Whether the product is a prescription or nonprescription product;

(vii) Whether adverse drug experience abated after drug use stopped or dose reduced;

(viii) Whether adverse drug experience reappeared after reintroduction of drug;

(ix) Lot number;

(x) Expiration date;

(xi) National Drug Code (NDC) number; and

(xii) Concomitant medical products and therapy dates.

(4) Initial reporter information.

(i) Name, address, and telephone number;

(ii) Whether the initial reporter is a health care professional; and

(iii) Occupation, if a health care professional.

(5) Manufacturer, packer, or distributor information.

(i) Manufacturer, packer, or distributor name and contact office address;

(ii) Telephone number;

(iii) Report source, such as spontaneous, literature, or study;

(iv) Date the report was received by manufacturer, packer, or distributor;

(v) Whether the ICSR is a 15-day “Alert report”;

(vi) Whether the ICSR is an initial report or followup report; and

(vii) Unique case identification number, which must be the same in the initial report and any subsequent followup report(s).

(e) Electronic format for submissions. (1) Each report required to be submitted to FDA under this section, including the ICSR and any ICSR attachments, must be submitted in an electronic format that FDA can process, review, and archive. FDA will issue guidance on how to provide the electronic submission (e.g., method of transmission, media, file formats, preparation and organization of files).

(2) Each person identified in paragraph (c)(1)(i) of this section may request, in writing, a temporary waiver of the requirements in paragraph (e)(1) of this section. These waivers will be granted on a limited basis for good cause shown. FDA will issue guidance on requesting a waiver of the requirements in paragraph (e)(1) of this section.

(f) Patient privacy. Manufacturers, packers, and distributors should not include in reports under this section the names and addresses of individual patients; instead, the manufacturer, packer, and distributor should assign a unique code for identification of the patient. The manufacturer, packer, and distributor should include the name of the reporter from whom the information was received as part of the initial reporter information, even when the reporter is the patient. The names of patients, individual reporters, health care professionals, hospitals, and geographical identifiers in adverse drug experience reports are not releasable to the public under FDA's public information regulations in part 20 of this chapter.

(g) Recordkeeping. (1) Each manufacturer, packer, and distributor must maintain for a period of 10 years records of all adverse drug experiences required under this section to be reported, including raw data and any correspondence relating to the adverse drug experiences, and the records required to be maintained under paragraph (c)(3) of this section.

(2) Manufacturers and packers may retain the records required in paragraph (f)(1) of this section as part of its complaint files maintained under § 211.198 of this chapter.

(3) Manufacturers, packers, and distributors must permit any authorized FDA employee, at all reasonable times, to have access to and copy and verify the records established and maintained under this section.

(h) Disclaimer. A report or information submitted by a manufacturer, packer, or distributor under this section (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the manufacturer, packer, or distributor, or by FDA, that the report or information constitutes an admission that the drug caused or contributed to an adverse effect. The manufacturer, packer, or distributor need not admit, and may deny, that the report or information submitted under this section constitutes an admission that the drug caused or contributed to an adverse effect.

(a) Applicability. Marketed prescription drug products that are not the subject of an approved new drug or abbreviated new drug application are subject to this section.

(b) Notification of a permanent discontinuance or an interruption in manufacturing. The manufacturer of each product subject to this section must make the notifications required under § 314.81(b)(3)(iii) of this chapter and otherwise comply with § 314.81(b)(3)(iii) of this chapter. If the manufacturer of a product subject to this section fails to provide notification as required under § 314.81(b)(3)(iii), FDA will send a letter to the manufacturer and otherwise follow the procedures set forth under § 314.81(b)(3)(iii)(e).

(c) Drug shortages list. FDA will include on the drug shortages list required by § 314.81(b)(3)(iii)(d) drug products that are subject to this section that it determines to be in shortage. For such drug products, FDA will provide the names of each manufacturer rather than the names of each applicant. With respect to information collected under this paragraph, FDA will observe the confidentiality and disclosure provisions set forth in § 314.81(b)(3)(iii)(d)(2).

(a) Requirement for a patient package insert. The safe and effective use of oral contraceptive drug products requires that patients be fully informed of the benefits and the risks involved in their use. An oral contraceptive drug product that does not comply with the requirements of this section is misbranded under section 502 of the Federal Food, Drug, and Cosmetic Act. Each dispenser of an oral contraceptive drug product shall provide a patient package insert to each patient (or to an agent of the patient) to whom the product is dispensed, except that the dispenser may provide the insert to the parent or legal guardian of a legally incompetent patient (or to the agent of either). The patient package insert is required to be placed in or accompany each package dispensed to the patient.

(b) Distribution requirements. (1) For oral contraceptive drug products, the manufacturer and distributor shall provide a patient package insert in or with each package of the drug product that the manufacturer or distributor intends to be dispensed to a patient.

(2) Patient package inserts for oral contraceptives dispensed in acute-care hospitals or long-term care facilities will be considered to have been provided in accordance with this section if provided to the patient before administration of the first oral contraceptive and every 30 days thereafter, as long as the therapy continues.

(c) Contents of patient package insert. A patient package insert for an oral contraceptive drug product is required to contain the following:

(1) The name of the drug.

(2) A summary including a statement concerning the effectiveness of oral contraceptives in preventing pregnancy, the contraindications to the drug's use, and a statement of the risks and benefits associated with the drug's use.

(3) A statement comparing the effectiveness of oral contraceptives to other methods of contraception.

(4) A boxed warning concerning the increased risks associated with cigarette smoking and oral contraceptive use.

(5) A discussion of the contraindications to use, including information that the patient should provide to the prescriber before taking the drug.

(6) A statement of medical conditions that are not contraindications to use but deserve special consideration in connection with oral contraceptive use and about which the patient should inform the prescriber.

(7) A warning regarding the most serious side effects of oral contraceptives.

(8) A statement of other serious adverse reactions and potential safety hazards that may result from the use of oral contraceptives.

(9) A statement concerning common, but less serious side effects which may help the patient evaluate the benefits and risks from the use of oral contraceptives.

(10) Information on precautions the patients should observe while taking oral contraceptives, including the following:

(i) A statement of risks to the mother and unborn child from the use of oral contraceptives before or during early pregnancy;

(ii) A statement concerning excretion of the drug in human milk and associated risks to the nursing infant;

(iii) A statement about laboratory tests which may be affected by oral contraceptives; and

(iv) A statement that identifies activities and drugs, foods, or other substances the patient should avoid because of their interactions with oral contraceptives.

(11) Information about how to take oral contraceptives properly, including information about what to do if the patient forgets to take the product, information about becoming pregnant after discontinuing use of the drug, a statement that the drug product has been prescribed for the use of the patient and should not be used for other conditions or given to others, and a statement that the patient's pharmacist or practitioner has a more technical leaflet about the drug product that the patient may ask to review.

(12) A statement of the possible benefits associated with oral contraceptive use.

(13) The following information about the drug product and the patient package insert:

(i) The name and place of business of the manufacturer, packer, or distributor, or the name and place of business of the dispenser of the product.

(ii) The date, identified as such, of the most recent revision of the patient package insert placed prominently immediately after the last section of the labeling.

(d) Other indications. The patient package insert may identify indications in addition to contraception that are identified in the professional labeling for the drug product.

(e) Labeling guidance texts. The Food and Drug Administration issues informal labeling guidance texts under § 10.90(b)(9) of this chapter to provide assistance in meeting the requirements of this section. A request for a copy of the guidance texts should be directed to the Center for Drug Evaluation and Research, Division of Reproductive and Urologic Products, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002.

(f) Requirement to supplement approved application. Holders of approved applications for oral contraceptive drug products that are subject to the requirements of this section are required to submit supplements under § 314.70(c) of this chapter to provide for the labeling required by this section. Such labeling may be put into use without advance approval by the Food and Drug Administration.

(a) The drugs listed in this paragraph (a) have been determined by rulemaking procedures to be new drugs within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act. An approved new drug application under section 505 of the Federal Food, Drug, and Cosmetic Act and part 314 of this chapter is required for marketing the following drugs:

(1) Aerosol drug products for human use containing 1,1,1-trichloroethane.

(2) Aerosol drug products containing zirconium.

(3) Amphetamines (amphetamine, dextroamphetamine, and their salts, and levamfetamine and its salts) for human use.

(4) Camphorated oil drug products.

(5) Certain halogenated salicylanilides (tribromsalan (TBS, 3,4′,5-tribromosalicylanilide), dibromsalan (DBS, 4′, 5-dibromosalicylanilide), metabromsalan (MBS, 3, 5-dibromosalicylanilide), and 3,3′, 4,5′-tetrachlorosalicylanilide (TC-SA)) as an ingredient in drug products.

(6) Chloroform used as an ingredient (active or inactive) in drug products.

(7) Cobalt preparations intended for use by man.

(8) Intrauterine devices for human use for the purpose of contraception that incorporate heavy metals, drugs, or other active substances.

(9) Oral prenatal drugs containing fluorides intended for human use.

(10) Parenteral drug products in plastic containers.

(11) [Reserved]

(12) Sweet spirits of nitre drug products.

(13) Thorium dioxide for drug use.

(14) Timed release dosage forms.

(15) Vinyl chloride as an ingredient, including propellant, in aerosol drug products.

(b) [Reserved]

(a) On January 8, 1963 (28 FR 183), the Commissioner of Food and Drugs exempted investigational radioactive new drugs from part 312 of this chapter provided they were shipped in complete conformity with the regulations issued by the Nuclear Regulatory Commission. This exemption also applied to investigational radioactive biologics.

(b) It is the opinion of the Nuclear Regulatory Commission, and the Food and Drug Administration that this exemption should not apply for certain specific drugs and that these drugs should be appropriately labeled for uses for which safety and effectiveness can be demonstrated by new drug applications or through licensing under the Public Health Service Act (42 U.S.C. 262 et seq.) in the case of biologics. Continued distribution under the investigational exemption when the drugs are intended for established uses will not be permitted.

(c) Based on its experience in regulating investigational radioactive pharmaceuticals, the Nuclear Regulatory Commission has compiled a list of reactor-produced isotopes for which it considers that applicants may reasonably be expected to submit adequate evidence of safety and effectiveness for use as recommended in appropriate labeling. Such use may include, among others, the uses in this tabulation:

(d)(1) In view of the extent of experience with the isotopes listed in paragraph (c) of this section, the Nuclear Regulatory Commission and the Food and Drug Administration conclude that such isotopes should not be distributed under investigational-use labeling when they are actually intended for use in medical practice.

(2) The exemption referred to in paragraph (a) of this section, as applied to any drug or biologic containing any of the isotopes listed in paragraph (c) of this section, in the “chemical form” and intended for the uses stated, is terminated on March 3, 1972, except as provided in paragraph (d)(3) of this section.

(3) The exemption referred to in paragraph (a) of this section, as applied to any drug or biologic containing any of the isotopes listed in paragraph (c) of this section, in the “chemical form” and intended for the uses stated, for which drug a new drug application or a “Investigational New Drug Application” was submitted prior to March 3, 1972, or for which biologic an application for product license or “Investigational New Drug Application” was submitted prior to March 3, 1972, is terminated on August 20, 1976, unless an approvable notice was issued on or before August 20, 1976, in which case the exemption is terminated either upon the subsequent issuance of a nonapprovable notice for the new drug application or on November 20, 1976, whichever occurs first.

(e) No exemption from section 505 of the act or from part 312 of this chapter is in effect or has been in effect for radioactive drugs prepared from accelerator-produced radioisotopes, naturally occurring isotopes, or nonradioactive substances used in conjunction with isotopes.

(f)(1) Based on its experience in regulating investigational radioactive pharmaceuticals, the Nuclear Regulatory Commission has compiled a list of reactor-produced isotopes for which it considers that applicants may reasonably be expected to submit adequate evidence of safety and effectiveness for use as recommended in appropriate labeling; such use may include, among others, the uses in this tabulation:

(2) In view of the extent of experience with the isotopes listed in paragraph (f)(1) of this section, the Nuclear Regulatory Commission and the Food and Drug Administration conclude that they should not be distributed under investigational-use labeling when they are actually intended for use in medical practice.

(3) Any manufacturer or distributor interested in continuing to ship in interstate commerce drugs containing the isotopes listed in paragraph (f)(1) of this section for any of the indications listed, shall submit, on or before August 25, 1975 to the Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, a new drug application or a “Investigational New Drug Application” for each such drug for which the manufacturer or distributor does not have an approved new drug application pursuant to section 505(b) of the act. If the drug is a biologic, a “Investigational New Drug Application” or an application for a license under section 351 of the Public Health Service Act shall be submitted to the Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002, in lieu of any submission to the Center for Drug Evaluation and Research.

(4) The exemption referred to in paragraph (a) of this section, as applied to any drug or biologic containing any of the isotopes listed in paragraph (f)(1) of this section, in the “chemical form” and intended for the uses stated, is terminated on August 26, 1975 except as provided in paragraph (f)(5) of this section.

(5)(i) Except as provided in paragraph (f)(5)(ii) of this section, the exemption referred to in paragraph (a) of this section, as applied to any drug containing any of the isotopes listed in paragraph (f)(1) of this section, in the “chemical form” and intended for the uses stated, for which drug a new drug application or “Investigational New Drug Application” was submitted to the Center for Drug Evaluation and Research on or before August 25, 1975 is terminated on August 20, 1976, unless an approvable notice was issued on or before August 20, 1976, in which case the exemption is terminated either upon the subsequent issuance of a nonapprovable notice for the new drug application or on November 20, 1976, whichever occurs first.

(ii) The exemption referred to in paragraph (a) of this section, as applied to any biologic containing any of the isotopes listed in paragraph (f)(1) of this section in the “chemical form” and intended for the uses stated, for which biologic an application for product license or “Investigational New Drug Application” was submitted to the Center for Biologics Evaluation and Research on or before August 25, 1975 is terminated on October 20, 1976, unless an approvable notice was issued on or before October 20, 1976, in which case the exemption is terminated either upon the subsequent issuance of a nonapprovable notice for the new drug application or on January 20, 1977, whichever occurs first.

(g) The exemption referred to in paragraph (a) of this section, as applied to any drug intended solely for investigational use as part of a research project, which use had been approved on or before July 25, 1975 in accordance with 10 CFR 35.11 (or equivalent regulation of an Agreement State) is terminated on February 20, 1976 if the manufacturer of such drug or the sponsor of the investigation of such drug submits on or before August 25, 1975 to the Food and Drug Administration, Bureau of Drugs, HFD-150, 5600 Fishers Lane, Rockville, MD 20857, the following information:

(1) The research project title;

(2) A brief description of the purpose of the project;

(3) The name of the investigator responsible;

(4) The name and license number of the institution holding the specific license under 10 CFR 35.11 (or equivalent regulation of an Agreement State);

(5) The name and maximum amount per subject of the radionuclide used;

(6) The number of subjects involved; and

(7) The date on which the administration of the radioactive drugs is expected to be completed.

(h) The exemption referred to in paragraph (a) of this section, as applied to any drug not referred to in paragraphs (d), (f), and (g) of this section, is terminated on August 26, 1975.

(a) Any parenteral drug product packaged in a plastic immediate container is not generally recognized as safe and effective, is a new drug within the meaning of section 201(p) of the act, and requires an approved new drug application as a condition for marketing. An “Investigational New Drug Application” set forth in part 312 of this chapter is required for clinical investigations designed to obtain evidence of safety and effectiveness.

(b) As used in this section, the term “large volume parenteral drug product” means a terminally sterilized aqueous drug product packaged in a single-dose container with a capacity of 100 milliliters or more and intended to be administered or used intravenously in a human.

(c) Until the results of compatibility studies are evaluated, a large volume parenteral drug product for intravenous use in humans that is packaged in a plastic immediate container on or after April 16, 1979, is misbranded unless its labeling contains a warning that includes the following information:

(1) A statement that additives may be incompatible.

(2) A statement that, if additive drugs are introduced into the parenteral system, aseptic techniques should be used and the solution should be thoroughly mixed.

(3) A statement that a solution containing an additive drug should not be stored.

(d) This section does not apply to a biological product licensed under the Public Health Service Act of July 1, 1944 (42 U.S.C. 201).

(a) Requirement for a patient package insert. FDA concludes that the safe and effective use of drug products containing estrogens requires that patients be fully informed of the benefits and risks involved in the use of these drugs. Accordingly, except as provided in paragraph (e) of this section, each estrogen drug product restricted to prescription distribution, including products containing estrogens in fixed combinations with other drugs, shall be dispensed to patients with a patient package insert containing information concerning the drug's benefits and risks. An estrogen drug product that does not comply with the requirements of this section is misbranded under section 502(a) of the Federal Food, Drug, and Cosmetic Act.

(b) Distribution requirements. (1) For estrogen drug products, the manufacturer and distributor shall provide a patient package insert in or with each package of the drug product that the manufacturer or distributor intends to be dispensed to a patient.

(2) In the case of estrogen drug products in bulk packages intended for multiple dispensing, and in the case of injectables in multiple-dose vials, a sufficient number of patient labeling pieces shall be included in or with each package to assure that one piece can be included with each package or dose dispensed or administered to every patient. Each bulk package shall be labeled with instructions to the dispensor to include one patient labeling piece with each package dispensed or, in the case of injectables, with each dose administered to the patient. This section does not preclude the manufacturer or labeler from distributing additional patient labeling pieces to the dispensor.

(3) Patient package inserts for estrogens dispensed in acute-care hospitals or long-term care facilities will be considered to have been provided in accordance with this section if provided to the patient before administration of the first estrogen and every 30 days thereafter, as long as the therapy continues.

(c) Patient package insert contents. A patient package insert for an estrogen drug product is required to contain the following information:

(1) The name of the drug.

(2) The name and place of business of the manufacturer, packer, or distributor.

(3) A statement regarding the benefits and proper uses of estrogens.

(4) The contraindications to use, i.e., when estrogens should not be used.

(5) A description of the most serious risks associated with the use of estrogens.

(6) A brief summary of other side effects of estrogens.

(7) Instructions on how a patient may reduce the risks of estrogen use.

(8) The date, identified as such, of the most recent revision of the patient package insert.

(d) Guidance language. The Food and Drug Administration issues informal labeling guidance texts under § 10.90(b)(9) of this chapter to provide assistance in meeting the requirements of paragraph (c) of this section. Requests for a copy of the guidance text should be directed to the Center for Drug Evaluation and Research, Division of Reproductive and Urologic Products, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002.

(e) Exemptions. This section does not apply to estrogen-progestogen oral contraceptives. Labeling requirements for these products are set forth in § 310.501.

(f) Requirement to supplement approved application. Holders of approved applications for estrogen drug products that are subject to the requirements of this section must submit supplements under § 314.70(c) of this chapter to provide for the labeling required by paragraph (a) of this section. Such labeling may be put into use without advance approval by the Food and Drug Administration.

(a) The University Group Diabetes Program clinical trial has reported an association between the administration of tolbutamide and increased cardiovascular mortality. The Food and Drug Administration has concluded that this reported association provides adequate basis for a warning in the labeling. In view of the similarities in chemical structure and mode of action, the Food and Drug Administration also believes it is prudent from a safety standpoint to consider that the possible increased risk of cardiovascular mortality from tolbutamide applies to all other sulfonylurea drugs as well. Therefore, the labeling for oral hypoglycemic drugs of the sulfonylurea class shall include a warning concerning the possible increased risk of cardiovascular mortality associated with such use, as set forth in paragraph (b) of this section.

(b) Labeling for oral hypoglycemic drugs of the sulfonylurea class shall include in boldface type at the beginning of the “Warnings” section of the labeling the following statement:

Drug products containing elemental iron or iron salts as an active ingredient in solid oral dosage form, e.g., tablets or capsules shall meet the following requirements:

(a) Labeling. (1) The label of any drug in solid oral dosage form (e.g., tablets or capsules) that contains iron or iron salts for use as an iron source shall bear the following statement:

(2)(i) The warning statement required by paragraph (a)(1) of this section shall appear prominently and conspicuously on the information panel of the immediate container label.

(ii) If a drug product is packaged in unit-dose packaging, and if the immediate container bears labeling but not a label, the warning statement required by paragraph (a)(1) of this section shall appear prominently and conspicuously on the immediate container labeling in a way that maximizes the likelihood that the warning is intact until all of the dosage units to which it applies are used.

(3) Where the immediate container is not the retail package, the warning statement required by paragraph (a)(1) of this section shall also appear prominently and conspicuously on the information panel of the retail package label.

(4) The warning statement shall appear on any labeling that contains warnings.

(5) The warning statement required by paragraph (a)(1) of this section shall be set off in a box by use of hairlines.

(b) The iron-containing inert tablets supplied in monthly packages of oral contraceptives are categorically exempt from the requirements of paragraph (a) of this section.

(a) Antihistamines, bromides, and scopolamine compounds, either singly or in combinations, have been marketed as ingredients in over-the-counter (OTC) drug products for use as daytime sedatives. The following claims have been made for daytime sedative products: “occasional simple nervous tension,” “nervous irritability,” “nervous tension headache,” “simple nervousness due to common every day overwork and fatigue,” “a relaxed feeling,” “calming down and relaxing,” “gently soothe away the tension,” “calmative,” “resolving that irritability that ruins your day,” “helps you relax,” “restlessness,” “when you're under occasional stress . . . helps you work relaxed.” Based on evidence presently available, there are no ingredients that can be generally recognized as safe and effective for use as OTC daytime sedatives.

(b) Any OTC drug product that is labeled, represented, or promoted as an OTC daytime sedative (or any similar or related indication) is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted as an OTC daytime sedative (or any similar or related indication) is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) Any OTC daytime sedative drug product introduced into interstate commerce after December 24, 1979, that is not in compliance with this section is subject to regulatory action.

(a) Amino acids, aminobenzoic acid, ascorbic acid, benzoic acid, biotin and all other B-vitamins, dexpanthenol, estradiol and other topical hormones, jojoba oil, lanolin, nucleic acids, polysorbate 20, polysorbate 60, sulfanilamide, sulfur 1 percent on carbon in a fraction of paraffinic hydrocarbons, tetracaine hydrochloride, urea, and wheat germ oil have been marketed as ingredients in OTC drug products for external use as hair growers or for hair loss prevention. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these or any other ingredients intended for OTC external use as a hair grower or for hair loss prevention. Based on evidence currently available, all labeling claims for OTC hair grower and hair loss prevention drug products for external use are either false, misleading, or unsupported by scientific data. Therefore, any OTC drug product for external use containing an ingredient offered for use as a hair grower or for hair loss prevention cannot be considered generally recognized as safe and effective for its intended use.

(b) Any OTC drug product that is labeled, represented, or promoted for external use as a hair grower or for hair loss prevention is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC external use as a hair grower or for hair loss prevention is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After January 8, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(a) Any product that bears labeling claims that it will arouse or increase sexual desire, or that it will improve sexual performance, is an aphrodisiac drug product. Anise, cantharides, don qual, estrogens, fennel, ginseng, golden seal, gotu kola, Korean ginseng, licorice, mandrake, methyltestosterone, minerals, nux vomica, Pega Palo, sarsaparilla, strychnine, testosterone, vitamins, yohimbine, yohimbine hydrochloride, and yohimbinum have been present as ingredients in such drug products. Androgens (e.g., testosterone and methyltestosterone) and estrogens are powerful hormones when administered internally and are not safe for use except under the supervision of a physician. There is a lack of adequate data to establish general recognition of the safety and effectiveness of any of these ingredients, or any other ingredient, for OTC use as an aphrodisiac. Labeling claims for aphrodisiacs for OTC use are either false, misleading, or unsupported by scientific data. The following claims are examples of some that have been made for aphrodisiac drug products for OTC use: “acts as an aphrodisiac;” “arouses or increases sexual desire and improves sexual performance;” “helps restore sexual vigor, potency, and performance;” “improves performance, staying power, and sexual potency;” and “builds virility and sexual potency.” Based on evidence currently available, any OTC drug product containing ingredients for use as an aphrodisiac cannot be generally recognized as safe and effective.

(b) Any OTC drug product that is labeled, represented, or prompted for use as an aphrodisiac is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act, (the act), for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as an aphrodisiac is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After January 8, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(a) Thiamine hydrochloride (vitamin B-1) has been marketed as an ingredient in over-the-counter (OTC) drug products for oral use as an insect repellent (an orally administered drug product intended to keep insects away). There is a lack of adequate data to establish the effectiveness of this, or any other ingredient for OTC oral use as an insect repellent. Labeling claims for OTC orally administered insect repellent drug products are either false, misleading, or unsupported by scientific data. The following claims are examples of some that have been made for orally administered OTC insect repellent drug products: “Oral mosquito repellent,” “mosquitos avoid you,” “bugs stay away,” “keep mosquitos away for 12 to 24 hours,” and “the newest way to fight mosquitos.” Therefore, any drug product containing ingredients offered for oral use as an insect repellent cannot be generally recognized as safe and effective.

(b) Any OTC drug product that is labeled, represented, or promoted for oral use as an insect repellent is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug and Cosmetic Act for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted OTC for oral use as an insect repellent is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) Any such drug product in interstate commerce after December 17, 1985, that is not in compliance with this section is subject to regulatory action.

(a) The term “hormone” is used broadly to describe a chemical substance formed in some organ of the body, such as the adrenal glands or the pituitary, and carried to another organ or tissue, where it has a specific effect. Hormones include, for example, estrogens, progestins, androgens, anabolic steroids, and adrenal corticosteroids, and synthetic analogs. Estrogens, progesterone, pregnenolone, and pregnenolone acetate have been present as ingredients in OTC drug products marketed for topical use as hormone creams. However, there is a lack of adequate data to establish effectiveness for any OTC drug use of these ingredients. Therefore, with the exception of those hormones identified in paragraph (e) of this section, any OTC drug product containing an ingredient offered for use as a topically applied hormone cannot be considered generally recognized as safe and effective for its intended use. The intended use of the product may be inferred from the product's labeling, promotional material, advertising, and any other relevant factor. The use of the word “hormone” in the text of the labeling or in the ingredient statement is an implied drug claim. The claim implied by the use of this term is that the product will have a therapeutic or some other physiological effect on the body. Therefore, reference to a product as a “hormone cream” or any statement in the labeling indicating that “hormones” are present in the product, or any statement that features or emphasizes the presence of a hormone ingredient in the product, will be considered to be a therapeutic claim for the product, or a claim that the product will affect the structure or function of the body, and will consequently cause the product to be a drug.

(b) Any OTC drug product that is labeled, represented, or promoted as a topically applied hormone-containing product for drug use, with the exception of those hormones identified in paragraph (e) of this section, is regarded as a new drug within the meaning of section 201(p) of the act, for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as a topically applied hormone-containing drug product is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After March 9, 1994, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(e) This section does not apply to hydrocortisone and hydrocortisone acetate labeled, represented, or promoted for OTC topical use in accordance with part 348 of this chapter.

(a) Aminacrine hydrochloride, benzocaine, bismuth subnitrate, calomel, camphor, cholesterol, ergot fluid extract, hexachlorophene, ichthammol, isobutamben, juniper tar (oil of cade), lanolin, magnesium sulfate, menthol, methyl salicylate, oxyguinoline sulfate, petrolatum, phenol, pine tar, rosin, rosin cerate, sassafras oil, sulfur, thymol, triclosan, and zinc oxide have been present in OTC boil treatment drug products. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these or any other ingredient for OTC use for the treatment of boils. Treatment is defined as reducing the size of a boil or reducing an infection related to a boil. Treatment has involved the use of “drawing salves” for these purposes. These “drawing salves” contained various ingredients. Based on evidence currently available, any OTC drug product offered for the treatment of boils cannot be considered generally recognized as safe and effective.

(b) Any OTC drug product that is labeled, represented, or promoted for the treatment of boils is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any OTC boil treatment drug product is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After May 7, 1991, any such OTC drug product that contains aminacrine hydrochloride, bismuth subnitrate, calomel, camphor, cholesterol, ergot fluid extract, hexachlorophene, isobutamben, juniper tar (oil of cade), lanolin, magnesium sulfate, menthol, methyl salicylate, oxyguinoline sulfate, petrolatum, phenol, pine tar, rosin, rosin cerate, sassafras oil, thymol, or zinc oxide initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(e) After May 16, 1994, any such OTC drug product that contains benzocaine, ichthammol, sulfur, or triclosan initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(f) This section does not apply to drug products that contain benzocaine labeled, represented, or promoted for OTC topical use in accordance with part 348 of this chapter.

(a) The amino acids glycine, alanine, and glutamic acid (alone or in combination) and the ingredient sabal have been present in over-the-counter (OTC) drug products to relieve the symptoms of benign prostatic hypertrophy, e.g., urinary urgency and frequency, excessive urinating at night, and delayed urination. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these or any other ingredients for OTC use in relieving the symptoms of benign prostatic hypertrophy. In addition, there is no definitive evidence that any drug product offered for the relief of the symptoms of benign prostatic hypertrophy would alter the obstructive or inflammatory signs and symptoms of this condition. Therefore, self-medication with OTC drug products might unnecessarily delay diagnosis and treatment of progressive obstruction and secondary infections. Based on evidence currently available, any OTC drug product containing ingredients offered for use in relieving the symptoms of benign prostatic hypertrophy cannot be generally recognized as safe and effective.

(b) Any OTC drug product that is labeled, represented, or promoted to relieve the symptoms of benign prostatic hypertrophy is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use to relieve the symptoms of benign prostatic hypertrophy is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After August 27, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(a) Atropine sulfate, belladonna alkaloids, and belladonna alkaloids as contained in Atropa belladonna and Datura stramonium have been present as ingredients in cough-cold drug products for use as an anticholinergic. Anticholinergic drugs have been marketed OTC in cough-cold drug products to relieve excessive secretions of the nose and eyes, symptoms that are commonly associated with hay fever, allergy, rhinitis, and the common cold. Atropine sulfate for oral use as an anticholinergic is probably safe at dosages that have been used in marketed cough-cold products (0.2 to 0.3 milligram); however, there are inadequate data to establish general recognition of the effectiveness of this ingredient. The belladonna alkaloids, which contain atropine (d, dl hyoscyamine) and scopolamine (l- hyoscine), are probably safe for oral use at dosages that have been used in marketed cough-cold products (0.2 milligram) but there are inadequate data to establish general recognition of the effectiveness of these ingredients as an anticholinergic for cough-cold use. Belladonna alkaloids for inhalation use, as contained in Atropa belladonna and Datura stramonium, are neither safe nor effective as an OTC anticholinergic. There are inadequate safety and effectiveness data to establish general recognition of the safety and/or effectiveness or any of these ingredients, or any other ingredient, for OTC use as an anticholinergic in cough-cold drug products.

(b) Any OTC cough-cold drug product that is labeled, represented, or promoted for use as an anticholinergic is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act, for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any cough-cold drug product labeled, represented, or promoted for OTC use as an anticholinergic is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After the effective date of the final regulation, any such OTC cough-cold drug product that is labeled, represented, or promoted for use as an anticholinergic may not be initially introduced or initially delivered for introduction into interstate commerce unless it is the subject of an approved new drug application.

(a) Allantoin, carbamide peroxide in anhydrous glycerin, water soluble chlorophyllins, and hydrogen peroxide in aqueous solution have been present in oral mucosal injury drug products for use as oral wound healing agents. Oral wound healing agents have been marketed as aids in the healing of minor oral wounds by means other than cleansing and irrigating, or by serving as a protectant. Allantoin, carbamide peroxide in anhydrous glycerin, water soluble chlorophyllins, and hydrogen peroxide in aqueous solution are safe for use as oral wound healing agents, but there are inadequate data to establish general recognition of the effectiveness of these ingredients as oral wound healing agents.

(b) Any OTC drug product that is labeled, represented, or promoted for use as an oral wound healing agent is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act, for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as an oral wound healing agent is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After the effective date of the final regulation, any OTC drug product that is labeled, represented, or promoted for use as an oral wound healing agent may not be initially introduced or initially delivered for introduction into interstate commerce unless it is the subject of an approved new drug application.

(a) Denatonium benzoate and sucrose octaacetate have been present in OTC nailbiting and thumbsucking deterrent drug products. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these and any other ingredients (e.g., cayenne pepper) for OTC use as a nailbiting or thumbsucking deterrent. Based on evidence currently available, any OTC drug product containing ingredients offered for use as a nailbiting or thumbsucking deterrent cannot be generally recognized as safe and effective.

(b) Any OTC drug product that is labeled, represented, and promoted as a nailbiting or thumbsucking deterrent is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act) for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as a nailbiting or thumbsucking deterrent is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After March 2, 1994, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(a) l-lysine (lysine, lysine hydrochloride), Lactobacillus acidophilus, and Lactobacillus bulgaricus have been present in orally administered OTC drug products to treat fever blisters and cold sores. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these or any other orally administered ingredients for OTC use to treat or relieve the symptoms or discomfort of fever blisters and cold sores. Based on evidence currently available, any OTC drug product for oral administration containing ingredients offered for use in treating or relieving the symptoms or discomfort of fever blisters and cold sores cannot be generally recognized as safe and effective.

(b) Any OTC drug product for oral administration that is labeled, represented, or promoted to treat or relieve the symptoms or discomfort of fever blisters and cold sores is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product for oral administration labeled, represented, or promoted for OTC use to treat or relieve the symptoms or discomfort of fever blisters and cold sores is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After December 30, 1992, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(a) Any product that bears labeling claims such as for “temporary relief of discomfort from ingrown toenails,” or “ingrown toenail relief product,” or “ingrown toenail reliever,” or similar claims is considered an ingrown toenail relief drug product. Benzocaine, chlorobutanol, chloroxylenol, dibucaine, tannic acid, and urea have been present as ingredients in such products. There is lack of adequate data to establish general recognition of the safety and effectiveness of these or any other ingredients for OTC use for ingrown toenail relief. Based on evidence currently available, any OTC drug product containing ingredients offered for use for ingrown toenail relief cannot be generally recognized as safe and effective.

(b) Any OTC drug product that is labeled, represented, or promoted for ingrown toenail relief is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use for ingrown toenail relief is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After March 9, 1994, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(e) This section does not apply to sodium sulfide labeled, represented, or promoted for OTC topical use for ingrown toenail relief in accordance with part 358, subpart D of this chapter, after June 6, 2003.

(a) Betaine hydrochloride, glutamic acid hydrochloride, diluted hydrochloric acid, and pepsin have been present as ingredients in over-the-counter (OTC) drug products for use as stomach acidifiers. Because of the lack of adequate data to establish the effectiveness of these or any other ingredients for use in treating achlorhydria and hypochlorhydria, and because such conditions are asymptomatic, any OTC drug product containing ingredients offered for use as a stomach acidifier cannot be considered generally recognized as safe and effective.

(b) Any OTC drug product that is labeled, represented, or promoted for use as a stomach acidifier is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act, for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted as a stomach acidifier for OTC use is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After the effective date of the final regulation, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(a) Hypophosphatemia is a condition in which an abnormally low plasma level of phosphate occurs in the blood. This condition is not amenable to self-diagnosis or self-treatment. Treatment of this condition should be restricted to the supervision of a physician. For this reason, any drug product containing ingredients offered for OTC use in the treatment of hypophosphatemia cannot be considered generally recognized as safe and effective.

(b) Any drug product that is labeled, represented, or promoted for OTC use in the treatment of hypophosphatemia is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use in the treatment of hypophosphatemia is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of his chapter.

(d) After November 12, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(a) Hyperphosphatemia is a condition in which an abnormally high plasma level of phosphate occurs in the blood. This condition in not amenable to self-diagnosis or self-treatment. Treatment of this condition should be restricted to the supervision of a physician. For this reason, any drug product containing ingredients offered for OTC use in the treatment of hyperphosphatemia cannot be considered generally recognized as safe and effective.

(b) Any drug product that is labeled, represented, or promoted for OTC use in the treatment of hyperphosphatemia is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for use in the treatment of hyperphosphatemia is safe and effective for the purpose intended must comply with the requirements and procedures governing use of investigational new drugs set forth in part 312 of this chapter.

(d) After November 12, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(a) Hemicellulase, pancreatin, and pancrelipase have been present as ingredients in exocrine pancreatic insufficiency drug products. Pancreatin and pancrelipase are composed of enzymes: amylase, trypsin (protease), and lipase. Significant differences have been shown in the bioavailability of marketed exocrine pancreatic insufficiency drug products produced by different manufacturers. These differences raise a potential for serious risk to patients using these drug products. The bioavailability of pancreatic enzymes is dependent on the process used to manufacture the drug products. Information on this process is not included in an OTC drug monograph. Therefore, the safe and effective use of these enzymes for treating exocrine pancreatic insufficiency cannot be regulated adequately by an OTC drug monograph. Information on the product's formulation, manufacture, quality control procedures, and final formulation effectiveness testing are necessary in an approved application to ensure that a company has the ability to manufacture a proper bioactive formulation. In addition, continuous physician monitoring of patients who take these drug products is a collateral measure necessary to the safe and effective use of these enzymes, causing such products to be available by prescription only.

(b) Any drug product that is labeled, represented, or promoted for OTC use in the treatment of exocrine pancreatic insufficiency is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use in the treatment of exocrine pancreatic insufficiency is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After May 7, 1991, any such OTC drug product that contains hemicellulase initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(e) After October 24, 1995, any such OTC drug product that contains pancreatin or pancrelipase initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(a) Any product that bears labeling claims that it “helps stop or reduce the cigarette urge,” “helps break the cigarette habit,” “helps stop or reduce smoking,” or similar claims is a smoking deterrent drug product. Cloves, coriander, eucalyptus oil, ginger (Jamaica), lemon oil (terpeneless), licorice root extract, lobeline (in the form of lobeline sulfate or natural lobelia alkaloids or Lobelia inflata herb), menthol, methyl salicylate, povidone-silver nitrate, quinine ascorbate, silver acetate, silver nitrate, and thymol have been present as ingredients in such drug products. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these or any other ingredients for OTC use as a smoking deterrent. Based on evidence currently available, any OTC drug product containing ingredients offered for use as a smoking deterrent cannot be generally recognized as safe and effective.

(b) Any OTC drug product that is labeled, represented, or promoted as a smoking deterrent is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as a smoking deterrent is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After May 7, 1991, any such OTC drug product containing cloves, coriander, eucalyptus oil, ginger (Jamaica), lemon oil (terpeneless), licorice root extract, menthol, methyl salicylate, quinine ascorbate, silver nitrate, and/or thymol initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. After December 1, 1993, any such OTC drug product containing lobeline (in the form of lobeline sulfate or natural lobelia alkaloids or Lobelia inflata herb), povidone-silver nitrate, silver acetate, or any other ingredients initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(a) A number of active ingredients have been present in OTC drug products for various uses, as described below. However, based on evidence currently available, there are inadequate data to establish general recognition of the safety and effectiveness of these ingredients for the specified uses:

(1) Topical acne drug products.

(2) Anticaries drug products - (i) Approved as of May 7, 1991.

(ii) Approved as of October 7, 1996.

(3) Antidiarrheal drug products - (i) Approved as of May 7, 1991.

(ii) Approved as of April 19, 2004; April 18, 2005, for products with annual sales less than $25,000.

(4) Antiperspirant drug products - (i) Ingredients - Approved as of May 7, 1991.

(ii) Approved as of December 9, 2004; June 9, 2005, for products with annual sales less than $25,000.

(5) [Reserved]

(6) Cold, cough, allergy, bronchodilator, and antiasthmatic drug products - (i) Antihistamine drug products - (A) Ingredients.

(B) Ingredients.

(ii) Nasal decongestant drug products - (A) Approved as of May 7, 1991.

(B) Approved as of August 23, 1995.

(C) Approved as of April 11, 2007; October 11, 2007, for products with annual sales less than $25,000. Any ingredient(s) labeled with claims or directions for use for sinusitis or for relief of nasal congestion associated with sinusitis.

(iii) Expectorant drug products.

(iv) Bronchodilator drug products - (A) Approved as of October 2, 1987.

(B) Approved as of January 29, 1996. Any combination drug product containing theophylline (e.g., theophylline and ephedrine, or theophylline and ephedrine and phenobarbital).

(C) Approved as of June 19, 1996. Any ingredient(s) in a pressurized metered-dose inhaler container.

(D) Approved as of October 29, 2001. Any oral bronchodilator active ingredient (e.g., ephedrine, ephedrine hydrochloride, ephedrine sulfate, racephedrine hydrochloride, or any other ephedrine salt) in combination with any analgesic(s) or analgesic-antipyretic(s), anticholinergic, antihistamine, oral antitussive, or stimulant active ingredient.

(7) Dandruff/seborrheic dermatitis/psoriasis drug products.

(8) Digestive aid drug products - (i) Approved as of May 7, 1991.

(ii) Approved as of November 10, 1993.

(iii) Charcoal, activated

(9) [Reserved]

(10) External analgesic drug products - (i) Analgesic and anesthetic drug products.

(ii) Counterirritant drug products.

(iii) Male genital desensitizer drug products.

(iv) Diaper rash drug products. Any ingredient(s) labeled with claims or directions for use in the treatment and/or prevention of diaper rash.

(v) Fever blister and cold sore treatment drug products.

(vi) Insect bite and sting drug products.

(vii) Poison ivy, poison oak, and poison sumac drug products.

(11) [Reserved]

(12) Laxative drug products - (i)(A) Bulk laxatives.

(i)(B) Bulk laxatives - Approved as of March 29, 2007.

(ii) Saline laxative.

(iii) Stool softener.

(iv)(A) Stimulant laxatives - Approved as of May 7, 1991.

(iv)(B) Stimulant laxatives - Approved as of January 29, 1999.

(C) Stimulant laxatives - Approved as of November 5, 2002.

(13) [Reserved]

(14) Oral health care drug products (nonantimicrobial).

(15) Topical otic drug products - (i) For the prevention of swimmer's ear and for the drying of water-clogged ears, approved as of May 7, 1991.

(ii) For the prevention of swimmer's ear, approved as of August 15, 1995.

(16) Poison treatment drug products.

(17) Skin bleaching drug products.

(18) Skin protectant drug products - (i)(A) Ingredients - Approved as of May 7, 1991.

(B) Ingredients - Approved as of June 4, 2004; June 6, 2005, for products with annual sales less than $25,000.

(ii) Astringent drug products.

(iii) Diaper rash drug products.

(iv) Fever blister and cold sore treatment drug products.

(v) Insect bite and sting drug products - (A) Ingredients - Approved as of November 10, 1993.

(B) Ingredients - Approved as of June 4, 2004; June 6, 2005, for products with annual sales less than $25,000.

(vi) Poison ivy, poison oak, and poison sumac drug products - (A) Ingredients - Approved as of November 10, 1993.

(B) Ingredients - Approved as of June 4, 2004; June 6, 2005, for products with annual sales less than $25,000.

(19) [Reserved]

(20) Weight control drug products.

(21) Ophthalmic drug products. (i) Ophthalmic anesthetic drug products.

(ii) Ophthalmic anti-infective drug products.

(iii) Ophthalmic astringent drug products.

(iv) Ophthalmic demulcent drug products.

(v) Ophthalmic vasoconstrictor drug products.

(22) Topical antifungal drug products. (i) Diaper rash drug products. Any ingredient(s) labeled with claims or directions for use in the treatment and/or prevention of diaper rash.

(ii) Ingredients.

(iii) Any ingredient(s) labeled with claims or directions for use on the scalp or on the nails.

(iv) Ingredients.

(23) Internal analgesic drug products - (i) Approved as of November 10, 1993.

(ii) Approved as of February 22, 1999.

(24) Orally administered menstrual drug products - (i) Approved as of November 10, 1993.

(ii) Approved as of February 22, 1999.

(25) Pediculicide drug products - (i) Approved as of November 10, 1993.

(ii) Approved as of June 14, 1994. The combination of pyrethrum extract (formerly named pyrethrins) and piperonyl butoxide in an aerosol dosage formulation.

(26) Anorectal drug products - (i) Anticholinergic drug products.

(ii) Antiseptic drug products.

(iii) Astringent drug products.

(iv) Counterirritant drug products.

(v) Keratolytic drug products.

(vi) Local anesthetic drug products.

(vii) Other drug products.

(viii) Protectant drug products.

(ix) Vasoconstrictor drug products.

(x) Wound healinq drug products.

(xi) Combination drug products. Any combination drug product containing hydrocortisone and pramoxine hydrochloride.

(27) Topical antimicrobial drug products - (i) First aid antiseptic drug products.

(ii) Diaper rash drug products.

(iii) Consumer antiseptic hand wash drug products. Approved as of September 6, 2017.

(iv) Consumer antiseptic body wash drug products. Approved as of September 6, 2017.

(v) [Reserved]

(vi) Health care personnel hand wash drug products. Approved as of December 20, 2018.

(vii) [Reserved]

(viii) Surgical hand scrub drug products. Approved as of December 20, 2018.

(ix) [Reserved]

(x) Patient antiseptic skin preparation drug products. Approved as of December 20, 2018.

(28) Vaginal contraceptive drug products - (i) Approved as of October 22, 1998.

(ii) Approved as of November 5, 2002.

(29) Sunscreen drug products. (i) Ingredients.

(ii) Any ingredients labeled with any of the following or similar claims. Instant protection or protection immediately upon application.

Claims for “all-day” protection or extended wear claims citing a specific number of hours of protection that is inconsistent with the directions for application in 21 CFR 201.327.

(30) [Reserved]

(b) Any OTC drug product that is labeled, represented, or promoted for the uses specified and containing any active ingredient(s) as specified in paragraph (a) of this section is regarded as a new drug within the meaning of section 210(p) of the Federal Food, Drug, and Cosmetic Act (the Act), for which an approved new drug application under section 505 of the Act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the Act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for the OTC uses and containing any active ingredient(s) as specified in paragraph (a) of this section is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) Any OTC drug product that is not in compliance with this section is subject to regulatory action if initially introduced or initially delivered for introduction into interstate commerce after the dates specified in paragraphs (d)(1) through (d)(42) of this section.

(1) May 7, 1991, for products subject to paragraphs (a)(1) through (a)(2)(i), (a)(3)(i), (a)(4)(i), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) (except as covered by paragraph (d)(3) of this section), (a)(8)(i), (a)(10)(i) through (a)(10)(iii), (a)(12)(i)(A), (a)(12)(ii) through (a)(12)(iv)(A), (a)(14) through (a)(15)(i), (a)(16) through (a)(18)(i)(A), (a)(18)(ii) (except as covered by paragraph (d)(22) of this section), (a)(18)(iii), (a)(18)(iv), (a)(18)(v)(A), and (a)(18)(vi)(A) of this section.

(2) February 10, 1992, for products subject to paragraph (a)(20) of this section.

(3) December 4, 1992, for products subject to paragraph (a)(7) of this section that contain menthol as an antipruritic in combination with the antidandruff ingredient coal tar identified in § 358.710(a)(1) of this chapter. This section does not apply to products allowed by § 358.720(b) of this chapter after April 5, 2007.

(4) February 28, 1990, for products subject to paragraph (a)(6)(iii) of this section, except those that contain ipecac.

(5) September 14, 1993, for products subject to paragraph (a)(6)(iii) of this section that contain ipecac.

(6) December 9, 1993, for products subject to paragraph (a)(6)(i)(B) of this section.

(7) March 6, 1989, for products subject to paragraph (a)(21) of this section, except those that contain ophthalmic anti-infective ingredients listed in paragraph (a)(21)(ii).

(8) June 18, 1993, for products subject to paragraph (a)(21) of this section that contain ophthalmic anti-infective ingredients.

(9) June 18, 1993, for products subject to paragraph (a)(10)(iv) of this section.

(10) June 18, 1993, for products subject to paragraph (a)(22)(i) of this section.

(11) November 10, 1993, for products subject to paragraphs (a)(8)(ii), (a)(10)(v) through (a)(10)(vii), (a)(18)(ii) (except products that contain ferric subsulfate as covered by paragraph (d)(22) of this section and except products that contain calcium acetate monohydrate as covered by paragraph (d)(39) of this section) through (a)(18)(v)(A), (a)(18)(vi)(A), (a)(22)(ii), (a)(23)(i), (a)(24)(i), and (a)(25) of this section.

(12) March 2, 1994, for products subject to paragraph (a)(22)(iii) of this section.

(13) August 5, 1991, for products subject to paragraph (a)(26) of this section, except for those that contain live yeast cell derivative and a combination of hydrocortisone and pramoxine hydrochloride.

(14) September 2, 1994, for products subject to paragraph (a)(26)(vii) and (a)(26)(x) of this section that contain live yeast cell derivative.

(15) September 23, 1994, for products subject to paragraph (a)(22)(iv) of this section.

(16) June 14, 1994, for products subject to paragraph (a)(25)(ii) of this section.

(17) April 19, 2004, for products subject to paragraph (a)(3)(ii) of this section. April 18, 2005, for products with annual sales less than $25,000.

(18) August 15, 1995, for products subject to paragraph (a)(15)(ii) of this section.

(19) October 2, 1987, for products subject to paragraph (a)(6)(iv)(A) of this section.

(20) January 29, 1996, for products subject to paragraph (a)(6)(iv)(B) of this section.

(21) April 21, 1994, for products subject to paragraph (a)(8)(iii) of this section.

(22) April 21, 1993, for products subject to paragraph (a)(18)(ii) of this section that contain ferric subsulfate.

(23) August 23, 1995, for products subject to paragraph (a)(6)(ii)(B) of this section.

(24) October 7, 1996, for products subject to paragraph (a)(2)(ii) of this section.

(25) June 19, 1996, for products subject to paragraph (a)(6)(iv)(C) of this section.

(26) February 22, 1999, for products subject to paragraphs (a)(23)(ii) and (a)(24)(ii) of this section.

(27) [Reserved]

(28) October 22, 1998, for products subject to paragraphs (a)(27) and (a)(28)(i) of this section.

(29) January 29, 1999, for products subject to paragraph (a)(12)(iv)(B) of this section.

(30) November 5, 2002, for products subject to paragraph (a)(12)(iv)(C) of this section.

(31) December 31, 2002, for products subject to paragraph (a)(29)(i) of this section.

(32) June 4, 2004, for products subject to paragraphs (a)(18)(i)(B), (a)(18)(v)(B), and (a)(18)(vi)(B) of this section. June 6, 2005, for products with annual sales less than $25,000.

(33) October 29, 2001, for products subject to paragraph (a)(6)(iv)(D) of this section.

(34) December 9, 2004, for products subject to paragraph (a)(4)(ii) of this section. June 9, 2005, for products with annual sales less than $25,000.

(35) [Reserved]

(36) November 5, 2002, for products subject to paragraph (a)(28)(ii) of this section.

(37) September 25, 2003, for products subject to paragraph (a)(26)(xi) of this section.

(38) October 1, 2007, for products subject to paragraph (a)(12)(i)(B) of this section.

(39) September 6, 2010, for products subject to paragraph (a)(18)(ii) of this section that contain calcium acetate monohydrate, except as provided in § 347.20(b) of this chapter.

(40) December 17, 2012, for products subject to paragraph (a)(29)(ii) of this section. December 17, 2013, for products with annual sales less than $25,000.

(41) September 6, 2017, for products subject to paragraph (a)(27)(iii) or (iv) of this section.

(42) December 20, 2018, for products subject to paragraphs (a)(27)(vi) through (x) of this section.

(a) Quinine sulfate alone or in combination with vitamin E has been present in over-the-counter (OTC) drug products for the treatment and/or prevention of nocturnal leg muscle cramps, i.e., a condition of localized pain in the lower extremities usually occurring in middle life and beyond with no regular pattern concerning time or severity. There is a lack of adequate data to establish general recognition of the safety and effectiveness of quinine sulfate, vitamin E, or any other ingredients for OTC use in the treatment and/or prevention of nocturnal leg muscle cramps. In the doses used to treat or prevent this condition, quinine sulfate has caused adverse events such as transient visual and auditory disturbances, dizziness, fever, nausea, vomiting, and diarrhea. Quinine sulfate may cause unpredictable serious and life-threatening hypersensitivity reactions requiring medical intervention and hospitalization; fatalities have been reported. The risk associated with use of quinine sulfate, in the absence of evidence of its effectiveness, outweighs any potential benefit in treating and/or preventing this benign, self-limiting condition. Based upon the adverse benefit-to-risk ratio, any drug product containing quinine or quinine sulfate cannot be considered generally recognized as safe for the treatment and/or prevention of nocturnal leg muscle cramps.

(b) Any OTC drug product that is labeled, represented, or promoted for the treatment and/or prevention of nocturnal leg muscle cramps is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use for the treatment and/or prevention of nocturnal leg muscle cramps is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After February 22, 1995, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(a) Quinine and quinine salts have been used OTC for the treatment and/or prevention of malaria, a serious and potentially life-threatening disease. Quinine is no longer the drug of choice for the treatment and/or prevention of most types of malaria. In addition, there are serious and complicating aspects of the disease itself and some potentially serious and life-threatening risks associated with the use of quinine at doses employed for the treatment of malaria. There is a lack of adequate data to establish general recognition of the safety of quinine drug products for OTC use in the treatment and/or prevention of malaria. Therefore, quinine or quinine salts cannot be safely and effectively used for the treatment and/or prevention of malaria except under the care and supervision of a doctor.

(b) Any OTC drug product containing quinine or quinine salts that is labeled, represented, or promoted for the treatment and/or prevention of malaria is regarded as a new drug within the meaning of section 201(p) of the act, for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use for the treatment and/or prevention of malaria is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After April 20, 1998, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(a) Colloidal silver ingredients and silver salts have been marketed in over-the-counter (OTC) drug products for the treatment and prevention of numerous disease conditions. There are serious and complicating aspects to many of the diseases these silver ingredients purport to treat or prevent. Further, there is a lack of adequate data to establish general recognition of the safety and effectiveness of colloidal silver ingredients or silver salts for OTC use in the treatment or prevention of any disease. These ingredients and salts include, but are not limited to, silver proteins, mild silver protein, strong silver protein, silver, silver ion, silver chloride, silver cyanide, silver iodide, silver oxide, and silver phosphate.

(b) Any OTC drug product containing colloidal silver ingredients or silver salts that is labeled, represented, or promoted for the treatment and/or prevention of any disease is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act) for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any drug product containing colloidal silver or silver salts labeled, represented, or promoted for any OTC drug use is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs as set forth in part 312 of this chapter.

(d) After September 16, 1999, any such OTC drug product containing colloidal silver or silver salts initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

(a) This part contains procedures and requirements governing the use of investigational new drugs, including procedures and requirements for the submission to, and review by, the Food and Drug Administration of investigational new drug applications (IND's). An investigational new drug for which an IND is in effect in accordance with this part is exempt from the premarketing approval requirements that are otherwise applicable and may be shipped lawfully for the purpose of conducting clinical investigations of that drug.

(b) References in this part to regulations in the Code of Federal Regulations are to chapter I of title 21, unless otherwise noted.

(a) Applicability. Except as provided in this section, this part applies to all clinical investigations of products that are subject to section 505 of the Federal Food, Drug, and Cosmetic Act or to the licensing provisions of the Public Health Service Act (58 Stat. 632, as amended (42 U.S.C. 201 et seq.)).

(b) Exemptions. (1) The clinical investigation of a drug product that is lawfully marketed in the United States is exempt from the requirements of this part if all the following apply:

(i) The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use nor intended to be used to support any other significant change in the labeling for the drug;

(ii) If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the investigation is not intended to support a significant change in the advertising for the product;

(iii) The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product;

(iv) The investigation is conducted in compliance with the requirements for institutional review set forth in part 56 and with the requirements for informed consent set forth in part 50; and

(v) The investigation is conducted in compliance with the requirements of § 312.7.

(2)(i) A clinical investigation involving an in vitro diagnostic biological product listed in paragraph (b)(2)(ii) of this section is exempt from the requirements of this part if (a) it is intended to be used in a diagnostic procedure that confirms the diagnosis made by another, medically established, diagnostic product or procedure and (b) it is shipped in compliance with § 312.160.

(ii) In accordance with paragraph (b)(2)(i) of this section, the following products are exempt from the requirements of this part: (a) blood grouping serum; (b) reagent red blood cells; and (c) anti-human globulin.

(3) A drug intended solely for tests in vitro or in laboratory research animals is exempt from the requirements of this part if shipped in accordance with § 312.160.

(4) FDA will not accept an application for an investigation that is exempt under the provisions of paragraph (b)(1) of this section.

(5) A clinical investigation involving use of a placebo is exempt from the requirements of this part if the investigation does not otherwise require submission of an IND.

(6) A clinical investigation involving an exception from informed consent under § 50.24 of this chapter is not exempt from the requirements of this part.

(c) Bioavailability studies. The applicability of this part to in vivo bioavailability studies in humans is subject to the provisions of § 320.31.

(d) Unlabeled indication. This part does not apply to the use in the practice of medicine for an unlabeled indication of a new drug product approved under part 314 or of a licensed biological product.

(e) Guidance. FDA may, on its own initiative, issue guidance on the applicability of this part to particular investigational uses of drugs. On request, FDA will advise on the applicability of this part to a planned clinical investigation.

(a) The definitions and interpretations of terms contained in section 201 of the Act apply to those terms when used in this part:

(b) The following definitions of terms also apply to this part:

Act means the Federal Food, Drug, and Cosmetic Act (secs. 201-902, 52 Stat. 1040 et seq., as amended (21 U.S.C. 301-392)).

Clinical investigation means any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice.

Contract research organization means a person that assumes, as an independent contractor with the sponsor, one or more of the obligations of a sponsor, e.g., design of a protocol, selection or monitoring of investigations, evaluation of reports, and preparation of materials to be submitted to the Food and Drug Administration.

FDA means the Food and Drug Administration.

IND means an investigational new drug application. For purposes of this part, “IND” is synonymous with “Notice of Claimed Investigational Exemption for a New Drug.”

Independent ethics committee (IEC) means a review panel that is responsible for ensuring the protection of the rights, safety, and well-being of human subjects involved in a clinical investigation and is adequately constituted to provide assurance of that protection. An institutional review board (IRB), as defined in § 56.102(g) of this chapter and subject to the requirements of part 56 of this chapter, is one type of IEC.

Investigational new drug means a new drug or biological drug that is used in a clinical investigation. The term also includes a biological product that is used in vitro for diagnostic purposes. The terms “investigational drug” and “investigational new drug” are deemed to be synonymous for purposes of this part.

Investigator means an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. “Subinvestigator” includes any other individual member of that team.

Marketing application means an application for a new drug submitted under section 505(b) of the act or a biologics license application for a biological product submitted under the Public Health Service Act.

Sponsor means a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor, not a sponsor-investigator, and the employees are investigators.

Sponsor-Investigator means an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. The term does not include any person other than an individual. The requirements applicable to a sponsor-investigator under this part include both those applicable to an investigator and a sponsor.

Subject means a human who participates in an investigation, either as a recipient of the investigational new drug or as a control. A subject may be a healthy human or a patient with a disease.

(a) The immediate package of an investigational new drug intended for human use shall bear a label with the statement “Caution: New Drug - Limited by Federal (or United States) law to investigational use.”

(b) The label or labeling of an investigational new drug shall not bear any statement that is false or misleading in any particular and shall not represent that the investigational new drug is safe or effective for the purposes for which it is being investigated.

(c) The appropriate FDA Center Director, according to the procedures set forth in §§ 201.26 or 610.68 of this chapter, may grant an exception or alternative to the provision in paragraph (a) of this section, to the extent that this provision is not explicitly required by statute, for specified lots, batches, or other units of a human drug product that is or will be included in the Strategic National Stockpile.

(a) Promotion of an investigational new drug. A sponsor or investigator, or any person acting on behalf of a sponsor or investigator, shall not represent in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug. This provision is not intended to restrict the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media. Rather, its intent is to restrict promotional claims of safety or effectiveness of the drug for a use for which it is under investigation and to preclude commercialization of the drug before it is approved for commercial distribution.

(b) Commercial distribution of an investigational new drug. A sponsor or investigator shall not commercially distribute or test market an investigational new drug.

(c) Prolonging an investigation. A sponsor shall not unduly prolong an investigation after finding that the results of the investigation appear to establish sufficient data to support a marketing application.

(a) General criteria for charging. (1) A sponsor must meet the applicable requirements in paragraph (b) of this section for charging in a clinical trial or paragraph (c) of this section for charging for expanded access to an investigational drug for treatment use under subpart I of this part, except that sponsors need not fulfill the requirements in this section to charge for an approved drug obtained from another entity not affiliated with the sponsor for use as part of the clinical trial evaluation (e.g., in a clinical trial of a new use of the approved drug, for use of the approved drug as an active control).

(2) A sponsor must justify the amount to be charged in accordance with paragraph (d) of this section.

(3) A sponsor must obtain prior written authorization from FDA to charge for an investigational drug.

(4) FDA will withdraw authorization to charge if it determines that charging is interfering with the development of a drug for marketing approval or that the criteria for the authorization are no longer being met.

(b) Charging in a clinical trial - (1) Charging for a sponsor's drug. A sponsor who wishes to charge for its investigational drug, including investigational use of its approved drug, must:

(i) Provide evidence that the drug has a potential clinical benefit that, if demonstrated in the clinical investigations, would provide a significant advantage over available products in the diagnosis, treatment, mitigation, or prevention of a disease or condition;

(ii) Demonstrate that the data to be obtained from the clinical trial would be essential to establishing that the drug is effective or safe for the purpose of obtaining initial approval of a drug, or would support a significant change in the labeling of an approved drug (e.g., new indication, inclusion of comparative safety information); and

(iii) Demonstrate that the clinical trial could not be conducted without charging because the cost of the drug is extraordinary to the sponsor. The cost may be extraordinary due to manufacturing complexity, scarcity of a natural resource, the large quantity of drug needed (e.g., due to the size or duration of the trial), or some combination of these or other extraordinary circumstances (e.g., resources available to a sponsor).

(2) Duration of charging in a clinical trial. Unless FDA specifies a shorter period, charging may continue for the length of the clinical trial.

(c) Charging for expanded access to investigational drug for treatment use. (1) A sponsor who wishes to charge for expanded access to an investigational drug for treatment use under subpart I of this part must provide reasonable assurance that charging will not interfere with developing the drug for marketing approval.

(2) For expanded access under § 312.320 (treatment IND or treatment protocol), such assurance must include:

(i) Evidence of sufficient enrollment in any ongoing clinical trial(s) needed for marketing approval to reasonably assure FDA that the trial(s) will be successfully completed as planned;

(ii) Evidence of adequate progress in the development of the drug for marketing approval; and

(iii) Information submitted under the general investigational plan (§ 312.23(a)(3)(iv)) specifying the drug development milestones the sponsor plans to meet in the next year.

(3) The authorization to charge is limited to the number of patients authorized to receive the drug under the treatment use, if there is a limitation.

(4) Unless FDA specifies a shorter period, charging for expanded access to an investigational drug for treatment use under subpart I of this part may continue for 1 year from the time of FDA authorization. A sponsor may request that FDA reauthorize charging for additional periods.

(d) Costs recoverable when charging for an investigational drug. (1) A sponsor may recover only the direct costs of making its investigational drug available.

(i) Direct costs are costs incurred by a sponsor that can be specifically and exclusively attributed to providing the drug for the investigational use for which FDA has authorized cost recovery. Direct costs include costs per unit to manufacture the drug (e.g., raw materials, labor, and nonreusable supplies and equipment used to manufacture the quantity of drug needed for the use for which charging is authorized) or costs to acquire the drug from another manufacturing source, and direct costs to ship and handle (e.g., store) the drug.

(ii) Indirect costs include costs incurred primarily to produce the drug for commercial sale (e.g., costs for facilities and equipment used to manufacture the supply of investigational drug, but that are primarily intended to produce large quantities of drug for eventual commercial sale) and research and development, administrative, labor, or other costs that would be incurred even if the clinical trial or treatment use for which charging is authorized did not occur.

(2) For expanded access to an investigational drug for treatment use under §§ 312.315 (intermediate-size patient populations) and 312.320 (treatment IND or treatment protocol), in addition to the direct costs described in paragraph (d)(1)(i) of this section, a sponsor may recover the costs of monitoring the expanded access IND or protocol, complying with IND reporting requirements, and other administrative costs directly associated with the expanded access IND.

(3) To support its calculation for cost recovery, a sponsor must provide supporting documentation to show that the calculation is consistent with the requirements of paragraphs (d)(1) and, if applicable, (d)(2) of this section. The documentation must be accompanied by a statement that an independent certified public accountant has reviewed and approved the calculations.

(a) A sponsor may request FDA to waive applicable requirement under this part. A waiver request may be submitted either in an IND or in an information amendment to an IND. In an emergency, a request may be made by telephone or other rapid communication means. A waiver request is required to contain at least one of the following:

(1) An explanation why the sponsor's compliance with the requirement is unnecessary or cannot be achieved;

(2) A description of an alternative submission or course of action that satisfies the purpose of the requirement; or

(3) Other information justifying a waiver.

(b) FDA may grant a waiver if it finds that the sponsor's noncompliance would not pose a significant and unreasonable risk to human subjects of the investigation and that one of the following is met:

(1) The sponsor's compliance with the requirement is unnecessary for the agency to evaluate the application, or compliance cannot be achieved;

(2) The sponsor's proposed alternative satisfies the requirement; or

(3) The applicant's submission otherwise justifies a waiver.

(a) A sponsor shall submit an IND to FDA if the sponsor intends to conduct a clinical investigation with an investigational new drug that is subject to § 312.2(a).

(b) A sponsor shall not begin a clinical investigation subject to § 312.2(a) until the investigation is subject to an IND which is in effect in accordance with § 312.40.

(c) A sponsor shall submit a separate IND for any clinical investigation involving an exception from informed consent under § 50.24 of this chapter. Such a clinical investigation is not permitted to proceed without the prior written authorization from FDA. FDA shall provide a written determination 30 days after FDA receives the IND or earlier.

An IND may be submitted for one or more phases of an investigation. The clinical investigation of a previously untested drug is generally divided into three phases. Although in general the phases are conducted sequentially, they may overlap. These three phases of an investigation are a follows:

(a) Phase 1. (1) Phase 1 includes the initial introduction of an investigational new drug into humans. Phase 1 studies are typically closely monitored and may be conducted in patients or normal volunteer subjects. These studies are designed to determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. During Phase 1, sufficient information about the drug's pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, Phase 2 studies. The total number of subjects and patients included in Phase 1 studies varies with the drug, but is generally in the range of 20 to 80.

(2) Phase 1 studies also include studies of drug metabolism, structure-activity relationships, and mechanism of action in humans, as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes.

(b) Phase 2. Phase 2 includes the controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks associated with the drug. Phase 2 studies are typically well controlled, closely monitored, and conducted in a relatively small number of patients, usually involving no more than several hundred subjects.

(c) Phase 3. Phase 3 studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling. Phase 3 studies usually include from several hundred to several thousand subjects.

(a) FDA's primary objectives in reviewing an IND are, in all phases of the investigation, to assure the safety and rights of subjects, and, in Phase 2 and 3, to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug's effectiveness and safety. Therefore, although FDA's review of Phase 1 submissions will focus on assessing the safety of Phase 1 investigations, FDA's review of Phases 2 and 3 submissions will also include an assessment of the scientific quality of the clinical investigations and the likelihood that the investigations will yield data capable of meeting statutory standards for marketing approval.

(b) The amount of information on a particular drug that must be submitted in an IND to assure the accomplishment of the objectives described in paragraph (a) of this section depends upon such factors as the novelty of the drug, the extent to which it has been studied previously, the known or suspected risks, and the developmental phase of the drug.

(c) The central focus of the initial IND submission should be on the general investigational plan and the protocols for specific human studies. Subsequent amendments to the IND that contain new or revised protocols should build logically on previous submissions and should be supported by additional information, including the results of animal toxicology studies or other human studies as appropriate. Annual reports to the IND should serve as the focus for reporting the status of studies being conducted under the IND and should update the general investigational plan for the coming year.

(d) The IND format set forth in § 312.23 should be followed routinely by sponsors in the interest of fostering an efficient review of applications. Sponsors are expected to exercise considerable discretion, however, regarding the content of information submitted in each section, depending upon the kind of drug being studied and the nature of the available information. Section 312.23 outlines the information needed for a commercially sponsored IND for a new molecular entity. A sponsor-investigator who uses, as a research tool, an investigational new drug that is already subject to a manufacturer's IND or marketing application should follow the same general format, but ordinarily may, if authorized by the manufacturer, refer to the manufacturer's IND or marketing application in providing the technical information supporting the proposed clinical investigation. A sponsor-investigator who uses an investigational drug not subject to a manufacturer's IND or marketing application is ordinarily required to submit all technical information supporting the IND, unless such information may be referenced from the scientific literature.

(a) A sponsor who intends to conduct a clinical investigation subject to this part shall submit an “Investigational New Drug Application” (IND) including, in the following order:

(1) Cover sheet (Form FDA-1571). A cover sheet for the application containing the following:

(i) The name, address, and telephone number of the sponsor, the date of the application, and the name of the investigational new drug.

(ii) Identification of the phase or phases of the clinical investigation to be conducted.

(iii) A commitment not to begin clinical investigations until an IND covering the investigations is in effect.

(iv) A commitment that an Institutional Review Board (IRB) that complies with the requirements set forth in part 56 will be responsible for the initial and continuing review and approval of each of the studies in the proposed clinical investigation and that the investigator will report to the IRB proposed changes in the research activity in accordance with the requirements of part 56.

(v) A commitment to conduct the investigation in accordance with all other applicable regulatory requirements.

(vi) The name and title of the person responsible for monitoring the conduct and progress of the clinical investigations.

(vii) The name(s) and title(s) of the person(s) responsible under § 312.32 for review and evaluation of information relevant to the safety of the drug.

(viii) If a sponsor has transferred any obligations for the conduct of any clinical study to a contract research organization, a statement containing the name and address of the contract research organization, identification of the clinical study, and a listing of the obligations transferred. If all obligations governing the conduct of the study have been transferred, a general statement of this transfer - in lieu of a listing of the specific obligations transferred - may be submitted.

(ix) The signature of the sponsor or the sponsor's authorized representative. If the person signing the application does not reside or have a place of business within the United States, the IND is required to contain the name and address of, and be countersigned by, an attorney, agent, or other authorized official who resides or maintains a place of business within the United States.

(2) A table of contents.

(3) Introductory statement and general investigational plan. (i) A brief introductory statement giving the name of the drug and all active ingredients, the drug's pharmacological class, the structural formula of the drug (if known), the formulation of the dosage form(s) to be used, the route of administration, and the broad objectives and planned duration of the proposed clinical investigation(s).

(ii) A brief summary of previous human experience with the drug, with reference to other IND's if pertinent, and to investigational or marketing experience in other countries that may be relevant to the safety of the proposed clinical investigation(s).

(iii) If the drug has been withdrawn from investigation or marketing in any country for any reason related to safety or effectiveness, identification of the country(ies) where the drug was withdrawn and the reasons for the withdrawal.

(iv) A brief description of the overall plan for investigating the drug product for the following year. The plan should include the following: (a) The rationale for the drug or the research study; (b) the indication(s) to be studied; (c) the general approach to be followed in evaluating the drug; (d) the kinds of clinical trials to be conducted in the first year following the submission (if plans are not developed for the entire year, the sponsor should so indicate); (e) the estimated number of patients to be given the drug in those studies; and (f) any risks of particular severity or seriousness anticipated on the basis of the toxicological data in animals or prior studies in humans with the drug or related drugs.

(4) [Reserved]

(5) Investigator's brochure. If required under § 312.55, a copy of the investigator's brochure, containing the following information:

(i) A brief description of the drug substance and the formulation, including the structural formula, if known.

(ii) A summary of the pharmacological and toxicological effects of the drug in animals and, to the extent known, in humans.

(iii) A summary of the pharmacokinetics and biological disposition of the drug in animals and, if known, in humans.

(iv) A summary of information relating to safety and effectiveness in humans obtained from prior clinical studies. (Reprints of published articles on such studies may be appended when useful.)

(v) A description of possible risks and side effects to be anticipated on the basis of prior experience with the drug under investigation or with related drugs, and of precautions or special monitoring to be done as part of the investigational use of the drug.

(6) Protocols. (i) A protocol for each planned study. (Protocols for studies not submitted initially in the IND should be submitted in accordance with § 312.30(a).) In general, protocols for Phase 1 studies may be less detailed and more flexible than protocols for Phase 2 and 3 studies. Phase 1 protocols should be directed primarily at providing an outline of the investigation - an estimate of the number of patients to be involved, a description of safety exclusions, and a description of the dosing plan including duration, dose, or method to be used in determining dose - and should specify in detail only those elements of the study that are critical to safety, such as necessary monitoring of vital signs and blood chemistries. Modifications of the experimental design of Phase 1 studies that do not affect critical safety assessments are required to be reported to FDA only in the annual report.

(ii) In Phases 2 and 3, detailed protocols describing all aspects of the study should be submitted. A protocol for a Phase 2 or 3 investigation should be designed in such a way that, if the sponsor anticipates that some deviation from the study design may become necessary as the investigation progresses, alternatives or contingencies to provide for such deviation are built into the protocols at the outset. For example, a protocol for a controlled short-term study might include a plan for an early crossover of nonresponders to an alternative therapy.

(iii) A protocol is required to contain the following, with the specific elements and detail of the protocol reflecting the above distinctions depending on the phase of study:

(a) A statement of the objectives and purpose of the study.

(b) The name and address and a statement of the qualifications (curriculum vitae or other statement of qualifications) of each investigator, and the name of each subinvestigator (e.g., research fellow, resident) working under the supervision of the investigator; the name and address of the research facilities to be used; and the name and address of each reviewing Institutional Review Board.

(c) The criteria for patient selection and for exclusion of patients and an estimate of the number of patients to be studied.

(d) A description of the design of the study, including the kind of control group to be used, if any, and a description of methods to be used to minimize bias on the part of subjects, investigators, and analysts.

(e) The method for determining the dose(s) to be administered, the planned maximum dosage, and the duration of individual patient exposure to the drug.

(f) A description of the observations and measurements to be made to fulfill the objectives of the study.

(g) A description of clinical procedures, laboratory tests, or other measures to be taken to monitor the effects of the drug in human subjects and to minimize risk.

(7) Chemistry, manufacturing, and control information. (i) As appropriate for the particular investigations covered by the IND, a section describing the composition, manufacture, and control of the drug substance and the drug product. Although in each phase of the investigation sufficient information is required to be submitted to assure the proper identification, quality, purity, and strength of the investigational drug, the amount of information needed to make that assurance will vary with the phase of the investigation, the proposed duration of the investigation, the dosage form, and the amount of information otherwise available. FDA recognizes that modifications to the method of preparation of the new drug substance and dosage form and changes in the dosage form itself are likely as the investigation progresses. Therefore, the emphasis in an initial Phase 1 submission should generally be placed on the identification and control of the raw materials and the new drug substance. Final specifications for the drug substance and drug product are not expected until the end of the investigational process.

(ii) It should be emphasized that the amount of information to be submitted depends upon the scope of the proposed clinical investigation. For example, although stability data are required in all phases of the IND to demonstrate that the new drug substance and drug product are within acceptable chemical and physical limits for the planned duration of the proposed clinical investigation, if very short-term tests are proposed, the supporting stability data can be correspondingly limited.

(iii) As drug development proceeds and as the scale or production is changed from the pilot-scale production appropriate for the limited initial clinical investigations to the larger-scale production needed for expanded clinical trials, the sponsor should submit information amendments to supplement the initial information submitted on the chemistry, manufacturing, and control processes with information appropriate to the expanded scope of the investigation.

(iv) Reflecting the distinctions described in this paragraph (a)(7), and based on the phase(s) to be studied, the submission is required to contain the following:

(a) Drug substance. A description of the drug substance, including its physical, chemical, or biological characteristics; the name and address of its manufacturer; the general method of preparation of the drug substance; the acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug substance; and information sufficient to support stability of the drug substance during the toxicological studies and the planned clinical studies. Reference to the current edition of the United States Pharmacopeia - National Formulary may satisfy relevant requirements in this paragraph.

(b) Drug product. A list of all components, which may include reasonable alternatives for inactive compounds, used in the manufacture of the investigational drug product, including both those components intended to appear in the drug product and those which may not appear but which are used in the manufacturing process, and, where applicable, the quantitative composition of the investigational drug product, including any reasonable variations that may be expected during the investigational stage; the name and address of the drug product manufacturer; a brief general description of the manufacturing and packaging procedure as appropriate for the product; the acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug product; and information sufficient to assure the product's stability during the planned clinical studies. Reference to the current edition of the United States Pharmacopeia - National Formulary may satisfy certain requirements in this paragraph.

(c) A brief general description of the composition, manufacture, and control of any placebo used in a controlled clinical trial.

(d) Labeling. A copy of all labels and labeling to be provided to each investigator.

(e) Environmental analysis requirements. A claim for categorical exclusion under § 25.30 or 25.31 or an environmental assessment under § 25.40.

(8) Pharmacology and toxicology information. Adequate information about pharmacological and toxicological studies of the drug involving laboratory animals or in vitro, on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations. The kind, duration, and scope of animal and other tests required varies with the duration and nature of the proposed clinical investigations. Guidance documents are available from FDA that describe ways in which these requirements may be met. Such information is required to include the identification and qualifications of the individuals who evaluated the results of such studies and concluded that it is reasonably safe to begin the proposed investigations and a statement of where the investigations were conducted and where the records are available for inspection. As drug development proceeds, the sponsor is required to submit informational amendments, as appropriate, with additional information pertinent to safety.

(i) Pharmacology and drug disposition. A section describing the pharmacological effects and mechanism(s) of action of the drug in animals, and information on the absorption, distribution, metabolism, and excretion of the drug, if known.

(ii) Toxicology. (a) An integrated summary of the toxicological effects of the drug in animals and in vitro. Depending on the nature of the drug and the phase of the investigation, the description is to include the results of acute, subacute, and chronic toxicity tests; tests of the drug's effects on reproduction and the developing fetus; any special toxicity test related to the drug's particular mode of administration or conditions of use (e.g., inhalation, dermal, or ocular toxicology); and any in vitro studies intended to evaluate drug toxicity.

(b) For each toxicology study that is intended primarily to support the safety of the proposed clinical investigation, a full tabulation of data suitable for detailed review.

(iii) For each nonclinical laboratory study subject to the good laboratory practice regulations under part 58, a statement that the study was conducted in compliance with the good laboratory practice regulations in part 58, or, if the study was not conducted in compliance with those regulations, a brief statement of the reason for the noncompliance.

(9) Previous human experience with the investigational drug. A summary of previous human experience known to the applicant, if any, with the investigational drug. The information is required to include the following:

(i) If the investigational drug has been investigated or marketed previously, either in the United States or other countries, detailed information about such experience that is relevant to the safety of the proposed investigation or to the investigation's rationale. If the drug has been the subject of controlled trials, detailed information on such trials that is relevant to an assessment of the drug's effectiveness for the proposed investigational use(s) should also be provided. Any published material that is relevant to the safety of the proposed investigation or to an assessment of the drug's effectiveness for its proposed investigational use should be provided in full. Published material that is less directly relevant may be supplied by a bibliography.

(ii) If the drug is a combination of drugs previously investigated or marketed, the information required under paragraph (a)(9)(i) of this section should be provided for each active drug component. However, if any component in such combination is subject to an approved marketing application or is otherwise lawfully marketed in the United States, the sponsor is not required to submit published material concerning that active drug component unless such material relates directly to the proposed investigational use (including publications relevant to component-component interaction).

(iii) If the drug has been marketed outside the United States, a list of the countries in which the drug has been marketed and a list of the countries in which the drug has been withdrawn from marketing for reasons potentially related to safety or effectiveness.

(10) Additional information. In certain applications, as described below, information on special topics may be needed. Such information shall be submitted in this section as follows:

(i) Drug dependence and abuse potential. If the drug is a psychotropic substance or otherwise has abuse potential, a section describing relevant clinical studies and experience and studies in test animals.

(ii) Radioactive drugs. If the drug is a radioactive drug, sufficient data from animal or human studies to allow a reasonable calculation of radiation-absorbed dose to the whole body and critical organs upon administration to a human subject. Phase 1 studies of radioactive drugs must include studies which will obtain sufficient data for dosimetry calculations.

(iii) Pediatric studies. Plans for assessing pediatric safety and effectiveness.

(iv) Other information. A brief statement of any other information that would aid evaluation of the proposed clinical investigations with respect to their safety or their design and potential as controlled clinical trials to support marketing of the drug.

(11) Relevant information. If requested by FDA, any other relevant information needed for review of the application.

(b) Information previously submitted. The sponsor ordinarily is not required to resubmit information previously submitted, but may incorporate the information by reference. A reference to information submitted previously must identify the file by name, reference number, volume, and page number where the information can be found. A reference to information submitted to the agency by a person other than the sponsor is required to contain a written statement that authorizes the reference and that is signed by the person who submitted the information.

(c) Material in a foreign language. The sponsor shall submit an accurate and complete English translation of each part of the IND that is not in English. The sponsor shall also submit a copy of each original literature publication for which an English translation is submitted.

(d) Number of copies. The sponsor shall submit an original and two copies of all submissions to the IND file, including the original submission and all amendments and reports.

(e) Numbering of IND submissions. Each submission relating to an IND is required to be numbered serially using a single, three-digit serial number. The initial IND is required to be numbered 000; each subsequent submission (e.g., amendment, report, or correspondence) is required to be numbered chronologically in sequence.

(f) Identification of exception from informed consent. If the investigation involves an exception from informed consent under § 50.24 of this chapter, the sponsor shall prominently identify on the cover sheet that the investigation is subject to the requirements in § 50.24 of this chapter.

Once an IND is in effect, a sponsor shall amend it as needed to ensure that the clinical investigations are conducted according to protocols included in the application. This section sets forth the provisions under which new protocols may be submitted and changes in previously submitted protocols may be made. Whenever a sponsor intends to conduct a clinical investigation with an exception from informed consent for emergency research as set forth in § 50.24 of this chapter, the sponsor shall submit a separate IND for such investigation.

(a) New protocol. Whenever a sponsor intends to conduct a study that is not covered by a protocol already contained in the IND, the sponsor shall submit to FDA a protocol amendment containing the protocol for the study. Such study may begin provided two conditions are met: (1) The sponsor has submitted the protocol to FDA for its review; and (2) the protocol has been approved by the Institutional Review Board (IRB) with responsibility for review and approval of the study in accordance with the requirements of part 56. The sponsor may comply with these two conditions in either order.

(b) Changes in a protocol. (1) A sponsor shall submit a protocol amendment describing any change in a Phase 1 protocol that significantly affects the safety of subjects or any change in a Phase 2 or 3 protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study. Examples of changes requiring an amendment under this paragraph include:

(i) Any increase in drug dosage or duration of exposure of individual subjects to the drug beyond that in the current protocol, or any significant increase in the number of subjects under study.

(ii) Any significant change in the design of a protocol (such as the addition or dropping of a control group).

(iii) The addition of a new test or procedure that is intended to improve monitoring for, or reduce the risk of, a side effect or adverse event; or the dropping of a test intended to monitor safety.

(2)(i) A protocol change under paragraph (b)(1) of this section may be made provided two conditions are met:

(a) The sponsor has submitted the change to FDA for its review; and

(b) The change has been approved by the IRB with responsibility for review and approval of the study. The sponsor may comply with these two conditions in either order.

(ii) Notwithstanding paragraph (b)(2)(i) of this section, a protocol change intended to eliminate an apparent immediate hazard to subjects may be implemented immediately provided FDA is subsequently notified by protocol amendment and the reviewing IRB is notified in accordance with § 56.104(c).

(c) New investigator. A sponsor shall submit a protocol amendment when a new investigator is added to carry out a previously submitted protocol, except that a protocol amendment is not required when a licensed practitioner is added in the case of a treatment protocol under § 312.315 or § 312.320. Once the investigator is added to the study, the investigational drug may be shipped to the investigator and the investigator may begin participating in the study. The sponsor shall notify FDA of the new investigator within 30 days of the investigator being added.

(d) Content and format. A protocol amendment is required to be prominently identified as such (i.e., “Protocol Amendment: New Protocol”, “Protocol Amendment: Change in Protocol”, or “Protocol Amendment: New Investigator”), and to contain the following:

(1)(i) In the case of a new protocol, a copy of the new protocol and a brief description of the most clinically significant differences between it and previous protocols.

(ii) In the case of a change in protocol, a brief description of the change and reference (date and number) to the submission that contained the protocol.

(iii) In the case of a new investigator, the investigator's name, the qualifications to conduct the investigation, reference to the previously submitted protocol, and all additional information about the investigator's study as is required under § 312.23(a)(6)(iii)(b).

(2) Reference, if necessary, to specific technical information in the IND or in a concurrently submitted information amendment to the IND that the sponsor relies on to support any clinically significant change in the new or amended protocol. If the reference is made to supporting information already in the IND, the sponsor shall identify by name, reference number, volume, and page number the location of the information.

(3) If the sponsor desires FDA to comment on the submission, a request for such comment and the specific questions FDA's response should address.

(e) When submitted. A sponsor shall submit a protocol amendment for a new protocol or a change in protocol before its implementation. Protocol amendments to add a new investigator or to provide additional information about investigators may be grouped and submitted at 30-day intervals. When several submissions of new protocols or protocol changes are anticipated during a short period, the sponsor is encouraged, to the extent feasible, to include these all in a single submission.

(a) Requirement for information amendment. A sponsor shall report in an information amendment essential information on the IND that is not within the scope of a protocol amendment, IND safety reports, or annual report. Examples of information requiring an information amendment include:

(1) New toxicology, chemistry, or other technical information; or

(2) A report regarding the discontinuance of a clinical investigation.

(b) Content and format of an information amendment. An information amendment is required to bear prominent identification of its contents (e.g., “Information Amendment: Chemistry, Manufacturing, and Control”, “Information Amendment: Pharmacology-Toxicology”, “Information Amendment: Clinical”), and to contain the following:

(1) A statement of the nature and purpose of the amendment.

(2) An organized submission of the data in a format appropriate for scientific review.

(3) If the sponsor desires FDA to comment on an information amendment, a request for such comment.

(c) When submitted. Information amendments to the IND should be submitted as necessary but, to the extent feasible, not more than every 30 days.

(a) Definitions. The following definitions of terms apply to this section:

Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.

Life-threatening adverse event or life-threatening suspected adverse reaction. An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death.

Serious adverse event or serious suspected adverse reaction. An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the investigator or sponsor, it results in any of the following outcomes: Death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.

Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, “reasonable possibility” means there is evidence to suggest a causal relationship between the drug and the adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.

Unexpected adverse event or unexpected suspected adverse reaction. An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the investigator brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure listed only cerebral vascular accidents. “Unexpected,” as used in this definition, also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation.

(b) Review of safety information. The sponsor must promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from foreign or domestic sources, including information derived from any clinical or epidemiological investigations, animal or in vitro studies, reports in the scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory authorities and reports of foreign commercial marketing experience for drugs that are not marketed in the United States.

(c)(1) IND safety reports. The sponsor must notify FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days after the sponsor determines that the information qualifies for reporting under paragraph (c)(1)(i), (c)(1)(ii), (c)(1)(iii), or (c)(1)(iv) of this section. In each IND safety report, the sponsor must identify all IND safety reports previously submitted to FDA concerning a similar suspected adverse reaction, and must analyze the significance of the suspected adverse reaction in light of previous, similar reports or any other relevant information.

(i) Serious and unexpected suspected adverse reaction. The sponsor must report any suspected adverse reaction that is both serious and unexpected. The sponsor must report an adverse event as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the drug and the adverse event, such as:

(A) A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome);

(B) One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture);

(C) An aggregate analysis of specific events observed in a clinical trial (such as known consequences of the underlying disease or condition under investigation or other events that commonly occur in the study population independent of drug therapy) that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group.

(ii) Findings from other studies. The sponsor must report any findings from epidemiological studies, pooled analysis of multiple studies, or clinical studies (other than those reported under paragraph (c)(1)(i) of this section), whether or not conducted under an IND, and whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug. Ordinarily, such a finding would result in a safety-related change in the protocol, informed consent, investigator brochure (excluding routine updates of these documents), or other aspects of the overall conduct of the clinical investigation.

(iii) Findings from animal or in vitro testing. The sponsor must report any findings from animal or in vitro testing, whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug, such as reports of mutagenicity, teratogenicity, or carcinogenicity, or reports of significant organ toxicity at or near the expected human exposure. Ordinarily, any such findings would result in a safety-related change in the protocol, informed consent, investigator brochure (excluding routine updates of these documents), or other aspects of the overall conduct of the clinical investigation.

(iv) Increased rate of occurrence of serious suspected adverse reactions. The sponsor must report any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.

(v) Submission of IND safety reports. The sponsor must submit each IND safety report in a narrative format or on FDA Form 3500A or in an electronic format that FDA can process, review, and archive. FDA will periodically issue guidance on how to provide the electronic submission (e.g., method of transmission, media, file formats, preparation and organization of files). The sponsor may submit foreign suspected adverse reactions on a Council for International Organizations of Medical Sciences (CIOMS) I Form instead of a FDA Form 3500A. Reports of overall findings or pooled analyses from published and unpublished in vitro, animal, epidemiological, or clinical studies must be submitted in a narrative format. Each notification to FDA must bear prominent identification of its contents, i.e., “IND Safety Report,” and must be transmitted to the review division in the Center for Drug Evaluation and Research or in the Center for Biologics Evaluation and Research that has responsibility for review of the IND. Upon request from FDA, the sponsor must submit to FDA any additional data or information that the agency deems necessary, as soon as possible, but in no case later than 15 calendar days after receiving the request.

(2) Unexpected fatal or life-threatening suspected adverse reaction reports. The sponsor must also notify FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case later than 7 calendar days after the sponsor's initial receipt of the information.

(3) Reporting format or frequency. FDA may require a sponsor to submit IND safety reports in a format or at a frequency different than that required under this paragraph. The sponsor may also propose and adopt a different reporting format or frequency if the change is agreed to in advance by the director of the FDA review division that has responsibility for review of the IND.

(4) Investigations of marketed drugs. A sponsor of a clinical study of a drug marketed or approved in the United States that is conducted under an IND is required to submit IND safety reports for suspected adverse reactions that are observed in the clinical study, at domestic or foreign study sites. The sponsor must also submit safety information from the clinical study as prescribed by the postmarketing safety reporting requirements (e.g., §§ 310.305, 314.80, and 600.80 of this chapter).

(5) Reporting study endpoints. Study endpoints (e.g., mortality or major morbidity) must be reported to FDA by the sponsor as described in the protocol and ordinarily would not be reported under paragraph (c) of this section. However, if a serious and unexpected adverse event occurs for which there is evidence suggesting a causal relationship between the drug and the event (e.g., death from anaphylaxis), the event must be reported under § 312.32(c)(1)(i) as a serious and unexpected suspected adverse reaction even if it is a component of the study endpoint (e.g., all-cause mortality).

(d) Followup. (1) The sponsor must promptly investigate all safety information it receives.

(2) Relevant followup information to an IND safety report must be submitted as soon as the information is available and must be identified as such, i.e., “Followup IND Safety Report.”

(3) If the results of a sponsor's investigation show that an adverse event not initially determined to be reportable under paragraph (c) of this section is so reportable, the sponsor must report such suspected adverse reaction in an IND safety report as soon as possible, but in no case later than 15 calendar days after the determination is made.

(e) Disclaimer. A safety report or other information submitted by a sponsor under this part (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the sponsor or FDA that the report or information constitutes an admission that the drug caused or contributed to an adverse event. A sponsor need not admit, and may deny, that the report or information submitted by the sponsor constitutes an admission that the drug caused or contributed to an adverse event.

A sponsor shall within 60 days of the anniversary date that the IND went into effect, submit a brief report of the progress of the investigation that includes:

(a) Individual study information. A brief summary of the status of each study in progress and each study completed during the previous year. The summary is required to include the following information for each study:

(1) The title of the study (with any appropriate study identifiers such as protocol number), its purpose, a brief statement identifying the patient population, and a statement as to whether the study is completed.

(2) The total number of subjects initially planned for inclusion in the study; the number entered into the study to date, tabulated by age group, gender, and race; the number whose participation in the study was completed as planned; and the number who dropped out of the study for any reason.

(3) If the study has been completed, or if interim results are known, a brief description of any available study results.

(b) Summary information. Information obtained during the previous year's clinical and nonclinical investigations, including:

(1) A narrative or tabular summary showing the most frequent and most serious adverse experiences by body system.

(2) A summary of all IND safety reports submitted during the past year.

(3) A list of subjects who died during participation in the investigation, with the cause of death for each subject.

(4) A list of subjects who dropped out during the course of the investigation in association with any adverse experience, whether or not thought to be drug related.

(5) A brief description of what, if anything, was obtained that is pertinent to an understanding of the drug's actions, including, for example, information about dose response, information from controlled trials, and information about bioavailability.

(6) A list of the preclinical studies (including animal studies) completed or in progress during the past year and a summary of the major preclinical findings.

(7) A summary of any significant manufacturing or microbiological changes made during the past year.

(c) A description of the general investigational plan for the coming year to replace that submitted 1 year earlier. The general investigational plan shall contain the information required under § 312.23(a)(3)(iv).

(d) If the investigator brochure has been revised, a description of the revision and a copy of the new brochure.

(e) A description of any significant Phase 1 protocol modifications made during the previous year and not previously reported to the IND in a protocol amendment.

(f) A brief summary of significant foreign marketing developments with the drug during the past year, such as approval of marketing in any country or withdrawal or suspension from marketing in any country.

(g) If desired by the sponsor, a log of any outstanding business with respect to the IND for which the sponsor requests or expects a reply, comment, or meeting.

(a) At any time a sponsor may withdraw an effective IND without prejudice.

(b) If an IND is withdrawn, FDA shall be so notified, all clinical investigations conducted under the IND shall be ended, all current investigators notified, and all stocks of the drug returned to the sponsor or otherwise disposed of at the request of the sponsor in accordance with § 312.59.

(c) If an IND is withdrawn because of a safety reason, the sponsor shall promptly so inform FDA, all participating investigators, and all reviewing Institutional Review Boards, together with the reasons for such withdrawal.

(a) An investigational new drug may be used in a clinical investigation if the following conditions are met:

(1) The sponsor of the investigation submits an IND for the drug to FDA; the IND is in effect under paragraph (b) of this section; and the sponsor complies with all applicable requirements in this part and parts 50 and 56 with respect to the conduct of the clinical investigations; and

(2) Each participating investigator conducts his or her investigation in compliance with the requirements of this part and parts 50 and 56.

(b) An IND goes into effect:

(1) Thirty days after FDA receives the IND, unless FDA notifies the sponsor that the investigations described in the IND are subject to a clinical hold under § 312.42; or

(2) On earlier notification by FDA that the clinical investigations in the IND may begin. FDA will notify the sponsor in writing of the date it receives the IND.

(c) A sponsor may ship an investigational new drug to investigators named in the IND:

(1) Thirty days after FDA receives the IND; or

(2) On earlier FDA authorization to ship the drug.

(d) An investigator may not administer an investigational new drug to human subjects until the IND goes into effect under paragraph (b) of this section.

(a) FDA may at any time during the course of the investigation communicate with the sponsor orally or in writing about deficiencies in the IND or about FDA's need for more data or information.

(b) On the sponsor's request, FDA will provide advice on specific matters relating to an IND. Examples of such advice may include advice on the adequacy of technical data to support an investigational plan, on the design of a clinical trial, and on whether proposed investigations are likely to produce the data and information that is needed to meet requirements for a marketing application.

(c) Unless the communication is accompanied by a clinical hold order under § 312.42, FDA communications with a sponsor under this section are solely advisory and do not require any modification in the planned or ongoing clinical investigations or response to the agency.

(a) General. A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. The clinical hold order may apply to one or more of the investigations covered by an IND. When a proposed study is placed on clinical hold, subjects may not be given the investigational drug. When an ongoing study is placed on clinical hold, no new subjects may be recruited to the study and placed on the investigational drug; patients already in the study should be taken off therapy involving the investigational drug unless specifically permitted by FDA in the interest of patient safety.

(b) Grounds for imposition of clinical hold - (1) Clinical hold of a Phase 1 study under an IND. FDA may place a proposed or ongoing Phase 1 investigation on clinical hold if it finds that:

(i) Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury;

(ii) The clinical investigators named in the IND are not qualified by reason of their scientific training and experience to conduct the investigation described in the IND;

(iii) The investigator brochure is misleading, erroneous, or materially incomplete; or

(iv) The IND does not contain sufficient information required under § 312.23 to assess the risks to subjects of the proposed studies.

(v) The IND is for the study of an investigational drug intended to treat a life-threatening disease or condition that affects both genders, and men or women with reproductive potential who have the disease or condition being studied are excluded from eligibility because of a risk or potential risk from use of the investigational drug of reproductive toxicity (i.e., affecting reproductive organs) or developmental toxicity (i.e., affecting potential offspring). The phrase “women with reproductive potential” does not include pregnant women. For purposes of this paragraph, “life-threatening illnesses or diseases” are defined as “diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted.” The clinical hold would not apply under this paragraph to clinical studies conducted:

(A) Under special circumstances, such as studies pertinent only to one gender (e.g., studies evaluating the excretion of a drug in semen or the effects on menstrual function);

(B) Only in men or women, as long as a study that does not exclude members of the other gender with reproductive potential is being conducted concurrently, has been conducted, or will take place within a reasonable time agreed upon by the agency; or

(C) Only in subjects who do not suffer from the disease or condition for which the drug is being studied.

(2) Clinical hold of a Phase 2 or 3 study under an IND. FDA may place a proposed or ongoing Phase 2 or 3 investigation on clinical hold if it finds that:

(i) Any of the conditions in paragraphs (b)(1)(i) through (b)(1)(v) of this section apply; or

(ii) The plan or protocol for the investigation is clearly deficient in design to meet its stated objectives.

(3) Clinical hold of an expanded access IND or expanded access protocol. FDA may place an expanded access IND or expanded access protocol on clinical hold under the following conditions:

(i) Final use. FDA may place a proposed expanded access IND or treatment use protocol on clinical hold if it is determined that:

(A) The pertinent criteria in subpart I of this part for permitting the expanded access use to begin are not satisfied; or

(B) The expanded access IND or expanded access protocol does not comply with the requirements for expanded access submissions in subpart I of this part.

(ii) Ongoing use. FDA may place an ongoing expanded access IND or expanded access protocol on clinical hold if it is determined that the pertinent criteria in subpart I of this part for permitting the expanded access are no longer satisfied.

(4) Clinical hold of any study that is not designed to be adequate and well-controlled. FDA may place a proposed or ongoing investigation that is not designed to be adequate and well-controlled on clinical hold if it finds that:

(i) Any of the conditions in paragraph (b)(1) or (b)(2) of this section apply; or

(ii) There is reasonable evidence the investigation that is not designed to be adequate and well-controlled is impeding enrollment in, or otherwise interfering with the conduct or completion of, a study that is designed to be an adequate and well-controlled investigation of the same or another investigational drug; or

(iii) Insufficient quantities of the investigational drug exist to adequately conduct both the investigation that is not designed to be adequate and well-controlled and the investigations that are designed to be adequate and well-controlled; or

(iv) The drug has been studied in one or more adequate and well-controlled investigations that strongly suggest lack of effectiveness; or

(v) Another drug under investigation or approved for the same indication and available to the same patient population has demonstrated a better potential benefit/risk balance; or

(vi) The drug has received marketing approval for the same indication in the same patient population; or

(vii) The sponsor of the study that is designed to be an adequate and well-controlled investigation is not actively pursuing marketing approval of the investigational drug with due diligence; or

(viii) The Commissioner determines that it would not be in the public interest for the study to be conducted or continued. FDA ordinarily intends that clinical holds under paragraphs (b)(4)(ii), (b)(4)(iii) and (b)(4)(v) of this section would only apply to additional enrollment in nonconcurrently controlled trials rather than eliminating continued access to individuals already receiving the investigational drug.

(5) Clinical hold of any investigation involving an exception from informed consent under § 50.24 of this chapter. FDA may place a proposed or ongoing investigation involving an exception from informed consent under § 50.24 of this chapter on clinical hold if it is determined that:

(i) Any of the conditions in paragraphs (b)(1) or (b)(2) of this section apply; or

(ii) The pertinent criteria in § 50.24 of this chapter for such an investigation to begin or continue are not submitted or not satisfied.

(6) Clinical hold of any investigation involving an exception from informed consent under § 50.23(d) of this chapter. FDA may place a proposed or ongoing investigation involving an exception from informed consent under § 50.23(d) of this chapter on clinical hold if it is determined that:

(i) Any of the conditions in paragraphs (b)(1) or (b)(2) of this section apply; or

(ii) A determination by the President to waive the prior consent requirement for the administration of an investigational new drug has not been made.

(c) Discussion of deficiency. Whenever FDA concludes that a deficiency exists in a clinical investigation that may be grounds for the imposition of clinical hold FDA will, unless patients are exposed to immediate and serious risk, attempt to discuss and satisfactorily resolve the matter with the sponsor before issuing the clinical hold order.

(d) Imposition of clinical hold. The clinical hold order may be made by telephone or other means of rapid communication or in writing. The clinical hold order will identify the studies under the IND to which the hold applies, and will briefly explain the basis for the action. The clinical hold order will be made by or on behalf of the Division Director with responsibility for review of the IND. As soon as possible, and no more than 30 days after imposition of the clinical hold, the Division Director will provide the sponsor a written explanation of the basis for the hold.

(e) Resumption of clinical investigations. An investigation may only resume after FDA (usually the Division Director, or the Director's designee, with responsibility for review of the IND) has notified the sponsor that the investigation may proceed. Resumption of the affected investigation(s) will be authorized when the sponsor corrects the deficiency(ies) previously cited or otherwise satisfies the agency that the investigation(s) can proceed. FDA may notify a sponsor of its determination regarding the clinical hold by telephone or other means of rapid communication. If a sponsor of an IND that has been placed on clinical hold requests in writing that the clinical hold be removed and submits a complete response to the issue(s) identified in the clinical hold order, FDA shall respond in writing to the sponsor within 30-calendar days of receipt of the request and the complete response. FDA's response will either remove or maintain the clinical hold, and will state the reasons for such determination. Notwithstanding the 30-calendar day response time, a sponsor may not proceed with a clinical trial on which a clinical hold has been imposed until the sponsor has been notified by FDA that the hold has been lifted.

(f) Appeal. If the sponsor disagrees with the reasons cited for the clinical hold, the sponsor may request reconsideration of the decision in accordance with § 312.48.

(g) Conversion of IND on clinical hold to inactive status. If all investigations covered by an IND remain on clinical hold for 1 year or more, the IND may be placed on inactive status by FDA under § 312.45.

(a) General. This section describes the procedures under which FDA may terminate an IND. If an IND is terminated, the sponsor shall end all clinical investigations conducted under the IND and recall or otherwise provide for the disposition of all unused supplies of the drug. A termination action may be based on deficiencies in the IND or in the conduct of an investigation under an IND. Except as provided in paragraph (d) of this section, a termination shall be preceded by a proposal to terminate by FDA and an opportunity for the sponsor to respond. FDA will, in general, only initiate an action under this section after first attempting to resolve differences informally or, when appropriate, through the clinical hold procedures described in § 312.42.

(b) Grounds for termination - (1) Phase 1. FDA may propose to terminate an IND during Phase 1 if it finds that:

(i) Human subjects would be exposed to an unreasonable and significant risk of illness or injury.

(ii) The IND does not contain sufficient information required under § 312.23 to assess the safety to subjects of the clinical investigations.

(iii) The methods, facilities, and controls used for the manufacturing, processing, and packing of the investigational drug are inadequate to establish and maintain appropriate standards of identity, strength, quality, and purity as needed for subject safety.

(iv) The clinical investigations are being conducted in a manner substantially different than that described in the protocols submitted in the IND.

(v) The drug is being promoted or distributed for commercial purposes not justified by the requirements of the investigation or permitted by § 312.7.

(vi) The IND, or any amendment or report to the IND, contains an untrue statement of a material fact or omits material information required by this part.

(vii) The sponsor fails promptly to investigate and inform the Food and Drug Administration and all investigators of serious and unexpected adverse experiences in accordance with § 312.32 or fails to make any other report required under this part.

(viii) The sponsor fails to submit an accurate annual report of the investigations in accordance with § 312.33.

(ix) The sponsor fails to comply with any other applicable requirement of this part, part 50, or part 56.

(x) The IND has remained on inactive status for 5 years or more.

(xi) The sponsor fails to delay a proposed investigation under the IND or to suspend an ongoing investigation that has been placed on clinical hold under § 312.42(b)(4).

(2) Phase 2 or 3. FDA may propose to terminate an IND during Phase 2 or Phase 3 if FDA finds that:

(i) Any of the conditions in paragraphs (b)(1)(i) through (b)(1)(xi) of this section apply; or

(ii) The investigational plan or protocol(s) is not reasonable as a bona fide scientific plan to determine whether or not the drug is safe and effective for use; or

(iii) There is convincing evidence that the drug is not effective for the purpose for which it is being investigated.

(3) FDA may propose to terminate a treatment IND if it finds that:

(i) Any of the conditions in paragraphs (b)(1)(i) through (x) of this section apply; or

(ii) Any of the conditions in § 312.42(b)(3) apply.

(c) Opportunity for sponsor response. (1) If FDA proposes to terminate an IND, FDA will notify the sponsor in writing, and invite correction or explanation within a period of 30 days.

(2) On such notification, the sponsor may provide a written explanation or correction or may request a conference with FDA to provide the requested explanation or correction. If the sponsor does not respond to the notification within the allocated time, the IND shall be terminated.

(3) If the sponsor responds but FDA does not accept the explanation or correction submitted, FDA shall inform the sponsor in writing of the reason for the nonacceptance and provide the sponsor with an opportunity for a regulatory hearing before FDA under part 16 on the question of whether the IND should be terminated. The sponsor's request for a regulatory hearing must be made within 10 days of the sponsor's receipt of FDA's notification of nonacceptance.

(d) Immediate termination of IND. Notwithstanding paragraphs (a) through (c) of this section, if at any time FDA concludes that continuation of the investigation presents an immediate and substantial danger to the health of individuals, the agency shall immediately, by written notice to the sponsor from the Director of the Center for Drug Evaluation and Research or the Director of the Center for Biologics Evaluation and Research, terminate the IND. An IND so terminated is subject to reinstatement by the Director on the basis of additional submissions that eliminate such danger. If an IND is terminated under this paragraph, the agency will afford the sponsor an opportunity for a regulatory hearing under part 16 on the question of whether the IND should be reinstated.

(a) If no subjects are entered into clinical studies for a period of 2 years or more under an IND, or if all investigations under an IND remain on clinical hold for 1 year or more, the IND may be placed by FDA on inactive status. This action may be taken by FDA either on request of the sponsor or on FDA's own initiative. If FDA seeks to act on its own initiative under this section, it shall first notify the sponsor in writing of the proposed inactive status. Upon receipt of such notification, the sponsor shall have 30 days to respond as to why the IND should continue to remain active.

(b) If an IND is placed on inactive status, all investigators shall be so notified and all stocks of the drug shall be returned or otherwise disposed of in accordance with § 312.59.

(c) A sponsor is not required to submit annual reports to an IND on inactive status. An inactive IND is, however, still in effect for purposes of the public disclosure of data and information under § 312.130.

(d) A sponsor who intends to resume clinical investigation under an IND placed on inactive status shall submit a protocol amendment under § 312.30 containing the proposed general investigational plan for the coming year and appropriate protocols. If the protocol amendment relies on information previously submitted, the plan shall reference such information. Additional information supporting the proposed investigation, if any, shall be submitted in an information amendment. Notwithstanding the provisions of § 312.30, clinical investigations under an IND on inactive status may only resume (1) 30 days after FDA receives the protocol amendment, unless FDA notifies the sponsor that the investigations described in the amendment are subject to a clinical hold under § 312.42, or (2) on earlier notification by FDA that the clinical investigations described in the protocol amendment may begin.

(e) An IND that remains on inactive status for 5 years or more may be terminated under § 312.44.

(a) General. Meetings between a sponsor and the agency are frequently useful in resolving questions and issues raised during the course of a clinical investigation. FDA encourages such meetings to the extent that they aid in the evaluation of the drug and in the solution of scientific problems concerning the drug, to the extent that FDA's resources permit. The general principle underlying the conduct of such meetings is that there should be free, full, and open communication about any scientific or medical question that may arise during the clinical investigation. These meetings shall be conducted and documented in accordance with part 10.

(b) “End-of-Phase 2” meetings and meetings held before submission of a marketing application. At specific times during the drug investigation process, meetings between FDA and a sponsor can be especially helpful in minimizing wasteful expenditures of time and money and thus in speeding the drug development and evaluation process. In particular, FDA has found that meetings at the end of Phase 2 of an investigation (end-of-Phase 2 meetings) are of considerable assistance in planning later studies and that meetings held near completion of Phase 3 and before submission of a marketing application (“pre-NDA” meetings) are helpful in developing methods of presentation and submission of data in the marketing application that facilitate review and allow timely FDA response.

(1) End-of-Phase 2 meetings - (i) Purpose. The purpose of an end-of-phase 2 meeting is to determine the safety of proceeding to Phase 3, to evaluate the Phase 3 plan and protocols and the adequacy of current studies and plans to assess pediatric safety and effectiveness, and to identify any additional information necessary to support a marketing application for the uses under investigation.

(ii) Eligibility for meeting. While the end-of-Phase 2 meeting is designed primarily for IND's involving new molecular entities or major new uses of marketed drugs, a sponsor of any IND may request and obtain an end-of-Phase 2 meeting.

(iii) Timing. To be most useful to the sponsor, end-of-Phase 2 meetings should be held before major commitments of effort and resources to specific Phase 3 tests are made. The scheduling of an end-of-Phase 2 meeting is not, however, intended to delay the transition of an investigation from Phase 2 to Phase 3.

(iv) Advance information. At least 1 month in advance of an end-of-Phase 2 meeting, the sponsor should submit background information on the sponsor's plan for Phase 3, including summaries of the Phase 1 and 2 investigations, the specific protocols for Phase 3 clinical studies, plans for any additional nonclinical studies, plans for pediatric studies, including a time line for protocol finalization, enrollment, completion, and data analysis, or information to support any planned request for waiver or deferral of pediatric studies, and, if available, tentative labeling for the drug. The recommended contents of such a submission are described more fully in FDA Staff Manual Guide 4850.7 that is publicly available under FDA's public information regulations in part 20.

(v) Conduct of meeting. Arrangements for an end-of-Phase 2 meeting are to be made with the division in FDA's Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research which is responsible for review of the IND. The meeting will be scheduled by FDA at a time convenient to both FDA and the sponsor. Both the sponsor and FDA may bring consultants to the meeting. The meeting should be directed primarily at establishing agreement between FDA and the sponsor of the overall plan for Phase 3 and the objectives and design of particular studies. The adequacy of the technical information to support Phase 3 studies and/or a marketing application may also be discussed. FDA will also provide its best judgment, at that time, of the pediatric studies that will be required for the drug product and whether their submission will be deferred until after approval. Agreements reached at the meeting on these matters will be recorded in minutes of the conference that will be taken by FDA in accordance with § 10.65 and provided to the sponsor. The minutes along with any other written material provided to the sponsor will serve as a permanent record of any agreements reached. Barring a significant scientific development that requires otherwise, studies conducted in accordance with the agreement shall be presumed to be sufficient in objective and design for the purpose of obtaining marketing approval for the drug.

(2) “Pre-NDA” and “pre-BLA” meetings. FDA has found that delays associated with the initial review of a marketing application may be reduced by exchanges of information about a proposed marketing application. The primary purpose of this kind of exchange is to uncover any major unresolved problems, to identify those studies that the sponsor is relying on as adequate and well-controlled to establish the drug's effectiveness, to identify the status of ongoing or needed studies adequate to assess pediatric safety and effectiveness, to acquaint FDA reviewers with the general information to be submitted in the marketing application (including technical information), to discuss appropriate methods for statistical analysis of the data, and to discuss the best approach to the presentation and formatting of data in the marketing application. Arrangements for such a meeting are to be initiated by the sponsor with the division responsible for review of the IND. To permit FDA to provide the sponsor with the most useful advice on preparing a marketing application, the sponsor should submit to FDA's reviewing division at least 1 month in advance of the meeting the following information:

(i) A brief summary of the clinical studies to be submitted in the application.

(ii) A proposed format for organizing the submission, including methods for presenting the data.

(iii) Information on the status of needed or ongoing pediatric studies.

(iv) Any other information for discussion at the meeting.

(a) General. The Food and Drug Administration is committed to resolving differences between sponsors and FDA reviewing divisions with respect to requirements for IND's as quickly and amicably as possible through the cooperative exchange of information and views.

(b) Administrative and procedural issues. When administrative or procedural disputes arise, the sponsor should first attempt to resolve the matter with the division in FDA's Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research which is responsible for review of the IND, beginning with the consumer safety officer assigned to the application. If the dispute is not resolved, the sponsor may raise the matter with the person designated as ombudsman, whose function shall be to investigate what has happened and to facilitate a timely and equitable resolution. Appropriate issues to raise with the ombudsman include resolving difficulties in scheduling meetings and obtaining timely replies to inquiries. Further details on this procedure are contained in FDA Staff Manual Guide 4820.7 that is publicly available under FDA's public information regulations in part 20.

(c) Scientific and medical disputes. (1) When scientific or medical disputes arise during the drug investigation process, sponsors should discuss the matter directly with the responsible reviewing officials. If necessary, sponsors may request a meeting with the appropriate reviewing officials and management representatives in order to seek a resolution. Requests for such meetings shall be directed to the director of the division in FDA's Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research which is responsible for review of the IND. FDA will make every attempt to grant requests for meetings that involve important issues and that can be scheduled at mutually convenient times.

(2) The “end-of-Phase 2” and “pre-NDA” meetings described in § 312.47(b) will also provide a timely forum for discussing and resolving scientific and medical issues on which the sponsor disagrees with the agency.

(3) In requesting a meeting designed to resolve a scientific or medical dispute, applicants may suggest that FDA seek the advice of outside experts, in which case FDA may, in its discretion, invite to the meeting one or more of its advisory committee members or other consultants, as designated by the agency. Applicants may rely on, and may bring to any meeting, their own consultants. For major scientific and medical policy issues not resolved by informal meetings, FDA may refer the matter to one of its standing advisory committees for its consideration and recommendations.

Sponsors are responsible for selecting qualified investigators, providing them with the information they need to conduct an investigation properly, ensuring proper monitoring of the investigation(s), ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND, maintaining an effective IND with respect to the investigations, and ensuring that FDA and all participating investigators are promptly informed of significant new adverse effects or risks with respect to the drug. Additional specific responsibilities of sponsors are described elsewhere in this part.

(a) A sponsor may transfer responsibility for any or all of the obligations set forth in this part to a contract research organization. Any such transfer shall be described in writing. If not all obligations are transferred, the writing is required to describe each of the obligations being assumed by the contract research organization. If all obligations are transferred, a general statement that all obligations have been transferred is acceptable. Any obligation not covered by the written description shall be deemed not to have been transferred.

(b) A contract research organization that assumes any obligation of a sponsor shall comply with the specific regulations in this chapter applicable to this obligation and shall be subject to the same regulatory action as a sponsor for failure to comply with any obligation assumed under these regulations. Thus, all references to “sponsor” in this part apply to a contract research organization to the extent that it assumes one or more obligations of the sponsor.

(a) Selecting investigators. A sponsor shall select only investigators qualified by training and experience as appropriate experts to investigate the drug.

(b) Control of drug. A sponsor shall ship investigational new drugs only to investigators participating in the investigation.

(c) Obtaining information from the investigator. Before permitting an investigator to begin participation in an investigation, the sponsor shall obtain the following:

(1) A signed investigator statement (Form FDA-1572) containing:

(i) The name and address of the investigator;

(ii) The name and code number, if any, of the protocol(s) in the IND identifying the study(ies) to be conducted by the investigator;

(iii) The name and address of any medical school, hospital, or other research facility where the clinical investigation(s) will be conducted;

(iv) The name and address of any clinical laboratory facilities to be used in the study;

(v) The name and address of the IRB that is responsible for review and approval of the study(ies);

(vi) A commitment by the investigator that he or she:

(a) Will conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, the rights, or welfare of subjects;

(b) Will comply with all requirements regarding the obligations of clinical investigators and all other pertinent requirements in this part;

(c) Will personally conduct or supervise the described investigation(s);

(d) Will inform any potential subjects that the drugs are being used for investigational purposes and will ensure that the requirements relating to obtaining informed consent (21 CFR part 50) and institutional review board review and approval (21 CFR part 56) are met;

(e) Will report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with § 312.64;

(f) Has read and understands the information in the investigator's brochure, including the potential risks and side effects of the drug; and

(g) Will ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments.

(vii) A commitment by the investigator that, for an investigation subject to an institutional review requirement under part 56, an IRB that complies with the requirements of that part will be responsible for the initial and continuing review and approval of the clinical investigation and that the investigator will promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others, and will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to the human subjects.

(viii) A list of the names of the subinvestigators (e.g., research fellows, residents) who will be assisting the investigator in the conduct of the investigation(s).

(2) Curriculum vitae. A curriculum vitae or other statement of qualifications of the investigator showing the education, training, and experience that qualifies the investigator as an expert in the clinical investigation of the drug for the use under investigation.

(3) Clinical protocol. (i) For Phase 1 investigations, a general outline of the planned investigation including the estimated duration of the study and the maximum number of subjects that will be involved.

(ii) For Phase 2 or 3 investigations, an outline of the study protocol including an approximation of the number of subjects to be treated with the drug and the number to be employed as controls, if any; the clinical uses to be investigated; characteristics of subjects by age, sex, and condition; the kind of clinical observations and laboratory tests to be conducted; the estimated duration of the study; and copies or a description of case report forms to be used.

(4) Financial disclosure information. Sufficient accurate financial information to allow the sponsor to submit complete and accurate certification or disclosure statements required under part 54 of this chapter. The sponsor shall obtain a commitment from the clinical investigator to promptly update this information if any relevant changes occur during the course of the investigation and for 1 year following the completion of the study.

(d) Selecting monitors. A sponsor shall select a monitor qualified by training and experience to monitor the progress of the investigation.

(a) The sponsor shall monitor the progress of all investigations involving an exception from informed consent under § 50.24 of this chapter. When the sponsor receives from the IRB information concerning the public disclosures required by § 50.24(a)(7)(ii) and (a)(7)(iii) of this chapter, the sponsor promptly shall submit to the IND file and to Docket Number 95S-0158 in the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852, copies of the information that was disclosed, identified by the IND number.

(b) The sponsor also shall monitor such investigations to identify when an IRB determines that it cannot approve the research because it does not meet the criteria in the exception in § 50.24(a) of this chapter or because of other relevant ethical concerns. The sponsor promptly shall provide this information in writing to FDA, investigators who are asked to participate in this or a substantially equivalent clinical investigation, and other IRB's that are asked to review this or a substantially equivalent investigation.

(a) Before the investigation begins, a sponsor (other than a sponsor-investigator) shall give each participating clinical investigator an investigator brochure containing the information described in § 312.23(a)(5).

(b) The sponsor shall, as the overall investigation proceeds, keep each participating investigator informed of new observations discovered by or reported to the sponsor on the drug, particularly with respect to adverse effects and safe use. Such information may be distributed to investigators by means of periodically revised investigator brochures, reprints or published studies, reports or letters to clinical investigators, or other appropriate means. Important safety information is required to be relayed to investigators in accordance with § 312.32.

(a) The sponsor shall monitor the progress of all clinical investigations being conducted under its IND.

(b) A sponsor who discovers that an investigator is not complying with the signed agreement (Form FDA-1572), the general investigational plan, or the requirements of this part or other applicable parts shall promptly either secure compliance or discontinue shipments of the investigational new drug to the investigator and end the investigator's participation in the investigation. If the investigator's participation in the investigation is ended, the sponsor shall require that the investigator dispose of or return the investigational drug in accordance with the requirements of § 312.59 and shall notify FDA.

(c) The sponsor shall review and evaluate the evidence relating to the safety and effectiveness of the drug as it is obtained from the investigator. The sponsors shall make such reports to FDA regarding information relevant to the safety of the drug as are required under § 312.32. The sponsor shall make annual reports on the progress of the investigation in accordance with § 312.33.

(d) A sponsor who determines that its investigational drug presents an unreasonable and significant risk to subjects shall discontinue those investigations that present the risk, notify FDA, all institutional review boards, and all investigators who have at any time participated in the investigation of the discontinuance, assure the disposition of all stocks of the drug outstanding as required by § 312.59, and furnish FDA with a full report of the sponsor's actions. The sponsor shall discontinue the investigation as soon as possible, and in no event later than 5 working days after making the determination that the investigation should be discontinued. Upon request, FDA will confer with a sponsor on the need to discontinue an investigation.

(a) A sponsor shall maintain adequate records showing the receipt, shipment, or other disposition of the investigational drug. These records are required to include, as appropriate, the name of the investigator to whom the drug is shipped, and the date, quantity, and batch or code mark of each such shipment.

(b) A sponsor shall maintain complete and accurate records showing any financial interest in § 54.4(a)(3)(i), (a)(3)(ii), (a)(3)(iii), and (a)(3)(iv) of this chapter paid to clinical investigators by the sponsor of the covered study. A sponsor shall also maintain complete and accurate records concerning all other financial interests of investigators subject to part 54 of this chapter.

(c) A sponsor shall retain the records and reports required by this part for 2 years after a marketing application is approved for the drug; or, if an application is not approved for the drug, until 2 years after shipment and delivery of the drug for investigational use is discontinued and FDA has been so notified.

(d) A sponsor shall retain reserve samples of any test article and reference standard identified in, and used in any of the bioequivalence or bioavailability studies described in, § 320.38 or § 320.63 of this chapter, and release the reserve samples to FDA upon request, in accordance with, and for the period specified in § 320.38.

(a) FDA inspection. A sponsor shall upon request from any properly authorized officer or employee of the Food and Drug Administration, at reasonable times, permit such officer or employee to have access to and copy and verify any records and reports relating to a clinical investigation conducted under this part. Upon written request by FDA, the sponsor shall submit the records or reports (or copies of them) to FDA. The sponsor shall discontinue shipments of the drug to any investigator who has failed to maintain or make available records or reports of the investigation as required by this part.

(b) Controlled substances. If an investigational new drug is a substance listed in any schedule of the Controlled Substances Act (21 U.S.C. 801; 21 CFR part 1308), records concerning shipment, delivery, receipt, and disposition of the drug, which are required to be kept under this part or other applicable parts of this chapter shall, upon the request of a properly authorized employee of the Drug Enforcement Administration of the U.S. Department of Justice, be made available by the investigator or sponsor to whom the request is made, for inspection and copying. In addition, the sponsor shall assure that adequate precautions are taken, including storage of the investigational drug in a securely locked, substantially constructed cabinet, or other securely locked, substantially constructed enclosure, access to which is limited, to prevent theft or diversion of the substance into illegal channels of distribution.

The sponsor shall assure the return of all unused supplies of the investigational drug from each individual investigator whose participation in the investigation is discontinued or terminated. The sponsor may authorize alternative disposition of unused supplies of the investigational drug provided this alternative disposition does not expose humans to risks from the drug. The sponsor shall maintain written records of any disposition of the drug in accordance with § 312.57.

An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator's care; and for the control of drugs under investigation. An investigator shall, in accordance with the provisions of part 50 of this chapter, obtain the informed consent of each human subject to whom the drug is administered, except as provided in §§ 50.23 or 50.24 of this chapter. Additional specific responsibilities of clinical investigators are set forth in this part and in parts 50 and 56 of this chapter.

An investigator shall administer the drug only to subjects under the investigator's personal supervision or under the supervision of a subinvestigator responsible to the investigator. The investigator shall not supply the investigational drug to any person not authorized under this part to receive it.

(a) Disposition of drug. An investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects. If the investigation is terminated, suspended, discontinued, or completed, the investigator shall return the unused supplies of the drug to the sponsor, or otherwise provide for disposition of the unused supplies of the drug under § 312.59.

(b) Case histories. An investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall document that informed consent was obtained prior to participation in the study.

(c) Record retention. An investigator shall retain records required to be maintained under this part for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified.

(a) Progress reports. The investigator shall furnish all reports to the sponsor of the drug who is responsible for collecting and evaluating the results obtained. The sponsor is required under § 312.33 to submit annual reports to FDA on the progress of the clinical investigations.

(b) Safety reports. An investigator must immediately report to the sponsor any serious adverse event, whether or not considered drug related, including those listed in the protocol or investigator brochure and must include an assessment of whether there is a reasonable possibility that the drug caused the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the drug and the event (e.g., death from anaphylaxis). In that case, the investigator must immediately report the event to the sponsor. The investigator must record nonserious adverse events and report them to the sponsor according to the timetable for reporting specified in the protocol.

(c) Final report. An investigator shall provide the sponsor with an adequate report shortly after completion of the investigator's participation in the investigation.

(d) Financial disclosure reports. The clinical investigator shall provide the sponsor with sufficient accurate financial information to allow an applicant to submit complete and accurate certification or disclosure statements as required under part 54 of this chapter. The clinical investigator shall promptly update this information if any relevant changes occur during the course of the investigation and for 1 year following the completion of the study.

An investigator shall assure that an IRB that complies with the requirements set forth in part 56 will be responsible for the initial and continuing review and approval of the proposed clinical study. The investigator shall also assure that he or she will promptly report to the IRB all changes in the research activity and all unanticipated problems involving risk to human subjects or others, and that he or she will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.

An investigator shall upon request from any properly authorized officer or employee of FDA, at reasonable times, permit such officer or employee to have access to, and copy and verify any records or reports made by the investigator pursuant to § 312.62. The investigator is not required to divulge subject names unless the records of particular individuals require a more detailed study of the cases, or unless there is reason to believe that the records do not represent actual case studies, or do not represent actual results obtained.

If the investigational drug is subject to the Controlled Substances Act, the investigator shall take adequate precautions, including storage of the investigational drug in a securely locked, substantially constructed cabinet, or other securely locked, substantially constructed enclosure, access to which is limited, to prevent theft or diversion of the substance into illegal channels of distribution.

(a) If FDA has information indicating that an investigator (including a sponsor-investigator) has repeatedly or deliberately failed to comply with the requirements of this part, part 50 or part 56 of this chapter, or has repeatedly or deliberately submitted to FDA or to the sponsor false information in any required report, the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research will furnish the investigator written notice of the matter complained of and offer the investigator an opportunity to explain the matter in writing, or, at the option of the investigator, in an informal conference. If an explanation is offered and accepted by the applicable Center, the Center will discontinue the disqualification proceeding. If an explanation is offered but not accepted by the applicable Center, the investigator will be given an opportunity for a regulatory hearing under part 16 of this chapter on the question of whether the investigator is eligible to receive test articles under this part and eligible to conduct any clinical investigation that supports an application for a research or marketing permit for products regulated by FDA.

(b) After evaluating all available information, including any explanation presented by the investigator, if the Commissioner determines that the investigator has repeatedly or deliberately failed to comply with the requirements of this part, part 50 or part 56 of this chapter, or has repeatedly or deliberately submitted to FDA or to the sponsor false information in any required report, the Commissioner will notify the investigator, the sponsor of any investigation in which the investigator has been named as a participant, and the reviewing institutional review boards (IRBs) that the investigator is not eligible to receive test articles under this part. The notification to the investigator, sponsor, and IRBs will provide a statement of the basis for such determination. The notification also will explain that an investigator determined to be ineligible to receive test articles under this part will be ineligible to conduct any clinical investigation that supports an application for a research or marketing permit for products regulated by FDA, including drugs, biologics, devices, new animal drugs, foods, including dietary supplements, that bear a nutrient content claim or a health claim, infant formulas, food and color additives, and tobacco products.

(c) Each application or submission to FDA under the provisions of this chapter containing data reported by an investigator who has been determined to be ineligible to receive FDA-regulated test articles is subject to examination to determine whether the investigator has submitted unreliable data that are essential to the continuation of an investigation or essential to the approval of a marketing application, or essential to the continued marketing of an FDA-regulated product.

(d) If the Commissioner determines, after the unreliable data submitted by the investigator are eliminated from consideration, that the data remaining are inadequate to support a conclusion that it is reasonably safe to continue the investigation, the Commissioner will notify the sponsor, who shall have an opportunity for a regulatory hearing under part 16 of this chapter. If a danger to the public health exists, however, the Commissioner shall terminate the IND immediately and notify the sponsor and the reviewing IRBs of the termination. In such case, the sponsor shall have an opportunity for a regulatory hearing before FDA under part 16 on the question of whether the IND should be reinstated. The determination that an investigation may not be considered in support of a research or marketing application or a notification or petition submission does not, however, relieve the sponsor of any obligation under any other applicable regulation to submit to FDA the results of the investigation.

(e) If the Commissioner determines, after the unreliable data submitted by the investigator are eliminated from consideration, that the continued approval of the product for which the data were submitted cannot be justified, the Commissioner will proceed to withdraw approval of the product in accordance with the applicable provisions of the relevant statutes.

(f) An investigator who has been determined to be ineligible under paragraph (b) of this section may be reinstated as eligible when the Commissioner determines that the investigator has presented adequate assurances that the investigator will employ all test articles, and will conduct any clinical investigation that supports an application for a research or marketing permit for products regulated by FDA, solely in compliance with the applicable provisions of this chapter.

The purpose of this section is to establish procedures designed to expedite the development, evaluation, and marketing of new therapies intended to treat persons with life-threatening and severely-debilitating illnesses, especially where no satisfactory alternative therapy exists. As stated § 314.105(c) of this chapter, while the statutory standards of safety and effectiveness apply to all drugs, the many kinds of drugs that are subject to them, and the wide range of uses for those drugs, demand flexibility in applying the standards. The Food and Drug Administration (FDA) has determined that it is appropriate to exercise the broadest flexibility in applying the statutory standards, while preserving appropriate guarantees for safety and effectiveness. These procedures reflect the recognition that physicians and patients are generally willing to accept greater risks or side effects from products that treat life-threatening and severely-debilitating illnesses, than they would accept from products that treat less serious illnesses. These procedures also reflect the recognition that the benefits of the drug need to be evaluated in light of the severity of the disease being treated. The procedure outlined in this section should be interpreted consistent with that purpose.

This section applies to new drug and biological products that are being studied for their safety and effectiveness in treating life-threatening or severely-debilitating diseases.

(a) For purposes of this section, the term “life-threatening” means:

(1) Diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted; and

(2) Diseases or conditions with potentially fatal outcomes, where the end point of clinical trial analysis is survival.

(b) For purposes of this section, the term “severely debilitating” means diseases or conditions that cause major irreversible morbidity.

(c) Sponsors are encouraged to consult with FDA on the applicability of these procedures to specific products.

For products intended to treat life-threatening or severely-debilitating illnesses, sponsors may request to meet with FDA-reviewing officials early in the drug development process to review and reach agreement on the design of necessary preclinical and clinical studies. Where appropriate, FDA will invite to such meetings one or more outside expert scientific consultants or advisory committee members. To the extent FDA resources permit, agency reviewing officials will honor requests for such meetings

(a) Pre-investigational new drug (IND) meetings. Prior to the submission of the initial IND, the sponsor may request a meeting with FDA-reviewing officials. The primary purpose of this meeting is to review and reach agreement on the design of animal studies needed to initiate human testing. The meeting may also provide an opportunity for discussing the scope and design of phase 1 testing, plans for studying the drug product in pediatric populations, and the best approach for presentation and formatting of data in the IND.

(b) End-of-phase 1 meetings. When data from phase 1 clinical testing are available, the sponsor may again request a meeting with FDA-reviewing officials. The primary purpose of this meeting is to review and reach agreement on the design of phase 2 controlled clinical trials, with the goal that such testing will be adequate to provide sufficient data on the drug's safety and effectiveness to support a decision on its approvability for marketing, and to discuss the need for, as well as the design and timing of, studies of the drug in pediatric patients. For drugs for life-threatening diseases, FDA will provide its best judgment, at that time, whether pediatric studies will be required and whether their submission will be deferred until after approval. The procedures outlined in § 312.47(b)(1) with respect to end-of-phase 2 conferences, including documentation of agreements reached, would also be used for end-of-phase 1 meetings.

If the preliminary analysis of phase 2 test results appears promising, FDA may ask the sponsor to submit a treatment protocol to be reviewed under the procedures and criteria listed in §§ 312.305 and 312.320. Such a treatment protocol, if requested and granted, would normally remain in effect while the complete data necessary for a marketing application are being assembled by the sponsor and reviewed by FDA (unless grounds exist for clinical hold of ongoing protocols, as provided in § 312.42(b)(3)(ii)).

(a) FDA's application of the statutory standards for marketing approval shall recognize the need for a medical risk-benefit judgment in making the final decision on approvability. As part of this evaluation, consistent with the statement of purpose in § 312.80, FDA will consider whether the benefits of the drug outweigh the known and potential risks of the drug and the need to answer remaining questions about risks and benefits of the drug, taking into consideration the severity of the disease and the absence of satisfactory alternative therapy.

(b) In making decisions on whether to grant marketing approval for products that have been the subject of an end-of-phase 1 meeting under § 312.82, FDA will usually seek the advice of outside expert scientific consultants or advisory committees. Upon the filing of such a marketing application under § 314.101 or part 601 of this chapter, FDA will notify the members of the relevant standing advisory committee of the application's filing and its availability for review.

(c) If FDA concludes that the data presented are not sufficient for marketing approval, FDA will issue a complete response letter under § 314.110 of this chapter or the biological product licensing procedures. Such letter, in describing the deficiencies in the application, will address why the results of the research design agreed to under § 312.82, or in subsequent meetings, have not provided sufficient evidence for marketing approval. Such letter will also describe any recommendations made by the advisory committee regarding the application.

(d) Marketing applications submitted under the procedures contained in this section will be subject to the requirements and procedures contained in part 314 or part 600 of this chapter, as well as those in this subpart.

Concurrent with marketing approval, FDA may seek agreement from the sponsor to conduct certain postmarketing (phase 4) studies to delineate additional information about the drug's risks, benefits, and optimal use. These studies could include, but would not be limited to, studying different doses or schedules of administration than were used in phase 2 studies, use of the drug in other patient populations or other stages of the disease, or use of the drug over a longer period of time.

At the discretion of the agency, FDA may undertake focused regulatory research on critical rate-limiting aspects of the preclinical, chemical/manufacturing, and clinical phases of drug development and evaluation. When initiated, FDA will undertake such research efforts as a means for meeting a public health need in facilitating the development of therapies to treat life-threatening or severely debilitating illnesses.

For drugs covered under this section, the Commissioner and other agency officials will monitor the progress of the conduct and evaluation of clinical trials and be involved in facilitating their appropriate progress.

All of the safeguards incorporated within parts 50, 56, 312, 314, and 600 of this chapter designed to ensure the safety of clinical testing and the safety of products following marketing approval apply to drugs covered by this section. This includes the requirements for informed consent (part 50 of this chapter) and institutional review boards (part 56 of this chapter). These safeguards further include the review of animal studies prior to initial human testing (§ 312.23), and the monitoring of adverse drug experiences through the requirements of IND safety reports (§ 312.32), safety update reports during agency review of a marketing application (§ 314.50 of this chapter), and postmarketing adverse reaction reporting (§ 314.80 of this chapter).

(a) Imports. An investigational new drug offered for import into the United States complies with the requirements of this part if it is subject to an IND that is in effect for it under § 312.40 and: (1) The consignee in the United States is the sponsor of the IND; (2) the consignee is a qualified investigator named in the IND; or (3) the consignee is the domestic agent of a foreign sponsor, is responsible for the control and distribution of the investigational drug, and the IND identifies the consignee and describes what, if any, actions the consignee will take with respect to the investigational drug.

(b) Exports. An investigational new drug may be exported from the United States for use in a clinical investigation under any of the following conditions:

(1) An IND is in effect for the drug under § 312.40, the drug complies with the laws of the country to which it is being exported, and each person who receives the drug is an investigator in a study submitted to and allowed to proceed under the IND; or

(2) The drug has valid marketing authorization in Australia, Canada, Israel, Japan, New Zealand, Switzerland, South Africa, or in any country in the European Union or the European Economic Area, and complies with the laws of the country to which it is being exported, section 802(b)(1)(A), (f), and (g) of the act, and § 1.101 of this chapter; or

(3) The drug is being exported to Australia, Canada, Israel, Japan, New Zealand, Switzerland, South Africa, or to any country in the European Union or the European Economic Area, and complies with the laws of the country to which it is being exported, the applicable provisions of section 802(c), (f), and (g) of the act, and § 1.101 of this chapter. Drugs exported under this paragraph that are not the subject of an IND are exempt from the label requirement in § 312.6(a); or

(4) Except as provided in paragraph (b)(5) of this section, the person exporting the drug sends a written certification to the Office of International Programs (HFG-1), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, at the time the drug is first exported and maintains records documenting compliance with this paragraph. The certification shall describe the drug that is to be exported (i.e., trade name (if any), generic name, and dosage form), identify the country or countries to which the drug is to be exported, and affirm that:

(i) The drug is intended for export;

(ii) The drug is intended for investigational use in a foreign country;

(iii) The drug meets the foreign purchaser's or consignee's specifications;

(iv) The drug is not in conflict with the importing country's laws;

(v) The outer shipping package is labeled to show that the package is intended for export from the United States;

(vi) The drug is not sold or offered for sale in the United States;

(vii) The clinical investigation will be conducted in accordance with § 312.120;

(viii) The drug is manufactured, processed, packaged, and held in substantial conformity with current good manufacturing practices;

(ix) The drug is not adulterated within the meaning of section 501(a)(1), (a)(2)(A), (a)(3), (c), or (d) of the act;

(x) The drug does not present an imminent hazard to public health, either in the United States, if the drug were to be reimported, or in the foreign country; and

(xi) The drug is labeled in accordance with the foreign country's laws.

(5) In the event of a national emergency in a foreign country, where the national emergency necessitates exportation of an investigational new drug, the requirements in paragraph (b)(4) of this section apply as follows:

(i) Situations where the investigational new drug is to be stockpiled in anticipation of a national emergency. There may be instances where exportation of an investigational new drug is needed so that the drug may be stockpiled and made available for use by the importing country if and when a national emergency arises. In such cases:

(A) A person may export an investigational new drug under paragraph (b)(4) of this section without making an affirmation with respect to any one or more of paragraphs (b)(4)(i), (b)(4)(iv), (b)(4)(vi), (b)(4)(vii), (b)(4)(viii), and/or (b)(4)(ix) of this section, provided that he or she:

(1) Provides a written statement explaining why compliance with each such paragraph is not feasible or is contrary to the best interests of the individuals who may receive the investigational new drug;

(2) Provides a written statement from an authorized official of the importing country's government. The statement must attest that the official agrees with the exporter's statement made under paragraph (b)(5)(i)(A)(1) of this section; explain that the drug is to be stockpiled solely for use of the importing country in a national emergency; and describe the potential national emergency that warrants exportation of the investigational new drug under this provision; and

(3) Provides a written statement showing that the Secretary of Health and Human Services (the Secretary), or his or her designee, agrees with the findings of the authorized official of the importing country's government. Persons who wish to obtain a written statement from the Secretary should direct their requests to Secretary's Operations Center, Office of Emergency Operations and Security Programs, Office of Public Health Emergency Preparedness, Office of the Secretary, Department of Health and Human Services, 200 Independence Ave. SW., Washington, DC 20201. Requests may be also be sent by FAX: 202-619-7870 or by e-mail: HHS.SOC@hhs.gov.

(B) Exportation may not proceed until FDA has authorized exportation of the investigational new drug. FDA may deny authorization if the statements provided under paragraphs (b)(5)(i)(A)(1) or (b)(5)(i)(A)(2) of this section are inadequate or if exportation is contrary to public health.

(ii) Situations where the investigational new drug is to be used for a sudden and immediate national emergency. There may be instances where exportation of an investigational new drug is needed so that the drug may be used in a sudden and immediate national emergency that has developed or is developing. In such cases:

(A) A person may export an investigational new drug under paragraph (b)(4) of this section without making an affirmation with respect to any one or more of paragraphs (b)(4)(i), (b)(4)(iv), (b)(4)(v), (b)(4)(vi), (b)(4)(vii), (b)(4)(viii), (b)(4)(ix), and/or (b)(4)(xi), provided that he or she:

(1) Provides a written statement explaining why compliance with each such paragraph is not feasible or is contrary to the best interests of the individuals who are expected to receive the investigational new drug and

(2) Provides sufficient information from an authorized official of the importing country's government to enable the Secretary, or his or her designee, to decide whether a national emergency has developed or is developing in the importing country, whether the investigational new drug will be used solely for that national emergency, and whether prompt exportation of the investigational new drug is necessary. Persons who wish to obtain a determination from the Secretary should direct their requests to Secretary's Operations Center, Office of Emergency Operations and Security Programs, Office of Public Health Emergency Preparedness, Office of the Secretary, Department of Health and Human Services, 200 Independence Ave. SW., Washington, DC 20201. Requests may be also be sent by FAX: 202-619-7870 or by e-mail: HHS.SOC@hhs.gov.

(B) Exportation may proceed without prior FDA authorization.

(c) Limitations. Exportation under paragraph (b) of this section may not occur if:

(1) For drugs exported under paragraph (b)(1) of this section, the IND pertaining to the clinical investigation is no longer in effect;

(2) For drugs exported under paragraph (b)(2) of this section, the requirements in section 802(b)(1), (f), or (g) of the act are no longer met;

(3) For drugs exported under paragraph (b)(3) of this section, the requirements in section 802(c), (f), or (g) of the act are no longer met;

(4) For drugs exported under paragraph (b)(4) of this section, the conditions underlying the certification or the statements submitted under paragraph (b)(5) of this section are no longer met; or

(5) For any investigational new drugs under this section, the drug no longer complies with the laws of the importing country.

(d) Insulin and antibiotics. New insulin and antibiotic drug products may be exported for investigational use in accordance with section 801(e)(1) of the act without complying with this section.

(a) Acceptance of studies. (1) FDA will accept as support for an IND or application for marketing approval (an application under section 505 of the act or section 351 of the Public Health Service Act (the PHS Act) (42 U.S.C. 262)) a well-designed and well-conducted foreign clinical study not conducted under an IND, if the following conditions are met:

(i) The study was conducted in accordance with good clinical practice (GCP). For the purposes of this section, GCP is defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials in a way that provides assurance that the data and reported results are credible and accurate and that the rights, safety, and well-being of trial subjects are protected. GCP includes review and approval (or provision of a favorable opinion) by an independent ethics committee (IEC) before initiating a study, continuing review of an ongoing study by an IEC, and obtaining and documenting the freely given informed consent of the subject (or a subject's legally authorized representative, if the subject is unable to provide informed consent) before initiating a study. GCP does not require informed consent in life-threatening situations when the IEC reviewing the study finds, before initiation of the study, that informed consent is not feasible and either that the conditions present are consistent with those described in § 50.23 or § 50.24(a) of this chapter, or that the measures described in the study protocol or elsewhere will protect the rights, safety, and well-being of subjects; and

(ii) FDA is able to validate the data from the study through an onsite inspection if the agency deems it necessary.

(2) Although FDA will not accept as support for an IND or application for marketing approval a study that does not meet the conditions of paragraph (a)(1) of this section, FDA will examine data from such a study.

(3) Marketing approval of a new drug based solely on foreign clinical data is governed by § 314.106 of this chapter.

(b) Supporting information. A sponsor or applicant who submits data from a foreign clinical study not conducted under an IND as support for an IND or application for marketing approval must submit to FDA, in addition to information required elsewhere in parts 312, 314, or 601 of this chapter, a description of the actions the sponsor or applicant took to ensure that the research conformed to GCP as described in paragraph (a)(1)(i) of this section. The description is not required to duplicate information already submitted in the IND or application for marketing approval. Instead, the description must provide either the following information or a cross-reference to another section of the submission where the information is located:

(1) The investigator's qualifications;

(2) A description of the research facilities;

(3) A detailed summary of the protocol and results of the study and, should FDA request, case records maintained by the investigator or additional background data such as hospital or other institutional records;

(4) A description of the drug substance and drug product used in the study, including a description of the components, formulation, specifications, and, if available, bioavailability of the specific drug product used in the clinical study;

(5) If the study is intended to support the effectiveness of a drug product, information showing that the study is adequate and well controlled under § 314.126 of this chapter;

(6) The name and address of the IEC that reviewed the study and a statement that the IEC meets the definition in § 312.3 of this chapter. The sponsor or applicant must maintain records supporting such statement, including records of the names and qualifications of IEC members, and make these records available for agency review upon request;

(7) A summary of the IEC's decision to approve or modify and approve the study, or to provide a favorable opinion;

(8) A description of how informed consent was obtained;

(9) A description of what incentives, if any, were provided to subjects to participate in the study;

(10) A description of how the sponsor(s) monitored the study and ensured that the study was carried out consistently with the study protocol; and

(11) A description of how investigators were trained to comply with GCP (as described in paragraph (a)(1)(i) of this section) and to conduct the study in accordance with the study protocol, and a statement on whether written commitments by investigators to comply with GCP and the protocol were obtained. Any signed written commitments by investigators must be maintained by the sponsor or applicant and made available for agency review upon request.

(c) Waivers. (1) A sponsor or applicant may ask FDA to waive any applicable requirements under paragraphs (a)(1) and (b) of this section. A waiver request may be submitted in an IND or in an information amendment to an IND, or in an application or in an amendment or supplement to an application submitted under part 314 or 601 of this chapter. A waiver request is required to contain at least one of the following:

(i) An explanation why the sponsor's or applicant's compliance with the requirement is unnecessary or cannot be achieved;

(ii) A description of an alternative submission or course of action that satisfies the purpose of the requirement; or

(iii) Other information justifying a waiver.

(2) FDA may grant a waiver if it finds that doing so would be in the interest of the public health.

(d) Records. A sponsor or applicant must retain the records required by this section for a foreign clinical study not conducted under an IND as follows:

(1) If the study is submitted in support of an application for marketing approval, for 2 years after an agency decision on that application;

(2) If the study is submitted in support of an IND but not an application for marketing approval, for 2 years after the submission of the IND.

(a) The existence of an investigational new drug application will not be disclosed by FDA unless it has previously been publicly disclosed or acknowledged.

(b) The availability for public disclosure of all data and information in an investigational new drug application for a new drug will be handled in accordance with the provisions established in § 314.430 for the confidentiality of data and information in applications submitted in part 314. The availability for public disclosure of all data and information in an investigational new drug application for a biological product will be governed by the provisions of §§ 601.50 and 601.51.

(c) Notwithstanding the provisions of § 314.430, FDA shall disclose upon request to an individual to whom an investigational new drug has been given a copy of any IND safety report relating to the use in the individual.

(d) The availability of information required to be publicly disclosed for investigations involving an exception from informed consent under § 50.24 of this chapter will be handled as follows: Persons wishing to request the publicly disclosable information in the IND that was required to be filed in Docket Number 95S-0158 in the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852, shall submit a request under the Freedom of Information Act.

(a) A sponsor must send an initial IND submission to the Center for Drug Evaluation and Research (CDER) or to the Center for Biologics Evaluation and Research (CBER), depending on the Center responsible for regulating the product as follows:

(1) For drug products regulated by CDER. Send the IND submission to the Central Document Room, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266.

(2) For biological products regulated by CDER. Send the IND submission to the Central Document Room, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266.

(3) For biological products regulated by CBER. Send the IND submission to the Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002.

(b) On receiving the IND, the responsible Center will inform the sponsor which one of the divisions in CDER or CBER is responsible for the IND. Amendments, reports, and other correspondence relating to matters covered by the IND should be sent to the appropriate center at the address indicated in this section and marked to the attention of the responsible division. The outside wrapper of each submission shall state what is contained in the submission, for example, “IND Application”, “Protocol Amendment”, etc.

(c) All correspondence relating to export of an investigational drug under § 312.110(b)(2) shall be submitted to the International Affairs Staff (HFY-50), Office of Health Affairs, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.

(a) FDA has made available guidance documents under § 10.115 of this chapter to help you to comply with certain requirements of this part.

(b) The Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) maintain lists of guidance documents that apply to the centers' regulations. The lists are maintained on the Internet and are published annually in the Federal Register. A request for a copy of the CDER list should be directed to the Office of Training and Communications, Division of Drug Information, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002. A request for a copy of the CBER list should be directed to the Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Communication, Outreach and Development, 10903 New Hampshire Ave., Bldg. 71, Rm. 3103, Silver Spring, MD 20993-0002.

(a) Authorization to ship. (1)(i) A person may ship a drug intended solely for tests in vitro or in animals used only for laboratory research purposes if it is labeled as follows:

(ii) A person may ship a biological product for investigational in vitro diagnostic use that is listed in § 312.2(b)(2)(ii) if it is labeled as follows:

(2) A person shipping a drug under paragraph (a) of this section shall use due diligence to assure that the consignee is regularly engaged in conducting such tests and that the shipment of the new drug will actually be used for tests in vitro or in animals used only for laboratory research.

(3) A person who ships a drug under paragraph (a) of this section shall maintain adequate records showing the name and post office address of the expert to whom the drug is shipped and the date, quantity, and batch or code mark of each shipment and delivery. Records of shipments under paragraph (a)(1)(i) of this section are to be maintained for a period of 2 years after the shipment. Records and reports of data and shipments under paragraph (a)(1)(ii) of this section are to be maintained in accordance with § 312.57(b). The person who ships the drug shall upon request from any properly authorized officer or employee of the Food and Drug Administration, at reasonable times, permit such officer or employee to have access to and copy and verify records required to be maintained under this section.

(b) Termination of authorization to ship. FDA may terminate authorization to ship a drug under this section if it finds that:

(1) The sponsor of the investigation has failed to comply with any of the conditions for shipment established under this section; or

(2) The continuance of the investigation is unsafe or otherwise contrary to the public interest or the drug is used for purposes other than bona fide scientific investigation. FDA will notify the person shipping the drug of its finding and invite immediate correction. If correction is not immediately made, the person shall have an opportunity for a regulatory hearing before FDA pursuant to part 16.

(c) Disposition of unused drug. The person who ships the drug under paragraph (a) of this section shall assure the return of all unused supplies of the drug from individual investigators whenever the investigation discontinues or the investigation is terminated. The person who ships the drug may authorize in writing alternative disposition of unused supplies of the drug provided this alternative disposition does not expose humans to risks from the drug, either directly or indirectly (e.g., through food-producing animals). The shipper shall maintain records of any alternative disposition.

(a) Scope. This subpart contains the requirements for the use of investigational new drugs and approved drugs where availability is limited by a risk evaluation and mitigation strategy (REMS) when the primary purpose is to diagnose, monitor, or treat a patient's disease or condition. The aim of this subpart is to facilitate the availability of such drugs to patients with serious diseases or conditions when there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the patient's disease or condition.

(b) Definitions. The following definitions of terms apply to this subpart:

Immediately life-threatening disease or condition means a stage of disease in which there is reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment.

Serious disease or condition means a disease or condition associated with morbidity that has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient, but the morbidity need not be irreversible, provided it is persistent or recurrent. Whether a disease or condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one.

The criteria, submission requirements, safeguards, and beginning treatment information set out in this section apply to all expanded access uses described in this subpart. Additional criteria, submission requirements, and safeguards that apply to specific types of expanded access are described in §§ 312.310 through 312.320.

(a) Criteria. FDA must determine that:

(1) The patient or patients to be treated have a serious or immediately life-threatening disease or condition, and there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition;

(2) The potential patient benefit justifies the potential risks of the treatment use and those potential risks are not unreasonable in the context of the disease or condition to be treated; and

(3) Providing the investigational drug for the requested use will not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval of the expanded access use or otherwise compromise the potential development of the expanded access use.

(b) Submission. (1) An expanded access submission is required for each type of expanded access described in this subpart. The submission may be a new IND or a protocol amendment to an existing IND. Information required for a submission may be supplied by referring to pertinent information contained in an existing IND if the sponsor of the existing IND grants a right of reference to the IND.

(2) The expanded access submission must include:

(i) A cover sheet (Form FDA 1571) meeting the requirements of § 312.23(a);

(ii) The rationale for the intended use of the drug, including a list of available therapeutic options that would ordinarily be tried before resorting to the investigational drug or an explanation of why the use of the investigational drug is preferable to the use of available therapeutic options;

(iii) The criteria for patient selection or, for an individual patient, a description of the patient's disease or condition, including recent medical history and previous treatments of the disease or condition;

(iv) The method of administration of the drug, dose, and duration of therapy;

(v) A description of the facility where the drug will be manufactured;

(vi) Chemistry, manufacturing, and controls information adequate to ensure the proper identification, quality, purity, and strength of the investigational drug;

(vii) Pharmacology and toxicology information adequate to conclude that the drug is reasonably safe at the dose and duration proposed for expanded access use (ordinarily, information that would be adequate to permit clinical testing of the drug in a population of the size expected to be treated); and

(viii) A description of clinical procedures, laboratory tests, or other monitoring necessary to evaluate the effects of the drug and minimize its risks.

(3) The expanded access submission and its mailing cover must be plainly marked “EXPANDED ACCESS SUBMISSION.” If the expanded access submission is for a treatment IND or treatment protocol, the applicable box on Form FDA 1571 must be checked.

(c) Safeguards. The responsibilities of sponsors and investigators set forth in subpart D of this part are applicable to expanded access use under this subpart as described in this paragraph.

(1) A licensed physician under whose immediate direction an investigational drug is administered or dispensed for an expanded access use under this subpart is considered an investigator, for purposes of this part, and must comply with the responsibilities for investigators set forth in subpart D of this part to the extent they are applicable to the expanded access use.

(2) An individual or entity that submits an expanded access IND or protocol under this subpart is considered a sponsor, for purposes of this part, and must comply with the responsibilities for sponsors set forth in subpart D of this part to the extent they are applicable to the expanded access use.

(3) A licensed physician under whose immediate direction an investigational drug is administered or dispensed, and who submits an IND for expanded access use under this subpart is considered a sponsor-investigator, for purposes of this part, and must comply with the responsibilities for sponsors and investigators set forth in subpart D of this part to the extent they are applicable to the expanded access use.

(4) Investigators. In all cases of expanded access, investigators are responsible for reporting adverse drug events to the sponsor, ensuring that the informed consent requirements of part 50 of this chapter are met, ensuring that IRB review of the expanded access use is obtained in a manner consistent with the requirements of part 56 of this chapter, and maintaining accurate case histories and drug disposition records and retaining records in a manner consistent with the requirements of § 312.62. Depending on the type of expanded access, other investigator responsibilities under subpart D may also apply.

(5) Sponsors. In all cases of expanded access, sponsors are responsible for submitting IND safety reports and annual reports (when the IND or protocol continues for 1 year or longer) to FDA as required by §§ 312.32 and 312.33, ensuring that licensed physicians are qualified to administer the investigational drug for the expanded access use, providing licensed physicians with the information needed to minimize the risk and maximize the potential benefits of the investigational drug (the investigator's brochure must be provided if one exists for the drug), maintaining an effective IND for the expanded access use, and maintaining adequate drug disposition records and retaining records in a manner consistent with the requirements of § 312.57. Depending on the type of expanded access, other sponsor responsibilities under subpart D may also apply.

(d) Beginning treatment - (1) INDs. An expanded access IND goes into effect 30 days after FDA receives the IND or on earlier notification by FDA that the expanded access use may begin.

(2) Protocols. With the following exceptions, expanded access use under a protocol submitted under an existing IND may begin as described in § 312.30(a).

(i) Expanded access use under the emergency procedures described in § 312.310(d) may begin when the use is authorized by the FDA reviewing official.

(ii) Expanded access use under § 312.320 may begin 30 days after FDA receives the protocol or upon earlier notification by FDA that use may begin.

(3) Clinical holds. FDA may place any expanded access IND or protocol on clinical hold as described in § 312.42.

Under this section, FDA may permit an investigational drug to be used for the treatment of an individual patient by a licensed physician.

(a) Criteria. The criteria in § 312.305(a) must be met; and the following determinations must be made:

(1) The physician must determine that the probable risk to the person from the investigational drug is not greater than the probable risk from the disease or condition; and

(2) FDA must determine that the patient cannot obtain the drug under another IND or protocol.

(b) Submission. The expanded access submission must include information adequate to demonstrate that the criteria in § 312.305(a) and paragraph (a) of this section have been met. The expanded access submission must meet the requirements of § 312.305(b).

(1) If the drug is the subject of an existing IND, the expanded access submission may be made by the sponsor or by a licensed physician.

(2) A sponsor may satisfy the submission requirements by amending its existing IND to include a protocol for individual patient expanded access.

(3) A licensed physician may satisfy the submission requirements by obtaining from the sponsor permission for FDA to refer to any information in the IND that would be needed to support the expanded access request (right of reference) and by providing any other required information not contained in the IND (usually only the information specific to the individual patient).

(c) Safeguards. (1) Treatment is generally limited to a single course of therapy for a specified duration unless FDA expressly authorizes multiple courses or chronic therapy.

(2) At the conclusion of treatment, the licensed physician or sponsor must provide FDA with a written summary of the results of the expanded access use, including adverse effects.

(3) FDA may require sponsors to monitor an individual patient expanded access use if the use is for an extended duration.

(4) When a significant number of similar individual patient expanded access requests have been submitted, FDA may ask the sponsor to submit an IND or protocol for the use under § 312.315 or § 312.320.

(d) Emergency procedures. If there is an emergency that requires the patient to be treated before a written submission can be made, FDA may authorize the expanded access use to begin without a written submission. The FDA reviewing official may authorize the emergency use by telephone.

(1) Emergency expanded access use may be requested by telephone, facsimile, or other means of electronic communications. For investigational biological drug products regulated by the Center for Biologics Evaluation and Research, the request should be directed to the Office of Communication, Outreach and Development, Center for Biologics Evaluation and Research, 240-402-8010 or 1-800-835-4709, e-mail: ocod@fda.hhs.gov. For all other investigational drugs, the request for authorization should be directed to the Division of Drug Information, Center for Drug Evaluation and Research, 301-796-3400, e-mail: druginfo@fda.hhs.gov. After normal working hours (8 a.m. to 4:30 p.m.), the request should be directed to the FDA Emergency Call Center, 866-300-4374, e-mail: emergency.operations@fda.hhs.gov.

(2) The licensed physician or sponsor must explain how the expanded access use will meet the requirements of §§ 312.305 and 312.310 and must agree to submit an expanded access submission within 15 working days of FDA's authorization of the use.

Under this section, FDA may permit an investigational drug to be used for the treatment of a patient population smaller than that typical of a treatment IND or treatment protocol. FDA may ask a sponsor to consolidate expanded access under this section when the agency has received a significant number of requests for individual patient expanded access to an investigational drug for the same use.

(a) Need for expanded access. Expanded access under this section may be needed in the following situations:

(1) Drug not being developed. The drug is not being developed, for example, because the disease or condition is so rare that the sponsor is unable to recruit patients for a clinical trial.

(2) Drug being developed. The drug is being studied in a clinical trial, but patients requesting the drug for expanded access use are unable to participate in the trial. For example, patients may not be able to participate in the trial because they have a different disease or stage of disease than the one being studied or otherwise do not meet the enrollment criteria, because enrollment in the trial is closed, or because the trial site is not geographically accessible.

(3) Approved or related drug. (i) The drug is an approved drug product that is no longer marketed for safety reasons or is unavailable through marketing due to failure to meet the conditions of the approved application, or

(ii) The drug contains the same active moiety as an approved drug product that is unavailable through marketing due to failure to meet the conditions of the approved application or a drug shortage.

(b) Criteria. The criteria in § 312.305(a) must be met; and FDA must determine that:

(1) There is enough evidence that the drug is safe at the dose and duration proposed for expanded access use to justify a clinical trial of the drug in the approximate number of patients expected to receive the drug under expanded access; and

(2) There is at least preliminary clinical evidence of effectiveness of the drug, or of a plausible pharmacologic effect of the drug to make expanded access use a reasonable therapeutic option in the anticipated patient population.

(c) Submission. The expanded access submission must include information adequate to satisfy FDA that the criteria in § 312.305(a) and paragraph (b) of this section have been met. The expanded access submission must meet the requirements of § 312.305(b). In addition:

(1) The expanded access submission must state whether the drug is being developed or is not being developed and describe the patient population to be treated.

(2) If the drug is not being actively developed, the sponsor must explain why the drug cannot currently be developed for the expanded access use and under what circumstances the drug could be developed.

(3) If the drug is being studied in a clinical trial, the sponsor must explain why the patients to be treated cannot be enrolled in the clinical trial and under what circumstances the sponsor would conduct a clinical trial in these patients.

(d) Safeguards. (1) Upon review of the IND annual report, FDA will determine whether it is appropriate for the expanded access to continue under this section.

(i) If the drug is not being actively developed or if the expanded access use is not being developed (but another use is being developed), FDA will consider whether it is possible to conduct a clinical study of the expanded access use.

(ii) If the drug is being actively developed, FDA will consider whether providing the investigational drug for expanded access use is interfering with the clinical development of the drug.

(iii) As the number of patients enrolled increases, FDA may ask the sponsor to submit an IND or protocol for the use under § 312.320.

(2) The sponsor is responsible for monitoring the expanded access protocol to ensure that licensed physicians comply with the protocol and the regulations applicable to investigators.

Under this section, FDA may permit an investigational drug to be used for widespread treatment use.

(a) Criteria. The criteria in § 312.305(a) must be met, and FDA must determine that:

(1) Trial status. (i) The drug is being investigated in a controlled clinical trial under an IND designed to support a marketing application for the expanded access use, or

(ii) All clinical trials of the drug have been completed; and

(2) Marketing status. The sponsor is actively pursuing marketing approval of the drug for the expanded access use with due diligence; and

(3) Evidence. (i) When the expanded access use is for a serious disease or condition, there is sufficient clinical evidence of safety and effectiveness to support the expanded access use. Such evidence would ordinarily consist of data from phase 3 trials, but could consist of compelling data from completed phase 2 trials; or

(ii) When the expanded access use is for an immediately life-threatening disease or condition, the available scientific evidence, taken as a whole, provides a reasonable basis to conclude that the investigational drug may be effective for the expanded access use and would not expose patients to an unreasonable and significant risk of illness or injury. This evidence would ordinarily consist of clinical data from phase 3 or phase 2 trials, but could be based on more preliminary clinical evidence.

(b) Submission. The expanded access submission must include information adequate to satisfy FDA that the criteria in § 312.305(a) and paragraph (a) of this section have been met. The expanded access submission must meet the requirements of § 312.305(b).

(c) Safeguard. The sponsor is responsible for monitoring the treatment protocol to ensure that licensed physicians comply with the protocol and the regulations applicable to investigators.

(a) This part sets forth procedures and requirements for the submission to, and the review by, the Food and Drug Administration of applications and abbreviated applications to market a new drug under section 505 of the Federal Food, Drug, and Cosmetic Act, as well as amendments, supplements, and postmarketing reports to them.

(b) This part does not apply to drug products subject to licensing by FDA under the Public Health Service Act (58 Stat. 632 as amended (42 U.S.C. 201 et seq.)) and subchapter F of chapter I of title 21 of the Code of Federal Regulations.

(c) References in this part to regulations in the Code of Federal Regulations are to chapter I of title 21, unless otherwise noted.

The purpose of this part is to establish an efficient and thorough drug review process in order to: (a) Facilitate the approval of drugs shown to be safe and effective; and (b) ensure the disapproval of drugs not shown to be safe and effective. These regulations are also intended to establish an effective system for FDA's surveillance of marketed drugs. These regulations shall be construed in light of these objectives.

(a) The definitions and interpretations contained in section 201 of the Federal Food, Drug, and Cosmetic Act apply to those terms when used in this part and part 320 of this chapter.

(b) The following definitions of terms apply to this part and part 320 of this chapter:

180-day exclusivity period is the 180-day period beginning on the date of the first commercial marketing of the drug (including the commercial marketing of the reference listed drug) by any first applicant. The 180-day period ends on the day before the date on which an ANDA submitted by an applicant other than a first applicant could be approved.

505(b)(2) application is an NDA submitted under section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act for a drug for which at least some of the investigations described in section 505(b)(1)(A) of the Federal Food, Drug, and Cosmetic Act and relied upon by the applicant for approval of the NDA were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted.

Abbreviated application, abbreviated new drug application, or ANDA is the application described under § 314.94, including all amendments and supplements to the application.

Acknowledgment letter is a written, postmarked communication from FDA to an applicant stating that the Agency has determined that an ANDA is sufficiently complete to permit a substantive review. An acknowledgment letter indicates that the ANDA is regarded as received.

Act is the Federal Food, Drug, and Cosmetic Act (section 201 et seq. (21 U.S.C. 301 et seq.)).

Active ingredient is any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. The term includes those components that may undergo chemical change in the manufacture of the drug product and be present in the drug product in a modified form intended to furnish the specified activity or effect.

Active moiety is the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.

ANDA holder is the applicant that owns an approved ANDA.

Applicant is any person who submits an NDA (including a 505(b)(2) application) or ANDA or an amendment or supplement to an NDA or ANDA under this part to obtain FDA approval of a new drug and any person who owns an approved NDA (including a 505(b)(2) application) or ANDA.

Application, new drug application, or NDA is the application described under § 314.50, including all amendments and supplements to the application. An NDA refers to “stand-alone” applications submitted under section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act and to 505(b)(2) applications.

Approval letter is a written communication to an applicant from FDA approving an NDA or an ANDA.

Assess the effects of the change is to evaluate the effects of a manufacturing change on the identity, strength, quality, purity, and potency of a drug product as these factors may relate to the safety or effectiveness of the drug product.

Authorized generic drug is a listed drug, as defined in this section, that has been approved under section 505(c) of the Federal Food, Drug, and Cosmetic Act and is marketed, sold, or distributed directly or indirectly to the retail class of trade with labeling, packaging (other than repackaging as the listed drug in blister packs, unit doses, or similar packaging for use in institutions), product code, labeler code, trade name, or trademark that differs from that of the listed drug.

Bioavailability is the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of drug action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by scientifically valid measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of drug action.

Bioequivalence is the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. Where there is an intentional difference in rate (e.g., in certain extended-release dosage forms), certain pharmaceutical equivalents or alternatives may be considered bioequivalent if there is no significant difference in the extent to which the active ingredient or moiety from each product becomes available at the site of drug action. This applies only if the difference in the rate at which the active ingredient or moiety becomes available at the site of drug action is intentional and is reflected in the proposed labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug. For drug products that are not intended to be absorbed into the bloodstream, bioequivalence may be assessed by scientifically valid measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of drug action.

Bioequivalence requirement is a requirement imposed by FDA for in vitro and/or in vivo testing of specified drug products that must be satisfied as a condition of marketing.

Class 1 resubmission is the resubmission of an NDA or efficacy supplement, following receipt of a complete response letter, that contains one or more of the following: Final printed labeling, draft labeling, certain safety updates, stability updates to support provisional or final dating periods, commitments to perform postmarketing studies (including proposals for such studies), assay validation data, final release testing on the last lots used to support approval, minor reanalyses of previously submitted data, and other comparatively minor information.

Class 2 resubmission is the resubmission of an NDA or efficacy supplement, following receipt of a complete response letter, that includes any item not specified in the definition of “Class 1 resubmission,” including any item that would require presentation to an advisory committee.

Commercial marketing is the introduction or delivery for introduction into interstate commerce of a drug product described in an ANDA, outside the control of the ANDA applicant, except that the term does not include transfer of the drug product for investigational use under part 312 of this chapter or transfer of the drug product to parties identified in the ANDA for reasons other than sale. Commercial marketing includes the introduction or delivery for introduction into interstate commerce of the reference listed drug by the ANDA applicant.

Complete response letter is a written communication to an applicant from FDA usually describing all of the deficiencies that the Agency has identified in an NDA or ANDA that must be satisfactorily addressed before it can be approved.

Component is any ingredient intended for use in the manufacture of a drug product, including those that may not appear in such drug product.

Date of approval is the date on the approval letter from FDA stating that the NDA or ANDA is approved, except that the date of approval for an NDA described in section 505(x)(1) of the Federal Food, Drug, and Cosmetic Act is determined as described in section 505(x)(2) of the Federal Food, Drug, and Cosmetic Act. “Date of approval” refers only to a final approval and not to a tentative approval.

Dosage form is the physical manifestation containing the active and inactive ingredients that delivers a dose of the drug product. This includes such factors as:

(1) The physical appearance of the drug product;

(2) The physical form of the drug product prior to dispensing to the patient;

(3) The way the product is administered; and

(4) The design features that affect frequency of dosing.

Drug product is a finished dosage form, e.g., tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients.

Drug substance is an active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body, but does not include intermediates used in the synthesis of such ingredient.

Efficacy supplement is a supplement to an approved NDA proposing to make one or more related changes from among the following changes to product labeling:

(1) Add or modify an indication or claim;

(2) Revise the dose or dose regimen;

(3) Provide for a new route of administration;

(4) Make a comparative efficacy claim naming another drug product;

(5) Significantly alter the intended patient population;

(6) Change the marketing status from prescription to over-the-counter use;

(7) Provide for, or provide evidence of effectiveness necessary for, the traditional approval of a product originally approved under subpart H of this part; or

(8) Incorporate other information based on at least one adequate and well-controlled clinical study.

FDA or Agency is the Food and Drug Administration.

First applicant is an ANDA applicant that, on the first day on which a substantially complete application containing a paragraph IV certification is submitted for approval of a drug, submits a substantially complete application that contains, and for which the applicant lawfully maintains, a paragraph IV certification for the drug.

Inactive ingredient is any component other than an active ingredient.

Listed drug is a new drug product that has been approved under section 505(c) of the Federal Food, Drug, and Cosmetic Act for safety and effectiveness or under section 505(j) of the Federal Food, Drug, and Cosmetic Act, which has not been withdrawn or suspended under section 505(e)(1) through (5) or section 505(j)(6) of the Federal Food, Drug, and Cosmetic Act, and which has not been withdrawn from sale for what FDA has determined are reasons of safety or effectiveness. Listed drug status is evidenced by the drug product's identification in the current edition of FDA's “Approved Drug Products With Therapeutic Equivalence Evaluations” (the list) as an approved drug. A drug product is deemed to be a listed drug on the date of approval for the NDA or ANDA for that drug product.

NDA holder is the applicant that owns an approved NDA.

Newly acquired information is data, analyses, or other information not previously submitted to the Agency, which may include (but is not limited to) data derived from new clinical studies, reports of adverse events, or new analyses of previously submitted data (e.g., meta-analyses) if the studies, events, or analyses reveal risks of a different type or greater severity or frequency than previously included in submissions to FDA.

Original application or original NDA is a pending NDA for which FDA has never issued a complete response letter or approval letter, or an NDA that was submitted again after FDA had refused to file it or after it was withdrawn without being approved.

Paragraph IV acknowledgment letter is a written, postmarked communication from FDA to an applicant stating that the Agency has determined that a 505(b)(2) application or ANDA containing a paragraph IV certification is sufficiently complete to permit a substantive review. A paragraph IV acknowledgment letter indicates that the 505(b)(2) application is regarded as filed or the ANDA is regarded as received.

Paragraph IV certification is a patent certification of invalidity, unenforceability, or noninfringement described in § 314.50(i)(1)(i)(A)(4) or § 314.94(a)(12)(i)(A)(4).

Patent owner is the owner of the patent for which information is submitted for an NDA.

Pharmaceutical alternatives are drug products that contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each such drug product individually meets either the identical or its own respective compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates.

Pharmaceutical equivalents are drug products in identical dosage forms and route(s) of administration that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, or, in the case of modified-release dosage forms that require a reservoir or overage or such forms as prefilled syringes where residual volume may vary, that deliver identical amounts of the active drug ingredient over the identical dosing period; do not necessarily contain the same inactive ingredients; and meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates.

Postmark is an independently verifiable evidentiary record of the date on which a document is transmitted, in an unmodifiable format, to another party. For postmarks made by the U.S. Postal Service or a designated delivery service, the date of transmission is the date on which the document is received by the domestic mail service of the U.S. Postal Service or by a designated delivery service. For postmarks documenting an electronic event, the date of transmission is the date (in a particular time zone) that FDA sends the electronic transmission on its host system as evidenced by a verifiable record. If the sender and the intended recipient are located in different time zones, it is the sender's time zone that provides the controlling date of electronic transmission.

Reference listed drug is the listed drug identified by FDA as the drug product upon which an applicant relies in seeking approval of its ANDA.

Reference standard is the drug product selected by FDA that an applicant seeking approval of an ANDA must use in conducting an in vivo bioequivalence study required for approval.

Resubmission, in the context of a complete response letter, is submission by the applicant of all materials needed to fully address all deficiencies identified in the complete response letter. An NDA or ANDA for which FDA issued a complete response letter, but which was withdrawn before approval and later submitted again, is not a resubmission.

Right of reference or use is the authority to rely upon, and otherwise use, an investigation for the purpose of obtaining approval of an NDA, including the ability to make available the underlying raw data from the investigation for FDA audit, if necessary.

Same drug product formulation is the formulation of the drug product submitted for approval and any formulations that have minor differences in composition or method of manufacture from the formulation submitted for approval, but are similar enough to be relevant to the Agency's determination of bioequivalence.

Specification is the quality standard (i.e., tests, analytical procedures, and acceptance criteria) provided in an approved NDA or ANDA to confirm the quality of drug substances, drug products, intermediates, raw materials, reagents, components, in-process materials, container closure systems, and other materials used in the production of a drug substance or drug product. For the purpose of this definition, acceptance criteria means numerical limits, ranges, or other criteria for the tests described.

Strength is the amount of drug substance contained in, delivered, or deliverable from a drug product, which includes:

(1)(i) The total quantity of drug substance in mass or units of activity in a dosage unit or container closure (e.g., weight/unit dose, weight/volume or weight/weight in a container closure, or units/volume or units/weight in a container closure); and/or, as applicable.

(ii) The concentration of the drug substance in mass or units of activity per unit volume or mass (e.g., weight/weight, weight/volume, or units/volume); or

(2) Such other criteria the Agency establishes for determining the amount of drug substance contained in, delivered, or deliverable from a drug product if the weights and measures described in paragraph (i) of this definition do not apply (e.g., certain drug-device combination products for which the amount of drug substance is emitted per use or unit time).

Substantially complete application is an ANDA that on its face is sufficiently complete to permit a substantive review. Sufficiently complete means that the ANDA contains all the information required under section 505(j)(2)(A) of the Federal Food, Drug, and Cosmetic Act and does not contain a deficiency described in § 314.101(d) and (e).

Tentative approval is notification that an NDA or ANDA otherwise meets the requirements for approval under the Federal Food, Drug, and Cosmetic Act, but cannot be approved because there is a 7-year period of orphan exclusivity for a listed drug under section 527 of the Federal Food, Drug, and Cosmetic Act and § 316.31 of this chapter, or that a 505(b)(2) application or ANDA otherwise meets the requirements for approval under the Federal Food, Drug, and Cosmetic Act, but cannot be approved until the conditions in § 314.107(b)(1)(iii), (b)(3), or (c) are met; because there is a period of exclusivity for the listed drug under § 314.108; because there is a period of pediatric exclusivity for the listed drug under section 505A of the Federal Food, Drug, and Cosmetic Act; because there is a period of exclusivity for the listed drug under section 505E of the Federal Food, Drug, and Cosmetic Act; or because a court order pursuant to 35 U.S.C. 271(e)(4)(A) orders that the NDA or ANDA may be approved no earlier than the date specified. A drug product that is granted tentative approval is not an approved drug and will not be approved until FDA issues an approval letter after any necessary additional review of the NDA or ANDA.

The list is the list of approved drug products published in FDA's current “Approved Drug Products With Therapeutic Equivalence Evaluations,” available electronically on FDA's Web site at http://www.fda.gov/cder.

Therapeutic equivalents are approved drug products that are pharmaceutical equivalents for which bioequivalence has been demonstrated, and that can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.

NDAs and supplements to approved NDAs are required to be submitted in the form and contain the information, as appropriate for the particular submission, required under this section. Three copies of the NDA are required: An archival copy, a review copy, and a field copy. An NDA for a new chemical entity will generally contain an application form, an index, a summary, five or six technical sections, case report tabulations of patient data, case report forms, drug samples, and labeling, including, if applicable, any Medication Guide required under part 208 of this chapter. Other NDAs will generally contain only some of those items, and information will be limited to that needed to support the particular submission. These include an NDA of the type described in section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act, an amendment, and a supplement. The NDA is required to contain reports of all investigations of the drug product sponsored by the applicant, and all other information about the drug pertinent to an evaluation of the NDA that is received or otherwise obtained by the applicant from any source. FDA will maintain guidance documents on the format and content of NDAs to assist applicants in their preparation.

(a) Application form. The applicant must submit a completed and signed application form that contains the following:

(1) The name and address of the applicant; the date of the NDA; the NDA number if previously issued (for example, if the NDA is a resubmission or an amendment or supplement); the name of the drug product, including its established, proprietary, code, and chemical names; the dosage form and strength; the route of administration; the identification numbers of all INDs (as defined in § 312.3(b) of this chapter) that are referenced in the NDA; the identification numbers of all drug master files and other applications under this part that are referenced in the NDA; and the drug product's proposed indications for use.

(2) A statement whether the submission is an original submission, a 505(b)(2) application, a resubmission, or a supplement to an application under § 314.70.

(3) A statement whether the applicant proposes to market the drug product as a prescription or an over-the-counter product.

(4) A check-list identifying what enclosures required under this section the applicant is submitting.

(5) The applicant, or the applicant's attorney, agent, or other authorized official must sign the NDA. If the person signing the NDA does not reside or have a place of business within the United States, the NDA is required to contain the name and address of, and be countersigned by, an attorney, agent, or other authorized official who resides or maintains a place of business within the United States.

(b) Index. The archival copy of the NDA is required to contain a comprehensive index by volume number and page number to the summary under paragraph (c) of this section, the technical sections under paragraph (d) of this section, and the supporting information under paragraph (f) of this section.

(c) Summary. (1) An NDA is required to contain a summary of the NDA in enough detail that the reader may gain a good general understanding of the data and information in the NDA, including an understanding of the quantitative aspects of the data. The summary is not required for supplements under § 314.70. Resubmissions of an NDA should contain an updated summary, as appropriate. The summary should discuss all aspects of the NDA, and synthesize the information into a well-structured and unified document. The summary should be written at approximately the level of detail required for publication in, and meet the editorial standards generally applied by, refereed scientific and medical journals. In addition to the agency personnel reviewing the summary in the context of their review of the NDA, FDA may furnish the summary to FDA advisory committee members and agency officials whose duties require an understanding of the NDA. To the extent possible, data in the summary should be presented in tabular and graphic forms. FDA has prepared a guideline under § 10.90(b) that provides information about how to prepare a summary. The summary required under this paragraph may be used by FDA or the applicant to prepare the Summary Basis of Approval document for public disclosure (under § 314.430(e)(2)(ii)) when the NDA is approved.

(2) The summary is required to contain the following information:

(i) The proposed text of the labeling, including, if applicable, any Medication Guide required under part 208 of this chapter, for the drug, with annotations to the information in the summary and technical sections of the NDA that support the inclusion of each statement in the labeling, and, if the NDA is for a prescription drug, statements describing the reasons for omitting a section or subsection of the labeling format in § 201.57 of this chapter.

(ii) A statement identifying the pharmacologic class of the drug and a discussion of the scientific rationale for the drug, its intended use, and the potential clinical benefits of the drug product.

(iii) A brief description of the marketing history, if any, of the drug outside the United States, including a list of the countries in which the drug has been marketed, a list of any countries in which the drug has been withdrawn from marketing for any reason related to safety or effectiveness, and a list of countries in which applications for marketing are pending. The description is required to describe both marketing by the applicant and, if known, the marketing history of other persons.

(iv) A summary of the chemistry, manufacturing, and controls section of the NDA.

(v) A summary of the nonclinical pharmacology and toxicology section of the NDA.

(vi) A summary of the human pharmacokinetics and bioavailability section of the NDA.

(vii) A summary of the microbiology section of the NDA (for anti-infective drugs only).

(viii) A summary of the clinical data section of the NDA, including the results of statistical analyses of the clinical trials.

(ix) A concluding discussion that presents the benefit and risk considerations related to the drug, including a discussion of any proposed additional studies or surveillance the applicant intends to conduct postmarketing.

(d) Technical sections. The NDA is required to contain the technical sections described below. Each technical section is required to contain data and information in sufficient detail to permit the agency to make a knowledgeable judgment about whether to approve the NDA or whether grounds exist under section 505(d) of the Federal Food, Drug, and Cosmetic Act to refuse to approve the NDA. The required technical sections are as follows:

(1) Chemistry, manufacturing, and controls section. A section describing the composition, manufacture, and specification of the drug substance and the drug product, including the following:

(i) Drug substance. A full description of the drug substance including its physical and chemical characteristics and stability; the name and address of its manufacturer; the method of synthesis (or isolation) and purification of the drug substance; the process controls used during manufacture and packaging; and the specifications necessary to ensure the identity, strength, quality, and purity of the drug substance and the bioavailability of the drug products made from the substance, including, for example, tests, analytical procedures, and acceptance criteria relating to stability, sterility, particle size, and crystalline form. The NDA may provide additionally for the use of alternatives to meet any of these requirements, including alternative sources, process controls, and analytical procedures. Reference to the current edition of the U.S. Pharmacopeia and the National Formulary may satisfy relevant requirements in this paragraph.

(ii)((a)) Drug product. A list of all components used in the manufacture of the drug product (regardless of whether they appear in the drug product) and a statement of the composition of the drug product; the specifications for each component; the name and address of each manufacturer of the drug product; a description of the manufacturing and packaging procedures and in-process controls for the drug product; the specifications necessary to ensure the identity, strength, quality, purity, potency, and bioavailability of the drug product, including, for example, tests, analytical procedures, and acceptance criteria relating to sterility, dissolution rate, container closure systems; and stability data with proposed expiration dating. The NDA may provide additionally for the use of alternatives to meet any of these requirements, including alternative components, manufacturing and packaging procedures, in-process controls, and analytical procedures. Reference to the current edition of the U.S. Pharmacopeia and the National Formulary may satisfy relevant requirements in this paragraph.

(b) Unless provided by paragraph (d)(1)(ii)(a) of this section, for each batch of the drug product used to conduct a bioavailability or bioequivalence study described in § 320.38 or § 320.63 of this chapter or used to conduct a primary stability study: The batch production record; the specification for each component and for the drug product; the names and addresses of the sources of the active and noncompendial inactive components and of the container and closure system for the drug product; the name and address of each contract facility involved in the manufacture, processing, packaging, or testing of the drug product and identification of the operation performed by each contract facility; and the results of any test performed on the components used in the manufacture of the drug product as required by § 211.84(d) of this chapter and on the drug product as required by § 211.165 of this chapter.

(c) The proposed or actual master production record, including a description of the equipment, to be used for the manufacture of a commercial lot of the drug product or a comparably detailed description of the production process for a representative batch of the drug product.

(iii) Environmental impact. The NDA is required to contain either a claim for categorical exclusion under § 25.30 or 25.31 of this chapter or an environmental assessment under § 25.40 of this chapter.

(iv) The applicant may, at its option, submit a complete chemistry, manufacturing, and controls section 90 to 120 days before the anticipated submission of the remainder of the NDA. FDA will review such early submissions as resources permit.

(v) The applicant must include a statement certifying that the field copy of the NDA has been provided to the applicant's home FDA district office.

(2) Nonclinical pharmacology and toxicology section. A section describing, with the aid of graphs and tables, animal and in vitro studies with drug, including the following:

(i) Studies of the pharmacological actions of the drug in relation to its proposed therapeutic indication and studies that otherwise define the pharmacologic properties of the drug or are pertinent to possible adverse effects.

(ii) Studies of the toxicological effects of the drug as they relate to the drug's intended clinical uses, including, as appropriate, studies assessing the drug's acute, subacute, and chronic toxicity; carcinogenicity; and studies of toxicities related to the drug's particular mode of administration or conditions of use.

(iii) Studies, as appropriate, of the effects of the drug on reproduction and on the developing fetus.

(iv) Any studies of the absorption, distribution, metabolism, and excretion of the drug in animals.

(v) For each nonclinical laboratory study subject to the good laboratory practice regulations under part 58 a statement that it was conducted in compliance with the good laboratory practice regulations in part 58, or, if the study was not conducted in compliance with those regulations, a brief statement of the reason for the noncompliance.

(3) Human pharmacokinetics and bioavailability section. A section describing the human pharmacokinetic data and human bioavailability data, or information supporting a waiver of the submission of in vivo bioavailability data under subpart B of part 320, including the following:

(i) A description of each of the bioavailability and pharmacokinetic studies of the drug in humans performed by or on behalf of the applicant that includes a description of the analytical procedures and statistical methods used in each study and a statement with respect to each study that it either was conducted in compliance with the institutional review board regulations in part 56, or was not subject to the regulations under § 56.104 or § 56.105, and that it was conducted in compliance with the informed consent regulations in part 50.

(ii) If the NDA describes in the chemistry, manufacturing, and controls section tests, analytical procedures, and acceptance criteria needed to assure the bioavailability of the drug product or drug substance, or both, a statement in this section of the rationale for establishing the tests, analytical procedures, and acceptance criteria, including data and information supporting the rationale.

(iii) A summarizing discussion and analysis of the pharmacokinetics and metabolism of the active ingredients and the bioavailability or bioequivalence, or both, of the drug product.

(4) Microbiology section. If the drug is an anti-infective drug, a section describing the microbiology data, including the following:

(i) A description of the biochemical basis of the drug's action on microbial physiology.

(ii) A description of the antimicrobial spectra of the drug, including results of in vitro preclinical studies to demonstrate concentrations of the drug required for effective use.

(iii) A description of any known mechanisms of resistance to the drug, including results of any known epidemiologic studies to demonstrate prevalence of resistance factors.

(iv) A description of clinical microbiology laboratory procedures (for example, in vitro sensitivity discs) needed for effective use of the drug.

(5) Clinical data section. A section describing the clinical investigations of the drug, including the following:

(i) A description and analysis of each clinical pharmacology study of the drug, including a brief comparison of the results of the human studies with the animal pharmacology and toxicology data.

(ii) A description and analysis of each controlled clinical study pertinent to a proposed use of the drug, including the protocol and a description of the statistical analyses used to evaluate the study. If the study report is an interim analysis, this is to be noted and a projected completion date provided. Controlled clinical studies that have not been analyzed in detail for any reason (e.g., because they have been discontinued or are incomplete) are to be included in this section, including a copy of the protocol and a brief description of the results and status of the study.

(iii) A description of each uncontrolled clinical study, a summary of the results, and a brief statement explaining why the study is classified as uncontrolled.

(iv) A description and analysis of any other data or information relevant to an evaluation of the safety and effectiveness of the drug product obtained or otherwise received by the applicant from any source, foreign or domestic, including information derived from clinical investigations, including controlled and uncontrolled studies of uses of the drug other than those proposed in the NDA, commercial marketing experience, reports in the scientific literature, and unpublished scientific papers.

(v) An integrated summary of the data demonstrating substantial evidence of effectiveness for the claimed indications. Evidence is also required to support the dosage and administration section of the labeling, including support for the dosage and dose interval recommended. The effectiveness data must be presented by gender, age, and racial subgroups and must identify any modifications of dose or dose interval needed for specific subgroups. Effectiveness data from other subgroups of the population of patients treated, when appropriate, such as patients with renal failure or patients with different levels of severity of the disease, also must be presented.

(vi) A summary and updates of safety information, as follows:

(a) The applicant must submit an integrated summary of all available information about the safety of the drug product, including pertinent animal data, demonstrated or potential adverse effects of the drug, clinically significant drug/drug interactions, and other safety considerations, such as data from epidemiological studies of related drugs. The safety data must be presented by gender, age, and racial subgroups. When appropriate, safety data from other subgroups of the population of patients treated also must be presented, such as for patients with renal failure or patients with different levels of severity of the disease. A description of any statistical analyses performed in analyzing safety data should also be included, unless already included under paragraph (d)(5)(ii) of this section.

(b) The applicant must, under section 505(i) of the Federal Food, Drug, and Cosmetic Act, update periodically its pending NDA with new safety information learned about the drug that may reasonably affect the statement of contraindications, warnings, precautions, and adverse reactions in the draft labeling and, if applicable, any Medication Guide required under part 208 of this chapter. These “safety update reports” must include the same kinds of information (from clinical studies, animal studies, and other sources) and must be submitted in the same format as the integrated summary in paragraph (d)(5)(vi)(a) of this section. In addition, the reports must include the case report forms for each patient who died during a clinical study or who did not complete the study because of an adverse event (unless this requirement is waived). The applicant must submit these reports (1) 4 months after the initial submission; (2) in a resubmission following receipt of a complete response letter; and (3) at other times as requested by FDA. Before submitting the first such report, applicants are encouraged to consult with FDA regarding further details on its form and content.

(vii) If the drug has a potential for abuse, a description and analysis of studies or information related to abuse of the drug, including a proposal for scheduling under the Controlled Substances Act. A description of any studies related to overdosage is also required, including information on dialysis, antidotes, or other treatments, if known.

(viii) An integrated summary of the benefits and risks of the drug, including a discussion of why the benefits exceed the risks under the conditions stated in the labeling.

(ix) A statement with respect to each clinical study involving human subjects that it either was conducted in compliance with the institutional review board regulations in part 56, or was not subject to the regulations under § 56.104 or § 56.105, and that it was conducted in compliance with the informed consent regulations in part 50.

(x) If a sponsor has transferred any obligations for the conduct of any clinical study to a contract research organization, a statement containing the name and address of the contract research organization, identification of the clinical study, and a listing of the obligations transferred. If all obligations governing the conduct of the study have been transferred, a general statement of this transfer - in lieu of a listing of the specific obligations transferred - may be submitted.

(xi) If original subject records were audited or reviewed by the sponsor in the course of monitoring any clinical study to verify the accuracy of the case reports submitted to the sponsor, a list identifying each clinical study so audited or reviewed.

(6) Statistical section. A section describing the statistical evaluation of clinical data, including the following:

(i) A copy of the information submitted under paragraph (d)(5)(ii) of this section concerning the description and analysis of each controlled clinical study, and the documentation and supporting statistical analyses used in evaluating the controlled clinical studies.

(ii) A copy of the information submitted under paragraph (d)(5)(vi)(a) of this section concerning a summary of information about the safety of the drug product, and the documentation and supporting statistical analyses used in evaluating the safety information.

(7) Pediatric use section. A section describing the investigation of the drug for use in pediatric populations, including an integrated summary of the information (the clinical pharmacology studies, controlled clinical studies, or uncontrolled clinical studies, or other data or information) that is relevant to the safety and effectiveness and benefits and risks of the drug in pediatric populations for the claimed indications, a reference to the full descriptions of such studies provided under paragraphs (d)(3) and (d)(5) of this section, and information required to be submitted under § 314.55.

(e) Samples and labeling. (1) Upon request from FDA, the applicant must submit the samples described below to the places identified in the Agency's request. FDA generally will ask applicants to submit samples directly to two or more Agency laboratories that will perform all necessary tests on the samples and validate the applicant's analytical procedures.

(i) Four representative samples of the following, each sample in sufficient quantity to permit FDA to perform three times each test described in the NDA to determine whether the drug substance and the drug product meet the specifications given in the NDA:

(a) The drug product proposed for marketing;

(b) The drug substance used in the drug product from which the samples of the drug product were taken; and

(c) Reference standards and blanks (except that reference standards recognized in an official compendium need not be submitted).

(ii) Samples of the finished market package, if requested by FDA.

(2) The applicant must submit the following in the archival copy of the NDA:

(i) Three copies of the analytical procedures and related descriptive information contained in the chemistry, manufacturing, and controls section under paragraph (d)(1) of this section for the drug substance and the drug product that are necessary for FDA's laboratories to perform all necessary tests on the samples and to validate the applicant's analytical procedures. The related descriptive information includes a description of each sample; the proposed regulatory specifications for the drug; a detailed description of the methods of analysis; supporting data for accuracy, specificity, precision and ruggedness; and complete results of the applicant's tests on each sample.

(ii) Copies of the label and all labeling for the drug product (including, if applicable, any Medication Guide required under part 208 of this chapter) for the drug product (4 copies of draft labeling or 12 copies of final printed labeling).

(f) Case report forms and tabulations. The archival copy of the NDA is required to contain the following case report tabulations and case report forms:

(1) Case report tabulations. The NDA is required to contain tabulations of the data from each adequate and well-controlled study under § 314.126 (Phase 2 and Phase 3 studies as described in §§ 312.21 (b) and (c) of this chapter), tabulations of the data from the earliest clinical pharmacology studies (Phase 1 studies as described in § 312.21(a) of this chapter), and tabulations of the safety data from other clinical studies. Routine submission of other patient data from uncontrolled studies is not required. The tabulations are required to include the data on each patient in each study, except that the applicant may delete those tabulations which the agency agrees, in advance, are not pertinent to a review of the drug's safety or effectiveness. Upon request, FDA will discuss with the applicant in a “pre-NDA” conference those tabulations that may be appropriate for such deletion. Barring unforeseen circumstances, tabulations agreed to be deleted at such a conference will not be requested during the conduct of FDA's review of the NDA. If such unforeseen circumstances do occur, any request for deleted tabulations will be made by the director of the FDA division responsible for reviewing the NDA, in accordance with paragraph (f)(3) of this section.

(2) Case report forms. The NDA is required to contain copies of individual case report forms for each patient who died during a clinical study or who did not complete the study because of an adverse event, whether believed to be drug related or not, including patients receiving reference drugs or placebo. This requirement may be waived by FDA for specific studies if the case report forms are unnecessary for a proper review of the study.

(3) Additional data. The applicant must submit to FDA additional case report forms and tabulations needed to conduct a proper review of the NDA, as requested by the director of the FDA division responsible for reviewing the NDA. The applicant's failure to submit information requested by FDA within 30 days after receipt of the request may result in the agency viewing any eventual submission as a major amendment under § 314.60 and extending the review period as necessary. If desired by the applicant, the FDA division director will verify in writing any request for additional data that was made orally.

(4) Presentation and format. Applicants are invited to meet with FDA before submitting an NDA to discuss the presentation and format of supporting information. If the applicant and FDA agree, the applicant may submit tabulations of patient data and case report forms in an alternate form.

(g) Other. The following general requirements apply to the submission of information within the summary under paragraph (c) of this section and within the technical sections under paragraph (d) of this section.

(1) The applicant ordinarily is not required to resubmit information previously submitted, but may incorporate the information by reference. A reference to information submitted previously is required to identify the file by name, reference number, volume, and page number in the agency's records where the information can be found. A reference to information submitted to the agency by a person other than the applicant is required to contain a written statement that authorizes the reference and that is signed by the person who submitted the information.

(2) The applicant must submit an accurate and complete English translation of each part of the NDA that is not in English. The applicant must submit a copy of each original literature publication for which an English translation is submitted.

(3) If an applicant who submits an NDA under section 505(b) of the Federal Food, Drug, and Cosmetic Act obtains a “right of reference or use,” as defined under § 314.3(b), to an investigation described in clause (A) of section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act, the applicant must include in its NDA a written statement signed by the owner of the data from each such investigation that the applicant may rely on in support of the approval of its NDA, and provide FDA access to, the underlying raw data that provide the basis for the report of the investigation submitted in its NDA.

(h) Patent information. The NDA is required to contain the patent information described under § 314.53.

(i) Patent certification - (1) Contents. A 505(b)(2) application is required to contain the following:

(i) Patents claiming drug substance, drug product, or method of use. (A) An appropriate patent certification or statement with respect to each patent issued by the U.S. Patent and Trademark Office that, in the opinion of the applicant and to the best of its knowledge, claims the drug substance or drug product on which investigations that are relied upon by the applicant for approval of its 505(b)(2) application were conducted or that claims an approved use for such drug and for which information is required to be filed under section 505(b) and (c) of the Federal Food, Drug, and Cosmetic Act and § 314.53. For each such patent, the applicant must provide the patent number and certify, in its opinion and to the best of its knowledge, one of the following circumstances:

(1) That the patent information has not been submitted to FDA. The applicant must entitle such a certification “Paragraph I Certification”;

(2) That the patent has expired. The applicant must entitle such a certification “Paragraph II Certification”;

(3) The date on which the patent will expire. The applicant must entitle such a certification “Paragraph III Certification”; or

(4)(i) That the patent is invalid, unenforceable, or will not be infringed by the manufacture, use, or sale of the drug product for which the 505(b)(2) application is submitted. The applicant must entitle such a certification “Paragraph IV Certification”. This certification must be submitted in the following form:

(ii) The certification must be accompanied by a statement that the applicant will comply with the requirements under § 314.52(a) with respect to providing a notice to each owner of the patent or its representative and to the NDA holder (or, if the NDA holder does not reside or maintain a place of business within the United States, its attorney, agent, or other authorized official) for the drug product that is claimed by the patent or a use of which is claimed by the patent and with the requirements under § 314.52(b) with respect to sending the notice and under § 314.52(c) with respect to the content of the notice.

(B) If the drug on which investigations that are relied upon by the applicant were conducted is itself a licensed generic drug of a patented drug first approved under section 505(b) of the Federal Food, Drug, and Cosmetic Act, an appropriate patent certification or statement under this section with respect to each patent that claims the first-approved patented drug or that claims an approved use for such a drug.

(C) If, before the date of submission of an original 505(b)(2) application, there is a drug product approved in an NDA that is pharmaceutically equivalent to the drug product for which the original 505(b)(2) application is submitted, an appropriate patent certification or statement under this section with respect to each patent that claims the drug substance or drug product or that claims an approved use for one such drug product.

(ii) No relevant patents. If, in the opinion of the applicant and to the best of its knowledge, there are no patents described in paragraph (i)(1)(i) of this section, a certification in the following form:

(iii) Method-of-use patent. (A) If information that is submitted under section 505(b) or (c) of the Federal Food, Drug, and Cosmetic Act and § 314.53 is for a method-of-use patent, and the labeling for the drug product for which the applicant is seeking approval does not include an indication or other condition of use that is covered by the method-of-use patent, a statement explaining that the method-of-use patent does not claim a proposed indication or other condition of use.

(B) If the labeling of the drug product for which the applicant is seeking approval includes an indication or other condition of use that, according to the patent information submitted under section 505(b) or (c) of the Federal Food, Drug, and Cosmetic Act and § 314.53 or in the opinion of the applicant, is claimed by a method-of-use patent, the applicant must submit an applicable certification under paragraph (i)(1)(i) of this section.

(2) [Reserved]

(3) Licensing agreements. If a 505(b)(2) application is submitted for a drug or method of using a drug claimed by a patent and the applicant has a licensing agreement with the patent owner, the applicant must submit a paragraph IV certification as to that patent and a statement that the applicant has been granted a patent license. If the patent owner consents to approval of the 505(b)(2) application (if otherwise eligible for approval) as of a specific date, the 505(b)(2) application must contain a written statement from the patent owner that it has a licensing agreement with the applicant and that it consents to approval of the 505(b)(2) application as of a specific date.

(4) Untimely filing of patent information. (i) If a patent described in paragraph (i)(1)(i)(A) of this section is issued and the holder of the approved NDA for the patented drug does not file with FDA the required information on the patent within 30 days of issuance of the patent, an applicant who submitted a 505(b)(2) application that, before the submission of the patent information, contained an appropriate patent certification or statement is not required to submit a patent certification or statement to address the patent or patent information that is late-listed with respect to the pending 505(b)(2) application. Except as provided in § 314.53(f)(1), an NDA holder's amendment to the description of the approved method(s) of use claimed by the patent will be considered untimely filing of patent information unless:

(A) The amendment to the description of the approved method(s) of use claimed by the patent is submitted within 30 days of patent issuance;

(B) The amendment to the description of the approved method(s) of use claimed by the patent is submitted within 30 days of approval of a corresponding change to product labeling; or

(C) The amendment to the description of the approved method(s) of use claimed by the patent is submitted within 30 days of a decision by the U.S. Patent and Trademark Office or by a Federal district court, the Court of Appeals for the Federal Circuit, or the U.S. Supreme Court that is specific to the patent and alters the construction of a method-of-use claim(s) of the patent, and the amendment contains a copy of the decision.

(ii) An applicant whose 505(b)(2) application is submitted after the NDA holder's untimely filing of patent information or whose 505(b)(2) application was previously filed but did not contain an appropriate patent certification or statement at the time of the patent submission must submit a certification under paragraph (i)(1)(i) of this section and/or a statement under paragraph (i)(1)(iii) of this section as to that patent.

(5) Disputed patent information. If an applicant disputes the accuracy or relevance of patent information submitted to FDA, the applicant may seek a confirmation of the correctness of the patent information in accordance with the procedures under § 314.53(f). Unless the patent information is withdrawn, the applicant must submit an appropriate certification or statement for each listed patent.

(6) Amended certifications. A patent certification or statement submitted under paragraphs (i)(1)(i) through (iii) of this section may be amended at any time before the approval of the 505(b)(2) application. An applicant must submit an amended certification as an amendment to a pending 505(b)(2) application. If an applicant with a pending 505(b)(2) application voluntarily makes a patent certification for an untimely filed patent, the applicant may withdraw the patent certification for the untimely filed patent. Once an amendment is submitted to change the certification, the 505(b)(2) application will no longer be considered to contain the prior certification.

(i) After finding of infringement. An applicant who has submitted a paragraph IV certification and is sued for patent infringement must submit an amendment to change its certification if a court enters a final decision from which no appeal has been or can be taken, or signs and enters a settlement order or consent decree in the action that includes a finding that the patent is infringed, unless the final decision, settlement order, or consent decree also finds the patent to be invalid. In its amendment, the applicant must certify under paragraph (i)(1)(i)(A)(3) of this section that the patent will expire on a specific date or, with respect to a patent claiming a method of use, the applicant may instead provide a statement under paragraph (i)(1)(iii) of this section if the applicant amends its 505(b)(2) application such that the applicant is no longer seeking approval for a method of use claimed by the patent. Once an amendment for the change has been submitted, the 505(b)(2) application will no longer be considered to contain a paragraph IV certification to the patent. If a final decision finds the patent to be invalid and infringed, an amended certification is not required.

(ii) After request to remove a patent or patent information from the list. If the list reflects that an NDA holder has requested that a patent or patent information be removed from the list and no ANDA applicant is eligible for 180-day exclusivity based on a paragraph IV certification to that patent, the patent or patent information will be removed and any applicant with a pending 505(b)(2) application (including a tentatively approved 505(b)(2) application) who has made a certification with respect to such patent must submit an amendment to withdraw its certification. In the amendment, the applicant must state the reason for withdrawing the certification or statement (that the patent has been removed from the list). If the list reflects that an NDA holder has requested that a patent or patent information be removed from the list and one or more first applicants are eligible for 180-day exclusivity based on a paragraph IV certification to that patent, the patent will remain listed until any 180-day exclusivity based on that patent has expired or has been extinguished. A 505(b)(2) applicant is not required to provide or maintain a certification to a patent or patent information that remains listed only for purposes of a first applicant's 180-day exclusivity for its ANDA. Once an amendment to withdraw the certification has been submitted, the 505(b)(2) application will no longer be considered to contain a paragraph IV certification to the patent. If removal of a patent from the list results in there being no patents listed for the listed drug(s) identified in the 505(b)(2) application, the applicant must submit an amended certification reflecting that there are no listed patents.

(iii) Other amendments. (A) Except as provided in paragraphs (i)(4) and (i)(6)(iii)(B) of this section:

(1) An applicant must amend a submitted certification or statement if, at any time before the approval of the 505(b)(2) application, the applicant learns that the submitted certification or statement is no longer accurate; and

(2) An applicant must submit an appropriate patent certification or statement under paragraph (i)(1) of this section if, after submission of the 505(b)(2) application, a new patent is issued by the U.S. Patent and Trademark Office that, in the opinion of the applicant and to the best of its knowledge, claims a listed drug relied upon or that claims an approved use for such listed drug for which information is required to be filed under section 505(b) and (c) of the Federal Food, Drug, and Cosmetic Act and § 314.53.

(B) An applicant is not required to submit a supplement to change a submitted certification when information on an otherwise applicable patent is submitted after the approval of the 505(b)(2) application.

(j) Claimed exclusivity. A new drug product, upon approval, may be entitled to a period of marketing exclusivity under the provisions of § 314.108. If an applicant believes its drug product is entitled to a period of exclusivity, it must submit with the NDA prior to approval the following information:

(1) A statement that the applicant is claiming exclusivity.

(2) A reference to the appropriate paragraph under § 314.108 that supports its claim.

(3) If the applicant claims exclusivity under § 314.108(b)(2), information to show that, to the best of its knowledge or belief, a drug has not previously been approved under section 505(b) of the Federal Food, Drug, and Cosmetic Act containing any active moiety in the drug for which the applicant is seeking approval.

(4) If the applicant claims exclusivity under § 314.108(b)(4) or (b)(5), the following information to show that the NDA contains “new clinical investigations” that are “essential to approval of the NDA or supplement” and were “conducted or sponsored by the applicant:”

(i) “New clinical investigations.” A certification that to the best of the applicant's knowledge each of the clinical investigations included in the NDA meets the definition of “new clinical investigation” set forth in § 314.108(a).

(ii) “Essential to approval.” A list of all published studies or publicly available reports of clinical investigations known to the applicant through a literature search that are relevant to the conditions for which the applicant is seeking approval, a certification that the applicant has thoroughly searched the scientific literature and, to the best of the applicant's knowledge, the list is complete and accurate and, in the applicant's opinion, such published studies or publicly available reports do not provide a sufficient basis for the approval of the conditions for which the applicant is seeking approval without reference to the new clinical investigation(s) in the NDA, and an explanation as to why the studies or reports are insufficient.

(iii) “Conducted or sponsored by.” If the applicant was the sponsor named in the Form FDA 1571 for an IND under which the new clinical investigation(s) that is essential to the approval of its NDA was conducted, identification of the IND by number. If the applicant was not the sponsor of the IND under which the clinical investigation(s) was conducted, a certification that the applicant or its predecessor in interest provided substantial support for the clinical investigation(s) that is essential to the approval of its NDA, and information supporting the certification. To demonstrate “substantial support,” an applicant must either provide a certified statement from a certified public accountant that the applicant provided 50 percent or more of the cost of conducting the study or provide an explanation of why FDA should consider the applicant to have conducted or sponsored the study if the applicant's financial contribution to the study is less than 50 percent or the applicant did not sponsor the investigational new drug. A predecessor in interest is an entity, e.g., a corporation, that the applicant has taken over, merged with, or purchased, or from which the applicant has purchased all rights to the drug. Purchase of nonexclusive rights to a clinical investigation after it is completed is not sufficient to satisfy this definition.

(k) Financial certification or disclosure statement. The NDA must contain a financial certification or disclosure statement or both as required by part 54 of this chapter.

(l) Format of an original NDA - (1) Archival copy. The applicant must submit a complete archival copy of the NDA that contains the information required under paragraphs (a) through (f) of this section. FDA will maintain the archival copy during the review of the NDA to permit individual reviewers to refer to information that is not contained in their particular technical sections of the NDA, to give other agency personnel access to the NDA for official business, and to maintain in one place a complete copy of the NDA. Except as required by paragraph (l)(1)(i) of this section, applicants may submit the archival copy on paper or in electronic format provided that electronic submissions are made in accordance with part 11 of this chapter.

(i) Labeling. The content of labeling required under § 201.100(d)(3) of this chapter (commonly referred to as the package insert or professional labeling), including all text, tables, and figures, must be submitted to the agency in electronic format as described in paragraph (l)(5) of this section. This requirement is in addition to the requirements of paragraph (e)(2)(ii) of this section that copies of the formatted label and all labeling be submitted. Submissions under this paragraph must be made in accordance with part 11 of this chapter, except for the requirements of § 11.10(a), (c) through (h), and (k), and the corresponding requirements of § 11.30.

(ii) [Reserved]

(2) Review copy. The applicant must submit a review copy of the NDA. Each of the technical sections, described in paragraphs (d)(1) through (6) of this section, in the review copy is required to be separately bound with a copy of the application form required under paragraph (a) of this section and a copy of the summary required under paragraph (c) of this section.

(3) Field copy. The applicant must submit a field copy of the NDA that contains the technical section described in paragraph (d)(1) of this section, a copy of the application form required under paragraph (a) of this section, a copy of the summary required under paragraph (c) of this section, and a certification that the field copy is a true copy of the technical section described in paragraph (d)(1) of this section contained in the archival and review copies of the NDA.

(4) Binding folders. The applicant may obtain from FDA sufficient folders to bind the archival, the review, and the field copies of the NDA.

(5) Electronic format submissions. Electronic format submissions must be in a form that FDA can process, review, and archive. FDA will periodically issue guidance on how to provide the electronic submission (e.g., method of transmission, media, file formats, preparation and organization of files).

(a) Notice of certification. For each patent that claims the listed drug or drugs relied upon or that claims a use for such listed drug or drugs and for which the 505(b)(2) applicant submits a paragraph IV certification, the applicant must send notice of such certification by registered or certified mail, return receipt requested, or by a designated delivery service, as defined in paragraph (g) of this section, to each of the following persons:

(1) Each owner of the patent that is the subject of the certification or the representative designated by the owner to receive the notice. The name and address of the patent owner or its representative may be obtained from the U.S. Patent and Trademark Office; and

(2) The holder of the approved NDA under section 505(b) of the Federal Food, Drug, and Cosmetic Act for each drug product which is claimed by the patent or a use of which is claimed by the patent and for which the applicant is seeking approval, or, if the NDA holder does not reside or maintain a place of business within the United States, the NDA holder's attorney, agent, or other authorized official. The name and address of the NDA holder or its attorney, agent, or authorized official may be obtained by sending a written or electronic communication to the Central Document Room, Attn: Orange Book Staff, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266, or to the Orange Book Staff at the email address listed on the Agency's Web site at http://www.fda.gov.

(3) This paragraph (a) does not apply to a method-of-use patent that does not claim a use for which the applicant is seeking approval.

(4) An applicant may send notice by an alternative method only if FDA has agreed in advance that the method will produce an acceptable form of documentation.

(b) Sending the notice. (1) Except as provided under paragraph (d) of this section, the applicant must send the notice required by paragraph (a) of this section on or after the date of filing described in § 314.101(a)(2) or (3), as applicable, but not later than 20 days after the date of the postmark on the paragraph IV acknowledgment letter. The 20-day clock described in this paragraph (b) begins on the day after the date of the postmark on the paragraph IV acknowledgment letter. When the 20th day falls on Saturday, Sunday, or a Federal holiday, the 20th day will be the next day that is not a Saturday, Sunday, or Federal holiday.

(2) Any notice required by paragraph (a) of this section is invalid if it is sent before the date of filing described in § 314.101(a)(2) or, if FDA notifies the applicant that FDA has refused to file the 505(b)(2) application, before the date described in § 314.101(a)(3) on which the 505(b)(2) application is filed. The applicant will not have complied with this paragraph (b) until it sends valid notice.

(3) The applicant must submit to FDA an amendment to its 505(b)(2) application that includes a statement certifying that the notice has been provided to each person identified under paragraph (a) of this section and that the notice met the content requirement under paragraph (c) of this section. A copy of the notice itself need not be submitted to the Agency.

(c) Content of a notice. In the notice, the applicant must cite section 505(b)(3)(D) of the Federal Food, Drug, and Cosmetic Act and the notice must include, but is not limited to, the following information:

(1) A statement that a 505(b)(2) application that contains any required bioavailability or bioequivalence studies has been submitted by the applicant and filed by FDA.

(2) The NDA number.

(3) The established name, if any, as defined in section 502(e)(3) of the Federal Food, Drug, and Cosmetic Act, of the proposed drug product.

(4) The active ingredient, strength, and dosage form of the proposed drug product.

(5) The patent number and expiration date of each patent on the list alleged to be invalid, unenforceable, or not infringed.

(6) A detailed statement of the factual and legal basis of the applicant's opinion that the patent is not valid, unenforceable, or will not be infringed. The applicant must include in the detailed statement:

(i) For each claim of a patent alleged not to be infringed, a full and detailed explanation of why the claim is not infringed.

(ii) For each claim of a patent alleged to be invalid or unenforceable, a full and detailed explanation of the grounds supporting the allegation.

(7) If the applicant alleges that the patent will not be infringed and the applicant seeks to preserve the option to later file a civil action for declaratory judgment in accordance with section 505(c)(3)(D) of the Federal Food, Drug, and Cosmetic Act, then the notice must be accompanied by an offer of confidential access to the 505(b)(2) application for the sole and limited purpose of evaluating possible infringement of the patent that is the subject of the paragraph IV certification.

(8) If the applicant does not reside or have a place of business in the United States, the name and address of an agent in the United States authorized to accept service of process for the applicant.

(d) Amendment or supplement to a 505(b)(2) application. (1) If, after the date of filing described in § 314.101(a)(2) or (3), as applicable, an applicant submits an amendment or supplement to its 505(b)(2) application that includes a paragraph IV certification, the applicant must send the notice required by paragraph (a) of this section at the same time that the amendment or supplement to the 505(b)(2) application is submitted to FDA, regardless of whether the applicant has already given notice with respect to another such certification contained in the 505(b)(2) application or in an amendment or supplement to the 505(b)(2) application.

(2) If, before the date of filing described in § 314.101(a)(2) or (3), as applicable, an applicant submits a paragraph IV certification in an amendment, the applicant must send the notice required by paragraph (a) of this section in accordance with the procedures in paragraph (b) of this section.

(3) An applicant that submits an amendment or supplement to seek approval of a different strength must provide notice of any paragraph IV certification in accordance with paragraph (d)(1) or (2) of this section, as applicable.

(e) Documentation of timely sending and receipt of notice. The applicant must amend its 505(b)(2) application to provide documentation of the date of receipt of the notice required under paragraph (a) of this section by each person provided the notice. The amendment must be submitted to FDA within 30 days after the last date on which notice was received by a person described in paragraph (a) of this section. The applicant's amendment also must include documentation that its notice was sent on a date that complies with the timeframe required by paragraph (b) or (d) of this section, as applicable. FDA will accept, as adequate documentation of the date the notice was sent, a copy of the registered mail receipt, certified mail receipt, or receipt from a designated delivery service, as defined in paragraph (g) of this section. FDA will accept as adequate documentation of the date of receipt a return receipt, a signature proof of delivery by a designated delivery service, or a letter acknowledging receipt by the person provided the notice. An applicant may rely on another form of documentation only if FDA has agreed to such documentation in advance. A copy of the notice itself need not be submitted to the Agency.

(f) Forty-five day period after receipt of notice. If the requirements of this section are met, the Agency will presume the notice to be complete and sufficient and will count the day following the date of receipt of the notice by the patent owner or its representative and by the approved NDA holder or its attorney, agent, or other authorized official as the first day of the 45-day period provided for in section 505(c)(3)(C) of the Federal Food, Drug, and Cosmetic Act. FDA may, if the applicant amends its 505(b)(2) application with a written statement that a later date should be used, count from such later date.

(g) Designated delivery services. (1) For purposes of this section, the term “designated delivery service” is any delivery service provided by a trade or business that the Agency determines:

(i) Is available to the general public throughout the United States;

(ii) Records electronically to its database, kept in the regular course of its business, or marks on the cover in which any item referred to in this section is to be delivered, the date on which such item was given to such trade or business for delivery; and

(iii) Provides overnight or 2-day delivery service throughout the United States.

(2) FDA may periodically issue guidance regarding designated delivery services.

(a) Who must submit patent information. This section applies to any applicant who submits to FDA an NDA or an amendment to it under section 505(b) of the Federal Food, Drug, and Cosmetic Act and § 314.50 or a supplement to an approved NDA under § 314.70, except as provided in paragraph (d)(2) of this section.

(b) Patents for which information must be submitted and patents for which information must not be submitted - (1) General requirements. An applicant described in paragraph (a) of this section must submit to its NDA the required information, on the required FDA declaration form, set forth in paragraph (c) of this section for each patent that claims the drug or a method of using the drug that is the subject of the NDA or amendment or supplement to it and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product. For purposes of this part, such patents consist of drug substance (active ingredient) patents, drug product (formulation and composition) patents, and method-of-use patents. For patents that claim the drug substance, the applicant must submit information only on those patents that claim the drug substance that is the subject of the pending or approved NDA or that claim a drug substance that is the same as the active ingredient that is the subject of the approved or pending NDA. For patents that claim only a polymorph that is the same as the active ingredient described in the approved or pending NDA, the applicant must certify in the required FDA declaration form that the applicant has test data, as set forth in paragraph (b)(2) of this section, demonstrating that a drug product containing the polymorph will perform the same as the drug product described in the NDA. For patents that claim a drug product, the applicant must submit information only on those patents that claim the drug product, as is defined in § 314.3, that is described in the pending or approved NDA. For patents that claim a method of use, the applicant must submit information only on those patents that claim indications or other conditions of use for which approval is sought or has been granted in the NDA. The applicant must separately identify each pending or approved method of use and related patent claim(s). For approved NDAs, the NDA holder's description of the patented method of use required by paragraph (c)(2)(ii)(P)(3) of this section must describe only the approved method(s) of use claimed by the patent for which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product. If the method(s) of use claimed by the patent does not cover an indication or other approved condition of use in its entirety, the applicant must describe only the specific approved method of use claimed by the patent for which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product. For approved NDAs, the NDA holder submitting information on the method-of-use patent must identify with specificity the section(s) and subsection(s) of the approved labeling that describes the method(s) of use claimed by the patent submitted. Process patents, patents claiming packaging, patents claiming metabolites, and patents claiming intermediates are not covered by this section, and information on these patents must not be submitted to FDA.

(2) Test data for submission of patent information for patents that claim only a polymorph. The test data, referenced in paragraph (b)(1) of this section, must include the following:

(i) A full description of the polymorphic form of the drug substance, including its physical and chemical characteristics and stability; the method of synthesis (or isolation) and purification of the drug substance; the process controls used during manufacture and packaging; and such specifications and analytical methods as are necessary to assure the identity, strength, quality, and purity of the polymorphic form of the drug substance;

(ii) The executed batch record for a drug product containing the polymorphic form of the drug substance and documentation that the batch was manufactured under current good manufacturing practice requirements;

(iii) Demonstration of bioequivalence between the executed batch of the drug product that contains the polymorphic form of the drug substance and the drug product as described in the NDA;

(iv) A list of all components used in the manufacture of the drug product containing the polymorphic form and a statement of the composition of the drug product; a statement of the specifications and analytical methods for each component; a description of the manufacturing and packaging procedures and in-process controls for the drug product; such specifications and analytical methods as are necessary to assure the identity, strength, quality, purity, and bioavailability of the drug product, including release and stability data complying with the approved product specifications to demonstrate pharmaceutical equivalence and comparable product stability; and

(v) Comparative in vitro dissolution testing on 12 dosage units each of the executed test batch and the NDA product.

(c) Reporting requirements - (1) General requirements. An applicant described in paragraph (a) of this section must submit the required patent information described in paragraph (c)(2) of this section for each patent that meets the requirements described in paragraph (b) of this section. We will not accept the patent information unless it is submitted on the appropriate form, Form FDA 3542 or 3542a, and contains the information required in paragraph (c)(2) of this section. These forms may be obtained on the Internet at http://www.fda.gov by searching for “forms”.

(2) Drug substance (active ingredient), drug product (formulation or composition), and method-of-use patents - (i) Original declaration. For each patent that claims a drug substance (active ingredient), drug product (formulation and composition), or method of use, the applicant must submit Form FDA 3542a. The following information and verification is required, subject to the exceptions listed in paragraph (c)(2)(i)(S) of this section:

(A) NDA number;

(B) The NDA applicant's name, full address, phone number and, if available, fax number and email address;

(C) Trade name (or proposed trade name) of new drug;

(D) Active ingredient(s) of new drug;

(E) Strength(s) of new drug;

(F) Dosage form(s) and route(s) of administration of new drug, and whether the applicant proposes to market the new drug for prescription use or over-the-counter use;

(G) U.S. patent number, issue date, and expiration date of patent submitted;

(H) The patent owner's name, full address, phone number and, if available, fax number and email address;

(I) The name, full address, phone number and, if available, fax number and email address of an agent or representative who resides or maintains a place of business within the United States authorized to receive notice of patent certification under section 505(b)(3) and (j)(2)(B) of the Federal Food, Drug, and Cosmetic Act and §§ 314.52 and 314.95 (if patent owner or NDA applicant or holder does not reside or have a place of business within the United States);

(J) Information on whether the patent has been submitted previously for the NDA or supplement;

(K) If the patent has been submitted previously for listing, identify all change(s) from the previously submitted patent information and specify whether the change is related to the patent or related to an FDA action or procedure;

(L) Information on whether the patent is a product-by-process patent in which the product claimed is novel;

(M) Information on the drug substance (active ingredient) patent, including the following:

(1) Whether the patent claims a drug substance that is an active ingredient in the drug product described in the NDA or supplement;

(2) Whether the patent claims only a polymorph that is the same active ingredient that is described in the pending NDA or supplement;

(3) Whether the applicant has test data, described in paragraph (b)(2) of this section, demonstrating that a drug product containing only the polymorph will perform the same as the drug product described in the NDA or supplement, and a description of the polymorphic form(s) claimed by the patent for which such test data exist;

(4) Whether the patent claims only a metabolite of the active ingredient; and

(5) Whether the patent claims only an intermediate;

(N) Information on the drug product (composition/formulation) patent, including the following:

(1) Whether the patent claims the drug product for which approval is being sought, as defined in § 314.3; and

(2) Whether the patent claims only an intermediate;

(O) Information on each method-of-use patent, including the following:

(1) Whether the patent claims one or more methods of using the drug product for which approval is being sought and a description of each pending method of use and related patent claim of the patent being submitted;

(2) Identification of the specific section(s) and subsection(s) of the proposed labeling for the drug product that describes the method of use claimed by the patent submitted; and

(3) An applicant that submits information for a patent that claims one or more methods of using the drug product must also submit information described in either paragraph (c)(2)(i)(M) or (N) of this section, regarding whether that patent also claims either the drug substance (active ingredient) or the drug product (composition/formulation).

(P) Whether there are no relevant patents that claim the drug substance (active ingredient), drug product (formulation or composition), or method(s) of use, for which the applicant is seeking approval and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product;

(Q) A signed verification that states:

(R) Information on whether the applicant, patent owner or attorney, agent, representative, or other authorized official signed the form; the name of the person; and the full address, phone number and, if available, the fax number and email address; and

(S) Exceptions to required submission of patent information:

(1) If an applicant submits the information described in paragraph (c)(2)(i)(M) of this section for a patent that claims the drug substance (active ingredient) and meets the requirements for listing on that basis, then the applicant is not required to provide the information described in paragraph (c)(2)(i)(N) of this section on whether that patent also claims the drug product (composition/formulation);

(2) If an applicant submits the information described in paragraph (c)(2)(i)(N) of this section for a patent that claims the drug product (composition/formulation) and meets the requirements for listing on that basis, then the applicant is not required to provide the information described in paragraph (c)(2)(i)(M) of this section on whether that patent also claims the drug substance (active ingredient);

(3) If the applicant submits a supplement for a change other than one of the changes listed under paragraph (d)(2)(i) of this section, then the patent information submission requirements of paragraph (d)(2)(ii) of this section apply.

(ii) Submission of patent information upon and after approval. Within 30 days after the date of approval of its NDA or supplement, the applicant must submit Form FDA 3542 for each patent that claims the drug substance (active ingredient), drug product (formulation and composition), or approved method of use. FDA will not list or publish patent information if it is not provided on this form or if the patent declaration does not contain the required information or indicates the patent is not eligible for listing. Patent information must also be submitted for patents issued after the date of approval of the NDA as required in paragraph (c)(2)(ii) of this section. As described in paragraph (d)(3) of this section, to be timely filed, patent information for patents issued after the date of approval of the NDA must be submitted to FDA within 30 days of the date of issuance of the patent. If the applicant submits the required patent information within the 30 days, but we notify an applicant that a declaration form is incomplete or shows that the patent is not eligible for listing, the applicant must submit an acceptable declaration form within 15 days of FDA notification to be considered timely filed. The following information and verification statement is required, subject to the exceptions listed in paragraph (c)(2)(ii)(T) of this section:

(A) NDA number;

(B) The NDA holder's name, full address, phone number and, if available, fax number and email address;

(C) Trade name of new drug;

(D) Active ingredient(s) of new drug;

(E) Strength(s) of new drug;

(F) Dosage form(s) and route(s) of administration of new drug, and whether the new drug is approved for prescription use or over-the-counter use;

(G) Approval date of NDA or supplement;

(H) U.S. patent number, issue date, and expiration date of patent submitted;

(I) The patent owner's name, full address, phone number and, if available, fax number and email address;

(J) The name, full address, phone number and, if available, fax number and email address of an agent or representative who resides or maintains a place of business within the United States authorized to receive notice of patent certification under section 505(b)(3) and (j)(2)(B) of the Federal Food, Drug, and Cosmetic Act and §§ 314.52 and 314.95 (if patent owner or NDA applicant or holder does not reside or have a place of business within the United States);

(K) Information on whether the patent has been submitted previously for the NDA or supplement;

(L) If the patent has been submitted previously for listing, identify all change(s) from the previously submitted patent information and specify whether the change is related to the patent or related to an FDA action or procedure;

(M) Information on whether the patent is a product-by-process patent in which the product claimed is novel;

(N) Information on the drug substance (active ingredient) patent, including the following:

(1) Whether the patent claims a drug substance that is an active ingredient in the drug product described in the approved NDA;

(2) Whether the patent claims only a polymorph that is the same as the active ingredient that is described in the approved NDA;

(3) Whether the applicant has test data, described in paragraph (b)(2) of this section, demonstrating that a drug product containing only the polymorph will perform the same as the drug product described in the approved NDA and a description of the polymorphic form(s) claimed by the patent for which such test data exist;

(4) Whether the patent claims only a metabolite of the active ingredient; and

(5) Whether the patent claims only an intermediate;

(O) Information on the drug product (composition/formulation) patent, including the following:

(1) Whether the patent claims the approved drug product as defined in § 314.3; and

(2) Whether the patent claims only an intermediate;

(P) Information on each method-of-use patent, including the following:

(1) Whether the patent claims one or more approved methods of using the approved drug product and a description of each approved method of use and related patent claim of the patent being submitted;

(2) Identification of the specific section(s) and subsection(s) of the approved labeling for the drug product that describes the method of use claimed by the patent submitted;

(3) The description of the patented method of use as required for publication, which must contain adequate information to assist 505(b)(2) and ANDA applicants in determining whether a listed method-of-use patent claims a use for which the 505(b)(2) or ANDA applicant is not seeking approval (for example, if the method(s) of use claimed by the patent does not cover an indication or other approved condition of use in its entirety, then the applicant must describe only the specific approved method of use claimed by the patent for which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product); and

(4) An applicant that submits information for a patent that claims one or more methods of using the drug product must also submit information described in either paragraph (c)(2)(ii)(N) or (O) of this section, regarding whether that patent also claims either the drug substance (active ingredient) or the drug product (composition/formulation).

(Q) Whether there are no relevant patents that claim the approved drug substance (active ingredient), the approved drug product (formulation or composition), or approved method(s) of use and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product;

(R) A signed verification that states:

(S) Information on whether the applicant, patent owner or attorney, agent, representative, or other authorized official signed the form; the name of the person; and the full address, phone number and, if available, the fax number and email address; and

(T) Exceptions to required submission of patent information:

(1) If an applicant submits the information described in paragraph (c)(2)(ii)(N) of this section for a patent that claims the drug substance (active ingredient) and meets the requirements for listing on that basis, then the applicant is not required to provide the information described in paragraph (c)(2)(ii)(O) of this section on whether that patent also claims the drug product (composition/formulation).

(2) If an applicant submits the information described in paragraph (c)(2)(ii)(O) of this section for a patent that claims the drug product (composition/formulation) and meets the requirements for listing on that basis, then the applicant is not required to provide the information described in paragraph (c)(2)(ii)(N) of this section on whether that patent also claims the drug substance (active ingredient).

(3) If the applicant submits a supplement for a change other than one of the changes listed under paragraph (d)(2)(i) of this section, then the patent information submission requirements of paragraph (d)(2)(ii) of this section apply.

(3) No relevant patents. If the applicant believes that there are no relevant patents that claim the drug substance (active ingredient), drug product (formulation or composition), or the method(s) of use for which the applicant has received approval, and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product, the applicant will verify this information in the appropriate form, Form FDA 3542 or 3542a.

(4) Authorized signature. The declarations required by this section must be signed by the applicant or patent owner, or the applicant's or patent owner's attorney, agent (representative), or other authorized official.

(d) When and where to submit patent information - (1) Original NDA. An applicant must submit with its original NDA submitted under this part, the information described in paragraph (c) of this section on each drug substance (active ingredient), drug product (formulation and composition), and method-of-use patent issued before the NDA is filed with FDA and for which patent information is required to be submitted under this section. If a patent is issued after the NDA is filed with FDA but before the NDA is approved, the applicant must, within 30 days of the date of issuance of the patent, submit the required patent information in an amendment to the NDA under § 314.60.

(2) Supplements. (i) An applicant must submit patent information required under paragraph (c) of this section for a patent that claims the drug substance, drug product, or method of use for which approval is sought in any of the following supplements:

(A) To add or change the dosage form or route of administration;

(B) To add or change the strength; or

(C) To change the drug product from prescription use to over-the-counter use.

(ii) If the applicant submits a supplement for a change other than one of the changes listed under paragraph (d)(2)(i) of this section (for example, to change the formulation, to add a new indication or other condition of use, or to make any other patented change regarding the drug substance, drug product, or any method of use), the following patent information submission requirements apply:

(A) If existing patents for which information required by paragraph (c) of this section has already been submitted to FDA for the product approved in the original NDA claim the changed product, the applicant is not required to resubmit this patent information pursuant to paragraph (c) of this section unless the published description of the patented method of use would change upon approval of the supplement, and FDA will continue to list this patent information for the product;

(B) If one or more existing patents for which information has already been submitted to FDA no longer claim the changed product, the applicant must submit a request under paragraph (f)(2)(iv) of this section to remove that patent information from the list at the time of approval of the supplement;

(C) If one or more existing drug substance (active ingredient), drug product (formulation and composition), or method-of-use patents claim the changed product for which approval is sought in the supplement and such patent information has not been submitted to FDA, the applicant must submit the patent information required under paragraph (c) of this section.

(3) Newly issued patents. If a patent is issued for a drug substance, drug product, or method of use after an NDA is approved, the applicant must submit to FDA, as described in paragraph (d)(4) of this section, the required patent information within 30 days of the date of issuance of the patent. If the required patent information is not submitted within 30 days of the issuance of the patent, FDA will list the patent, but patent certifications or statements will be governed by the provisions regarding untimely filed patent information at §§ 314.50(i)(4) and (6) and 314.94(a)(12)(vi) and (viii).

(4) Submission of Forms FDA 3542a and 3542 - (i) Patent information submitted with the filing of an NDA, amendment, or supplement. The applicant must submit patent information required by paragraphs (c)(1) and (c)(2)(i) of this section and § 314.50(h) or § 314.70(f) on Form FDA 3542a to the Central Document Room, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266, or to FDA in an electronic format submission that complies with § 314.50(l)(5). Form FDA 3542a should not be submitted to the Orange Book Staff in the Office of Generic Drugs.

(ii) Patent information submitted upon and after approval of an NDA or supplement. The applicant must submit patent information required by paragraphs (c)(1) and (c)(2)(ii) of this section on Form FDA 3542 to the Central Document Room, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266, or to FDA in an electronic format submission that complies with § 314.50(l)(5). Form FDA 3542 should not be submitted to the Orange Book Staff in the Office of Generic Drugs.

(5) Submission date. Patent information will be considered to be submitted to FDA for purposes of paragraph (d)(3) of this section as of the earlier of the date the information submitted on Form FDA 3542 is date-stamped by the Central Document Room, or officially received by FDA in an electronic format submission that complies with § 314.50(l)(5).

(6) Identification. Each submission of patent information, except information submitted with an original NDA, must bear prominent identification as to its contents, i.e., “Patent Information,” or, if submitted after approval of an NDA, “Time Sensitive Patent Information.”

(e) Public disclosure of patent information. FDA will publish in the list the patent number and expiration date of each patent that is required to be, and is, submitted to FDA by an applicant, and for each method-of-use patent, the description of the method of use claimed by the patent as required by § 314.53(c)(2)(ii)(P)(3). FDA will publish such patent information upon approval of the NDA, or, if the patent information is submitted by the applicant after approval of an NDA as provided under paragraph (d)(2) of this section, as soon as possible after the submission to the Agency of the patent information. A request for copies of the submitted patent information must be sent in writing to the Freedom of Information Staff at the address listed on the Agency's Web site at http://www.fda.gov. The submitted patent information, and requests to remove a patent or patent information from the list, may be subject to public disclosure.

(f) Correction of patent information errors - (1) Requests by persons other than the NDA holder. If any person disputes the accuracy or relevance of patent information submitted to the Agency under this section and published by FDA in the list, or believes that an NDA holder has failed to submit required patent information, that person must first notify the Agency in a written or electronic communication titled “314.53(f) Patent Listing Dispute.” The patent listing dispute communication must include a statement of dispute that describes the specific grounds for disagreement regarding the accuracy or relevance of patent information for FDA to send to the applicable NDA holder. For a dispute regarding the accuracy or relevance of patent information regarding an approved method of using the drug product, this statement of dispute must be only a narrative description (no more than 250 words) of the person's interpretation of the scope of the patent. This statement of dispute must only contain information for which the person consents to disclosure because FDA will send the text of the statement to the applicable NDA holder without review or redaction. The patent listing dispute communication should be directed to the Central Document Room, Attn: Orange Book Staff, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266, or to the Orange Book Staff at the email address listed on the Agency's Web site at http://www.fda.gov.

(i) Communication with the NDA holder - (A) Drug substance or drug product claim. For requests submitted under this paragraph (f)(1) that are directed to the accuracy or relevance of submitted patent information regarding a drug substance or drug product claim, the Agency will send the statement of dispute to the applicable NDA holder. The NDA holder must confirm the correctness of the patent information and include the signed verification required by paragraph (c)(2)(ii)(R) of this section or withdraw or amend the patent information in accordance with paragraph (f)(2) of this section within 30 days of the date on which the Agency sends the statement of dispute. Unless the NDA holder withdraws or amends its patent information in response to the patent listing dispute, the Agency will not change the patent information in the Orange Book.

(B) Method-of-use claim. For requests submitted under this paragraph (f)(1) that are directed to the accuracy or relevance of submitted patent information regarding an approved method of using the drug product, FDA will send the statement of dispute to the NDA holder. The NDA holder must confirm the correctness of its description of the approved method of use claimed by the patent that has been included as the “Use Code” in the Orange Book, or withdraw or amend the patent information in accordance with paragraph (f)(2) of this section, provide a narrative description (no more than 250 words) of the NDA holder's interpretation of the scope of the patent that explains why the existing or amended “Use Code” describes only the specific approved method of use claimed by the patent for which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product, and include the signed verification required by paragraph (c)(2)(ii)(R) of this section within 30 days of the date on which the Agency sends the statement of dispute. The narrative description must only contain information for which the NDA holder consents to disclosure because FDA will send the text of the statement to the person who submitted the patent listing dispute without review or redaction.

(1) If the NDA holder confirms the correctness of the patent information, provides the narrative description required by paragraph (f)(1)(i)(B) of this section, and includes the signed verification required by paragraph (c)(2)(ii)(R) of this section within 30 days of the date on which the Agency sends the statement of dispute, the Agency will not change the patent information in the Orange Book.

(2) If the NDA holder responds to the patent listing dispute with amended patent information in accordance with paragraph (f)(2) of this section, provides the narrative description required by paragraph (f)(1)(i)(B) of this section, and includes the signed verification required by paragraph (c)(2)(ii)(R) of this section within 30 days of the date on which the Agency sends the statement of dispute, FDA will update the Orange Book to reflect the amended patent information.

(ii) Patent certification or statement during and after patent listing dispute. A 505(b)(2) application or ANDA must contain an appropriate certification or statement for each listed patent, including the disputed patent, during and after the patent listing dispute.

(iii) Information on patent listing disputes. FDA will promptly post information on its Web site regarding whether a patent listing dispute has been submitted for a published description of a patented method of use for a drug product and whether the NDA holder has timely responded to the patent listing dispute.

(2) Requests by the NDA holder - (i) Patents or patent claims that no longer meet the statutory requirements for listing. If the NDA holder determines that a patent or patent claim no longer meets the requirements for listing in section 505(b)(1) or (c)(2) of the Federal Food, Drug, and Cosmetic Act (including if there has been a judicial finding of invalidity for a listed patent, from which no appeal has been or can be taken), the NDA holder is required to promptly notify FDA to amend the patent information or withdraw the patent or patent information and request that the patent or patent information be removed from the list. If the NDA holder is required by court order to amend patent information or withdraw a patent from the list, it must submit an amendment to its NDA that includes a copy of the order, within 14 days of the date the order was entered, to the Central Document Room, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266. The amendment to the NDA must bear the identification described in paragraph (d)(6) of this section. FDA will remove a patent or patent information from the list if there is no first applicant eligible for 180-day exclusivity based on a paragraph IV certification to that patent or after the 180-day exclusivity period of a first applicant based on that patent has expired or has been extinguished.

(ii) Patent term restoration. If the term of a listed patent is extended pursuant to 35 U.S.C. 156(e), the NDA holder must submit on Form FDA 3542 a correction to the expiration date of the patent. This correction must be submitted within 30 days of receipt of a certificate of extension as described in 35 U.S.C. 156(e)(1) or documentation of an extension of the term of the patent as described in 35 U.S.C. 156(e)(2).

(iii) Submission of corrections or changes to patent information. Corrections or changes to previously submitted patent information, other than withdrawal of a patent and requests to remove a patent from the list, must be submitted on Form FDA 3542 or 3542a, as appropriate, in an amendment or supplement to the NDA. The amendment or supplement to the NDA must bear the identification described in paragraph (d)(6) of this section. We will not accept the corrections or changes unless they are submitted on the appropriate forms.

(iv) Submission of patent withdrawals and requests to remove a patent from the list. Withdrawal of a patent and requests to remove a patent from the list must be submitted to the same addresses described in paragraph (d)(4)(ii) of this section, except that the withdrawal or request to remove a patent from the list is not required to be submitted on Form FDA 3542 and may be submitted by letter. Withdrawal of a patent and a request to remove a patent from the list must contain the following information:

(A) The NDA number to which the request applies;

(B) Each product(s) approved in the NDA to which the request applies; and

(C) The patent number.

(a) The Federal Food, Drug, and Cosmetic Act does not permit approval of an ANDA for a new indication, nor does it permit approval of other changes in a listed drug if investigations, other than bioavailability or bioequivalence studies, are essential to the approval of the change. Any person seeking approval of a drug product that represents a modification of a listed drug (e.g., a new indication or new dosage form) and for which investigations, other than bioavailability or bioequivalence studies, are essential to the approval of the changes may, except as provided in paragraph (b) of this section, submit a 505(b)(2) application. This 505(b)(2) application need contain only that information needed to support the modification(s) of the listed drug.

(1) The applicant must submit a complete archival copy of the application that contains the following:

(i) The information required under § 314.50(a), (b), (c), (d)(1), (d)(3), (e), and (g), except that § 314.50(d)(1)(ii)(c) must contain the proposed or actual master production record, including a description of the equipment, to be used for the manufacture of a commercial lot of the drug product.

(ii) The information required under § 314.50 (d)(2), (d)(4) (if an anti-infective drug), (d)(5), (d)(6), and (f) as needed to support the safety and effectiveness of the drug product.

(iii) Identification of each listed drug for which FDA has made a finding of safety and effectiveness and on which finding the applicant relies in seeking approval of its proposed drug product by established name, if any, proprietary name, dosage form, strength, route of administration, name of listed drug's application holder, and listed drug's approved NDA number. The listed drug(s) identified as relied upon must include a drug product approved in an NDA that:

(A) Is pharmaceutically equivalent to the drug product for which the original 505(b)(2) application is submitted; and

(B) Was approved before the original 505(b)(2) application was submitted.

(iv) If the applicant is seeking approval only for a new indication and not for the indications approved for the listed drug on which the applicant relies, a certification so stating.

(v) Any patent information required under section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act with respect to any patent which claims the drug for which approval is sought or a method of using such drug and to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product.

(vi) Any patent certification or statement required under section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act with respect to any relevant patents that claim the listed drug(s) on which investigations relied on by the applicant for approval of the application were conducted, or that claim a use for the listed drug(s). A 505(b)(2) applicant seeking approval of a drug that is pharmaceutically equivalent to a listed drug approved in an NDA implicitly relies upon one such pharmaceutically equivalent listed drug.

(vii) If the applicant believes the change for which it is seeking approval is entitled to a period of exclusivity, the information required under § 314.50(j).

(2) The applicant must submit a review copy that contains the technical sections described in § 314.50(d)(1), except that the section described in § 314.50(d)(1)(ii)(c) must contain the proposed or actual master production record, including a description of the equipment, to be used for the manufacture of a commercial lot of the drug product, and § 314.50(d)(3), and the technical sections described in § 314.50(d)(2), (d)(4) through (6), and (f) when needed to support the modification. Each of the technical sections in the review copy is required to be separately bound with a copy of the information required under § 314.50(a), (b), and (c) and a copy of the proposed labeling.

(3) The information required by § 314.50 (d)(2), (d)(4) (if an anti-infective drug), (d)(5), (d)(6), and (f) for the listed drug on which the applicant relies must be satisfied by reference to the listed drug under paragraph (a)(1)(iii) of this section.

(4) The applicant must submit a field copy of the 505(b)(2) application that contains the technical section described in § 314.50(d)(1), a copy of the information required under § 314.50(a) and (c), and certification that the field copy is a true copy of the technical section described in § 314.50(d)(1) contained in the archival and review copies of the 505(b)(2) application.

(b) A 505(b)(2) application may not be submitted under this section for a drug product whose only difference from a listed drug is that:

(1) The extent to which its active ingredient(s) is absorbed or otherwise made available to the site of action is less than that of the listed drug; or

(2) The rate at which its active ingredient(s) is absorbed or otherwise made available to the site of action is unintentionally less than that of the listed drug.

(a) Required assessment. Except as provided in paragraphs (b), (c), and (d) of this section, each application for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration shall contain data that are adequate to assess the safety and effectiveness of the drug product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the drug is safe and effective. Where the course of the disease and the effects of the drug are sufficiently similar in adults and pediatric patients, FDA may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults usually supplemented with other information obtained in pediatric patients, such as pharmacokinetic studies. Studies may not be needed in each pediatric age group, if data from one age group can be extrapolated to another. Assessments of safety and effectiveness required under this section for a drug product that represents a meaningful therapeutic benefit over existing treatments for pediatric patients must be carried out using appropriate formulations for each age group(s) for which the assessment is required.

(b) Deferred submission. (1) FDA may, on its own initiative or at the request of an applicant, defer submission of some or all assessments of safety and effectiveness described in paragraph (a) of this section until after approval of the drug product for use in adults. Deferral may be granted if, among other reasons, the drug is ready for approval in adults before studies in pediatric patients are complete, or pediatric studies should be delayed until additional safety or effectiveness data have been collected. If an applicant requests deferred submission, the request must provide a certification from the applicant of the grounds for delaying pediatric studies, a description of the planned or ongoing studies, and evidence that the studies are being or will be conducted with due diligence and at the earliest possible time.

(2) If FDA determines that there is an adequate justification for temporarily delaying the submission of assessments of pediatric safety and effectiveness, the drug product may be approved for use in adults subject to the requirement that the applicant submit the required assessments within a specified time.

(c) Waivers - (1) General. FDA may grant a full or partial waiver of the requirements of paragraph (a) of this section on its own initiative or at the request of an applicant. A request for a waiver must provide an adequate justification.

(2) Full waiver. An applicant may request a waiver of the requirements of paragraph (a) of this section if the applicant certifies that:

(i) The drug product does not represent a meaningful therapeutic benefit over existing treatments for pediatric patients and is not likely to be used in a substantial number of pediatric patients;

(ii) Necessary studies are impossible or highly impractical because, e.g., the number of such patients is so small or geographically dispersed; or

(iii) There is evidence strongly suggesting that the drug product would be ineffective or unsafe in all pediatric age groups.

(3) Partial waiver. An applicant may request a waiver of the requirements of paragraph (a) of this section with respect to a specified pediatric age group, if the applicant certifies that:

(i) The drug product does not represent a meaningful therapeutic benefit over existing treatments for pediatric patients in that age group, and is not likely to be used in a substantial number of patients in that age group;

(ii) Necessary studies are impossible or highly impractical because, e.g., the number of patients in that age group is so small or geographically dispersed;

(iii) There is evidence strongly suggesting that the drug product would be ineffective or unsafe in that age group; or

(iv) The applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary for that age group have failed.

(4) FDA action on waiver. FDA shall grant a full or partial waiver, as appropriate, if the agency finds that there is a reasonable basis on which to conclude that one or more of the grounds for waiver specified in paragraphs (c)(2) or (c)(3) of this section have been met. If a waiver is granted on the ground that it is not possible to develop a pediatric formulation, the waiver will cover only those pediatric age groups requiring that formulation. If a waiver is granted because there is evidence that the product would be ineffective or unsafe in pediatric populations, this information will be included in the product's labeling.

(5) Definition of “meaningful therapeutic benefit”. For purposes of this section and § 201.23 of this chapter, a drug will be considered to offer a meaningful therapeutic benefit over existing therapies if FDA estimates that:

(i) If approved, the drug would represent a significant improvement in the treatment, diagnosis, or prevention of a disease, compared to marketed products adequately labeled for that use in the relevant pediatric population. Examples of how improvement might be demonstrated include, for example, evidence of increased effectiveness in treatment, prevention, or diagnosis of disease, elimination or substantial reduction of a treatment-limiting drug reaction, documented enhancement of compliance, or evidence of safety and effectiveness in a new subpopulation; or

(ii) The drug is in a class of drugs or for an indication for which there is a need for additional therapeutic options.

(d) Exemption for orphan drugs. This section does not apply to any drug for an indication or indications for which orphan designation has been granted under part 316, subpart C, of this chapter.

(a) Submission of NDA. FDA generally assumes that when an original NDA, supplement to an approved NDA, or resubmission of an NDA or supplement is submitted to the Agency for review, the applicant believes that the Agency can approve the NDA, supplement, or resubmission as submitted. However, the applicant may submit an amendment to an NDA, supplement, or resubmission that has been filed under § 314.101 but is not yet approved.

(b) Submission of major amendment. (1) Submission of a major amendment to an original NDA, efficacy supplement, or resubmission of an NDA or efficacy supplement within 3 months of the end of the initial review cycle constitutes an agreement by the applicant under section 505(c) of the Federal Food, Drug, and Cosmetic Act to extend the initial review cycle by 3 months. (For references to a resubmission of an NDA or efficacy supplement in paragraph (b) of this section, the timeframe for reviewing the resubmission is the “review cycle” rather than the “initial review cycle.”) FDA may instead defer review of the amendment until the subsequent review cycle. If the agency extends the initial review cycle for an original NDA, efficacy supplement, or resubmission under this paragraph, the division responsible for reviewing the NDA, supplement, or resubmission will notify the applicant of the extension. The initial review cycle for an original NDA, efficacy supplement, or resubmission of an NDA or efficacy supplement may be extended only once due to submission of a major amendment. FDA may, at its discretion, review any subsequent major amendment during the initial review cycle (as extended) or defer review until the subsequent review cycle.

(2) Submission of a major amendment to an original NDA, efficacy supplement, or resubmission of an NDA or efficacy supplement more than 3 months before the end of the initial review cycle will not extend the cycle. FDA may, at its discretion, review such an amendment during the initial review cycle or defer review until the subsequent review cycle.

(3) Submission of an amendment to an original NDA, efficacy supplement, or resubmission of an NDA or efficacy supplement that is not a major amendment will not extend the initial review cycle. FDA may, at its discretion, review such an amendment during the initial review cycle or defer review until the subsequent review cycle.

(4) Submission of a major amendment to a manufacturing supplement within 2 months of the end of the initial review cycle constitutes an agreement by the applicant under section 505(c) of the Federal Food, Drug, and Cosmetic Act to extend the initial review cycle by 2 months. FDA may instead defer review of the amendment until the subsequent review cycle. If the agency extends the initial review cycle for a manufacturing supplement under this paragraph, the division responsible for reviewing the supplement will notify the applicant of the extension. The initial review cycle for a manufacturing supplement may be extended only once due to submission of a major amendment. FDA may, at its discretion, review any subsequent major amendment during the initial review cycle (as extended) or defer review until the subsequent review cycle.

(5) Submission of an amendment to a supplement other than an efficacy or manufacturing supplement will not extend the initial review cycle. FDA may, at its discretion, review such an amendment during the initial review cycle or defer review until the subsequent review cycle.

(6) A major amendment may not include data to support an indication or claim that was not included in the original NDA, supplement, or resubmission, but it may include data to support a minor modification of an indication or claim that was included in the original NDA, supplement, or resubmission.

(7) When FDA defers review of an amendment until the subsequent review cycle, the agency will notify the applicant of the deferral in the complete response letter sent to the applicant under § 314.110 of this part.

(c) Limitation on certain amendments. (1) An unapproved NDA may not be amended if all of the following conditions apply:

(i) The unapproved NDA is for a drug for which a previous NDA has been approved and granted a period of exclusivity in accordance with section 505(c)(3)(E)(ii) of the Federal Food, Drug, and Cosmetic Act that has not expired;

(ii) The applicant seeks to amend the unapproved NDA to include a published report of an investigation that was conducted or sponsored by the applicant entitled to exclusivity for the drug;

(iii) The applicant has not obtained a right of reference or use to the investigation described in paragraph (c)(1)(ii) of this section; and

(iv) The report of the investigation described in paragraph (c)(1)(ii) of this section would be essential to the approval of the unapproved NDA.

(2) The submission of an amendment described in paragraph (c)(1) of this section will cause the unapproved NDA to be deemed to be withdrawn by the applicant under § 314.65 on the date of receipt by FDA of the amendment. The amendment will be considered a resubmission of the NDA, which may not be accepted except as provided in accordance with section 505(c)(3)(E)(ii) of the Federal Food, Drug, and Cosmetic Act.

(d) Field copy. The applicant must submit a field copy of each amendment to a section of the NDA described in § 314.50(d)(1). The applicant must include in its submission of each such amendment to FDA a statement certifying that a field copy of the amendment has been sent to the applicant's home FDA district office.

(e) Different drug. An applicant may not amend a 505(b)(2) application to seek approval of a drug that is a different drug from the drug in the original submission of the 505(b)(2) application. For purposes of this paragraph (e), a drug is a different drug if it has been modified to have a different active ingredient, different route of administration, different dosage form, or difference in excipients that requires either a separate clinical study to establish safety or effectiveness or, for topical products, that requires a separate in vivo demonstration of bioequivalence. However, notwithstanding the limitation described in this paragraph (e), an applicant may amend the 505(b)(2) application to seek approval of a different strength.

(f) Patent certification requirements. (1) An amendment to a 505(b)(2) application is required to contain an appropriate patent certification or statement described in § 314.50(i) or a recertification for a previously submitted paragraph IV certification if approval is sought for any of the following types of amendments:

(i) To add a new indication or other condition of use;

(ii) To add a new strength;

(iii) To make other than minor changes in product formulation; or

(iv) To change the physical form or crystalline structure of the active ingredient.

(2) If the amendment to the 505(b)(2) application does not contain a patent certification or statement, the applicant must verify that the proposed change described in the amendment is not one of the types of amendments described in paragraph (f)(1) of this section.

An applicant may at any time withdraw an application that is not yet approved by notifying the Food and Drug Administration in writing. If, by the time it receives such notice, the agency has identified any deficiencies in the application, we will list such deficiencies in the letter we send the applicant acknowledging the withdrawal. A decision to withdraw the application is without prejudice to refiling. The agency will retain the application and will provide a copy to the applicant on request under the fee schedule in § 20.45 of FDA's public information regulations.

(a) Changes to an approved NDA. (1)(i) Except as provided in paragraph (a)(1)(ii) of this section, the applicant must notify FDA about each change in each condition established in an approved NDA beyond the variations already provided for in the NDA. The notice is required to describe the change fully. Depending on the type of change, the applicant must notify FDA about the change in a supplement under paragraph (b) or (c) of this section or by inclusion of the information in the annual report to the NDA under paragraph (d) of this section.

(ii) The submission and grant of a written request for an exception or alternative under § 201.26 of this chapter satisfies the applicable requirements in paragraphs (a) through (c) of this section. However, any grant of a request for an exception or alternative under § 201.26 of this chapter must be reported as part of the annual report to the NDA under paragraph (d) of this section.

(2) The NDA holder must assess the effects of the change before distributing a drug product made with a manufacturing change.

(3) Notwithstanding the requirements of paragraphs (b) and (c) of this section, an applicant must make a change provided for in those paragraphs in accordance with a regulation or guidance that provides for a less burdensome notification of the change (for example, by submission of a supplement that does not require approval prior to distribution of the product or in an annual report).

(4) The applicant must promptly revise all promotional labeling and advertising to make it consistent with any labeling change implemented in accordance with paragraphs (b) and (c) of this section.

(5) Except for a supplement providing for a change in the labeling, the applicant must include in each supplement and amendment to a supplement providing for a change under paragraph (b) or (c) of this section a statement certifying that a field copy has been provided in accordance with § 314.440(a)(4).

(6) A supplement or annual report must include a list of all changes contained in the supplement or annual report. For supplements, this list must be provided in the submission.

(b) Changes requiring supplement submission and approval prior to distribution of the product made using the change (major changes). (1) A supplement must be submitted for any change in the drug substance, drug product, production process, quality controls, equipment, or facilities that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product.

(2) These changes include, but are not limited to:

(i) Except those described in paragraphs (c) and (d) of this section, changes in the qualitative or quantitative formulation of the drug product, including inactive ingredients, or in the specifications provided in the approved NDA;

(ii) Changes requiring completion of studies in accordance with part 320 of this chapter to demonstrate the equivalence of the drug product to the drug product as manufactured without the change or to the reference listed drug;

(iii) Changes that may affect drug substance or drug product sterility assurance, such as changes in drug substance, drug product, or component sterilization method(s) or an addition, deletion, or substitution of steps in an aseptic processing operation;

(iv) Changes in the synthesis or manufacture of the drug substance that may affect the impurity profile and/or the physical, chemical, or biological properties of the drug substance;

(v) The following labeling changes:

(A) Changes in labeling, except those described in paragraphs (c)(6)(iii), (d)(2)(ix), or (d)(2)(x) of this section;

(B) If applicable, any change to a Medication Guide required under part 208 of this chapter, except for changes in the information specified in § 208.20(b)(8)(iii) and (b)(8)(iv) of this chapter; and

(C) Any change to the information required by § 201.57(a) of this chapter, with the following exceptions that may be reported in an annual report under paragraph (d)(2)(x) of this section:

(1) Removal of a listed section(s) specified in § 201.57(a)(5) of this chapter; and

(2) Changes to the most recent revision date of the labeling as specified in § 201.57(a)(15) of this chapter.

(vi) Changes in a drug product container closure system that controls the drug product delivered to a patient or changes in the type (e.g., glass to high density polyethylene (HDPE), HDPE to polyvinyl chloride, vial to syringe) or composition (e.g., one HDPE resin to another HDPE resin) of a packaging component that may affect the impurity profile of the drug product.

(vii) Changes solely affecting a natural product, a recombinant DNA-derived protein/polypeptide, or a complex or conjugate of a drug substance with a monoclonal antibody for the following:

(A) Changes in the virus or adventitious agent removal or inactivation method(s);

(B) Changes in the source material or cell line; and

(C) Establishment of a new master cell bank or seed.

(viii) Changes to a drug product under an NDA that is subject to a validity assessment because of significant questions regarding the integrity of the data supporting that NDA.

(3) The applicant must obtain approval of a supplement from FDA prior to distribution of a drug product made using a change under paragraph (b) of this section. Except for submissions under paragraph (e) of this section, the following information must be contained in the supplement:

(i) A detailed description of the proposed change;

(ii) The drug product(s) involved;

(iii) The manufacturing site(s) or area(s) affected;

(iv) A description of the methods used and studies performed to assess the effects of the change;

(v) The data derived from such studies;

(vi) For a natural product, a recombinant DNA-derived protein/polypeptide, or a complex or conjugate of a drug substance with a monoclonal antibody, relevant validation protocols and a list of relevant standard operating procedures must be provided in addition to the requirements in paragraphs (b)(3)(iv) and (b)(3)(v) of this section; and

(vii) For sterilization process and test methodologies related to sterilization process validation, relevant validation protocols and a list of relevant standard operating procedures must be provided in addition to the requirements in paragraphs (b)(3)(iv) and (b)(3)(v) of this section.

(4) An applicant may ask FDA to expedite its review of a supplement for public health reasons or if a delay in making the change described in it would impose an extraordinary hardship on the applicant. Such a supplement should be plainly marked: “Prior Approval Supplement-Expedited Review Requested.”

(c) Changes requiring supplement submission at least 30 days prior to distribution of the drug product made using the change (moderate changes). (1) A supplement must be submitted for any change in the drug substance, drug product, production process, quality controls, equipment, or facilities that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. If the supplement provides for a labeling change under paragraph (c)(6)(iii) of this section, 12 copies of the final printed labeling must be included.

(2) These changes include, but are not limited to:

(i) A change in the container closure system that does not affect the quality of the drug product, except those described in paragraphs (b) and (d) of this section; and

(ii) Changes solely affecting a natural protein, a recombinant DNA-derived protein/polypeptide or a complex or conjugate of a drug substance with a monoclonal antibody, including:

(A) An increase or decrease in production scale during finishing steps that involves different equipment; and

(B) Replacement of equipment with that of a different design that does not affect the process methodology or process operating parameters.

(iii) Relaxation of an acceptance criterion or deletion of a test to comply with an official compendium that is consistent with FDA statutory and regulatory requirements.

(3) A supplement submitted under paragraph (c)(1) of this section is required to give a full explanation of the basis for the change and identify the date on which the change is to be made. The supplement must be labeled “Supplement - Changes Being Effected in 30 Days” or, if applicable under paragraph (c)(6) of this section, “Supplement - Changes Being Effected.”

(4) Pending approval of the supplement by FDA, except as provided in paragraph (c)(6) of this section, distribution of the drug product made using the change may begin not less than 30 days after receipt of the supplement by FDA. The information listed in paragraphs (b)(3)(i) through (b)(3)(vii) of this section must be contained in the supplement.

(5) The applicant must not distribute the drug product made using the change if within 30 days following FDA's receipt of the supplement, FDA informs the applicant that either:

(i) The change requires approval prior to distribution of the drug product in accordance with paragraph (b) of this section; or

(ii) Any of the information required under paragraph (c)(4) of this section is missing; the applicant must not distribute the drug product made using the change until the supplement has been amended to provide the missing information.

(6) The agency may designate a category of changes for the purpose of providing that, in the case of a change in such category, the holder of an approved NDA may commence distribution of the drug product involved upon receipt by the agency of a supplement for the change. These changes include, but are not limited to:

(i) Addition to a specification or changes in the methods or controls to provide increased assurance that the drug substance or drug product will have the characteristics of identity, strength, quality, purity, or potency that it purports or is represented to possess;

(ii) A change in the size and/or shape of a container for a nonsterile drug product, except for solid dosage forms, without a change in the labeled amount of drug product or from one container closure system to another;

(iii) Changes in the labeling to reflect newly acquired information, except for changes to the information required in § 201.57(a) of this chapter (which must be made under paragraph (b)(2)(v)(C) of this section), to accomplish any of the following:

(A) To add or strengthen a contraindication, warning, precaution, or adverse reaction for which the evidence of a causal association satisfies the standard for inclusion in the labeling under § 201.57(c) of this chapter;

(B) To add or strengthen a statement about drug abuse, dependence, psychological effect, or overdosage;

(C) To add or strengthen an instruction about dosage and administration that is intended to increase the safe use of the drug product;

(D) To delete false, misleading, or unsupported indications for use or claims for effectiveness; or

(E) Any labeling change normally requiring a supplement submission and approval prior to distribution of the drug product that FDA specifically requests be submitted under this provision.

(7) If the agency disapproves the supplemental NDA, it may order the manufacturer to cease distribution of the drug product(s) made with the manufacturing change.

(d) Changes to be described in an annual report (minor changes). (1) Changes in the drug substance, drug product, production process, quality controls, equipment, or facilities that have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product must be documented by the applicant in the next annual report in accordance with § 314.81(b)(2).

(2) These changes include, but are not limited to:

(i) Any change made to comply with a change to an official compendium, except a change described in paragraph (c)(2)(iii) of this section, that is consistent with FDA statutory and regulatory requirements.

(ii) The deletion or reduction of an ingredient intended to affect only the color of the drug product;

(iii) Replacement of equipment with that of the same design and operating principles except those equipment changes described in paragraph (c) of this section;

(iv) A change in the size and/or shape of a container containing the same number of dosage units for a nonsterile solid dosage form drug product, without a change from one container closure system to another;

(v) A change within the container closure system for a nonsterile drug product, based upon a showing of equivalency to the approved system under a protocol approved in the NDA or published in an official compendium;

(vi) An extension of an expiration dating period based upon full shelf life data on production batches obtained from a protocol approved in the NDA;

(vii) The addition or revision of an alternative analytical procedure that provides the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved NDA, or deletion of an alternative analytical procedure;

(viii) The addition by embossing, debossing, or engraving of a code imprint to a solid oral dosage form drug product other than a modified release dosage form, or a minor change in an existing code imprint;

(ix) A change in the labeling concerning the description of the drug product or in the information about how the drug product is supplied, that does not involve a change in the dosage strength or dosage form; and

(x) An editorial or similar minor change in labeling, including a change to the information allowed by paragraphs (b)(2)(v)(C)(1) and (2) of this section.

(3) For changes under this category, the applicant is required to submit in the annual report:

(i) A statement by the holder of the approved NDA that the effects of the change have been assessed;

(ii) A full description of the manufacturing and controls changes, including the manufacturing site(s) or area(s) involved;

(iii) The date each change was implemented;

(iv) Data from studies and tests performed to assess the effects of the change; and,

(v) For a natural product, recombinant DNA-derived protein/polypeptide, complex or conjugate of a drug substance with a monoclonal antibody, sterilization process or test methodology related to sterilization process validation, a cross-reference to relevant validation protocols and/or standard operating procedures.

(e) Protocols. An applicant may submit one or more protocols describing the specific tests and studies and acceptance criteria to be achieved to demonstrate the lack of adverse effect for specified types of manufacturing changes on the identity, strength, quality, purity, and potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. Any such protocols, if not included in the approved NDA, or changes to an approved protocol, must be submitted as a supplement requiring approval from FDA prior to distribution of a drug product produced with the manufacturing change. The supplement, if approved, may subsequently justify a reduced reporting category for the particular change because the use of the protocol for that type of change reduces the potential risk of an adverse effect.

(f) Patent information. The applicant must comply with the patent information requirements under section 505(c)(2) of the Federal Food, Drug, and Cosmetic Act and § 314.53.

(g) Claimed exclusivity. If an applicant claims exclusivity under § 314.108 upon approval of a supplement for change to its previously approved drug product, the applicant must include with its supplement the information required under § 314.50(j).

(h) Different drug. An applicant may not supplement a 505(b)(2) application to seek approval of a drug that is a different drug from the drug in the approved 505(b)(2) application. For purposes of this paragraph (h), a drug is a different drug if it has been modified to have a different active ingredient, different route of administration, different dosage form, or difference in excipients that requires either a separate clinical study to establish safety or effectiveness or, for topical products, that requires a separate in vivo demonstration of bioequivalence. However, notwithstanding the limitation described in this paragraph (h), an applicant may supplement the 505(b)(2) application to seek approval of a different strength.

(a) Only the applicant may submit a supplement to an application.

(b) All procedures and actions that apply to an application under § 314.50 also apply to supplements, except that the information required in the supplement is limited to that needed to support the change. A supplement is required to contain an archival copy and a review copy that include an application form and appropriate technical sections, samples, and labeling; except that a supplement for a change other than a change in labeling is required also to contain a field copy.

(c) All procedures and actions that apply to applications under this part, including actions by applicants and the Food and Drug Administration, also apply to supplements except as specified otherwise in this part.

(a) An applicant may transfer ownership of its application. At the time of transfer the new and former owners are required to submit information to the Food and Drug Administration as follows:

(1) The former owner shall submit a letter or other document that states that all rights to the application have been transferred to the new owner.

(2) The new owner shall submit an application form signed by the new owner and a letter or other document containing the following:

(i) The new owner's commitment to agreements, promises, and conditions made by the former owner and contained in the application;

(ii) The date that the change in ownership is effective; and

(iii) Either a statement that the new owner has a complete copy of the approved application, including supplements and records that are required to be kept under § 314.81, or a request for a copy of the application from FDA's files. FDA will provide a copy of the application to the new owner under the fee schedule in § 20.45 of FDA's public information regulations.

(b) The new owner shall advise FDA about any change in the conditions in the approved application under § 314.70, except the new owner may advise FDA in the next annual report about a change in the drug product's label or labeling to change the product's brand or the name of its manufacturer, packer, or distributor.

(a) Definitions. The following definitions of terms apply to this section:

Adverse drug experience. Any adverse event associated with the use of a drug in humans, whether or not considered drug related, including the following: An adverse event occurring in the course of the use of a drug product in professional practice; an adverse event occurring from drug overdose whether accidental or intentional; an adverse event occurring from drug abuse; an adverse event occurring from drug withdrawal; and any failure of expected pharmacological action.

Individual case safety report (ICSR). A description of an adverse drug experience related to an individual patient or subject.

ICSR attachments. Documents related to the adverse drug experience described in an ICSR, such as medical records, hospital discharge summaries, or other documentation.

Disability. A substantial disruption of a person's ability to conduct normal life functions.

Life-threatening adverse drug experience. Any adverse drug experience that places the patient, in the view of the initial reporter, at immediate risk of death from the adverse drug experience as it occurred, i.e., it does not include an adverse drug experience that, had it occurred in a more severe form, might have caused death.

Serious adverse drug experience. Any adverse drug experience occurring at any dose that results in any of the following outcomes: Death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.

Unexpected adverse drug experience. Any adverse drug experience that is not listed in the current labeling for the drug product. This includes events that may be symptomatically and pathophysiologically related to an event listed in the labeling, but differ from the event because of greater severity or specificity. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the labeling only listed cerebral vascular accidents. “Unexpected,” as used in this definition, refers to an adverse drug experience that has not been previously observed (i.e., included in the labeling) rather than from the perspective of such experience not being anticipated from the pharmacological properties of the pharmaceutical product.

(b) Review of adverse drug experiences. Each applicant having an approved application under § 314.50 or, in the case of a 505(b)(2) application, an effective approved application, must promptly review all adverse drug experience information obtained or otherwise received by the applicant from any source, foreign or domestic, including information derived from commercial marketing experience, postmarketing clinical investigations, postmarketing epidemiological/surveillance studies, reports in the scientific literature, and unpublished scientific papers. Applicants are not required to resubmit to FDA adverse drug experience reports forwarded to the applicant by FDA; however, applicants must submit all followup information on such reports to FDA. Any person subject to the reporting requirements under paragraph (c) of this section must also develop written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences to FDA.

(c) Reporting requirements. The applicant must submit to FDA adverse drug experience information as described in this section. Except as provided in paragraph (g)(2) of this section, these reports must be submitted to the Agency in electronic format as described in paragraph (g)(1) of this section.

(1)(i) Postmarketing 15-day “Alert reports”. The applicant must report each adverse drug experience that is both serious and unexpected, whether foreign or domestic, as soon as possible but no later than 15 calendar days from initial receipt of the information by the applicant.

(ii) Postmarketing 15-day “Alert reports” - followup. The applicant must promptly investigate all adverse drug experiences that are the subject of these postmarketing 15-day Alert reports and must submit followup reports within 15 calendar days of receipt of new information or as requested by FDA. If additional information is not obtainable, records should be maintained of the unsuccessful steps taken to seek additional information.

(iii) Submission of reports. The requirements of paragraphs (c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of postmarketing 15-day Alert reports, also apply to any person other than the applicant whose name appears on the label of an approved drug product as a manufacturer, packer, or distributor (nonapplicant). To avoid unnecessary duplication in the submission to FDA of reports required by paragraphs (c)(1)(i) and (c)(1)(ii) of this section, obligations of a nonapplicant may be met by submission of all reports of serious adverse drug experiences to the applicant. If a nonapplicant elects to submit adverse drug experience reports to the applicant rather than to FDA, the nonapplicant must submit, by any appropriate means, each report to the applicant within 5 calendar days of initial receipt of the information by the nonapplicant, and the applicant must then comply with the requirements of this section. Under this circumstance, the nonapplicant must maintain a record of this action which must include:

(A) A copy of each adverse drug experience report;

(B) The date the report was received by the nonapplicant;

(C) The date the report was submitted to the applicant; and

(D) The name and address of the applicant.

(2) Periodic adverse drug experience reports. (i) The applicant must report each adverse drug experience not reported under paragraph (c)(1)(i) of this section at quarterly intervals, for 3 years from the date of approval of the application, and then at annual intervals. The applicant must submit each quarterly report within 30 days of the close of the quarter (the first quarter beginning on the date of approval of the application) and each annual report within 60 days of the anniversary date of approval of the application. Upon written notice, FDA may extend or reestablish the requirement that an applicant submit quarterly reports, or require that the applicant submit reports under this section at different times than those stated. For example, the agency may reestablish a quarterly reporting requirement following the approval of a major supplement. Followup information to adverse drug experiences submitted in a periodic report may be submitted in the next periodic report.

(ii) Each periodic report is required to contain:

(A) Descriptive information. (1) A narrative summary and analysis of the information in the report;

(2) An analysis of the 15-day Alert reports submitted during the reporting interval (all 15-day Alert reports being appropriately referenced by the applicant's patient identification code, adverse reaction term(s), and date of submission to FDA);

(3) A history of actions taken since the last report because of adverse drug experiences (for example, labeling changes or studies initiated); and

(4) An index consisting of a line listing of the applicant's patient identification code, and adverse reaction term(s) for all ICSRs submitted under paragraph (c)(2)(ii)(B) of this section.

(B) ICSRs for serious, expected, and nonserious adverse drug experiences. An ICSR for each adverse drug experience not reported under paragraph (c)(1)(i) of this section (all serious, expected and nonserious adverse drug experiences). All such ICSRs must be submitted to FDA (either individually or in one or more batches) within the timeframe specified in paragraph (c)(2)(i) of this section. ICSRs must only be submitted to FDA once.

(iii) Periodic reporting, except for information regarding 15-day Alert reports, does not apply to adverse drug experience information obtained from postmarketing studies (whether or not conducted under an investigational new drug application), from reports in the scientific literature, and from foreign marketing experience.

(d) Scientific literature. A 15-day Alert report based on information in the scientific literature must be accompanied by a copy of the published article. The 15-day reporting requirements in paragraph (c)(1)(i) of this section (i.e., serious, unexpected adverse drug experiences) apply only to reports found in scientific and medical journals either as case reports or as the result of a formal clinical trial.

(e) Postmarketing studies. An applicant is not required to submit a 15-day Alert report under paragraph (c) of this section for an adverse drug experience obtained from a postmarketing study (whether or not conducted under an investigational new drug application) unless the applicant concludes that there is a reasonable possibility that the drug caused the adverse experience.

(f) Information reported on ICSRs. ICSRs include the following information:

(1) Patient information.

(i) Patient identification code;

(ii) Patient age at the time of adverse drug experience, or date of birth;

(iii) Patient gender; and

(iv) Patient weight.

(2) Adverse drug experience.

(i) Outcome attributed to adverse drug experience;

(ii) Date of adverse drug experience;

(iii) Date of ICSR submission;

(iv) Description of adverse drug experience (including a concise medical narrative);

(v) Adverse drug experience term(s);

(vi) Description of relevant tests, including dates and laboratory data; and

(vii) Other relevant patient history, including preexisting medical conditions.

(3) Suspect medical product(s).

(i) Name;

(ii) Dose, frequency, and route of administration used;

(iii) Therapy dates;

(iv) Diagnosis for use (indication);

(v) Whether the product is a prescription or nonprescription product;

(vi) Whether the product is a combination product as defined in § 3.2(e) of this chapter;

(vii) Whether adverse drug experience abated after drug use stopped or dose reduced;

(viii) Whether adverse drug experience reappeared after reintroduction of drug;

(ix) Lot number;

(x) Expiration date;

(xi) National Drug Code (NDC) number; and

(xii) Concomitant medical products and therapy dates.

(4) Initial reporter information.

(i) Name, address, and telephone number;

(ii) Whether the initial reporter is a health care professional; and

(iii) Occupation, if a health care professional.

(5) Applicant information.

(i) Applicant name and contact office address;

(ii) Telephone number;

(iii) Report source, such as spontaneous, literature, or study;

(iv) Date the report was received by applicant;

(v) Application number and type;

(vi) Whether the ICSR is a 15-day “Alert report”;

(vii) Whether the ICSR is an initial report or followup report; and

(viii) Unique case identification number, which must be the same in the initial report and any subsequent followup report(s).

(g) Electronic format for submissions. (1) Safety report submissions, including ICSRs, ICSR attachments, and the descriptive information in periodic reports, must be in an electronic format that FDA can process, review, and archive. FDA will issue guidance on how to provide the electronic submission (e.g., method of transmission, media, file formats, preparation and organization of files).

(2) An applicant or nonapplicant may request, in writing, a temporary waiver of the requirements in paragraph (g)(1) of this section. These waivers will be granted on a limited basis for good cause shown. FDA will issue guidance on requesting a waiver of the requirements in paragraph (g)(1) of this section.

(h) Multiple reports. An applicant should not include in reports under this section any adverse drug experiences that occurred in clinical trials if they were previously submitted as part of the approved application. If a report applies to a drug for which an applicant holds more than one approved application, the applicant should submit the report to the application that was first approved. If a report refers to more than one drug marketed by an applicant, the applicant should submit the report to the application for the drug listed first in the report.

(i) Patient privacy. An applicant should not include in reports under this section the names and addresses of individual patients; instead, the applicant should assign a unique code for identification of the patient. The applicant should include the name of the reporter from whom the information was received as part of the initial reporter information, even when the reporter is the patient. The names of patients, health care professionals, hospitals, and geographical identifiers in adverse drug experience reports are not releasable to the public under FDA's public information regulations in part 20 of this chapter.

(j) Recordkeeping. The applicant must maintain for a period of 10 years records of all adverse drug experiences known to the applicant, including raw data and any correspondence relating to adverse drug experiences.

(k) Withdrawal of approval. If an applicant fails to establish and maintain records and make reports required under this section, FDA may withdraw approval of the application and, thus, prohibit continued marketing of the drug product that is the subject of the application.

(l) Disclaimer. A report or information submitted by an applicant under this section (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the applicant or FDA that the report or information constitutes an admission that the drug caused or contributed to an adverse effect. An applicant need not admit, and may deny, that the report or information submitted under this section constitutes an admission that the drug caused or contributed to an adverse effect. For purposes of this provision, the term “applicant” also includes any person reporting under paragraph (c)(1)(iii) of this section.

(a) Applicability. Each applicant shall make the reports for each of its approved applications and abbreviated applications required under this section and section 505(k) of the act.

(b) Reporting requirements. The applicant shall submit to the Food and Drug Administration at the specified times two copies of the following reports:

(1) NDA - Field alert report. The applicant shall submit information of the following kinds about distributed drug products and articles to the FDA district office that is responsible for the facility involved within 3 working days of receipt by the applicant. The information may be provided by telephone or other rapid communication means, with prompt written followup. The report and its mailing cover should be plainly marked: “NDA - Field Alert Report.”

(i) Information concerning any incident that causes the drug product or its labeling to be mistaken for, or applied to, another article.

(ii) Information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug product, or any failure of one or more distributed batches of the drug product to meet the specification established for it in the application.

(2) Annual report. The applicant shall submit each year within 60 days of the anniversary date of U.S. approval of the application, two copies of the report to the FDA division responsible for reviewing the application. Each annual report is required to be accompanied by a completed transmittal Form FDA 2252 (Transmittal of Periodic Reports for Drugs for Human Use), and must include all the information required under this section that the applicant received or otherwise obtained during the annual reporting interval that ends on the U.S. anniversary date. The report is required to contain in the order listed:

(i) Summary. A brief summary of significant new information from the previous year that might affect the safety, effectiveness, or labeling of the drug product. The report is also required to contain a brief description of actions the applicant has taken or intends to take as a result of this new information, for example, submit a labeling supplement, add a warning to the labeling, or initiate a new study. The summary shall briefly state whether labeling supplements for pediatric use have been submitted and whether new studies in the pediatric population to support appropriate labeling for the pediatric population have been initiated. Where possible, an estimate of patient exposure to the drug product, with special reference to the pediatric population (neonates, infants, children, and adolescents) shall be provided, including dosage form.

(ii)(a) Distribution data. Information about the quantity of the drug product distributed under the approved application, including that distributed to distributors. The information is required to include the National Drug Code (NDC) number, the total number of dosage units of each strength or potency distributed (e.g., 100,000/5 milligram tablets, 50,000/10 milliliter vials), and the quantities distributed for domestic use and the quantities distributed for foreign use. Disclosure of financial or pricing data is not required.

(b) Authorized generic drugs. If applicable, the date each authorized generic drug (as defined in § 314.3) entered the market, the date each authorized generic drug ceased being distributed, and the corresponding trade or brand name. Each dosage form and/or strength is a different authorized generic drug and should be listed separately. The first annual report submitted on or after January 25, 2010 must include the information listed in this paragraph for any authorized generic drug that was marketed during the time period covered by an annual report submitted after January 1, 1999. If information is included in the annual report with respect to any authorized generic drug, a copy of that portion of the annual report must be sent to the Food and Drug Administration, Center for Drug Evaluation and Research, Office of New Drug Quality Assessment, Bldg. 21, rm. 2562, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, and marked “Authorized Generic Submission” or, by e-mail, to the Authorized Generics electronic mailbox at AuthorizedGenerics@fda.hhs.gov with “Authorized Generic Submission” indicated in the subject line. However, at such time that FDA has required that annual reports be submitted in an electronic format, the information required by this paragraph must be submitted as part of the annual report, in the electronic format specified for submission of annual reports at that time, and not as a separate submission under the preceding sentence in this paragraph.

(iii) Labeling. (a) Currently used professional labeling, patient brochures or package inserts (if any), and a representative sample of the package labels.

(b) The content of labeling required under § 201.100(d)(3) of this chapter (i.e., the package insert or professional labeling), including all text, tables, and figures, must be submitted in electronic format. Electronic format submissions must be in a form that FDA can process, review, and archive. FDA will periodically issue guidance on how to provide the electronic submission (e.g., method of transmission, media, file formats, preparation and organization of files). Submissions under this paragraph must be made in accordance with part 11 of this chapter, except for the requirements of § 11.10(a), (c) through (h), and (k), and the corresponding requirements of § 11.30.

(c) A summary of any changes in labeling that have been made since the last report listed by date in the order in which they were implemented, or if no changes, a statement of that fact.

(iv) Chemistry, manufacturing, and controls changes. (a) Reports of experiences, investigations, studies, or tests involving chemical or physical properties, or any other properties of the drug (such as the drug's behavior or properties in relation to microorganisms, including both the effects of the drug on microorganisms and the effects of microorganisms on the drug). These reports are only required for new information that may affect FDA's previous conclusions about the safety or effectiveness of the drug product.

(b) A full description of the manufacturing and controls changes not requiring a supplemental application under § 314.70 (b) and (c), listed by date in the order in which they were implemented.

(v) Nonclinical laboratory studies. Copies of unpublished reports and summaries of published reports of new toxicological findings in animal studies and in vitro studies (e.g., mutagenicity) conducted by, or otherwise obtained by, the applicant concerning the ingredients in the drug product. The applicant shall submit a copy of a published report if requested by FDA.

(vi) Clinical data. (a) Published clinical trials of the drug (or abstracts of them), including clinical trials on safety and effectiveness; clinical trials on new uses; biopharmaceutic, pharmacokinetic, and clinical pharmacology studies; and reports of clinical experience pertinent to safety (for example, epidemiologic studies or analyses of experience in a monitored series of patients) conducted by or otherwise obtained by the applicant. Review articles, papers describing the use of the drug product in medical practice, papers and abstracts in which the drug is used as a research tool, promotional articles, press clippings, and papers that do not contain tabulations or summaries of original data should not be reported.

(b) Summaries of completed unpublished clinical trials, or prepublication manuscripts if available, conducted by, or otherwise obtained by, the applicant. Supporting information should not be reported. (A study is considered completed 1 year after it is concluded.)

(c) Analysis of available safety and efficacy data in the pediatric population and changes proposed in the labeling based on this information. An assessment of data needed to ensure appropriate labeling for the pediatric population shall be included.

(vii) Status reports of postmarketing study commitments. A status report of each postmarketing study of the drug product concerning clinical safety, clinical efficacy, clinical pharmacology, and nonclinical toxicology that is required by FDA (e.g., accelerated approval clinical benefit studies, pediatric studies) or that the applicant has committed, in writing, to conduct either at the time of approval of an application for the drug product or a supplement to an application, or after approval of the application or a supplement. For pediatric studies, the status report shall include a statement indicating whether postmarketing clinical studies in pediatric populations were required by FDA under § 201.23 of this chapter. The status of these postmarketing studies shall be reported annually until FDA notifies the applicant, in writing, that the agency concurs with the applicant's determination that the study commitment has been fulfilled or that the study is either no longer feasible or would no longer provide useful information.

(a) Content of status report. The following information must be provided for each postmarketing study reported under this paragraph:

(1) Applicant's name.

(2) Product name. Include the approved drug product's established name and proprietary name, if any.

(3) NDA, ANDA, and supplement number.

(4) Date of U.S. approval of NDA or ANDA.

(5) Date of postmarketing study commitment.

(6) Description of postmarketing study commitment. The description must include sufficient information to uniquely describe the study. This information may include the purpose of the study, the type of study, the patient population addressed by the study and the indication(s) and dosage(s) that are to be studied.

(7) Schedule for completion and reporting of the postmarketing study commitment. The schedule should include the actual or projected dates for submission of the study protocol to FDA, completion of patient accrual or initiation of an animal study, completion of the study, submission of the final study report to FDA, and any additional milestones or submissions for which projected dates were specified as part of the commitment. In addition, it should include a revised schedule, as appropriate. If the schedule has been previously revised, provide both the original schedule and the most recent, previously submitted revision.

(8) Current status of the postmarketing study commitment. The status of each postmarketing study should be categorized using one of the following terms that describes the study's status on the anniversary date of U.S. approval of the application or other agreed upon date:

(i) Pending. The study has not been initiated, but does not meet the criterion for delayed.

(ii) Ongoing. The study is proceeding according to or ahead of the original schedule described under paragraph (b)(2)(vii)(a)(7) of this section.

(iii) Delayed. The study is behind the original schedule described under paragraph (b)(2)(vii)(a)(7) of this section.

(iv) Terminated. The study was ended before completion but a final study report has not been submitted to FDA.

(v) Submitted. The study has been completed or terminated and a final study report has been submitted to FDA.

(9) Explanation of the study's status. Provide a brief description of the status of the study, including the patient accrual rate (expressed by providing the number of patients or subjects enrolled to date, and the total planned enrollment), and an explanation of the study's status identified under paragraph (b)(2)(vii)(a)(8) of this section. If the study has been completed, include the date the study was completed and the date the final study report was submitted to FDA, as applicable. Provide a revised schedule, as well as the reason(s) for the revision, if the schedule under paragraph (b)(2)(vii)(a)(7) of this section has changed since the last report.

(b) Public disclosure of information. Except for the information described in this paragraph, FDA may publicly disclose any information described in paragraph (b)(2)(vii) of this section, concerning a postmarketing study, if the agency determines that the information is necessary to identify the applicant or to establish the status of the study, including the reasons, if any, for failure to conduct, complete, and report the study. Under this section, FDA will not publicly disclose trade secrets, as defined in § 20.61 of this chapter, or information, described in § 20.63 of this chapter, the disclosure of which would constitute an unwarranted invasion of personal privacy.

(viii) Status of other postmarketing studies. A status report of any postmarketing study not included under paragraph (b)(2)(vii) of this section that is being performed by, or on behalf of, the applicant. A status report is to be included for any chemistry, manufacturing, and controls studies that the applicant has agreed to perform and for all product stability studies.

(ix) Log of outstanding regulatory business. To facilitate communications between FDA and the applicant, the report may, at the applicant's discretion, also contain a list of any open regulatory business with FDA concerning the drug product subject to the application (e.g., a list of the applicant's unanswered correspondence with the agency, a list of the agency's unanswered correspondence with the applicant).

(3) Other reporting - (i) Advertisements and promotional labeling. The applicant shall submit specimens of mailing pieces and any other labeling or advertising devised for promotion of the drug product at the time of initial dissemination of the labeling and at the time of initial publication of the advertisement for a prescription drug product. Mailing pieces and labeling that are designed to contain samples of a drug product are required to be complete, except the sample of the drug product may be omitted. Each submission is required to be accompanied by a completed transmittal Form FDA-2253 (Transmittal of Advertisements and Promotional Labeling for Drugs for Human Use) and is required to include a copy of the product's current professional labeling. Form FDA-2253 is available on the Internet at http://www.fda.gov/opacom/morechoices/fdaforms/cder.html.

(ii) Special reports. Upon written request the agency may require that the applicant submit the reports under this section at different times than those stated.

(iii) Notification of a permanent discontinuance or an interruption in manufacturing. (a) An applicant of a prescription drug product must notify FDA in writing of a permanent discontinuance of manufacture of the drug product or an interruption in manufacturing of the drug product that is likely to lead to a meaningful disruption in supply of that drug in the United States if:

(1) The drug product is life supporting, life sustaining, or intended for use in the prevention or treatment of a debilitating disease or condition, including any such drug used in emergency medical care or during surgery; and

(2) The drug product is not a radiopharmaceutical drug product.

(b) Notifications required by paragraph (b)(3)(iii)(a) of this section must be submitted to FDA electronically in a format that FDA can process, review, and archive:

(1) At least 6 months prior to the date of the permanent discontinuance or interruption in manufacturing; or

(2) If 6 months' advance notice is not possible because the permanent discontinuance or interruption in manufacturing was not reasonably anticipated 6 months in advance, as soon as practicable thereafter, but in no case later than 5 business days after the permanent discontinuance or interruption in manufacturing occurs.

(c) Notifications required by paragraph (b)(3)(iii)(a) of this section must include the following information:

(1) The name of the drug subject to the notification, including the NDC for such drug;

(2) The name of the applicant;

(3) Whether the notification relates to a permanent discontinuance of the drug or an interruption in manufacturing of the drug;

(4) A description of the reason for the permanent discontinuance or interruption in manufacturing; and

(5) The estimated duration of the interruption in manufacturing.

(d)(1) FDA will maintain a publicly available list of drugs that are determined by FDA to be in shortage. This drug shortages list will include the following information:

(i) The names and NDC(s) for such drugs;

(ii) The name of each applicant for such drugs;

(iii) The reason for the shortage, as determined by FDA from the following categories: Requirements related to complying with good manufacturing practices; regulatory delay; shortage of an active ingredient; shortage of an inactive ingredient component; discontinuation of the manufacture of the drug; delay in shipping of the drug; demand increase for the drug; or other reason; and

(iv) The estimated duration of the shortage.

(2) FDA may choose not to make information collected to implement this paragraph available on the drug shortages list or available under section 506C(c) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 356c(c)) if FDA determines that disclosure of such information would adversely affect the public health (such as by increasing the possibility of hoarding or other disruption of the availability of the drug to patients). FDA will also not provide information on the public drug shortages list or under section 506C(c) of the Federal Food, Drug, and Cosmetic Act that is protected by 18 U.S.C. 1905 or 5 U.S.C. 552(b)(4), including trade secrets and commercial or financial information that is considered confidential or privileged under § 20.61 of this chapter.

(e) If an applicant fails to submit a notification as required under paragraph (b)(3)(iii)(a) of this section and in accordance with paragraph (b)(3)(iii)(b) of this section, FDA will issue a letter to the applicant informing it of such failure.

(1) Not later than 30 calendar days after the issuance of such a letter, the applicant must submit to FDA a written response setting forth the basis for noncompliance and providing the required notification under paragraph (b)(3)(iii)(a) of this section and including the information required under paragraph (b)(3)(iii)(c) of this section; and

(2) Not later than 45 calendar days after the issuance of a letter under paragraph (b)(3)(iii)(e) of this section, FDA will make the letter and the applicant's response to the letter public, unless, after review of the applicant's response, FDA determines that the applicant had a reasonable basis for not notifying FDA as required under paragraph (b)(3)(iii)(a) of this section.

(f) The following definitions of terms apply to paragraph (b)(3)(iii) of this section:

Drug shortage or shortage means a period of time when the demand or projected demand for the drug within the United States exceeds the supply of the drug.

Intended for use in the prevention or treatment of a debilitating disease or condition means a drug product intended for use in the prevention or treatment of a disease or condition associated with mortality or morbidity that has a substantial impact on day-to-day functioning.

Life supporting or life sustaining means a drug product that is essential to, or that yields information that is essential to, the restoration or continuation of a bodily function important to the continuation of human life.

Meaningful disruption means a change in production that is reasonably likely to lead to a reduction in the supply of a drug by a manufacturer that is more than negligible and affects the ability of the manufacturer to fill orders or meet expected demand for its product, and does not include interruptions in manufacturing due to matters such as routine maintenance or insignificant changes in manufacturing so long as the manufacturer expects to resume operations in a short period of time.

(iv) Withdrawal of approved drug product from sale. (a) Within 30 calendar days of the withdrawal of an approved drug from sale, applicants who are manufacturers, repackers, or relabelers subject to part 207 of this chapter must submit the following information about the drug, in accordance with the applicable requirements described in §§ 207.61 and 207.65:

(1) The National Drug Code (NDC);

(2) The identity of the drug by established name and by proprietary name, if any;

(3) The new drug application number or abbreviated application number;

(4) The date on which the drug is expected to be no longer in commercial distribution. FDA requests that the reason for withdrawal of the drug from sale be included with the information.

(b) Within 30 calendar days of the withdrawal of an approved drug from sale, applicants who are not subject to part 207 of this chapter must submit the information listed in paragraphs (b)(3)(iv)(a)(1) through (4) of this section. The information must be submitted either electronically or in writing to the Drug Registration and Listing Office, Food and Drug Administration, Center for Drug Evaluation and Research.

(c) Reporting under paragraph (b)(3)(iv)(a) of this section constitutes compliance with the requirements of § 207.57 of this chapter to update drug listing information with respect to the withdrawal from sale.

(c) General requirements - (1) Multiple applications. For all reports required by this section, the applicant shall submit the information common to more than one application only to the application first approved, and shall not report separately on each application. The submission is required to identify all the applications to which the report applies.

(2) Patient identification. Applicants should not include in reports under this section the names and addresses of individual patients; instead, the applicant should code the patient names whenever possible and retain the code in the applicant's files. The applicant shall maintain sufficient patient identification information to permit FDA, by using that information alone or along with records maintained by the investigator of a study, to identify the name and address of individual patients; this will ordinarily occur only when the agency needs to investigate the reports further or when there is reason to believe that the reports do not represent actual results obtained.

(d) Withdrawal of approval. If an applicant fails to make reports required under this section, FDA may withdraw approval of the application and, thus, prohibit continued marketing of the drug product that is the subject of the application.

(a) An applicant may ask the Food and Drug Administration to waive under this section any requirement that applies to the applicant under §§ 314.50 through 314.81. An applicant may ask FDA to waive under § 314.126(c) any criteria of an adequate and well-controlled study described in § 314.126(b). A waiver request under this section is required to be submitted with supporting documentation in an NDA, or in an amendment or supplement to an NDA. The waiver request is required to contain one of the following:

(1) An explanation why the applicant's compliance with the requirement is unnecessary or cannot be achieved;

(2) A description of an alternative submission that satisfies the purpose of the requirement; or

(3) Other information justifying a waiver.

(b) FDA may grant a waiver if it finds one of the following:

(1) The applicant's compliance with the requirement is unnecessary for the agency to evaluate the NDA or compliance cannot be achieved;

(2) The applicant's alternative submission satisfies the requirement; or

(3) The applicant's submission otherwise justifies a waiver.

(c) If FDA grants the applicant's waiver request with respect to a requirement under §§ 314.50 through 314.81, the waived requirement will not constitute a basis for refusal to approve an NDA under § 314.125.

(a) Abbreviated applications are suitable for the following drug products within the limits set forth under § 314.93:

(1) Drug products that are the same as a listed drug. A “listed drug” is defined in § 314.3. For determining the suitability of an abbreviated new drug application, the term “same as” means identical in active ingredient(s), dosage form, strength, route of administration, and conditions of use, except that conditions of use for which approval cannot be granted because of exclusivity or an existing patent may be omitted. If a listed drug has been voluntarily withdrawn from or not offered for sale by its manufacturer, a person who wishes to submit an abbreviated new drug application for the drug shall comply with § 314.122.

(2) [Reserved]

(3) Drug products that have been declared suitable for an abbreviated new drug application submission by FDA through the petition procedures set forth under § 10.30 of this chapter and § 314.93.

(b) FDA will publish in the list listed drugs for which abbreviated applications may be submitted. The list is available from the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402, 202-783-3238.

(a) The only changes from a listed drug for which the agency will accept a petition under this section are those changes described in paragraph (b) of this section. Petitions to submit ANDAs for other changes from a listed drug will not be approved.

(b) A person who wants to submit an ANDA for a drug product which is not identical to a listed drug in route of administration, dosage form, and strength, or in which one active ingredient is substituted for one of the active ingredients in a listed combination drug, must first obtain permission from FDA to submit such an ANDA.

(c) To obtain permission to submit an ANDA for a change described in paragraph (b) of this section, a person must submit and obtain approval of a petition requesting the change. A person seeking permission to request such a change from a reference listed drug shall submit a petition in accordance with § 10.20 of this chapter and in the format specified in § 10.30 of this chapter. The petition shall contain the information specified in § 10.30 of this chapter and any additional information required by this section. If any provision of § 10.20 or § 10.30 of this chapter is inconsistent with any provision of this section, the provisions of this section apply.

(d) The petitioner shall identify a listed drug and include a copy of the proposed labeling for the drug product that is the subject of the petition and a copy of the approved labeling for the listed drug. The petitioner may, under limited circumstances, identify more than one listed drug, for example, when the proposed drug product is a combination product that differs from the combination reference listed drug with regard to an active ingredient, and the different active ingredient is an active ingredient of a listed drug. The petitioner shall also include information to show that:

(1) The active ingredients of the proposed drug product are of the same pharmacological or therapeutic class as those of the reference listed drug.

(2) The drug product can be expected to have the same therapeutic effect as the reference listed drug when administered to patients for each condition of use in the reference listed drug's labeling for which the applicant seeks approval.

(3) If the proposed drug product is a combination product with one different active ingredient, including a different ester or salt, from the reference listed drug, that the different active ingredient has previously been approved in a listed drug or is a drug that does not meet the definition of “new drug” in section 201(p) of the Federal Food, Drug, and Cosmetic Act.

(e) No later than 90 days after the date a petition that is permitted under paragraph (a) of this section is submitted, FDA will approve or disapprove the petition.

(1) FDA will approve a petition properly submited under this section unless it finds that:

(i) Investigations must be conducted to show the safety and effectiveness of the drug product or of any of its active ingredients, its route of administration, dosage form, or strength which differs from the reference listed drug; or

(ii) For a petition that seeks to change an active ingredient, the drug product that is the subject of the petition is not a combination drug; or

(iii) For a combination drug product that is the subject of the petition and has an active ingredient different from the reference listed drug:

(A) The drug product may not be adequately evaluated for approval as safe and effective on the basis of the information required to be submitted under § 314.94; or

(B) The petition does not contain information to show that the different active ingredient of the drug product is of the same pharmacological or therapeutic class as the ingredient of the reference listed drug that is to be changed and that the drug product can be expected to have the same therapeutic effect as the reference listed drug when administered to patients for each condition of use in the listed drug's labeling for which the applicant seeks approval; or

(C) The different active ingredient is not an active ingredient in a listed drug or a drug that meets the requirements of section 201(p) of the Federal Food, Drug, and Cosmetic Act; or

(D) The remaining active ingredients are not identical to those of the listed combination drug; or

(iv) Any of the proposed changes from the listed drug would jeopardize the safe or effective use of the product so as to necessitate significant labeling changes to address the newly introduced safety or effectiveness problem; or

(v) FDA has determined that the reference listed drug has been withdrawn from sale for safety or effectiveness reasons under § 314.161, or the reference listed drug has been voluntarily withdrawn from sale and the agency has not determined whether the withdrawal is for safety or effectiveness reasons; or

(vi) A drug product is approved in an NDA for the change described in the petition.

(2) For purposes of this paragraph, “investigations must be conducted” means that information derived from animal or clinical studies is necessary to show that the drug product is safe or effective. Such information may be contained in published or unpublished reports.

(3) If FDA approves a petition submitted under this section, the agency's response may describe what additional information, if any, will be required to support an ANDA for the drug product. FDA may, at any time during the course of its review of an ANDA, request additional information required to evaluate the change approved under the petition.

(f)(1) FDA may withdraw approval of a petition if the agency receives any information demonstrating that the petition no longer satisfies the conditions under paragraph (e) of this section.

(2) If, after approval of a petition and before approval of an ANDA submitted pursuant to the approved petition, a drug product is approved in an NDA for the change described in the petition, the petition and the listed drug identified in the petition can no longer be the basis for ANDA submission, irrespective of whether FDA has withdrawn approval of the petition. A person seeking approval for such drug product must submit a new ANDA that identifies the pharmaceutically equivalent reference listed drug as the basis for ANDA submission and comply with applicable regulatory requirements.

ANDAs are required to be submitted in the form and contain the information required under this section. Three copies of the ANDA are required, an archival copy, a review copy, and a field copy. FDA will maintain guidance documents on the format and content of ANDAs to assist applicants in their preparation.

(a) ANDAs. Except as provided in paragraph (b) of this section, the applicant must submit a complete archival copy of the abbreviated new drug application that includes the following:

(1) Application form. The applicant must submit a completed and signed application form that contains the information described under § 314.50(a)(1), (a)(3), (a)(4), and (a)(5). The applicant must state whether the submission is an ANDA under this section or a supplement to an ANDA under § 314.97.

(2) Table of contents. The archival copy of the ANDA is required to contain a table of contents that shows the volume number and page number of the contents of the submission.

(3) Basis for ANDA submission. An ANDA must refer to a listed drug. Ordinarily, that listed drug will be the drug product selected by the Agency as the reference standard for conducting bioequivalence testing. The ANDA must contain:

(i) The name of the reference listed drug, including its dosage form and strength. For an ANDA based on an approved petition under § 10.30 of this chapter and § 314.93, the reference listed drug must be the same as the listed drug referenced in the approved petition.

(ii) A statement as to whether, according to the information published in the list, the reference listed drug is entitled to a period of marketing exclusivity under section 505(j)(5)(F) of the Federal Food, Drug, and Cosmetic Act.

(iii) For an ANDA based on an approved petition under § 10.30 of this chapter and § 314.93, a reference to the FDA-assigned docket number for the petition and a copy of FDA's correspondence approving the petition.

(4) Conditions of use. (i) A statement that the conditions of use prescribed, recommended, or suggested in the labeling proposed for the drug product have been previously approved for the reference listed drug.

(ii) A reference to the applicant's annotated proposed labeling and to the currently approved labeling for the reference listed drug provided under paragraph (a)(8) of this section.

(5) Active ingredients. (i) For a single-active-ingredient drug product, information to show that the active ingredient is the same as that of the reference single-active-ingredient listed drug, as follows:

(A) A statement that the active ingredient of the proposed drug product is the same as that of the reference listed drug.

(B) A reference to the applicant's annotated proposed labeling and to the currently approved labeling for the reference listed drug provided under paragraph (a)(8) of this section.

(ii) For a combination drug product, information to show that the active ingredients are the same as those of the reference listed drug except for any different active ingredient that has been the subject of an approved petition, as follows:

(A) A statement that the active ingredients of the proposed drug product are the same as those of the reference listed drug, or if one of the active ingredients differs from one of the active ingredients of the reference listed drug and the ANDA is submitted under the approval of a petition under § 314.93 to vary such active ingredient, information to show that the other active ingredients of the drug product are the same as the other active ingredients of the reference listed drug, information to show that the different active ingredient is an active ingredient of another listed drug or of a drug that does not meet the definition of “new drug” in section 201(p) of the Federal Food, Drug, and Cosmetic Act, and such other information about the different active ingredient that FDA may require.

(B) A reference to the applicant's annotated proposed labeling and to the currently approved labeling for the reference listed drug provided under paragraph (a)(8) of this section.

(6) Route of administration, dosage form, and strength. (i) Information to show that the route of administration, dosage form, and strength of the drug product are the same as those of the reference listed drug except for any differences that have been the subject of an approved petition, as follows:

(A) A statement that the route of administration, dosage form, and strength of the proposed drug product are the same as those of the reference listed drug.

(B) A reference to the applicant's annotated proposed labeling and to the currently approved labeling for the reference listed drug provided under paragraph (a)(8) of this section.

(ii) If the route of administration, dosage form, or strength of the drug product differs from the reference listed drug and the ANDA is submitted under an approved petition under § 314.93, such information about the different route of administration, dosage form, or strength that FDA may require.

(7) Bioequivalence. (i) Information that shows that the drug product is bioequivalent to the reference listed drug upon which the applicant relies. A complete study report must be submitted for the bioequivalence study upon which the applicant relies for approval. For all other bioequivalence studies conducted on the same drug product formulation as defined in § 314.3(b), the applicant must submit either a complete or summary report. If a summary report of a bioequivalence study is submitted and FDA determines that there may be bioequivalence issues or concerns with the product, FDA may require that the applicant submit a complete report of the bioequivalence study to FDA; or

(ii) If the ANDA is submitted pursuant to a petition approved under § 314.93, the results of any bioavailability or bioequivalence testing required by the Agency, or any other information required by the Agency to show that the active ingredients of the proposed drug product are of the same pharmacological or therapeutic class as those in the reference listed drug and that the proposed drug product can be expected to have the same therapeutic effect as the reference listed drug. If the proposed drug product contains a different active ingredient than the reference listed drug, FDA will consider the proposed drug product to have the same therapeutic effect as the reference listed drug if the applicant provides information demonstrating that:

(A) There is an adequate scientific basis for determining that substitution of the specific proposed dose of the different active ingredient for the dose of the member of the same pharmacological or therapeutic class in the reference listed drug will yield a resulting drug product whose safety and effectiveness have not been adversely affected.

(B) The unchanged active ingredients in the proposed drug product are bioequivalent to those in the reference listed drug.

(C) The different active ingredient in the proposed drug product is bioequivalent to an approved dosage form containing that ingredient and approved for the same indication as the proposed drug product or is bioequivalent to a drug product offered for that indication which does not meet the definition of “new drug” under section 201(p) of the Federal Food, Drug, and Cosmetic Act.

(iii) For each in vivo or in vitro bioequivalence study contained in the ANDA:

(A) A description of the analytical and statistical methods used in each study; and

(B) With respect to each study involving human subjects, a statement that the study either was conducted in compliance with the institutional review board regulations in part 56 of this chapter, or was not subject to the regulations under § 56.104 or § 56.105 of this chapter, and that it was conducted in compliance with the informed consent regulations in part 50 of this chapter.

(8) Labeling - (i) Listed drug labeling. A copy of the currently approved labeling (including, if applicable, any Medication Guide required under part 208 of this chapter) for the listed drug referred to in the ANDA, if the ANDA relies on a reference listed drug.

(ii) Copies of proposed labeling. Copies of the label and all labeling for the drug product including, if applicable, any Medication Guide required under part 208 of this chapter (4 copies of draft labeling or 12 copies of final printed labeling).

(iii) Statement on proposed labeling. A statement that the applicant's proposed labeling including, if applicable, any Medication Guide required under part 208 of this chapter is the same as the labeling of the reference listed drug except for differences annotated and explained under paragraph (a)(8)(iv) of this section.

(iv) Comparison of approved and proposed labeling. A side-by-side comparison of the applicant's proposed labeling including, if applicable, any Medication Guide required under part 208 of this chapter with the approved labeling for the reference listed drug with all differences annotated and explained. Labeling (including the container label, package insert, and, if applicable, Medication Guide) proposed for the drug product must be the same as the labeling approved for the reference listed drug, except for changes required because of differences approved under a petition filed under § 314.93 or because the drug product and the reference listed drug are produced or distributed by different manufacturers. Such differences between the applicant's proposed labeling and labeling approved for the reference listed drug may include differences in expiration date, formulation, bioavailability, or pharmacokinetics, labeling revisions made to comply with current FDA labeling guidelines or other guidance, or omission of an indication or other aspect of labeling protected by patent or accorded exclusivity under section 505(j)(5)(F) of the Federal Food, Drug, and Cosmetic Act.

(9) Chemistry, manufacturing, and controls. (i) The information required under § 314.50(d)(1), except that the information required under § 314.50(d)(1)(ii)(c) must contain the proposed or actual master production record, including a description of the equipment, to be used for the manufacture of a commercial lot of the drug product.

(ii) Inactive ingredients. Unless otherwise stated in paragraphs (a)(9)(iii) through (a)(9)(v) of this section, an applicant must identify and characterize the inactive ingredients in the proposed drug product and provide information demonstrating that such inactive ingredients do not affect the safety or efficacy of the proposed drug product.

(iii) Inactive ingredient changes permitted in drug products intended for parenteral use. Generally, a drug product intended for parenteral use must contain the same inactive ingredients and in the same concentration as the reference listed drug identified by the applicant under paragraph (a)(3) of this section. However, an applicant may seek approval of a drug product that differs from the reference listed drug in preservative, buffer, or antioxidant provided that the applicant identifies and characterizes the differences and provides information demonstrating that the differences do not affect the safety or efficacy of the proposed drug product.

(iv) Inactive ingredient changes permitted in drug products intended for ophthalmic or otic use. Generally, a drug product intended for ophthalmic or otic use must contain the same inactive ingredients and in the same concentration as the reference listed drug identified by the applicant under paragraph (a)(3) of this section. However, an applicant may seek approval of a drug product that differs from the reference listed drug in preservative, buffer, substance to adjust tonicity, or thickening agent provided that the applicant identifies and characterizes the differences and provides information demonstrating that the differences do not affect the safety or efficacy of the proposed drug product, except that, in a product intended for ophthalmic use, an applicant may not change a buffer or substance to adjust tonicity for the purpose of claiming a therapeutic advantage over or difference from the listed drug, e.g., by using a balanced salt solution as a diluent as opposed to an isotonic saline solution, or by making a significant change in the pH or other change that may raise questions of irritability.

(v) Inactive ingredient changes permitted in drug products intended for topical use. Generally, a drug product intended for topical use, solutions for aerosolization or nebulization, and nasal solutions shall contain the same inactive ingredients as the reference listed drug identified by the applicant under paragraph (a)(3) of this section. However, an ANDA may include different inactive ingredients provided that the applicant identifies and characterizes the differences and provides information demonstrating that the differences do not affect the safety or efficacy of the proposed drug product.

(10) Samples. The information required under § 314.50(e)(1) and (e)(2)(i). Samples need not be submitted until requested by FDA.

(11) Other. The information required under § 314.50(g).

(12) Patent certification - (i) Patents claiming drug substance, drug product, or method of use. (A) An appropriate patent certification or statement with respect to each patent issued by the U.S. Patent and Trademark Office that, in the opinion of the applicant and to the best of its knowledge, claims the reference listed drug or that claims a use of such listed drug for which the applicant is seeking approval under section 505(j) of the Federal Food, Drug, and Cosmetic Act and for which information is required to be filed under section 505(b) and (c) of the Federal Food, Drug, and Cosmetic Act and § 314.53. For each such patent, the applicant must provide the patent number and certify, in its opinion and to the best of its knowledge, one of the following circumstances:

(1) That the patent information has not been submitted to FDA. The applicant must entitle such a certification “Paragraph I Certification”;

(2) That the patent has expired. The applicant must entitle such a certification “Paragraph II Certification”;

(3) The date on which the patent will expire. The applicant must entitle such a certification “Paragraph III Certification”; or

(4)(i) That the patent is invalid, unenforceable, or will not be infringed by the manufacture, use, or sale of the drug product for which the ANDA is submitted. The applicant must entitle such a certification “Paragraph IV Certification”. This certification must be submitted in the following form:

(ii) The certification must be accompanied by a statement that the applicant will comply with the requirements under § 314.95(a) with respect to providing a notice to each owner of the patent or its representative and to the NDA holder (or, if the NDA holder does not reside or maintain a place of business within the United States, its attorney, agent, or other authorized official) for the listed drug, with the requirements under § 314.95(b) with respect to sending the notice, and with the requirements under § 314.95(c) with respect to the content of the notice.

(B) If the ANDA refers to a listed drug that is itself a licensed generic product of a patented drug first approved under section 505(b) of the Federal Food, Drug, and Cosmetic Act, an appropriate patent certification or statement under paragraph (a)(12)(i) and/or (iii) of this section with respect to each patent that claims the first-approved patented drug or that claims a use for such drug.

(ii) No relevant patents. If, in the opinion of the applicant and to the best of its knowledge, there are no patents described in paragraph (a)(12)(i) of this section, a certification in the following form:

(iii) Method-of-use patent. (A) If patent information is submitted under section 505(b) or (c) of the Federal Food, Drug, and Cosmetic Act and § 314.53 for a patent claiming a method of using the listed drug, and the labeling for the drug product for which the applicant is seeking approval does not include an indication or other condition of use that is covered by the method-of-use patent, a statement explaining that the method-of-use patent does not claim a proposed indication or other condition of use.

(B) If the labeling of the drug product for which the applicant is seeking approval includes an indication or other condition of use that, according to the patent information submitted under section 505(b) or (c) of the Federal Food, Drug, and Cosmetic Act and § 314.53 or in the opinion of the applicant, is claimed by a method-of-use patent, an applicable certification under paragraph (a)(12)(i) of this section.

(iv) [Reserved]

(v) Licensing agreements. If the ANDA is for a drug or method of using a drug claimed by a patent and the applicant has a licensing agreement with the patent owner, the applicant must submit a paragraph IV certification as to that patent and a statement that the applicant has been granted a patent license. If the patent owner consents to approval of the ANDA (if otherwise eligible for approval) as of a specific date, the ANDA must contain a written statement from the patent owner that it has a licensing agreement with the applicant and that it consents to approval of the ANDA as of a specific date.

(vi) Untimely filing of patent information. (A) If a patent on the listed drug is issued and the holder of the approved NDA for the listed drug does not file with FDA the required information on the patent within 30 days of issuance of the patent, an applicant who submitted an ANDA for that drug that contained an appropriate patent certification or statement before the submission of the patent information is not required to submit a patent certification or statement to address the patent or patent information that is late-listed with respect to the pending ANDA. Except as provided in § 314.53(f)(1), an NDA holder's amendment to the description of the approved method(s) of use claimed by the patent will be considered untimely filing of patent information unless:

(1) The amendment to the description of the approved method(s) of use claimed by the patent is submitted within 30 days of patent issuance;

(2) The amendment to the description of the approved method(s) of use claimed by the patent is submitted within 30 days of approval of a corresponding change to product labeling; or

(3) The amendment to the description of the approved method(s) of use claimed by the patent is submitted within 30 days of a decision by the U.S. Patent and Trademark Office or by a Federal district court, the Court of Appeals for the Federal Circuit, or the U.S. Supreme Court that is specific to the patent and alters the construction of a method-of-use claim(s) of the patent, and the amendment contains a copy of the decision.

(B) An applicant whose ANDA is submitted after the NDA holder's untimely filing of patent information, or whose pending ANDA was previously submitted but did not contain an appropriate patent certification or statement at the time of the patent submission, must submit a certification under paragraph (a)(12)(i) of this section and/or a statement under paragraph (a)(12)(iii) of this section as to that patent.

(vii) Disputed patent information. If an applicant disputes the accuracy or relevance of patent information submitted to FDA, the applicant may seek a confirmation of the correctness of the patent information in accordance with the procedures under § 314.53(f). Unless the patent information is withdrawn, the applicant must submit an appropriate certification or statement for each listed patent.

(viii) Amended certifications. A patent certification or statement submitted under paragraphs (a)(12)(i) through (iii) of this section may be amended at any time before the approval of the ANDA. If an applicant with a pending ANDA voluntarily makes a patent certification for an untimely filed patent, the applicant may withdraw the patent certification for the untimely filed patent. An applicant must submit an amended certification as an amendment to a pending ANDA. Once an amendment is submitted to change a certification, the ANDA will no longer be considered to contain the prior certification.

(A) After finding of infringement. An applicant who has submitted a paragraph IV certification and is sued for patent infringement must submit an amendment to change its certification if a court enters a final decision from which no appeal has been or can be taken, or signs and enters a settlement order or consent decree in the action that includes a finding that the patent is infringed, unless the final decision, settlement order, or consent decree also finds the patent to be invalid. In its amendment, the applicant must certify under paragraph (a)(12)(i)(A)(3) of this section that the patent will expire on a specific date or, with respect to a patent claiming a method of use, the applicant may instead provide a statement under paragraph (a)(12)(iii) of this section if the applicant amends its ANDA such that the applicant is no longer seeking approval for a method of use claimed by the patent. Once an amendment for the change has been submitted, the ANDA will no longer be considered to contain a paragraph IV certification to the patent. If a final judgment finds the patent to be invalid and infringed, an amended certification is not required.

(B) After request to remove a patent or patent information from the list. If the list reflects that an NDA holder has requested that a patent or patent information be removed from the list and no ANDA applicant is eligible for 180-day exclusivity based on a paragraph IV certification to that patent, the patent or patent information will be removed and any applicant with a pending ANDA (including a tentatively approved ANDA) who has made a certification with respect to such patent must submit an amendment to withdraw its certification. In the amendment, the applicant must state the reason for withdrawing the certification or statement (that the patent has been removed from the list). If the list reflects that an NDA holder has requested that a patent or patent information be removed from the list and one or more first applicants are eligible for 180-day exclusivity based on a paragraph IV certification to that patent, the patent will remain listed until any 180-day exclusivity based on that patent has expired or has been extinguished. After any applicable 180-day exclusivity has expired or has been extinguished, the patent or patent information will be removed and any applicant with a pending ANDA (including a tentatively approved ANDA) who has made a certification with respect to such patent must submit an amendment to withdraw its certification. Once an amendment to withdraw the certification has been submitted, the ANDA will no longer be considered to contain a paragraph IV certification to the patent. If removal of a patent from the list results in there being no patents listed for the listed drug identified in the ANDA, the applicant must submit an amended certification reflecting that there are no relevant patents.

(C) Other amendments. (1) Except as provided in paragraphs (a)(12)(vi) and (a)(12)(viii)(C)(2) of this section:

(i) An applicant must amend a submitted certification or statement if, at any time before the date of approval of the ANDA, the applicant learns that the submitted certification or statement is no longer accurate; and

(ii) An applicant must submit an appropriate patent certification or statement under paragraph (a)(12)(i) and/or (iii) of this section if, after submission of the ANDA, a new patent is issued by the U.S. Patent and Trademark Office that, in the opinion of the applicant and to the best of its knowledge, claims the reference listed drug or that claims an approved use for such reference listed drug and for which information is required to be filed under section 505(b) and (c) of the Federal Food, Drug, and Cosmetic Act and § 314.53. For a paragraph IV certification, the certification must not be submitted earlier than the first working day after the day the patent is published in the list.

(2) An applicant is not required to submit a supplement to change a submitted certification when information on a patent on the listed drug is submitted after the approval of the ANDA.

(13) Financial certification or disclosure statement. An ANDA must contain a financial certification or disclosure statement as required by part 54 of this chapter.

(b) Drug products subject to the Drug Efficacy Study Implementation (DESI) review. If the ANDA is for a duplicate of a drug product that is subject to FDA's DESI review (a review of drug products approved as safe between 1938 and 1962) or other DESI-like review and the drug product evaluated in the review is a listed drug, the applicant must comply with the provisions of paragraph (a) of this section.

(c) [Reserved]

(d) Format of an ANDA. (1) The applicant must submit a complete archival copy of the ANDA as required under paragraphs (a) and (c) of this section. FDA will maintain the archival copy during the review of the ANDA to permit individual reviewers to refer to information that is not contained in their particular technical sections of the ANDA, to give other Agency personnel access to the ANDA for official business, and to maintain in one place a complete copy of the ANDA.

(i) Format of submission. An applicant may submit portions of the archival copy of the ANDA in any form that the applicant and FDA agree is acceptable, except as provided in paragraph (d)(1)(ii) of this section.

(ii) Labeling. The content of labeling required under § 201.100(d)(3) of this chapter (commonly referred to as the package insert or professional labeling), including all text, tables, and figures, must be submitted to the agency in electronic format as described in paragraph (d)(1)(iii) of this section. This requirement applies to the content of labeling for the proposed drug product only and is in addition to the requirements of paragraph (a)(8)(ii) of this section that copies of the formatted label and all proposed labeling be submitted. Submissions under this paragraph must be made in accordance with part 11 of this chapter, except for the requirements of § 11.10(a), (c) through (h), and (k), and the corresponding requirements of § 11.30.

(iii) Electronic format submissions. Electronic format submissions must be in a form that FDA can process, review, and archive. FDA will periodically issue guidance on how to provide the electronic submission (e.g., method of transmission, media, file formats, preparation and organization of files).

(2) For ANDAs, the applicant must submit a review copy of the ANDA that contains two separate sections. One section must contain the information described under paragraphs (a)(2) through (6) and (8) and (9) of this section and section 505(j)(2)(A)(vii) of the Federal Food, Drug, and Cosmetic Act and a copy of the analytical procedures and descriptive information needed by FDA's laboratories to perform tests on samples of the proposed drug product and to validate the applicant's analytical procedures. The other section must contain the information described under paragraphs (a)(3), (7), and (8) of this section. Each of the sections in the review copy is required to contain a copy of the application form described under paragraph (a) of this section.

(3) [Reserved]

(4) The applicant may obtain from FDA sufficient folders to bind the archival, the review, and the field copies of the ANDA.

(5) The applicant must submit a field copy of the ANDA that contains the technical section described in paragraph (a)(9) of this section, a copy of the application form required under paragraph (a)(1) of this section, and a certification that the field copy is a true copy of the technical section described in paragraph (a)(9) of this section contained in the archival and review copies of the ANDA.

(a) Notice of certification. For each patent that claims the listed drug or that claims a use for such listed drug for which the applicant is seeking approval and for which the applicant submits a paragraph IV certification, the applicant must send notice of such certification by registered or certified mail, return receipt requested, or by a designated delivery service, as defined in paragraph (g) of this section to each of the following persons:

(1) Each owner of the patent that is the subject of the certification or the representative designated by the owner to receive the notice. The name and address of the patent owner or its representative may be obtained from the U.S. Patent and Trademark Office; and

(2) The holder of the approved NDA under section 505(b) of the Federal Food, Drug, and Cosmetic Act for the listed drug that is claimed by the patent and for which the applicant is seeking approval, or, if the NDA holder does not reside or maintain a place of business within the United States, the NDA holder's attorney, agent, or other authorized official. The name and address of the NDA holder or its attorney, agent, or authorized official may be obtained by sending a written or electronic communication to the Central Document Room, Attn: Orange Book Staff, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266 or to the Orange Book Staff at the email address listed on the Agency's Web site at http://www.fda.gov.

(3) This paragraph (a) does not apply to a method-of-use patent that does not claim a use for which the applicant is seeking approval.

(4) An applicant may send notice by an alternative method only if FDA has agreed in advance that the method will produce an acceptable form of documentation.

(b) Sending the notice. (1) Except as provided under paragraph (d) of this section, the applicant must send the notice required by paragraph (a) of this section on or after the date it receives a paragraph IV acknowledgment letter from FDA, but not later than 20 days after the date of the postmark on the paragraph IV acknowledgment letter. The 20-day clock described in this paragraph (b) begins on the day after the date of the postmark on the paragraph IV acknowledgment letter. When the 20th day falls on Saturday, Sunday, or a Federal holiday, the 20th day will be the next day that is not a Saturday, Sunday, or Federal holiday.

(2) Any notice required by paragraph (a) of this section is invalid if it is sent before the applicant's receipt of a paragraph IV acknowledgment letter, or before the first working day after the day the patent is published in the list. The applicant will not have complied with this paragraph (b) until it sends valid notice.

(3) The applicant must submit to FDA an amendment to its ANDA that includes a statement certifying that the notice has been provided to each person identified under paragraph (a) of this section and that the notice met the content requirements under paragraph (c) of this section. A copy of the notice itself need not be submitted to the Agency.

(c) Contents of a notice. In the notice, the applicant must cite section 505(j)(2)(B)(iv) of the Federal Food, Drug, and Cosmetic Act and the notice must include, but is not limited to, the following information:

(1) A statement that FDA has received an ANDA submitted by the applicant containing any required bioavailability or bioequivalence data or information.

(2) The ANDA number.

(3) A statement that the applicant has received the paragraph IV acknowledgment letter for the ANDA.

(4) The established name, if any, as defined in section 502(e)(3) of the Federal Food, Drug, and Cosmetic Act, of the proposed drug product.

(5) The active ingredient, strength, and dosage form of the proposed drug product.

(6) The patent number and expiration date of each listed patent for the reference listed drug alleged to be invalid, unenforceable, or not infringed.

(7) A detailed statement of the factual and legal basis of the applicant's opinion that the patent is not valid, unenforceable, or will not be infringed. The applicant must include in the detailed statement:

(i) For each claim of a patent alleged not to be infringed, a full and detailed explanation of why the claim is not infringed.

(ii) For each claim of a patent alleged to be invalid or unenforceable, a full and detailed explanation of the grounds supporting the allegation.

(8) If the applicant alleges that the patent will not be infringed and the applicant seeks to preserve the option to later file a civil action for declaratory judgment in accordance with section 505(j)(5)(C) of the Federal Food, Drug, and Cosmetic Act, then the notice must be accompanied by an offer of confidential access to the ANDA for the sole and limited purpose of evaluating possible infringement of the patent that is the subject of the paragraph IV certification.

(9) If the applicant does not reside or have a place of business in the United States, the name and address of an agent in the United States authorized to accept service of process for the applicant.

(d) Amendment or supplement to an ANDA. (1) If, after receipt of a paragraph IV acknowledgment letter or acknowledgment letter, an applicant submits an amendment or supplement to its ANDA that includes a paragraph IV certification, the applicant must send the notice required by paragraph (a) of this section at the same time that the amendment or supplement to the ANDA is submitted to FDA, regardless of whether the applicant has already given notice with respect to another such certification contained in the ANDA or in an amendment or supplement to the ANDA.

(2) If, before receipt of a paragraph IV acknowledgment letter, an applicant submits an amendment to its ANDA that includes a paragraph IV certification, the applicant must send the notice required by paragraph (a) of this section in accordance with the procedures in paragraph (b) of this section. If an ANDA applicant's notice of its paragraph IV certification is timely provided in accordance with paragraph (b) of this section and the applicant has not submitted a previous paragraph IV certification, FDA will base its determination of whether the applicant is a first applicant on the date of submission of the amendment containing the paragraph IV certification.

(3) An applicant that submits an amendment or supplement to seek approval of a different strength must provide notice of any paragraph IV certification in accordance with paragraph (d)(1) or (2) of this section, as applicable.

(e) Documentation of timely sending and receipt of notice. The applicant must amend its ANDA to provide documentation of the date of receipt of the notice required under paragraph (a) of this section by each person provided the notice. The amendment must be submitted to FDA within 30 days after the last date on which notice was received by a person described in paragraph (a) of this section. The applicant's amendment also must include documentation that its notice was sent on a date that complies with the timeframe required by paragraph (b) or (d) of this section, as applicable, and a dated printout of the entry for the reference listed drug in FDA's “Approved Drug Products With Therapeutic Equivalence Evaluations” (the list) that includes the patent that is the subject of the paragraph IV certification. FDA will accept, as adequate documentation of the date the notice was sent, a copy of the registered mail receipt, certified mail receipt, or receipt from a designated delivery service as defined in paragraph (g) of this section. FDA will accept as adequate documentation of the date of receipt a return receipt, signature proof of delivery by a designated delivery service, or a letter acknowledging receipt by the person provided the notice. An applicant may rely on another form of documentation only if FDA has agreed to such documentation in advance. A copy of the notice itself need not be submitted to the Agency.

(f) Forty-five day period after receipt of notice. If the requirements of this section are met, FDA will presume the notice to be complete and sufficient, and it will count the day following the date of receipt of the notice by the patent owner or its representative and by the approved NDA holder or its attorney, agent, or other authorized official as the first day of the 45-day period provided for in section 505(j)(5)(B)(iii) of the Federal Food, Drug, and Cosmetic Act. FDA may, if the applicant provides a written statement to FDA that a later date should be used, count from such later date.

(g) Designated delivery services. (1) For purposes of this section, the term “designated delivery service” means any delivery service provided by a trade or business that the Agency determines:

(i) Is available to the general public throughout the United States;

(ii) Records electronically to its database, kept in the regular course of its business, or marks on the cover in which any item referred to in this section is to be delivered, the date on which such item was given to such trade or business for delivery; and

(iii) Provides overnight or 2-day delivery service throughout the United States.

(2) FDA may periodically issue guidance regarding designated delivery services.

(a) ANDA. (1) An applicant may amend an ANDA that is submitted under § 314.94, but not yet approved, to revise existing information or provide additional information. Amendments containing bioequivalence studies must contain reports of all bioequivalence studies conducted by the applicant on the same drug product formulation, unless the information has previously been submitted to FDA in the ANDA. A complete study report must be submitted for any bioequivalence study upon which the applicant relies for approval. For all other bioequivalence studies conducted on the same drug product formulation as defined in § 314.3 of this chapter, the applicant must submit either a complete or summary report. If a summary report of a bioequivalence study is submitted and FDA determines that there may be bioequivalence issues or concerns with the product, FDA may require that the applicant submit a complete report of the bioequivalence study to FDA.

(2) Submission of an amendment containing significant data or information before the end of the initial review cycle constitutes an agreement between FDA and the applicant to extend the initial review cycle only for the time necessary to review the significant data or information and for no more than 180 days.

(b) Field copy. The applicant must submit a field copy of each amendment under § 314.94(a)(9). The applicant, other than a foreign applicant, must include in its submission of each such amendment to FDA a statement certifying that a field copy of the amendment has been sent to the applicant's home FDA district office.

(c) Different listed drug. An applicant may not amend an ANDA to seek approval of a drug referring to a listed drug that is different from the reference listed drug identified in the ANDA. This paragraph (c) applies if, at any time before the approval of the ANDA, a different listed drug is approved that is the pharmaceutical equivalent to the product in the ANDA and is designated as a reference listed drug. This paragraph (c) also applies if changes are proposed in an amendment to the ANDA such that the proposed product is a pharmaceutical equivalent to a different listed drug than the reference listed drug identified in the ANDA. A change of the reference listed drug must be submitted in a new ANDA. However, notwithstanding the limitation described in this paragraph (c), an applicant may amend the ANDA to seek approval of a different strength.

(d)(1) Patent certification requirements. An amendment to an ANDA is required to contain an appropriate patent certification or statement described in § 314.94(a)(12) or a recertification for a previously submitted paragraph IV certification if approval is sought for any of the following types of amendments:

(i) To add a new indication or other condition of use;

(ii) To add a new strength;

(iii) To make other than minor changes in product formulation; or

(iv) To change the physical form or crystalline structure of the active ingredient.

(2) If the amendment to the ANDA does not contain a patent certification or statement, the applicant must verify that the proposed change described in the amendment is not one of the types of amendments described in paragraph (d)(1) of this section.

(a) General requirements. The applicant must comply with the requirements of §§ 314.70 and 314.71 regarding the submission of supplemental ANDAs and other changes to an approved ANDA.

(b) Different listed drug. An applicant may not supplement an ANDA to seek approval of a drug referring to a listed drug that is different from the current reference listed drug identified in the ANDA. This paragraph (b) applies if changes are proposed in a supplement to the ANDA such that the proposed product is a pharmaceutical equivalent to a different listed drug than the reference listed drug identified in the ANDA. A change of reference listed drug must be submitted in a new ANDA. However, notwithstanding the limitation described in this paragraph (b), an applicant may supplement the ANDA to seek approval of a different strength.

(a) Each applicant having an approved abbreviated new drug application under § 314.94 that is effective must comply with the requirements of § 314.80 regarding the reporting and recordkeeping of adverse drug experiences.

(b) Each applicant must make the reports required under § 314.81 and section 505(k) of the Federal Food, Drug, and Cosmetic Act for each of its approved abbreviated applications.

(a) An applicant must comply with the requirements of § 314.65 regarding withdrawal by the applicant of an unapproved ANDA and § 314.72 regarding a change in ownership of an ANDA.

(b) An applicant may ask FDA to waive under this section any requirement that applies to the applicant under §§ 314.92 through 314.99. The applicant must comply with the requirements for a waiver under § 314.90. If FDA grants the applicant's waiver request with respect to a requirement under §§ 314.92 through 314.99, the waived requirement will not constitute a basis for refusal to approve an ANDA under § 314.127.

(a) Except as provided in paragraph (c) of this section, within 180 days of receipt of an application for a new drug under section 505(b) of the act or an abbreviated application for a new drug under section 505(j) of the act, FDA will review it and send the applicant either an approval letter under § 314.105 or a complete response letter under § 314.110. This 180-day period is called the “initial review cycle.”

(b) At any time before approval, an applicant may withdraw an application under § 314.65 or an abbreviated application under § 314.99 and later submit it again for consideration.

(c) The initial review cycle may be adjusted by mutual agreement between FDA and an applicant or as provided in §§ 314.60 and 314.96, as the result of a major amendment.

(a) Filing an NDA. (1) Within 60 days after FDA receives an NDA, the Agency will determine whether the NDA may be filed. The filing of an NDA means that FDA has made a threshold determination that the NDA is sufficiently complete to permit a substantive review.

(2) If FDA finds that none of the reasons in paragraphs (d) and (e) of this section for refusing to file the NDA apply, the Agency will file the NDA and notify the applicant in writing. In the case of a 505(b)(2) application that contains a paragraph IV certification, the applicant will be notified via a paragraph IV acknowledgment letter. The date of filing will be the date 60 days after the date FDA received the NDA. The date of filing begins the 180-day period described in section 505(c) of the Federal Food, Drug, and Cosmetic Act. This 180-day period is called the “filing clock.”

(3) If FDA refuses to file the NDA, the Agency will notify the applicant in writing and state the reason under paragraph (d) or (e) of this section for the refusal. If FDA refuses to file the NDA under paragraph (d) of this section, the applicant may request in writing within 30 days of the date of the Agency's notification an informal conference with the Agency about whether the Agency should file the NDA. If, following the informal conference, the applicant requests that FDA file the NDA (with or without amendments to correct the deficiencies), the Agency will file the NDA over protest under paragraph (a)(2) of this section, notify the applicant in writing, and review it as filed. If the NDA is filed over protest, the date of filing will be the date 60 days after the date the applicant requested the informal conference. The applicant need not resubmit a copy of an NDA that is filed over protest. If FDA refuses to file the NDA under paragraph (e) of this section, the applicant may amend the NDA and resubmit it, and the Agency will make a determination under this section whether it may be filed.

(b)(1) Receiving an ANDA. An ANDA will be evaluated after it is submitted to determine whether the ANDA may be received. Receipt of an ANDA means that FDA has made a threshold determination that the abbreviated application is substantially complete.

(2) If FDA finds that none of the reasons in paragraphs (d) and (e) of this section for considering the ANDA not to have been received applies, the ANDA is substantially complete and the Agency will receive the ANDA and notify the applicant in writing. If FDA determines, upon evaluation, that an ANDA was substantially complete as of the date it was submitted to FDA, FDA will consider the ANDA to have been received as of the date of submission. In the case of an ANDA that contains a paragraph IV certification, the applicant will be notified via a paragraph IV acknowledgment letter.

(3) If FDA considers the ANDA not to have been received under paragraph (d) or (e) of this section, FDA will notify the applicant of the refuse-to-receive decision. The applicant may then:

(i) Withdraw the ANDA under § 314.99; or

(ii) Correct the deficiencies and resubmit the ANDA; or

(iii) Take no action, in which case FDA may consider the ANDA withdrawn after 1 year.

(c) [Reserved]

(d) NDA or ANDA deficiencies. FDA may refuse to file an NDA or may not consider an ANDA to be received if any of the following applies:

(1) The NDA or ANDA does not contain a completed application form.

(2) The NDA or ANDA is not submitted in the form required under § 314.50 or § 314.94.

(3) The NDA or ANDA is incomplete because it does not on its face contain information required under section 505(b) or section 505(j) of the Federal Food, Drug, and Cosmetic Act and § 314.50 or § 314.94. In determining whether an ANDA is incomplete on its face, FDA will consider the nature (e.g., major or minor) of the deficiencies, including the number of deficiencies in the ANDA.

(4) The applicant fails to submit a complete environmental assessment, which addresses each of the items specified in the applicable format under § 25.40 of this chapter or fails to provide sufficient information to establish that the requested action is subject to categorical exclusion under § 25.30 or § 25.31 of this chapter.

(5) The NDA or ANDA does not contain an accurate and complete English translation of each part of the NDA or ANDA that is not in English.

(6) The NDA or ANDA does not contain a statement for each nonclinical laboratory study that the study was conducted in compliance with the requirements set forth in part 58 of this chapter, or, for each study not conducted in compliance with part 58 of this chapter, a brief statement of the reason for the noncompliance.

(7) The NDA or ANDA does not contain a statement for each clinical study that the study was conducted in compliance with the institutional review board regulations in part 56 of this chapter, or was not subject to those regulations, and that it was conducted in compliance with the informed consent regulations in part 50 of this chapter, or, if the study was subject to but was not conducted in compliance with those regulations, the NDA or ANDA does not contain a brief statement of the reason for the noncompliance.

(8) The drug product that is the subject of the submission is already covered by an approved NDA or ANDA and the applicant of the submission:

(i) Has an approved NDA or ANDA for the same drug product; or

(ii) Is merely a distributor and/or repackager of the already approved drug product.

(9) The NDA is submitted as a 505(b)(2) application for a drug that is a duplicate of a listed drug and is eligible for approval under section 505(j) of the Federal Food, Drug, and Cosmetic Act.

(e) Regulatory deficiencies. The Agency will refuse to file an NDA or will consider an ANDA not to have been received if any of the following applies:

(1) The drug product is subject to licensing by FDA under the Public Health Service Act (42 U.S.C. 201 et seq.) and subchapter F of this chapter.

(2) Submission of a 505(b)(2) application or an ANDA is not permitted under section 505(c)(3)(E)(ii), 505(j)(5)(F)(ii), 505A(b)(1)(A)(i)(I), 505A(c)(1)(A)(i)(I), or 505E(a) of the Federal Food, Drug, and Cosmetic Act.

(f) Outcome of FDA review. (1) Within 180 days after the date of filing, plus the period of time the review period was extended (if any), FDA will either:

(i) Approve the NDA; or

(ii) Issue a notice of opportunity for a hearing if the applicant asked FDA to provide it an opportunity for a hearing on an NDA in response to a complete response letter.

(2) Within 180 days after the date of receipt, plus the period of time the review clock was extended (if any), FDA will either approve or disapprove the ANDA. If FDA disapproves the ANDA, FDA will issue a notice of opportunity for hearing if the applicant asked FDA to provide it an opportunity for a hearing on an ANDA in response to a complete response letter.

(3) This paragraph (f) does not apply to NDAs or ANDAs that have been withdrawn from FDA review by the applicant.

(a) General principles. During the course of reviewing an application or an abbreviated application, FDA shall communicate with applicants about scientific, medical, and procedural issues that arise during the review process. Such communication may take the form of telephone conversations, letters, or meetings, whichever is most appropriate to discuss the particular issue at hand. Communications shall be appropriately documented in the application in accordance with § 10.65 of this chapter. Further details on the procedures for communication between FDA and applicants are contained in a staff manual guide that is publicly available.

(b) Notification of easily correctable deficiencies. FDA reviewers shall make every reasonable effort to communicate promptly to applicants easily correctable deficiencies found in an application or an abbreviated application when those deficiencies are discovered, particularly deficiencies concerning chemistry, manufacturing, and controls issues. The agency will also inform applicants promptly of its need for more data or information or for technical changes in the application or the abbreviated application needed to facilitate the agency's review. This early communication is intended to permit applicants to correct such readily identified deficiencies relatively early in the review process and to submit an amendment before the review period has elapsed. Such early communication would not ordinarily apply to major scientific issues, which require consideration of the entire pending application or abbreviated application by agency managers as well as reviewing staff. Instead, major scientific issues will ordinarily be addressed in a complete response letter.

(c) Ninety-day conference. Approximately 90 days after the agency receives the application, FDA will provide applicants with an opportunity to meet with agency reviewing officials. The purpose of the meeting will be to inform applicants of the general progress and status of their applications, and to advise applicants of deficiencies that have been identified by that time and that have not already been communicated. This meeting will be available on applications for all new chemical entities and major new indications of marketed drugs. Such meetings will be held at the applicant's option, and may be held by telephone if mutually agreed upon. Such meetings would not ordinarily be held on abbreviated applications because they are not submitted for new chemical entities or new indications.

(d) End-of-review conference. At the conclusion of FDA's review of an NDA as designated by the issuance of a complete response letter, FDA will provide the applicant with an opportunity to meet with agency reviewing officials. The purpose of the meeting will be to discuss what further steps need to be taken by the applicant before the application can be approved. Requests for such meetings must be directed to the director of the division responsible for reviewing the application.

(e) Other meetings. Other meetings between FDA and applicants may be held, with advance notice, to discuss scientific, medical, and other issues that arise during the review process. Requests for meetings shall be directed to the director of the division responsible for reviewing the application or abbreviated application. FDA will make every attempt to grant requests for meetings that involve important issues and that can be scheduled at mutually convenient times. However, “drop-in” visits (i.e., an unannounced and unscheduled visit by a company representative) are discouraged except for urgent matters, such as to discuss an important new safety issue.

(a) General. FDA is committed to resolving differences between applicants and FDA reviewing divisions with respect to technical requirements for applications or abbreviated applications as quickly and amicably as possible through the cooperative exchange of information and views.

(b) Administrative and procedural issues. When administrative or procedural disputes arise, the applicant should first attempt to resolve the matter with the division responsible for reviewing the application or abbreviated application, beginning with the consumer safety officer assigned to the application or abbreviated application. If resolution is not achieved, the applicant may raise the matter with the person designated as ombudsman, whose function shall be to investigate what has happened and to facilitate a timely and equitable resolution. Appropriate issues to raise with the ombudsman include resolving difficulties in scheduling meetings, obtaining timely replies to inquiries, and obtaining timely completion of pending reviews. Further details on this procedure are contained in a staff manual guide that is publicly available under FDA's public information regulations in part 20.

(c) Scientific and medical disputes. (1) Because major scientific issues are ordinarily communicated to applicants in a complete response letter pursuant to § 314.110, the “end-of-review conference” described in § 314.102(d) will provide a timely forum for discussing and resolving, if possible, scientific and medical issues on which the applicant disagrees with the agency. In addition, the “ninety-day conference” described in § 314.102(c) will provide a timely forum for discussing and resolving, if possible, issues identified by that date.

(2) When scientific or medical disputes arise at other times during the review process, applicants should discuss the matter directly with the responsible reviewing officials. If necessary, applicants may request a meeting with the appropriate reviewing officials and management representatives in order to seek a resolution. Ordinarily, such meetings would be held first with the Division Director, then with the Office Director, and finally with the Center Director if the matter is still unresolved. Requests for such meetings shall be directed to the director of the division responsible for reviewing the application or abrreviated application. FDA will make every attempt to grant requests for meetings that involve important issues and that can be scheduled at mutually convenient times.

(3) In requesting a meeting designed to resolve a scientific or medical dispute, applicants may suggest that FDA seek the advice of outside experts, in which case FDA may, in its discretion, invite to the meeting one or more of its advisory committee members or other consultants, as designated by the agency. Applicants may also bring their own consultants. For major scientific and medical policy issues not resolved by informal meetings, FDA may refer the matter to one of its standing advisory committees for its consideration and recommendations.

The Food and Drug Administration will inform the Drug Enforcement Administration under section 201(f) of the Controlled Substances Act (21 U.S.C. 801) when an application or abbreviated application is submitted for a drug that appears to have an abuse potential.

(a) FDA will approve an NDA and send the applicant an approval letter if none of the reasons in § 314.125 for refusing to approve the NDA applies. FDA will issue a tentative approval letter if an NDA otherwise meets the requirements for approval under the Federal Food, Drug, and Cosmetic Act, but cannot be approved because there is a 7-year period of orphan exclusivity for the listed drug under section 527 of the Federal Food, Drug, and Cosmetic Act and § 316.31 of this chapter, or if a 505(b)(2) application otherwise meets the requirements for approval under the Federal Food, Drug, and Cosmetic Act, but cannot be approved until the conditions in § 314.107(b)(3) are met; because there is a period of exclusivity for the listed drug under § 314.108; because there is a period of pediatric exclusivity for the listed drug under section 505A of the Federal Food, Drug, and Cosmetic Act; or because there is a period of exclusivity for the listed drug under section 505E of the Federal Food, Drug, and Cosmetic Act. A drug product that is granted tentative approval is not an approved drug and will not be approved until FDA issues an approval after any necessary additional review of the NDA. FDA's tentative approval of a drug product is based on information available to FDA at the time of the tentative approval letter (i.e., information in the 505(b)(2) application and the status of current good manufacturing practices of the facilities used in the manufacturing and testing of the drug product) and is therefore subject to change on the basis of new information that may come to FDA's attention. A new drug product may not be marketed until the date of approval.

(b) FDA will approve an NDA and issue the applicant an approval letter on the basis of draft labeling if the only deficiencies in the NDA concern editorial or similar minor deficiencies in the draft labeling. Such approval will be conditioned upon the applicant incorporating the specified labeling changes exactly as directed, and upon the applicant submitting to FDA a copy of the final printed labeling prior to marketing.

(c) FDA will approve an NDA after it determines that the drug meets the statutory standards for safety and effectiveness, manufacturing and controls, and labeling, and an ANDA after it determines that the drug meets the statutory standards for manufacturing and controls, labeling, and, where applicable, bioequivalence. While the statutory standards apply to all drugs, the many kinds of drugs that are subject to the statutory standards and the wide range of uses for those drugs demand flexibility in applying the standards. Thus FDA is required to exercise its scientific judgment to determine the kind and quantity of data and information an applicant is required to provide for a particular drug to meet the statutory standards. FDA makes its views on drug products and classes of drugs available through guidance documents, recommendations, and other statements of policy.

(d) FDA will approve an ANDA and send the applicant an approval letter if none of the reasons in § 314.127 for refusing to approve the ANDA applies. FDA will issue a tentative approval letter if an ANDA otherwise meets the requirements for approval under the Federal Food, Drug, and Cosmetic Act, but cannot be approved because there is a 7-year period of orphan exclusivity for the listed drug under section 527 of the Federal Food, Drug, and Cosmetic Act and § 316.31 of this chapter, or cannot be approved until the conditions in § 314.107(b)(3) or (c) are met; because there is a period of exclusivity for the listed drug under § 314.108; because there is a period of pediatric exclusivity for the listed drug under section 505A of the Federal Food, Drug, and Cosmetic Act; or because there is a period of exclusivity for the listed drug under section 505E of the Federal Food, Drug, and Cosmetic Act. A drug product that is granted tentative approval is not an approved drug and will not be approved until FDA issues an approval after any necessary additional review of the ANDA. FDA's tentative approval of a drug product is based on information available to FDA at the time of the tentative approval letter (i.e., information in the ANDA and the status of current good manufacturing practices of the facilities used in the manufacturing and testing of the drug product) and is therefore subject to change on the basis of new information that may come to FDA's attention. A new drug product may not be marketed until the date of approval.

(a) General. The acceptance of foreign data in an application generally is governed by § 312.120 of this chapter.

(b) As sole basis for marketing approval. An application based solely on foreign clinical data meeting U.S. criteria for marketing approval may be approved if: (1) The foreign data are applicable to the U.S. population and U.S. medical practice; (2) the studies have been performed by clinical investigators of recognized competence; and (3) the data may be considered valid without the need for an on-site inspection by FDA or, if FDA considers such an inspection to be necessary, FDA is able to validate the data through an on-site inspection or other appropriate means. Failure of an application to meet any of these criteria will result in the application not being approvable based on the foreign data alone. FDA will apply this policy in a flexible manner according to the nature of the drug and the data being considered.

(c) Consultation between FDA and applicants. Applicants are encouraged to meet with agency officials in a “presubmission” meeting when approval based solely on foreign data will be sought.

(a) General. A drug product may be introduced or delivered for introduction into interstate commerce when the 505(b)(2) application or ANDA for the drug product is approved. A 505(b)(2) application or ANDA for a drug product is approved on the date FDA issues an approval letter under § 314.105 for the 505(b)(2) application or ANDA.

(b) Effect of patent(s) on the listed drug. As described in paragraphs (b)(1) and (2) of this section, the status of patents listed for the listed drug(s) relied upon or reference listed drug, as applicable, must be considered in determining the first possible date on which a 505(b)(2) application or ANDA can be approved. The criteria in paragraphs (b)(1) and (2) of this section will be used to determine, for each relevant patent, the date that patent will no longer prevent approval. The first possible date on which the 505(b)(2) application or ANDA can be approved will be calculated for each patent, and the 505(b)(2) application or ANDA may be approved on the last applicable date.

(1) Timing of approval based on patent certification or statement. If none of the reasons in § 314.125 or § 314.127, as applicable, for refusing to approve the 505(b)(2) application or ANDA applies, and none of the reasons in paragraph (d) of this section for delaying approval applies, the 505(b)(2) application or ANDA may be approved as follows:

(i) Immediately, if the applicant certifies under § 314.50(i) or § 314.94(a)(12) that:

(A) The applicant is aware of a relevant patent but the patent information required under section 505(b) or (c) of the Federal Food, Drug, and Cosmetic Act has not been submitted to FDA; or

(B) The relevant patent has expired; or

(C) The relevant patent is invalid, unenforceable, or will not be infringed, except as provided in paragraphs (b)(3) and (c) of this section, and the 45-day period provided for in section 505(c)(3)(C) and (j)(5)(B)(iii) of the Federal Food, Drug, and Cosmetic Act has expired; or

(D) There are no relevant patents.

(ii) Immediately, if the applicant submits an appropriate statement under § 314.50(i) or § 314.94(a)(12) explaining that a method-of-use patent does not claim an indication or other condition of use for which the applicant is seeking approval, except that if the applicant also submits a paragraph IV certification to the patent, then the 505(b)(2) application or ANDA may be approved as provided in paragraph (b)(1)(i)(C) of this section.

(iii) On the date specified, if the applicant certifies under § 314.50(i) or § 314.94(a)(12) that the relevant patent will expire on a specified date.

(2) Patent information filed after submission of 505(b)(2) application or ANDA. If the holder of the approved NDA for the listed drug submits patent information required under § 314.53 after the date on which the 505(b)(2) application or ANDA was submitted to FDA, the 505(b)(2) applicant or ANDA applicant must comply with the requirements of § 314.50(i)(4) and (6) and § 314.94(a)(12)(vi) and (viii) regarding submission of an appropriate patent certification or statement. If the applicant submits an amendment certifying under § 314.50(i)(1)(i)(A)(4) or § 314.94(a)(12)(i)(A)(4) that the relevant patent is invalid, unenforceable, or will not be infringed, and complies with the requirements of § 314.52 or § 314.95, the 505(b)(2) application or ANDA may be approved immediately upon submission of documentation of receipt of notice of paragraph IV certification under § 314.52(e) or § 314.95(e). The 45-day period provided for in section 505(c)(3)(C) and (j)(5)(B)(iii) of the Federal Food, Drug, and Cosmetic Act does not apply in these circumstances.

(3) Disposition of patent litigation - (i) Approval upon expiration of 30-month period or 7 1/2 years from date of listed drug approval. (A) Except as provided in paragraphs (b)(3)(ii) through (viii) of this section, if, with respect to patents for which required information was submitted under § 314.53 before the date on which the 505(b)(2) application or ANDA was submitted to FDA (excluding an amendment or supplement to the 505(b)(2) application or ANDA), the applicant certifies under § 314.50(i) or § 314.94(a)(12) that the relevant patent is invalid, unenforceable, or will not be infringed, and the patent owner or its representative or the exclusive patent licensee brings suit for patent infringement within 45 days of receipt of the notice of certification from the applicant under § 314.52 or § 314.95, the 505(b)(2) application or ANDA may be approved 30 months after the later of the date of the receipt of the notice of certification by any owner of the listed patent or by the NDA holder (or its representative(s)) unless the court has extended or reduced the period because of a failure of either the plaintiff or defendant to cooperate reasonably in expediting the action; or

(B) If the patented drug product qualifies for 5 years of exclusive marketing under § 314.108(b)(2) and the patent owner or its representative or the exclusive patent licensee brings suit for patent infringement during the 1-year period beginning 4 years after the date of approval of the patented drug and within 45 days of receipt of the notice of certification from the applicant under § 314.52 or § 314.95, the 505(b)(2) application or ANDA may be approved at the expiration of the 7 1/2 years from the date of approval of the NDA for the patented drug product.

(ii) Federal district court decision of invalidity, unenforceability, or non-infringement. If before the expiration of the 30-month period, or 7 1/2 years where applicable, the district court decides that the patent is invalid, unenforceable, or not infringed (including any substantive determination that there is no cause of action for patent infringement or invalidity), the 505(b)(2) application or ANDA may be approved on:

(A) The date on which the court enters judgment reflecting the decision; or

(B) The date of a settlement order or consent decree signed and entered by the court stating that the patent that is the subject of the certification is invalid, unenforceable, or not infringed.

(iii) Appeal of Federal district court judgment of infringement. If before the expiration of the 30-month period, or 7 1/2 years where applicable, the district court decides that the patent has been infringed, and if the judgment of the district court is appealed, the 505(b)(2) application or ANDA may be approved on:

(A) The date on which the mandate is issued by the court of appeals entering judgment that the patent is invalid, unenforceable, or not infringed (including any substantive determination that there is no cause of action for patent infringement or invalidity); or

(B) The date of a settlement order or consent decree signed and entered by the court of appeals stating that the patent that is the subject of the certification is invalid, unenforceable, or not infringed.

(iv) Affirmation or non-appeal of Federal district court judgment of infringement. If before the expiration of the 30-month period, or 7 1/2 years where applicable, the district court decides that the patent has been infringed, and if the judgment of the district court is not appealed or is affirmed, the 505(b)(2) application or ANDA may be approved no earlier than the date specified by the district court in an order under 35 U.S.C. 271(e)(4)(A).

(v) Grant of preliminary injunction by Federal district court. If before the expiration of the 30-month period, or 7 1/2 years where applicable, the district court grants a preliminary injunction prohibiting the applicant from engaging in the commercial manufacture or sale of the drug product until the court decides the issues of patent validity and infringement, and if the court later decides that:

(A) The patent is invalid, unenforceable, or not infringed, the 505(b)(2) application or ANDA may be approved as provided in paragraph (b)(3)(ii) of this section; or

(B) The patent is infringed, the 505(b)(2) application or ANDA may be approved as provided in paragraph (b)(3)(iii) or (iv) of this section, whichever is applicable.

(vi) Written consent to approval by patent owner or exclusive patent licensee. If before the expiration of the 30-month period, or 7 1/2 years where applicable, the patent owner or the exclusive patent licensee (or their representatives) agrees in writing that the 505(b)(2) application or ANDA may be approved any time on or after the date of the consent, approval may be granted on or after that date.

(vii) Court order terminating 30-month or 7 1/2-year period. If before the expiration of the 30-month period, or 7 1/2 years where applicable, the court enters an order requiring the 30-month or 7 1/2-year period to be terminated, the 505(b)(2) application or ANDA may be approved in accordance with the court's order.

(viii) Court order of dismissal without a finding of infringement. If before the expiration of the 30-month period, or 7 1/2 years where applicable, the court(s) enter(s) an order of dismissal, with or without prejudice, without a finding of infringement in each pending suit for patent infringement brought within 45 days of receipt of the notice of paragraph IV certification sent by the 505(b)(2) or ANDA applicant, the 505(b)(2) application or ANDA may be approved on or after the date of the order.

(4) Tentative approval. FDA will issue a tentative approval letter when tentative approval is appropriate in accordance with this section. In order for a 505(b)(2) application or ANDA to be approved under paragraph (b)(3) of this section, the applicant must receive an approval letter from the Agency. Tentative approval of an NDA or ANDA does not constitute “approval” of an NDA or ANDA and cannot, absent an approval letter from the Agency, result in an approval under paragraph (b)(3) of this section.

(c) Timing of approval of subsequent ANDA. (1) If an ANDA contains a paragraph IV certification for a relevant patent and the ANDA is not that of a first applicant, the ANDA is regarded as the ANDA of a subsequent applicant. The ANDA of a subsequent applicant will not be approved during the period when any first applicant is eligible for 180-day exclusivity or during the 180-day exclusivity period of a first applicant. Any applicable 180-day exclusivity period cannot extend beyond the expiration of the patent upon which the 180-day exclusivity period was based.

(2) A first applicant must submit correspondence to its ANDA notifying FDA within 30 days of the date of its first commercial marketing of its drug product or the reference listed drug. If an applicant does not notify FDA, as required in this paragraph (c)(2), of this date, the date of first commercial marketing will be deemed to be the date of the drug product's approval.

(3) If FDA concludes that a first applicant is not actively pursuing approval of its ANDA, FDA may immediately approve an ANDA(s) of a subsequent applicant(s) if the ANDA(s) is otherwise eligible for approval.

(d) Delay due to exclusivity. The Agency will also delay the approval of a 505(b)(2) application or ANDA if delay is required by the exclusivity provisions in § 314.108; section 527 of the Federal Food, Drug, and Cosmetic Act and § 316.31 of this chapter; section 505A of the Federal Food, Drug, and Cosmetic Act; or section 505E of the Federal Food, Drug, and Cosmetic Act. When the approval of a 505(b)(2) application or ANDA is delayed under this section and § 314.108; section 527 of the Federal Food, Drug, and Cosmetic Act and § 316.31 of this chapter; section 505A of the Federal Food, Drug, and Cosmetic Act; or section 505E of the Federal Food, Drug, and Cosmetic Act, the 505(b)(2) application or ANDA will be approved on the latest of the days specified under this section and § 314.108; section 527 of the Federal Food, Drug, and Cosmetic Act and § 316.31 of this chapter; section 505A of the Federal Food, Drug, and Cosmetic Act; or section 505E of the Federal Food, Drug, and Cosmetic Act, as applicable.

(e) Notification of court actions or written consent to approval. (1) The applicant must submit the following information to FDA, as applicable:

(i) A copy of any judgment by the court (district court or mandate of the court of appeals) or settlement order or consent decree signed and entered by the court (district court or court of appeals) finding a patent described in paragraph (b)(3) of this section invalid, unenforceable, or not infringed, or finding the patent valid and infringed;

(ii) Written notification of whether or not any action by the court described in paragraph (e)(1)(i) of this section has been appealed within the time permitted for an appeal;

(iii) A copy of any order entered by the court terminating the 30-month or 7 1/2-year period as described in paragraph (b)(3)(i), (ii), (vii), or (viii) of this section;

(iv) A copy of any written consent to approval by the patent owner or exclusive patent licensee described in paragraph (b)(3)(vi) of this section;

(v) A copy of any preliminary injunction described in paragraph (b)(3)(v) of this section, and a copy of any subsequent court order lifting the injunction; and

(vi) A copy of any court order pursuant to 35 U.S.C. 271(e)(4)(A) ordering that a 505(b)(2) application or ANDA may be approved no earlier than the date specified (irrespective of whether the injunction relates to a patent described in paragraph (b)(3) of this section).

(2) All information required by paragraph (e)(1) of this section must be sent to the applicant's NDA or ANDA, as appropriate, within 14 days of the date of entry by the court, the date of appeal or expiration of the time for appeal, or the date of written consent to approval, as applicable.

(f) Forty-five day period after receipt of notice of paragraph IV certification - (1) Computation of 45-day time clock. The 45-day clock described in paragraph (b)(3) of this section as to each recipient required to receive notice of paragraph IV certification under § 314.52 or § 314.95 begins on the day after the date of receipt of the applicant's notice of paragraph IV certification by the recipient. When the 45th day falls on Saturday, Sunday, or a Federal holiday, the 45th day will be the next day that is not a Saturday, Sunday, or a Federal holiday.

(2) Notification of filing of legal action. (i) The 505(b)(2) or ANDA applicant must notify FDA in writing within 14 days of the filing of any legal action filed within 45 days of receipt of the notice of paragraph IV certification by any recipient. A 505(b)(2) applicant must send the notification to its NDA. An ANDA applicant must send the notification to its ANDA. The notification to FDA of the legal action must include:

(A) The 505(b)(2) application or ANDA number.

(B) The name of the 505(b)(2) or ANDA applicant.

(C) The established name of the drug product or, if no established name exists, the name(s) of the active ingredient(s), the drug product's strength, and dosage form.

(D) A statement that an action for patent infringement, identified by court, case number, and the patent number(s) of the patent(s) at issue in the action, has been filed in an appropriate court on a specified date.

(ii) A patent owner or NDA holder (or its representative(s)) may also notify FDA of the filing of any legal action for patent infringement. The notice should contain the information and be sent to the offices or divisions described in paragraph (f)(2)(i) of this section.

(iii) If the 505(b)(2) or ANDA applicant, the patent owner(s), the NDA holder, or its representative(s) does not notify FDA in writing before the expiration of the 45-day time period or the completion of the Agency's review of the 505(b)(2) application or ANDA, whichever occurs later, that a legal action for patent infringement was filed within 45 days of receipt of the notice of paragraph IV certification, the 505(b)(2) application or ANDA may be approved upon expiration of the 45-day period (if the 505(b)(2) or ANDA applicant confirms that a legal action for patent infringement has not been filed) or upon completion of the Agency's review of the 505(b)(2) application or ANDA, whichever is later.

(3) Waiver. If the patent owner or NDA holder who is an exclusive patent licensee (or its representative(s)) waives its opportunity to file a legal action for patent infringement within 45 days of a receipt of the notice of certification and the patent owner or NDA holder who is an exclusive patent licensee (or its representative(s)) submits to FDA a valid waiver before the 45 days elapse, the 505(b)(2) application or ANDA may be approved upon completion of the Agency's review of the NDA or ANDA. FDA will only accept a waiver in the following form:

(g) Conversion of approval to tentative approval. If FDA issues an approval letter in error or a court enters an order requiring, in the case of an already approved 505(b)(2) application or ANDA, that the date of approval be delayed, FDA will convert the approval to a tentative approval if appropriate.

(a) Definitions. The definitions in § 314.3 and the following definitions of terms apply to this section:

Approved under section 505(b) means an NDA submitted under section 505(b) and approved on or after October 10, 1962, or an application that was “deemed approved” under section 107(c)(2) of Public Law 87-781.

Bioavailability study means a study to determine the bioavailability or the pharmacokinetics of a drug.

Clinical investigation means any experiment other than a bioavailability study in which a drug is administered or dispensed to, or used on, human subjects.

Conducted or sponsored by the applicant with regard to an investigation means that before or during the investigation, the applicant was named in Form FDA-1571 filed with FDA as the sponsor of the investigational new drug application under which the investigation was conducted, or the applicant or the applicant's predecessor in interest, provided substantial support for the investigation. To demonstrate “substantial support,” an applicant must either provide a certified statement from a certified public accountant that the applicant provided 50 percent or more of the cost of conducting the study or provide an explanation why FDA should consider the applicant to have conducted or sponsored the study if the applicant's financial contribution to the study is less than 50 percent or the applicant did not sponsor the investigational new drug. A predecessor in interest is an entity, e.g., a corporation, that the applicant has taken over, merged with, or purchased, or from which the applicant has purchased all rights to the drug. Purchase of nonexclusive rights to a clinical investigation after it is completed is not sufficient to satisfy this definition.

Essential to approval means, with regard to an investigation, that there are no other data available that could support approval of the NDA.

New chemical entity means a drug that contains no active moiety that has been approved by FDA in any other NDA submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act.

New clinical investigation means an investigation in humans the results of which have not been relied on by FDA to demonstrate substantial evidence of effectiveness of a previously approved drug product for any indication or of safety for a new patient population and do not duplicate the results of another investigation that was relied on by the agency to demonstrate the effectiveness or safety in a new patient population of a previously approved drug product. For purposes of this section, data from a clinical investigation previously submitted for use in the comprehensive evaluation of the safety of a drug product but not to support the effectiveness of the drug product would be considered new.

(b) Submission of and timing of approval of a 505(b)(2) application or ANDA. (1) [Reserved]

(2) If a drug product that contains a new chemical entity was approved after September 24, 1984, in an NDA submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act, no person may submit a 505(b)(2) application or ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act for a drug product that contains the same active moiety as in the new chemical entity for a period of 5 years from the date of approval of the first approved NDA, except that the 505(b)(2) application or ANDA may be submitted after 4 years if it contains a certification of patent invalidity or noninfringement described in § 314.50(i)(1)(i)(A)(4) or § 314.94(a)(12)(i)(A)(4).

(3) The approval of a 505(b)(2) application or ANDA described in paragraph (b)(2) of this section will occur as provided in § 314.107(b)(1) or (2), unless the owner of a patent that claims the drug, the patent owner's representative, or exclusive licensee brings suit for patent infringement against the applicant during the 1-year period beginning 48 months after the date of approval of the NDA for the new chemical entity and within 45 days after receipt of the notice described at § 314.52 or § 314.95, in which case, approval of the 505(b)(2) application or ANDA will occur as provided in § 314.107(b)(3).

(4) If an NDA:

(i) Was submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act;

(ii) Was approved after September 24, 1984;

(iii) Was for a drug product that contains an active moiety that has been previously approved in another NDA under section 505(b) of the Federal Food, Drug, and Cosmetic Act; and

(iv) Contained reports of new clinical investigations (other than bioavailability studies) conducted or sponsored by the applicant that were essential to approval of the application, for a period of 3 years after the date of approval of the application, the Agency will not approve a 505(b)(2) application or an ANDA for the conditions of approval of the NDA, or an ANDA submitted pursuant to an approved petition under section 505(j)(2)(C) of the Federal Food, Drug, and Cosmetic Act that relies on the information supporting the conditions of approval of an original NDA.

(5) If a supplemental NDA:

(i) Was approved after September 24, 1984; and

(ii) Contained reports of new clinical investigations (other than bioavailability studies) that were conducted or sponsored by the applicant that were essential to approval of the supplemental NDA, for a period of 3 years after the date of approval of the supplemental application, the Agency will not approve a 505(b)(2) application or an ANDA for a change, or an ANDA submitted pursuant to an approved petition under section 505(j)(2)(C) of the Federal Food, Drug, and Cosmetic Act that relies on the information supporting a change approved in the supplemental NDA.

(a) Complete response letter. FDA will send the applicant a complete response letter if the agency determines that we will not approve the application or abbreviated application in its present form for one or more of the reasons given in § 314.125 or § 314.127, respectively.

(1) Description of specific deficiencies. A complete response letter will describe all of the specific deficiencies that the agency has identified in an application or abbreviated application, except as stated in paragraph (a)(3) of this section.

(2) Complete review of data. A complete response letter reflects FDA's complete review of the data submitted in an original application or abbreviated application (or, where appropriate, a resubmission) and any amendments that the agency has reviewed. The complete response letter will identify any amendments that the agency has not yet reviewed.

(3) Inadequate data. If FDA determines, after an application is filed or an abbreviated application is received, that the data submitted are inadequate to support approval, the agency might issue a complete response letter without first conducting required inspections and/or reviewing proposed product labeling.

(4) Recommendation of actions for approval. When possible, a complete response letter will recommend actions that the applicant might take to place the application or abbreviated application in condition for approval.

(b) Applicant actions. After receiving a complete response letter, the applicant must take one of following actions:

(1) Resubmission. Resubmit the application or abbreviated application, addressing all deficiencies identified in the complete response letter.

(i) A resubmission of an application or efficacy supplement that FDA classifies as a Class 1 resubmission constitutes an agreement by the applicant to start a new 2-month review cycle beginning on the date FDA receives the resubmission.

(ii) A resubmission of an application or efficacy supplement that FDA classifies as a Class 2 resubmission constitutes an agreement by the applicant to start a new 6-month review cycle beginning on the date FDA receives the resubmission.

(iii) A resubmission of an NDA supplement other than an efficacy supplement constitutes an agreement by the applicant to start a new review cycle the same length as the initial review cycle for the supplement (excluding any extension due to a major amendment of the initial supplement), beginning on the date FDA receives the resubmission.

(iv) A major resubmission of an abbreviated application constitutes an agreement by the applicant to start a new 6-month review cycle beginning on the date FDA receives the resubmission.

(v) A minor resubmission of an abbreviated application constitutes an agreement by the applicant to start a new review cycle beginning on the date FDA receives the resubmission.

(2) Withdrawal. Withdraw the application or abbreviated application. A decision to withdraw an application or abbreviated application is without prejudice to a subsequent submission.

(3) Request opportunity for hearing. Ask the agency to provide the applicant an opportunity for a hearing on the question of whether there are grounds for denying approval of the application or abbreviated application under section 505(d) or (j)(4) of the act, respectively. The applicant must submit the request to the Associate Director for Policy, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993. Within 60 days of the date of the request for an opportunity for a hearing, or within a different time period to which FDA and the applicant agree, the agency will either approve the application or abbreviated application under § 314.105, or refuse to approve the application under § 314.125 or abbreviated application under § 314.127 and give the applicant written notice of an opportunity for a hearing under § 314.200 and section 505(c)(1)(B) or (j)(5)(c) of the act on the question of whether there are grounds for denying approval of the application or abbreviated application under section 505(d) or (j)(4) of the act, respectively.

(c) Failure to take action. (1) An applicant agrees to extend the review period under section 505(c)(1) or (j)(5)(A) of the act until it takes any of the actions listed in paragraph (b) of this section. For an application or abbreviated application, FDA may consider an applicant's failure to take any of such actions within 1 year after issuance of a complete response letter to be a request by the applicant to withdraw the application, unless the applicant has requested an extension of time in which to resubmit the application. FDA will grant any reasonable request for such an extension. FDA may consider an applicant's failure to resubmit the application within the extended time period or to request an additional extension to be a request by the applicant to withdraw the application.

(2) If FDA considers an applicant's failure to take action in accordance with paragraph (c)(1) of this section to be a request to withdraw the application, the agency will notify the applicant in writing. The applicant will have 30 days from the date of the notification to explain why the application should not be withdrawn and to request an extension of time in which to resubmit the application. FDA will grant any reasonable request for an extension. If the applicant does not respond to the notification within 30 days, the application will be deemed to be withdrawn.

(a) An abbreviated new drug application that refers to, or a petition under section 505(j)(2)(C) of the act and § 314.93 that relies on, a listed drug that has been voluntarily withdrawn from sale in the United States must be accompanied by a petition seeking a determination whether the listed drug was withdrawn for safety or effectiveness reasons. The petition must be submitted under §§ 10.25(a) and 10.30 of this chapter and must contain all evidence available to the petitioner concerning the reasons for the withdrawal from sale.

(b) When a petition described in paragraph (a) of this section is submitted, the agency will consider the evidence in the petition and any other evidence before the agency, and determine whether the listed drug is withdrawn from sale for safety or effectiveness reasons, in accordance with the procedures in § 314.161.

(c) An abbreviated new drug application described in paragraph (a) of this section will be disapproved, under § 314.127(a)(11), and a 505(j)(2)(C) petition described in paragraph (a) of this section will be disapproved, under § 314.93(e)(1)(iv), unless the agency determines that the withdrawal of the listed drug was not for safety or effectiveness reasons.

(d) Certain drug products approved for safety and effectiveness that were no longer marketed on September 24, 1984, are not included in the list. Any person who wishes to obtain marketing approval for such a drug product under an abbreviated new drug application must petition FDA for a determination whether the drug product was withdrawn from the market for safety or effectiveness reasons and request that the list be amended to include the drug product. A person seeking such a determination shall use the petition procedures established in § 10.30 of this chapter. The petitioner shall include in the petition information to show that the drug product was approved for safety and effectiveness and all evidence available to the petitioner concerning the reason that marketing of the drug product ceased.

(a) The Food and Drug Administration will refuse to approve the NDA and for a new drug give the applicant written notice of an opportunity for a hearing under § 314.200 on the question of whether there are grounds for denying approval of the NDA under section 505(d) of the Federal Food, Drug, and Cosmetic Act, if:

(1) FDA sends the applicant a complete response letter under § 314.110;

(2) The applicant requests an opportunity for hearing for a new drug on the question of whether the NDA is approvable; and

(3) FDA finds that any of the reasons given in paragraph (b) of this section apply.

(b) FDA may refuse to approve an NDA for any of the following reasons, unless the requirement has been waived under § 314.90:

(1) The methods to be used in, and the facilities and controls used for, the manufacture, processing, packing, or holding of the drug substance or the drug product are inadequate to preserve its identity, strength, quality, purity, stability, and bioavailability.

(2) The investigations required under section 505(b) of the Federal Food, Drug, and Cosmetic Act do not include adequate tests by all methods reasonably applicable to show whether or not the drug is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling.

(3) The results of the tests show that the drug is unsafe for use under the conditions prescribed, recommended, or suggested in its proposed labeling or the results do not show that the drug product is safe for use under those conditions.

(4) There is insufficient information about the drug to determine whether the product is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling.

(5) There is a lack of substantial evidence consisting of adequate and well-controlled investigations, as defined in § 314.126, that the drug product will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in its proposed labeling.

(6) The proposed labeling is false or misleading in any particular.

(7) The NDA contains an untrue statement of a material fact.

(8) The drug product's proposed labeling does not comply with the requirements for labels and labeling in part 201.

(9) The NDA does not contain bioavailability or bioequivalence data required under part 320 of this chapter.

(10) A reason given in a letter refusing to file the NDA under § 314.101(d), if the deficiency is not corrected.

(11) The drug will be manufactured in whole or in part in an establishment that is not registered and not exempt from registration under section 510 of the Federal Food, Drug, and Cosmetic Act and part 207.

(12) The applicant does not permit a properly authorized officer or employee of the Department of Health and Human Services an adequate opportunity to inspect the facilities, controls, and any records relevant to the NDA.

(13) The methods to be used in, and the facilities and controls used for, the manufacture, processing, packing, or holding of the drug substance or the drug product do not comply with the current good manufacturing practice regulations in parts 210 and 211.

(14) The NDA does not contain an explanation of the omission of a report of any investigation of the drug product sponsored by the applicant, or an explanation of the omission of other information about the drug pertinent to an evaluation of the NDA that is received or otherwise obtained by the applicant from any source.

(15) A nonclinical laboratory study that is described in the NDA and that is essential to show that the drug is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling was not conducted in compliance with the good laboratory practice regulations in part 58 of this chapter and no reason for the noncompliance is provided or, if it is, the differences between the practices used in conducting the study and the good laboratory practice regulations do not support the validity of the study.

(16) Any clinical investigation involving human subjects described in the NDA, subject to the institutional review board regulations in part 56 of this chapter or informed consent regulations in part 50 of this chapter, was not conducted in compliance with those regulations such that the rights or safety of human subjects were not adequately protected.

(17) The applicant or contract research organization that conducted a bioavailability or bioequivalence study described in § 320.38 or § 320.63 of this chapter that is contained in the NDA refuses to permit an inspection of facilities or records relevant to the study by a properly authorized officer or employee of the Department of Health and Human Services or refuses to submit reserve samples of the drug products used in the study when requested by FDA.

(18) For a new drug, the NDA failed to contain the patent information required by section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act.

(19) The 505(b)(2) application failed to contain a patent certification or statement with respect to each listed patent for a drug product approved in an NDA that:

(i) Is pharmaceutically equivalent to the drug product for which the original 505(b)(2) application is submitted; and

(ii) Was approved before the original 505(b)(2) application was submitted.

(c) For drugs intended to treat life-threatening or severely-debilitating illnesses that are developed in accordance with §§ 312.80 through 312.88 of this chapter, the criteria contained in paragraphs (b) (3), (4), and (5) of this section shall be applied according to the considerations contained in § 312.84 of this chapter.

(a) The purpose of conducting clinical investigations of a drug is to distinguish the effect of a drug from other influences, such as spontaneous change in the course of the disease, placebo effect, or biased observation. The characteristics described in paragraph (b) of this section have been developed over a period of years and are recognized by the scientific community as the essentials of an adequate and well-controlled clinical investigation. The Food and Drug Administration considers these characteristics in determining whether an investigation is adequate and well-controlled for purposes of section 505 of the act. Reports of adequate and well-controlled investigations provide the primary basis for determining whether there is “substantial evidence” to support the claims of effectiveness for new drugs. Therefore, the study report should provide sufficient details of study design, conduct, and analysis to allow critical evaluation and a determination of whether the characteristics of an adequate and well-controlled study are present.

(b) An adequate and well-controlled study has the following characteristics:

(1) There is a clear statement of the objectives of the investigation and a summary of the proposed or actual methods of analysis in the protocol for the study and in the report of its results. In addition, the protocol should contain a description of the proposed methods of analysis, and the study report should contain a description of the methods of analysis ultimately used. If the protocol does not contain a description of the proposed methods of analysis, the study report should describe how the methods used were selected.

(2) The study uses a design that permits a valid comparison with a control to provide a quantitative assessment of drug effect. The protocol for the study and report of results should describe the study design precisely; for example, duration of treatment periods, whether treatments are parallel, sequential, or crossover, and whether the sample size is predetermined or based upon some interim analysis. Generally, the following types of control are recognized:

(i) Placebo concurrent control. The test drug is compared with an inactive preparation designed to resemble the test drug as far as possible. A placebo-controlled study may include additional treatment groups, such as an active treatment control or a dose-comparison control, and usually includes randomization and blinding of patients or investigators, or both.

(ii) Dose-comparison concurrent control. At least two doses of the drug are compared. A dose-comparison study may include additional treatment groups, such as placebo control or active control. Dose-comparison trials usually include randomization and blinding of patients or investigators, or both.

(iii) No treatment concurrent control. Where objective measurements of effectiveness are available and placebo effect is negligible, the test drug is compared with no treatment. No treatment concurrent control trials usually include randomization.

(iv) Active treatment concurrent control. The test drug is compared with known effective therapy; for example, where the condition treated is such that administration of placebo or no treatment would be contrary to the interest of the patient. An active treatment study may include additional treatment groups, however, such as a placebo control or a dose-comparison control. Active treatment trials usually include randomization and blinding of patients or investigators, or both. If the intent of the trial is to show similarity of the test and control drugs, the report of the study should assess the ability of the study to have detected a difference between treatments. Similarity of test drug and active control can mean either that both drugs were effective or that neither was effective. The analysis of the study should explain why the drugs should be considered effective in the study, for example, by reference to results in previous placebo-controlled studies of the active control drug.

(v) Historical control. The results of treatment with the test drug are compared with experience historically derived from the adequately documented natural history of the disease or condition, or from the results of active treatment, in comparable patients or populations. Because historical control populations usually cannot be as well assessed with respect to pertinent variables as can concurrent control populations, historical control designs are usually reserved for special circumstances. Examples include studies of diseases with high and predictable mortality (for example, certain malignancies) and studies in which the effect of the drug is self-evident (general anesthetics, drug metabolism).

(3) The method of selection of subjects provides adequate assurance that they have the disease or condition being studied, or evidence of susceptibility and exposure to the condition against which prophylaxis is directed.

(4) The method of assigning patients to treatment and control groups minimizes bias and is intended to assure comparability of the groups with respect to pertinent variables such as age, sex, severity of disease, duration of disease, and use of drugs or therapy other than the test drug. The protocol for the study and the report of its results should describe how subjects were assigned to groups. Ordinarily, in a concurrently controlled study, assignment is by randomization, with or without stratification.

(5) Adequate measures are taken to minimize bias on the part of the subjects, observers, and analysts of the data. The protocol and report of the study should describe the procedures used to accomplish this, such as blinding.

(6) The methods of assessment of subjects' response are well-defined and reliable. The protocol for the study and the report of results should explain the variables measured, the methods of observation, and criteria used to assess response.

(7) There is an analysis of the results of the study adequate to assess the effects of the drug. The report of the study should describe the results and the analytic methods used to evaluate them, including any appropriate statistical methods. The analysis should assess, among other things, the comparability of test and control groups with respect to pertinent variables, and the effects of any interim data analyses performed.

(c) The Director of the Center for Drug Evaluation and Research may, on the Director's own initiative or on the petition of an interested person, waive in whole or in part any of the criteria in paragraph (b) of this section with respect to a specific clinical investigation, either prior to the investigation or in the evaluation of a completed study. A petition for a waiver is required to set forth clearly and concisely the specific criteria from which waiver is sought, why the criteria are not reasonably applicable to the particular clinical investigation, what alternative procedures, if any, are to be, or have been employed, and what results have been obtained. The petition is also required to state why the clinical investigations so conducted will yield, or have yielded, substantial evidence of effectiveness, notwithstanding nonconformance with the criteria for which waiver is requested.

(d) For an investigation to be considered adequate for approval of a new drug, it is required that the test drug be standardized as to identity, strength, quality, purity, and dosage form to give significance to the results of the investigation.

(e) Uncontrolled studies or partially controlled studies are not acceptable as the sole basis for the approval of claims of effectiveness. Such studies carefully conducted and documented, may provide corroborative support of well-controlled studies regarding efficacy and may yield valuable data regarding safety of the test drug. Such studies will be considered on their merits in the light of the principles listed here, with the exception of the requirement for the comparison of the treated subjects with controls. Isolated case reports, random experience, and reports lacking the details which permit scientific evaluation will not be considered.

(a) FDA will refuse to approve an ANDA for a new drug under section 505(j) of the Federal Food, Drug, and Cosmetic Act for any of the following reasons, unless the requirement has been waived under § 314.99:

(1) The methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the drug product are inadequate to ensure and preserve its identity, strength, quality, and purity.

(2) Information submitted with the ANDA is insufficient to show that each of the proposed conditions of use has been previously approved for the listed drug referred to in the ANDA.

(3)(i) If the reference listed drug has only one active ingredient, information submitted with the ANDA is insufficient to show that the active ingredient is the same as that of the reference listed drug;

(ii) If the reference listed drug has more than one active ingredient, information submitted with the ANDA is insufficient to show that the active ingredients are the same as the active ingredients of the reference listed drug; or

(iii) If the reference listed drug has more than one active ingredient and if the ANDAis for a drug product that has an active ingredient different from the reference listed drug:

(A) Information submitted with the ANDA is insufficient to show:

(1) That the other active ingredients are the same as the active ingredients of the reference listed drug; or

(2) That the different active ingredient is an active ingredient of a listed drug or a drug that does not meet the requirements of section 201(p) of the Federal Food, Drug, and Cosmetic Act; or

(B) No petition to submit an ANDA for the drug product with the different active ingredient was approved under § 314.93.

(4)(i) If the ANDA is for a drug product whose route of administration, dosage form, or strength purports to be the same as that of the listed drug referred to in the ANDA, information submitted in the abbreviated new drug application is insufficient to show that the route of administration, dosage form, or strength is the same as that of the reference listed drug; or

(ii) If the ANDA is for a drug product whose route of administration, dosage form, or strength is different from that of the listed drug referred to in the application, no petition to submit an ANDA for the drug product with the different route of administration, dosage form, or strength was approved under § 314.93.

(5) If the ANDA was submitted under the approval of a petition under § 314.93, the ANDA did not contain the information required by FDA with respect to the active ingredient, route of administration, dosage form, or strength that is not the same as that of the reference listed drug.

(6)(i) Information submitted in the ANDA is insufficient to show that the drug product is bioequivalent to the listed drug referred to in the ANDA; or

(ii) If the ANDA was submitted under a petition approved under § 314.93, information submitted in the ANDA is insufficient to show that the active ingredients of the drug product are of the same pharmacological or therapeutic class as those of the reference listed drug and that the drug product can be expected to have the same therapeutic effect as the reference listed drug when administered to patients for each condition of use approved for the reference listed drug.

(7) Information submitted in the ANDA is insufficient to show that the labeling proposed for the drug is the same as the labeling approved for the listed drug referred to in the ANDA except for changes required because of differences approved in a petition under § 314.93 or because the drug product and the reference listed drug are produced or distributed by different manufacturers or because aspects of the listed drug's labeling are protected by patent, or by exclusivity, and such differences do not render the proposed drug product less safe or effective than the listed drug for all remaining, nonprotected conditions of use.

(8)(i) Information submitted in the ANDA or any other information available to FDA shows that:

(A) The inactive ingredients of the drug product are unsafe for use, as described in paragraph (a)(8)(ii) of this section, under the conditions prescribed, recommended, or suggested in the labeling proposed for the drug product; or

(B) The composition of the drug product is unsafe, as described in paragraph (a)(8)(ii) of this section, under the conditions prescribed, recommended, or suggested in the proposed labeling because of the type or quantity of inactive ingredients included or the manner in which the inactive ingredients are included.

(ii)(A) FDA will consider the inactive ingredients or composition of a drug product unsafe and refuse to approve an ANDA under paragraph (a)(8)(i) of this section if, on the basis of information available to the agency, there is a reasonable basis to conclude that one or more of the inactive ingredients of the proposed drug or its composition raises serious questions of safety or efficacy. From its experience with reviewing inactive ingredients, and from other information available to it, FDA may identify changes in inactive ingredients or composition that may adversely affect a drug product's safety or efficacy. The inactive ingredients or composition of a proposed drug product will be considered to raise serious questions of safety or efficacy if the product incorporates one or more of these changes. Examples of the changes that may raise serious questions of safety or efficacy include, but are not limited to, the following:

(1) A change in an inactive ingredient so that the product does not comply with an official compendium.

(2) A change in composition to include an inactive ingredient that has not been previously approved in a drug product for human use by the same route of administration.

(3) A change in the composition of a parenteral drug product to include an inactive ingredient that has not been previously approved in a parenteral drug product.

(4) A change in composition of a drug product for ophthalmic use to include an inactive ingredient that has not been previously approved in a drug for ophthalmic use.

(5) The use of a delivery or a modified release mechanism never before approved for the drug.

(6) A change in composition to include a significantly greater content of one or more inactive ingredients than previously used in the drug product.

(7) If the drug product is intended for topical administration, a change in the properties of the vehicle or base that might increase absorption of certain potentially toxic active ingredients thereby affecting the safety of the drug product, or a change in the lipophilic properties of a vehicle or base, e.g., a change from an oleaginous to a water soluble vehicle or base.

(B) FDA will consider an inactive ingredient in, or the composition of, a drug product intended for parenteral use to be unsafe and will refuse to approve the ANDA unless it contains the same inactive ingredients, other than preservatives, buffers, and antioxidants, in the same concentration as the listed drug, and, if it differs from the listed drug in a preservative, buffer, or antioxidant, the ANDA contains sufficient information to demonstrate that the difference does not affect the safety or efficacy of the drug product.

(C) FDA will consider an inactive ingredient in, or the composition of, a drug product intended for ophthalmic or otic use unsafe and will refuse to approve the ANDA unless it contains the same inactive ingredients, other than preservatives, buffers, substances to adjust tonicity, or thickening agents, in the same concentration as the listed drug, and if it differs from the listed drug in a preservative, buffer, substance to adjust tonicity, or thickening agent, the ANDA contains sufficient information to demonstrate that the difference does not affect the safety or efficacy of the drug product and the labeling does not claim any therapeutic advantage over or difference from the listed drug.

(9) Approval of the listed drug referred to in the ANDA has been withdrawn or suspended for grounds described in § 314.150(a) or FDA has published a notice of opportunity for hearing to withdraw approval of the reference listed drug under § 314.150(a).

(10) Approval of the listed drug referred to in the ANDA has been withdrawn under § 314.151 or FDA has proposed to withdraw approval of the reference listed drug under § 314.151(a).

(11) FDA has determined that the reference listed drug has been withdrawn from sale for safety or effectiveness reasons under § 314.161, or the reference listed drug has been voluntarily withdrawn from sale and the agency has not determined whether the withdrawal is for safety or effectiveness reasons, or approval of the reference listed drug has been suspended under § 314.153, or the agency has issued an initial decision proposing to suspend the reference listed drug under § 314.153(a)(1).

(12) The abbreviated new drug application does not meet any other requirement under section 505(j)(2)(A) of the Federal Food, Drug, and Cosmetic Act.

(13) The abbreviated new drug application contains an untrue statement of material fact.

(14) For an ANDA submitted pursuant to an approved petition under § 10.30 of this chapter and § 314.93, an NDA subsequently has been approved for the change described in the approved petition.

(b) FDA may refuse to approve an ANDA for a new drug if the applicant or contract research organization that conducted a bioavailability or bioequivalence study described in § 320.63 of this chapter that is contained in the ANDA refuses to permit an inspection of facilities or records relevant to the study by a properly authorized officer or employee of the Department of Health and Human Services or refuses to submit reserve samples of the drug products used in the study when requested by FDA.

(a) The Food and Drug Administration will notify the applicant, and, if appropriate, all other persons who manufacture or distribute identical, related, or similar drug products as defined in §§ 310.6 and 314.151(a) of this chapter and for a new drug afford an opportunity for a hearing on a proposal to withdraw approval of the application or abbreviated new drug application under section 505(e) of the act and under the procedure in § 314.200, if any of the following apply:

(1) The Secretary of Health and Human Services has suspended the approval of the application or abbreviated application for a new drug on a finding that there is an imminent hazard to the public health. FDA will promptly afford the applicant an expedited hearing following summary suspension on a finding of imminent hazard to health.

(2) FDA finds:

(i) That clinical or other experience, tests, or other scientific data show that the drug is unsafe for use under the conditions of use upon the basis of which the application or abbreviated application was approved; or

(ii) That new evidence of clinical experience, not contained in the application or not available to FDA until after the application or abbreviated application was approved, or tests by new methods, or tests by methods not deemed reasonably applicable when the application or abbreviated application was approved, evaluated together with the evidence available when the application or abbreviated application was approved, reveal that the drug is not shown to be safe for use under the conditions of use upon the basis of which the application or abbreviated application was approved; or

(iii) Upon the basis of new information before FDA with respect to the drug, evaluated together with the evidence available when the application or abbreviated application was approved, that there is a lack of substantial evidence from adequate and well-controlled investigations as defined in § 314.126, that the drug will have the effect it is purported or represented to have under the conditions of use prescribed, recommended, or suggested in its labeling; or

(iv) That the application or abbreviated application contains any untrue statement of a material fact; or

(v) That the patent information prescribed by section 505(c) of the act was not submitted within 30 days after the receipt of written notice from FDA specifying the failure to submit such information; or

(b) FDA may notify the applicant, and, if appropriate, all other persons who manufacture or distribute identical, related, or similar drug products as defined in § 310.6, and for a new drug afford an opportunity for a hearing on a proposal to withdraw approval of the application or abbreviated new drug application under section 505(e) of the act and under the procedure in § 314.200, if the agency finds:

(1) That the applicant has failed to establish a system for maintaining required records, or has repeatedly or deliberately failed to maintain required records or to make required reports under section 505(k) or 507(g) of the act and § 314.80, § 314.81, or § 314.98, or that the applicant has refused to permit access to, or copying or verification of, its records.

(2) That on the basis of new information before FDA, evaluated together with the evidence available when the application or abbreviated application was approved, the methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the drug are inadequate to ensure and preserve its identity, strength, quality, and purity and were not made adequate within a reasonable time after receipt of written notice from the agency.

(3) That on the basis of new information before FDA, evaluated together with the evidence available when the application or abbreviated application was approved, the labeling of the drug, based on a fair evaluation of all material facts, is false or misleading in any particular, and the labeling was not corrected by the applicant within a reasonable time after receipt of written notice from the agency.

(4) That the applicant has failed to comply with the notice requirements of section 510(j)(2) of the act.

(5) That the applicant has failed to submit bioavailability or bioequivalence data required under part 320 of this chapter.

(6) The application or abbreviated application does not contain an explanation of the omission of a report of any investigation of the drug product sponsored by the applicant, or an explanation of the omission of other information about the drug pertinent to an evaluation of the application or abbreviated application that is received or otherwise obtained by the applicant from any source.

(7) That any nonclinical laboratory study that is described in the application or abbreviated application and that is essential to show that the drug is safe for use under the conditions prescribed, recommended, or suggested in its labeling was not conducted in compliance with the good laboratory practice regulations in part 58 of this chapter and no reason for the noncompliance was provided or, if it was, the differences between the practices used in conducting the study and the good laboratory practice regulations do not support the validity of the study.

(8) Any clinical investigation involving human subjects described in the application or abbreviated application, subject to the institutional review board regulations in part 56 of this chapter or informed consent regulations in part 50 of this chapter, was not conducted in compliance with those regulations such that the rights or safety of human subjects were not adequately protected.

(9) That the applicant or contract research organization that conducted a bioavailability or bioequivalence study described in § 320.38 or § 320.63 of this chapter that is contained in the application or abbreviated application refuses to permit an inspection of facilities or records relevant to the study by a properly authorized officer or employee of the Department of Health and Human Services or refuses to submit reserve samples of the drug products used in the study when requested by FDA.

(10) That the labeling for the drug product that is the subject of the abbreviated new drug application is no longer consistent with that for the listed drug referred to in the abbreviated new drug application, except for differences approved in the abbreviated new drug application or those differences resulting from:

(i) A patent on the listed drug issued after approval of the abbreviated new drug application; or

(ii) Exclusivity accorded to the listed drug after approval of the abbreviated new drug application that do not render the drug product less safe or effective than the listed drug for any remaining, nonprotected condition(s) of use.

(c) FDA will withdraw approval of an application or abbreviated application if the applicant requests its withdrawal because the drug subject to the application or abbreviated application is no longer being marketed, provided none of the conditions listed in paragraphs (a) and (b) of this section applies to the drug. FDA will consider a written request for a withdrawal under this paragraph to be a waiver of an opportunity for hearing otherwise provided for in this section. Withdrawal of approval of an application or abbreviated application under this paragraph is without prejudice to refiling.

(d) FDA may notify an applicant that it believes a potential problem associated with a drug is sufficiently serious that the drug should be removed from the market and may ask the applicant to waive the opportunity for hearing otherwise provided for under this section, to permit FDA to withdraw approval of the application or abbreviated application for the product, and to remove voluntarily the product from the market. If the applicant agrees, the agency will not make a finding under paragraph (b) of this section, but will withdraw approval of the application or abbreviated application in a notice published in the Federal Register that contains a brief summary of the agency's and the applicant's views of the reasons for withdrawal.

(a) Approval of an abbreviated new drug application approved under § 314.105(d) may be withdrawn when the agency withdraws approval, under § 314.150(a) or under this section, of the approved drug referred to in the abbreviated new drug application. If the agency proposed to withdraw approval of a listed drug under § 314.150(a), the holder of an approved application for the listed drug has a right to notice and opportunity for hearing. The published notice of opportunity for hearing will identify all drug products approved under § 314.105(d) whose applications are subject to withdrawal under this section if the listed drug is withdrawn, and will propose to withdraw such drugs. Holders of approved applications for the identified drug products will be provided notice and an opportunity to respond to the proposed withdrawal of their applications as described in paragraphs (b) and (c) of this section.

(b)(1) The published notice of opportunity for hearing on the withdrawal of the listed drug will serve as notice to holders of identified abbreviated new drug applications of the grounds for the proposed withdrawal.

(2) Holders of applications for drug products identified in the notice of opportunity for hearing may submit written comments on the notice of opportunity for hearing issued on the proposed withdrawal of the listed drug. If an abbreviated new drug application holder submits comments on the notice of opportunity for hearing and a hearing is granted, the abbreviated new drug application holder may participate in the hearing as a nonparty participant as provided for in § 12.89 of this chapter.

(3) Except as provided in paragraphs (c) and (d) of this section, the approval of an abbreviated new drug application for a drug product identified in the notice of opportunity for hearing on the withdrawal of a listed drug will be withdrawn when the agency has completed the withdrawal of approval of the listed drug.

(c)(1) If the holder of an application for a drug identified in the notice of opportunity for hearing has submitted timely comments but does not have an opportunity to participate in a hearing because a hearing is not requested or is settled, the submitted comments will be considered by the agency, which will issue an initial decision. The initial decision will respond to the comments, and contain the agency's decision whether there are grounds to withdraw approval of the listed drug and of the abbreviated new drug applications on which timely comments were submitted. The initial decision will be sent to each abbreviated new drug application holder that has submitted comments.

(2) Abbreviated new drug application holders to whom the initial decision was sent may, within 30 days of the issuance of the initial decision, submit written objections.

(3) The agency may, at its discretion, hold a limited oral hearing to resolve dispositive factual issues that cannot be resolved on the basis of written submissions.

(4) If there are no timely objections to the initial decision, it will become final at the expiration of 30 days.

(5) If timely objections are submitted, they will be reviewed and responded to in a final decision.

(6) The written comments received, the initial decision, the evidence relied on in the comments and in the initial decision, the objections to the initial decision, and, if a limited oral hearing has been held, the transcript of that hearing and any documents submitted therein, shall form the record upon which the agency shall make a final decision.

(7) Except as provided in paragraph (d) of this section, any abbreviated new drug application whose holder submitted comments on the notice of opportunity for hearing shall be withdrawn upon the issuance of a final decision concluding that the listed drug should be withdrawn for grounds as described in § 314.150(a). The final decision shall be in writing and shall constitute final agency action, reviewable in a judicial proceeding.

(8) Documents in the record will be publicly available in accordance with § 10.20(j) of this chapter. Documents available for examination or copying will be placed on public display in the Division of Dockets Management (HFA-305), Food and Drug Administration, room. 1-23, 12420 Parklawn Dr., Rockville, MD 20857, promptly upon receipt in that office.

(d) If the agency determines, based upon information submitted by the holder of an abbreviated new drug application, that the grounds for withdrawal of the listed drug are not applicable to a drug identified in the notice of opportunity for hearing, the final decision will state that the approval of the abbreviated new drug application for such drug is not withdrawn.

If the Food and Drug Administration withdraws approval of an application or abbreviated application for a new drug, FDA will publish a notice in the Federal Register announcing the withdrawal of approval. If the application or abbreviated application was withdrawn for grounds described in § 314.150(a) or § 314.151, the notice will announce the removal of the drug from the list of approved drugs published under section 505(j)(6) of the act and shall satisfy the requirement of § 314.162(b).

(a) Suspension of approval. The approval of an abbreviated new drug application approved under § 314.105(d) shall be suspended for the period stated when:

(1) The Secretary of the Department of Health and Human Services, under the imminent hazard authority of section 505(e) of the act or the authority of this paragraph, suspends approval of a listed drug referred to in the abbreviated new drug application, for the period of the suspension;

(2) The agency, in the notice described in paragraph (b) of this section, or in any subsequent written notice given an abbreviated new drug application holder by the agency, concludes that the risk of continued marketing and use of the drug is inappropriate, pending completion of proceedings to withdraw or suspend approval under § 314.151 or paragraph (b) of this section; or

(3) The agency, under the procedures set forth in paragraph (b) of this section, issues a final decision stating the determination that the abbreviated application is suspended because the listed drug on which the approval of the abbreviated new drug application depends has been withdrawn from sale for reasons of safety or effectiveness or has been suspended under paragraph (b) of this section. The suspension will take effect on the date stated in the decision and will remain in effect until the agency determines that the marketing of the drug has resumed or that the withdrawal is not for safety or effectiveness reasons.

(b) Procedures for suspension of abbreviated new drug applications when a listed drug is voluntarily withdrawn for safety or effectiveness reasons. (1) If a listed drug is voluntarily withdrawn from sale, and the agency determines that the withdrawal from sale was for reasons of safety or effectiveness, the agency will send each holder of an approved abbreviated new drug application that is subject to suspension as a result of this determination a copy of the agency's initial decision setting forth the reasons for the determination. The initial decision will also be placed on file with the Division of Dockets Management (HFA-305), Food and Drug Administration, room 1-23, 12420 Parklawn Dr., Rockville, MD 20857.

(2) Each abbreviated new drug application holder will have 30 days from the issuance of the initial decision to present, in writing, comments and information bearing on the initial decision. If no comments or information is received, the initial decision will become final at the expiration of 30 days.

(3) Comments and information received within 30 days of the issuance of the initial decision will be considered by the agency and responded to in a final decision.

(4) The agency may, in its discretion, hold a limited oral hearing to resolve dispositive factual issues that cannot be resolved on the basis of written submissions.

(5) If the final decision affirms the agency's initial decision that the listed drug was withdrawn for reasons of safety or effectiveness, the decision will be published in the Federal Register in compliance with § 314.152, and will, except as provided in paragraph (b)(6) of this section, suspend approval of all abbreviated new drug applications identified under paragraph (b)(1) of this section and remove from the list the listed drug and any drug whose approval was suspended under this paragraph. The notice will satisfy the requirement of § 314.162(b). The agency's final decision and copies of materials on which it relies will also be filed with the Division of Dockets Management (address in paragraph (b)(1) of this section).

(6) If the agency determines in its final decision that the listed drug was withdrawn for reasons of safety or effectiveness but, based upon information submitted by the holder of an abbreviated new drug application, also determines that the reasons for the withdrawal of the listed drug are not relevant to the safety and effectiveness of the drug subject to such abbreviated new drug application, the final decision will state that the approval of such abbreviated new drug application is not suspended.

(7) Documents in the record will be publicly available in accordance with § 10.20(j) of this chapter. Documents available for examination or copying will be placed on public display in the Division of Dockets Management (address in paragraph (b)(1) of this section) promptly upon receipt in that office.

Upon the Food and Drug Administration's own initiative or upon request of an applicant, FDA may, on the basis of new data, approve an application or abbreviated application which it had previously refused, suspended, or withdrawn approval. FDA will publish a notice in the Federal Register announcing the approval.

(a) A determination whether a listed drug that has been voluntarily withdrawn from sale was withdrawn for safety or effectiveness reasons may be made by the agency at any time after the drug has been voluntarily withdrawn from sale, but must be made:

(1) Prior to approving an abbreviated new drug application that refers to the listed drug;

(2) Whenever a listed drug is voluntarily withdrawn from sale and abbreviated new drug applications that referred to the listed drug have been approved; and

(3) When a person petitions for such a determination under §§ 10.25(a) and 10.30 of this chapter.

(b) Any person may petition under §§ 10.25(a) and 10.30 of this chapter for a determination whether a listed drug has been voluntarily withdrawn for safety or effectiveness reasons. Any such petition must contain all evidence available to the petitioner concerning the reason that the drug is withdrawn from sale.

(c) If the agency determines that a listed drug is withdrawn from sale for safety or effectiveness reasons, the agency will, except as provided in paragraph (d) of this section, publish a notice of the determination in the Federal Register.

(d) If the agency determines under paragraph (a) of this section that a listed drug is withdrawn from sale for safety and effectiveness reasons and there are approved abbreviated new drug applications that are subject to suspension under section 505(j)(5) of the act, FDA will initiate a proceeding in accordance with § 314.153(b).

(e) A drug that the agency determines is withdrawn for safety or effectiveness reasons will be removed from the list, under § 314.162. The drug may be relisted if the agency has evidence that marketing of the drug has resumed or that the withdrawal is not for safety or effectiveness reasons. A determination that the drug is not withdrawn for safety or effectiveness reasons may be made at any time after its removal from the list, upon the agency's initiative, or upon the submission of a petition under §§ 10.25(a) and 10.30 of this chapter. If the agency determines that the drug is not withdrawn for safety or effectiveness reasons, the agency shall publish a notice of this determination in the Federal Register. The notice will also announce that the drug is relisted, under § 314.162(c). The notice will also serve to reinstate approval of all suspended abbreviated new drug applications that referred to the listed drug.

(a) FDA will remove a previously approved new drug product from the list for the period stated when:

(1) The agency withdraws or suspends approval of a new drug application or an abbreviated new drug application under § 314.150(a) or § 314.151 or under the imminent hazard authority of section 505(e) of the act, for the same period as the withdrawal or suspension of the application; or

(2) The agency, in accordance with the procedures in § 314.153(b) or § 314.161, issues a final decision stating that the listed drug was withdrawn from sale for safety or effectiveness reasons, or suspended under § 314.153(b), until the agency determines that the withdrawal from the market has ceased or is not for safety or effectiveness reasons.

(b) FDA will publish in the Federal Register a notice announcing the removal of a drug from the list.

(c) At the end of the period specified in paragraph (a)(1) or (a)(2) of this section, FDA will relist a drug that has been removed from the list. The agency will publish in the Federal Register a notice announcing the relisting of the drug.

All drugs, including those the Food and Drug Administration approves under section 505 of the act and this part, are subject to the adulteration and misbranding provisions in sections 501, 502, and 503 of the act. FDA is authorized to regulate approved new drugs by regulations issued through informal rulemaking under sections 501, 502, and 503 of the act.

(a) Notice of opportunity for hearing. The Director of the Center for Drug Evaluation and Research, Food and Drug Administration, will give the applicant, and all other persons who manufacture or distribute identical, related, or similar drug products as defined in § 310.6 of this chapter, notice and an opportunity for a hearing on the Center's proposal to refuse to approve an application or to withdraw the approval of an application or abbreviated application under section 505(e) of the act. The notice will state the reasons for the action and the proposed grounds for the order.

(1) The notice may be general (that is, simply summarizing in a general way the information resulting in the notice) or specific (that is, either referring to specific requirements in the statute and regulations with which there is a lack of compliance, or providing a detailed description and analysis of the specific facts resulting in the notice).

(2) FDA will publish the notice in the Federal Register and will state that the applicant, and other persons subject to the notice under § 310.6, who wishes to participate in a hearing, has 30 days after the date of publication of the notice to file a written notice of participation and request for hearing. The applicant, or other persons subject to the notice under § 310.6, who fails to file a written notice of participation and request for hearing within 30 days, waives the opportunity for a hearing.

(3) It is the responsibility of every manufacturer and distributor of a drug product to review every notice of opportunity for a hearing published in the Federal Register to determine whether it covers any drug product that person manufactures or distributes. Any person may request an opinion of the applicability of a notice to a specific product that may be identical, related, or similar to a product listed in a notice by writing to the Division of New Drugs and Labeling Compliance, Office of Compliance, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002. A person shall request an opinion within 30 days of the date of publication of the notice to be eligible for an opportunity for a hearing under the notice. If a person requests an opinion, that person's time for filing an appearance and request for a hearing and supporting studies and analyses begins on the date the person receives the opinion from FDA.

(b) FDA will provide the notice of opportunity for a hearing to applicants and to other persons subject to the notice under § 310.6, as follows:

(1) To any person who has submitted an application or abbreviated application, by delivering the notice in person or by sending it by registered or certified mail to the last address shown in the application or abbreviated application.

(2) To any person who has not submitted an application or abbreviated application but who is subject to the notice under § 310.6 of this chapter, by publication of the notice in the Federal Register.

(c)(1) Notice of participation and request for a hearing, and submission of studies and comments. The applicant, or any other person subject to the notice under § 310.6, who wishes to participate in a hearing, shall file with the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852, (i) within 30 days after the date of the publication of the notice (or of the date of receipt of an opinion requested under paragraph (a)(3) of this section) a written notice of participation and request for a hearing and (ii) within 60 days after the date of publication of the notice, unless a different period of time is specified in the notice of opportunity for a hearing, the studies on which the person relies to justify a hearing as specified in paragraph (d) of this section. The applicant, or other person, may incorporate by reference the raw data underlying a study if the data were previously submitted to FDA as part of an application, abbreviated application, or other report.

(2) FDA will not consider data or analyses submitted after 60 days in determining whether a hearing is warranted unless they are derived from well-controlled studies begun before the date of the notice of opportunity for hearing and the results of the studies were not available within 60 days after the date of publication of the notice. Nevertheless, FDA may consider other studies on the basis of a showing by the person requesting a hearing of inadvertent omission and hardship. The person requesting a hearing shall list in the request for hearing all studies in progress, the results of which the person intends later to submit in support of the request for a hearing. The person shall submit under paragraph (c)(1)(ii) of this section a copy of the complete protocol, a list of the participating investigators, and a brief status report of the studies.

(3) Any other interested person who is not subject to the notice of opportunity for a hearing may also submit comments on the proposal to withdraw approval of the application or abbreviated application. The comments are requested to be submitted within the time and under the conditions specified in this section.

(d) The person requesting a hearing is required to submit under paragraph (c)(1)(ii) of this section the studies (including all protocols and underlying raw data) on which the person relies to justify a hearing with respect to the drug product. Except, a person who requests a hearing on the refusal to approve an application is not required to submit additional studies and analyses if the studies upon which the person relies have been submitted in the application and in the format and containing the summaries required under § 314.50.

(1) If the grounds for FDA's proposed action concern the effectiveness of the drug, each request for hearing is required to be supported only by adequate and well-controlled clinical studies meeting all of the precise requirements of § 314.126 and, for combination drug products, § 300.50, or by other studies not meeting those requirements for which a waiver has been previously granted by FDA under § 314.126. Each person requesting a hearing shall submit all adequate and well-controlled clinical studies on the drug product, including any unfavorable analyses, views, or judgments with respect to the studies. No other data, information, or studies may be submitted.

(2) The submission is required to include a factual analysis of all the studies submitted. If the grounds for FDA's proposed action concern the effectiveness of the drug, the analysis is required to specify how each study accords, on a point-by-point basis, with each criterion required for an adequate well-controlled clinical investigation established under § 314.126 and, if the product is a combination drug product, with each of the requirements for a combination drug established in § 300.50, or the study is required to be accompanied by an appropriate waiver previously granted by FDA. If a study concerns a drug or dosage form or condition of use or mode of administration other than the one in question, that fact is required to be clearly stated. Any study conducted on the final marketed form of the drug product is required to be clearly identified.

(3) Each person requesting a hearing shall submit an analysis of the data upon which the person relies, except that the required information relating either to safety or to effectiveness may be omitted if the notice of opportunity for hearing does not raise any issue with respect to that aspect of the drug; information on compliance with § 300.50 may be omitted if the drug product is not a combination drug product. A financial certification or disclosure statement or both as required by part 54 of this chapter must accompany all clinical data submitted. FDA can most efficiently consider submissions made in the following format.

(e) Contentions that a drug product is not subject to the new drug requirements. A notice of opportunity for a hearing encompasses all issues relating to the legal status of each drug product subject to it, including identical, related, and similar drug products as defined in § 310.6. A notice of appearance and request for a hearing under paragraph (c)(1)(i) of this section is required to contain any contention that the product is not a new drug because it is generally recognized as safe and effective within the meaning of section 201(p) of the act, or because it is exempt from part or all of the new drug provisions of the act under the exemption for products marketed before June 25, 1938, contained in section 201(p) of the act or under section 107(c) of the Drug Amendments of 1962, or for any other reason. Each contention is required to be supported by a submission under paragraph (c)(1)(ii) of this section and the Commissioner of Food and Drugs will make an administrative determination on each contention. The failure of any person subject to a notice of opportunity for a hearing, including any person who manufactures or distributes an identical, related, or similar drug product as defined in § 310.6, to submit a notice of participation and request for hearing or to raise all such contentions constitutes a waiver of any contentions not raised.

(1) A contention that a drug product is generally recognized as safe and effective within the meaning of section 201(p) of the act is required to be supported by submission of the same quantity and quality of scientific evidence that is required to obtain approval of an application for the product, unless FDA has waived a requirement for effectiveness (under § 314.126) or safety, or both. The submission should be in the format and with the analyses required under paragraph (d) of this section. A person who fails to submit the required scientific evidence required under paragraph (d) waives the contention. General recognition of safety and effectiveness shall ordinarily be based upon published studies which may be corroborated by unpublished studies and other data and information.

(2) A contention that a drug product is exempt from part or all of the new drug provisions of the act under the exemption for products marketed before June 25, 1938, contained in section 201(p) of the act, or under section 107(c) of the Drug Amendments of 1962, is required to be supported by evidence of past and present quantitative formulas, labeling, and evidence of marketing. A person who makes such a contention should submit the formulas, labeling, and evidence of marketing in the following format.

(3) The Food and Drug Administration will not find a drug product, including any active ingredient, which is identical, related, or similar, as described in § 310.6, to a drug product, including any active ingredient for which an application is or at any time has been effective or deemed approved, or approved under section 505 of the act, to be exempt from part or all of the new drug provisions of the act.

(4) A contention that a drug product is not a new drug for any other reason is required to be supported by submission of the factual records, data, and information that are necessary and appropriate to support the contention.

(5) It is the responsibility of every person who manufactures or distributes a drug product in reliance upon a “grandfather” provision of the act to maintain files that contain the data and information necessary fully to document and support that status.

(f) Separation of functions. Separation of functions commences upon receipt of a request for hearing. The Director of the Center for Drug Evaluation and Research, Food and Drug Administration, will prepare an analysis of the request and a proposed order ruling on the matter. The analysis and proposed order, the request for hearing, and any proposed order denying a hearing and response under paragraph (g) (2) or (3) of this section will be submitted to the Office of the Commissioner of Food and Drugs for review and decision. When the Center for Drug Evaluation and Research recommends denial of a hearing on all issues on which a hearing is requested, no representative of the Center will participate or advise in the review and decision by the Commissioner. When the Center for Drug Evaluation and Research recommends that a hearing be granted on one or more issues on which a hearing is requested, separation of functions terminates as to those issues, and representatives of the Center may participate or advise in the review and decision by the Commissioner on those issues. The Commissioner may modify the text of the issues, but may not deny a hearing on those issues. Separation of functions continues with respect to issues on which the Center for Drug Evaluation and Research has recommended denial of a hearing. The Commissioner will neither evaluate nor rule on the Center's recommendation on such issues and such issues will not be included in the notice of hearing. Participants in the hearing may make a motion to the presiding officer for the inclusion of any such issue in the hearing. The ruling on such a motion is subject to review in accordance with § 12.35(b). Failure to so move constitutes a waiver of the right to a hearing on such an issue. Separation of functions on all issues resumes upon issuance of a notice of hearing. The Office of the General Counsel, Department of Health and Human Services, will observe the same separation of functions.

(g) Summary judgment. A person who requests a hearing may not rely upon allegations or denials but is required to set forth specific facts showing that there is a genuine and substantial issue of fact that requires a hearing with respect to a particular drug product specified in the request for hearing.

(1) Where a specific notice of opportunity for hearing (as defined in paragraph (a)(1) of this section) is used, the Commissioner will enter summary judgment against a person who requests a hearing, making findings and conclusions, denying a hearing, if it conclusively appears from the face of the data, information, and factual analyses in the request for the hearing that there is no genuine and substantial issue of fact which precludes the refusal to approve the application or abbreviated application or the withdrawal of approval of the application or abbreviated application; for example, no adequate and well-controlled clinical investigations meeting each of the precise elements of § 314.126 and, for a combination drug product, § 300.50 of this chapter, showing effectiveness have been identified. Any order entering summary judgment is required to set forth the Commissioner's findings and conclusions in detail and is required to specify why each study submitted fails to meet the requirements of the statute and regulations or why the request for hearing does not raise a genuine and substantial issue of fact.

(2) When following a general notice of opportunity for a hearing (as defined in paragraph (a)(1) of this section) the Director of the Center for Drug Evaluation and Research concludes that summary judgment against a person requesting a hearing should be considered, the Director will serve upon the person requesting a hearing by registered mail a proposed order denying a hearing. This person has 60 days after receipt of the proposed order to respond with sufficient data, information, and analyses to demonstrate that there is a genuine and substantial issue of fact which justifies a hearing.

(3) When following a general or specific notice of opportunity for a hearing a person requesting a hearing submits data or information of a type required by the statute and regulations, and the Director of the Center for Drug Evaluation and Research concludes that summary judgment against the person should be considered, the Director will serve upon the person by registered mail a proposed order denying a hearing. The person has 60 days after receipt of the proposed order to respond with sufficient data, information, and analyses to demonstrate that there is a genuine and substantial issue of fact which justifies a hearing.

(4) If review of the data, information, and analyses submitted show that the grounds cited in the notice are not valid, for example, that substantial evidence of effectiveness exists, the Commissioner will enter summary judgment for the person requesting the hearing, and rescind the notice of opportunity for hearing.

(5) If the Commissioner grants a hearing, it will begin within 90 days after the expiration of the time for requesting the hearing unless the parties otherwise agree in the case of denial of approval, and as soon as practicable in the case of withdrawal of approval.

(6) The Commissioner will grant a hearing if there exists a genuine and substantial issue of fact or if the Commissioner concludes that a hearing would otherwise be in the public interest.

(7) If the manufacturer or distributor of an identical, related, or similar drug product requests and is granted a hearing, the hearing may consider whether the product is in fact identical, related, or similar to the drug product named in the notice of opportunity for a hearing.

(8) A request for a hearing, and any subsequent grant or denial of a hearing, applies only to the drug products named in such documents.

(h) FDA will issue a notice withdrawing approval and declaring all products unlawful for drug products subject to a notice of opportunity for a hearing, including any identical, related, or similar drug product under § 310.6, for which an opportunity for a hearing is waived or for which a hearing is denied. The Commissioner may defer or stay the action pending a ruling on any related request for a hearing or pending any related hearing or other administrative or judicial proceeding.

Parts 10 through 16 apply to hearings relating to new drugs under section 505 (d) and (e) of the act.

(a) The Commissioner of Food and Drugs will certify the transcript and record. In any case in which the Commissioner enters an order without a hearing under § 314.200(g), the record certified by the Commissioner is required to include the requests for hearing together with the data and information submitted and the Commissioner's findings and conclusion.

(b) A manufacturer or distributor of an identical, related, or similar drug product under § 310.6 may seek judicial review of an order withdrawing approval of a new drug application, whether or not a hearing has been held, in a United States court of appeals under section 505(h) of the act.

(a) Imports. (1) A new drug may be imported into the United States if: (i) It is the subject of an approved application under this part; or (ii) it complies with the regulations pertaining to investigational new drugs under part 312; and it complies with the general regulations pertaining to imports under subpart E of part 1.

(2) A drug substance intended for use in the manufacture, processing, or repacking of a new drug may be imported into the United States if it complies with the labeling exemption in § 201.122 pertaining to shipments of drug substances in domestic commerce.

(b) Exports. (1) A new drug may be exported if it is the subject of an approved application under this part or it complies with the regulations pertaining to investigational new drugs under part 312.

(2) A new drug substance that is covered by an application approved under this part for use in the manufacture of an approved drug product may be exported by the applicant or any person listed as a supplier in the approved application, provided the drug substance intended for export meets the specification of, and is shipped with a copy of the labeling required for, the approved drug product.

(3) Insulin or an antibiotic drug may be exported without regard to the requirements in section 802 of the act if the insulin or antibiotic drug meets the requirements of section 801(e)(1) of the act.

(a) A drug master file is a submission of information to the Food and Drug Administration by a person (the drug master file holder) who intends it to be used for one of the following purposes: To permit the holder to incorporate the information by reference when the holder submits an investigational new drug application under part 312 or submits an application or an abbreviated application or an amendment or supplement to them under this part, or to permit the holder to authorize other persons to rely on the information to support a submission to FDA without the holder having to disclose the information to the person. FDA ordinarily neither independently reviews drug master files nor approves or disapproves submissions to a drug master file. Instead, the agency customarily reviews the information only in the context of an application under part 312 or this part. A drug master file may contain information of the kind required for any submission to the agency, including information about the following:

(1) [Reserved]

(2) Drug substance, drug substance intermediate, and materials used in their preparation, or drug product;

(3) Packaging materials;

(4) Excipient, colorant, flavor, essence, or materials used in their preparation;

(5) FDA-accepted reference information. (A person wishing to submit information and supporting data in a drug master file (DMF) that is not covered by Types II through IV DMF's must first submit a letter of intent to the Drug Master File Staff, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266.) FDA will then contact the person to discuss the proposed submission.

(b) An investigational new drug application or an application, abbreviated application, amendment, or supplement may incorporate by reference all or part of the contents of any drug master file in support of the submission if the holder authorizes the incorporation in writing. Each incorporation by reference is required to describe the incorporated material by name, reference number, volume, and page number of the drug master file.

(c) A drug master file is required to be submitted in two copies. The agency has prepared guidance that provides information about how to prepare a well-organized drug master file. If the drug master file holder adds, changes, or deletes any information in the file, the holder shall notify in writing, each person authorized to reference that information. Any addition, change, or deletion of information in a drug master file (except the list required under paragraph (d) of this section) is required to be submitted in two copies and to describe by name, reference number, volume, and page number the information affected in the drug master file.

(d) The drug master file is required to contain a complete list of each person currently authorized to incorporate by reference any information in the file, identifying by name, reference number, volume, and page number the information that each person is authorized to incorporate. If the holder restricts the authorization to particular drug products, the list is required to include the name of each drug product and the application number, if known, to which the authorization applies.

(e) The public availability of data and information in a drug master file, including the availability of data and information in the file to a person authorized to reference the file, is determined under part 20 and § 314.430.

(a) The Food and Drug Administration will determine the public availability of any part of an application or abbreviated application under this section and part 20 of this chapter. For purposes of this section, the application or abbreviated application includes all data and information submitted with or incorporated by reference in the application or abbreviated application, including investigational new drug applications, drug master files under § 314.420, supplements submitted under § 314.70 or § 314.97, reports under § 314.80 or § 314.98, and other submissions. For purposes of this section, safety and effectiveness data include all studies and tests of a drug on animals and humans and all studies and tests of the drug for identity, stability, purity, potency, and bioavailability.

(b) FDA will not publicly disclose the existence of an application or abbreviated application before an approval letter is sent to the applicant under § 314.105 or tentative approval letter is sent to the applicant under § 314.107, unless the existence of the application or abbreviated application has been previously publicly disclosed or acknowledged.

(c) If the existence of an unapproved application or abbreviated application has not been publicly disclosed or acknowledged, no data or information in the application or abbreviated application is available for public disclosure.

(d)(1) If the existence of an application or abbreviated application has been publicly disclosed or acknowledged before the agency sends an approval letter to the applicant, no data or information contained in the application or abbreviated application is available for public disclosure before the agency sends an approval letter, but the Commissioner may, in his or her discretion, disclose a summary of selected portions of the safety and effectiveness data that are appropriate for public consideration of a specific pending issue; for example, for consideration of an open session of an FDA advisory committee.

(2) Notwithstanding paragraph (d)(1) of this section, FDA will make available to the public upon request the information in the investigational new drug application that was required to be filed in Docket Number 95S-0158 in the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852, for investigations involving an exception from informed consent under § 50.24 of this chapter. Persons wishing to request this information shall submit a request under the Freedom of Information Act.

(e) After FDA sends an approval letter to the applicant, the following data and information in the application or abbreviated application are immediately available for public disclosure, unless the applicant shows that extraordinary circumstances exist. A list of approved applications and abbreviated applications, entitled “Approved Drug Products with Therapeutic Equivalence Evaluations,” is available from the Government Printing Office, Washington, DC 20402. This list is updated monthly.

(1) [Reserved]

(2) If the application applies to a new drug, all safety and effectiveness data previously disclosed to the public as set forth in § 20.81 and a summary or summaries of the safety and effectiveness data and information submitted with or incorporated by reference in the application. The summaries do not constitute the full reports of investigations under section 505(b)(1) of the act (21 U.S.C. 355(b)(1)) on which the safety or effectiveness of the drug may be approved. The summaries consist of the following:

(i) For an application approved before July 1, 1975, internal agency records that describe safety and effectiveness data and information, for example, a summary of the basis for approval or internal reviews of the data and information, after deletion of the following:

(a) Names and any information that would identify patients or test subjects or investigators.

(b) Any inappropriate gratuitous comments unnecessary to an objective analysis of the data and information.

(ii) For an application approved on or after July 1, 1975, a Summary Basis of Approval (SBA) document that contains a summary of the safety and effectiveness data and information evaluated by FDA during the drug approval process. The SBA is prepared in one of the following ways:

(a) Before approval of the application, the applicant may prepare a draft SBA which the Center for Drug Evaluation and Research will review and may revise. The draft may be submitted with the application or as an amendment.

(b) The Center for Drug Evaluation and Research may prepare the SBA.

(3) A protocol for a test or study, unless it is shown to fall within the exemption established for trade secrets and confidential commercial information in § 20.61.

(4) Adverse reaction reports, product experience reports, consumer complaints, and other similar data and information after deletion of the following:

(i) Names and any information that would identify the person using the product.

(ii) Names and any information that would identify any third party involved with the report, such as a physician or hospital or other institution.

(5) A list of all active ingredients and any inactive ingredients previously disclosed to the public as set forth in § 20.81.

(6) An assay procedure or other analytical procedure, unless it serves no regulatory or compliance purpose and is shown to fall within the exemption established for trade secrets and confidential commercial information in § 20.61.

(7) All correspondence and written summaries of oral discussions between FDA and the applicant relating to the application, under the provisions of part 20.

(f) All safety and effectiveness data and information which have been submitted in an application and which have not previously been disclosed to the public are available to the public, upon request, at the time any one of the following events occurs unless extraordinary circumstances are shown:

(1) No work is being or will be undertaken to have the application approved.

(2) A final determination is made that the application is not approvable and all legal appeals have been exhausted.

(3) Approval of the application is withdrawn and all legal appeals have been exhausted.

(4) A final determination has been made that the drug is not a new drug.

(5) For applications submitted under section 505(b) of the act, the effective date of the approval of the first abbreviated application submitted under section 505(j) of the act which refers to such drug, or the date on which the approval of an abbreviated application under section 505(j) of the act which refers to such drug could be made effective if such an abbreviated application had been submitted.

(6) For abbreviated applications submitted under section 505(j) of the act, when FDA sends an approval letter to the applicant.

(g) The following data and information in an application or abbreviated application are not available for public disclosure unless they have been previously disclosed to the public as set forth in § 20.81 of this chapter or they relate to a product or ingredient that has been abandoned and they do not represent a trade secret or confidential commercial or financial information under § 20.61 of this chapter:

(1) Manufacturing methods or processes, including quality control procedures.

(2) Production, sales distribution, and similar data and information, except that any compilation of that data and information aggregated and prepared in a way that does not reveal data or information which is not available for public disclosure under this provision is available for public disclosure.

(3) Quantitative or semiquantitative formulas.

(h) The compilations of information specified in § 20.117 are available for public disclosure.

(a) Applicants shall send applications, abbreviated applications, and other correspondence relating to matters covered by this part, except for products listed in paragraph (b) of this section, to the appropriate office identified below:

(1) Except as provided in paragraph (a)(4) of this section, an application under § 314.50 or § 314.54 submitted for filing should be directed to the Central Document Room, 5901-B Ammendale Rd., Beltsville, MD 20705-1266. Applicants may obtain information about folders for binding applications on the Internet at http://www.fda.gov/cder/ddms/binders.htm. After FDA has filed the application, the agency will inform the applicant which division is responsible for the application. Amendments, supplements, resubmissions, requests for waivers, and other correspondence about an application that has been filed should be addressed to 5901-B Ammendale Rd., Beltsville, MD 20705-1266, to the attention of the appropriate division.

(2) Except as provided in paragraph (a)(4) of this section, an abbreviated application under § 314.94, and amendments, supplements, and resubmissions should be directed to the Central Document Room, Center for Drug Evaluation and Research, Food and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266. This includes items sent by parcel post or overnight courier service. Correspondence not associated with an abbreviated application also should be addressed to 5901-B Ammendale Rd., Beltsville, MD 20705-1266.

(3) A request for an opportunity for a hearing under § 314.110 on the question of whether there are grounds for denying approval of an application, except an application under paragraph (b) of this section, should be directed to the Associate Director for Policy (HFD-5).

(4) The field copy of an application, an abbreviated application, amendments, supplements, resubmissions, requests for waivers, and other correspondence about an application and an abbreviated application shall be sent to the applicant's home FDA district office, except that a foreign applicant shall send the field copy to the appropriate address identified in paragraphs (a)(1) and (a)(2) of this section.

(b) Applicants shall send applications and other correspondence relating to matters covered by this part for the drug products listed below to the Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002, except applicants shall send a request for an opportunity for a hearing under § 314.110 on the question of whether there are grounds for denying approval of an application to the Center for Biologics Evaluation and Research, ATTN: Director, at the same address.

(1) Ingredients packaged together with containers intended for the collection, processing, or storage of blood and blood components;

(2) Plasma volume expanders and hydroxyethyl starch for leukapheresis;

(3) Blood component processing solutions and shelf life extenders; and

(4) Oxygen carriers.

(a) FDA has made available guidance documents under § 10.115 of this chapter to help you to comply with certain requirements of this part.

(b) The Center for Drug Evaluation and Research (CDER) maintains a list of guidance documents that apply to CDER's regulations. The list is maintained on the Internet and is published annually in the Federal Register. A request for a copy of the CDER list should be directed to the Office of Training and Communications, Division of Drug Information, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002.

This subpart applies to certain new drug products that have been studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments (e.g., ability to treat patients unresponsive to, or intolerant of, available therapy, or improved patient response over available therapy).

FDA may grant marketing approval for a new drug product on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity. Approval under this section will be subject to the requirement that the applicant study the drug further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome. Postmarketing studies would usually be studies already underway. When required to be conducted, such studies must also be adequate and well-controlled. The applicant shall carry out any such studies with due diligence.

(a) If FDA concludes that a drug product shown to be effective can be safely used only if distribution or use is restricted, FDA will require such postmarketing restrictions as are needed to assure safe use of the drug product, such as:

(1) Distribution restricted to certain facilities or physicians with special training or experience; or

(2) Distribution conditioned on the performance of specified medical procedures.

(b) The limitations imposed will be commensurate with the specific safety concerns presented by the drug product.

(a) For new drugs approved under §§ 314.510 and 314.520, FDA may withdraw approval, following a hearing as provided in part 15 of this chapter, as modified by this section, if:

(1) A postmarketing clinical study fails to verify clinical benefit;

(2) The applicant fails to perform the required postmarketing study with due diligence;

(3) Use after marketing demonstrates that postmarketing restrictions are inadequate to assure safe use of the drug product;

(4) The applicant fails to adhere to the postmarketing restrictions agreed upon;

(5) The promotional materials are false or misleading; or

(6) Other evidence demonstrates that the drug product is not shown to be safe or effective under its conditions of use.

(b) Notice of opportunity for a hearing. The Director of the Center for Drug Evaluation and Research will give the applicant notice of an opportunity for a hearing on the Center's proposal to withdraw the approval of an application approved under § 314.510 or § 314.520. The notice, which will ordinarily be a letter, will state generally the reasons for the action and the proposed grounds for the order.

(c) Submission of data and information. (1) If the applicant fails to file a written request for a hearing within 15 days of receipt of the notice, the applicant waives the opportunity for a hearing.

(2) If the applicant files a timely request for a hearing, the agency will publish a notice of hearing in the Federal Register in accordance with §§ 12.32(e) and 15.20 of this chapter.

(3) An applicant who requests a hearing under this section must, within 30 days of receipt of the notice of opportunity for a hearing, submit the data and information upon which the applicant intends to rely at the hearing.

(d) Separation of functions. Separation of functions (as specified in § 10.55 of this chapter) will not apply at any point in withdrawal proceedings under this section.

(e) Procedures for hearings. Hearings held under this section will be conducted in accordance with the provisions of part 15 of this chapter, with the following modifications:

(1) An advisory committee duly constituted under part 14 of this chapter will be present at the hearing. The committee will be asked to review the issues involved and to provide advice and recommendations to the Commissioner of Food and Drugs.

(2) The presiding officer, the advisory committee members, up to three representatives of the applicant, and up to three representatives of the Center may question any person during or at the conclusion of the person's presentation. No other person attending the hearing may question a person making a presentation. The presiding officer may, as a matter of discretion, permit questions to be submitted to the presiding officer for response by a person making a presentation.

(f) Judicial review. The Commissioner's decision constitutes final agency action from which the applicant may petition for judicial review. Before requesting an order from a court for a stay of action pending review, an applicant must first submit a petition for a stay of action under § 10.35 of this chapter.

Drug products approved under this program are subject to the postmarketing recordkeeping and safety reporting applicable to all approved drug products, as provided in §§ 314.80 and 314.81.

For drug products being considered for approval under this subpart, unless otherwise informed by the agency, applicants must submit to the agency for consideration during the preapproval review period copies of all promotional materials, including promotional labeling as well as advertisements, intended for dissemination or publication within 120 days following marketing approval. After 120 days following marketing approval, unless otherwise informed by the agency, the applicant must submit promotional materials at least 30 days prior to the intended time of initial dissemination of the labeling or initial publication of the advertisement.

If FDA determines after approval that the requirements established in § 314.520, § 314.530, or § 314.550 are no longer necessary for the safe and effective use of a drug product, it will so notify the applicant. Ordinarily, for drug products approved under § 314.510, these requirements will no longer apply when FDA determines that the required postmarketing study verifies and describes the drug product's clinical benefit and the drug product would be appropriate for approval under traditional procedures. For drug products approved under § 314.520, the restrictions would no longer apply when FDA determines that safe use of the drug product can be assured through appropriate labeling. FDA also retains the discretion to remove specific postapproval requirements upon review of a petition submitted by the sponsor in accordance with § 10.30.

This subpart applies to certain new drug products that have been studied for their safety and efficacy in ameliorating or preventing serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substances. This subpart applies only to those new drug products for which: Definitive human efficacy studies cannot be conducted because it would be unethical to deliberately expose healthy human volunteers to a lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substance; and field trials to study the product's effectiveness after an accidental or hostile exposure have not been feasible. This subpart does not apply to products that can be approved based on efficacy standards described elsewhere in FDA's regulations (e.g., accelerated approval based on surrogate markers or clinical endpoints other than survival or irreversible morbidity), nor does it address the safety evaluation for the products to which it does apply.

(a) FDA may grant marketing approval for a new drug product for which safety has been established and for which the requirements of § 314.600 are met based on adequate and well-controlled animal studies when the results of those animal studies establish that the drug product is reasonably likely to produce clinical benefit in humans. In assessing the sufficiency of animal data, the agency may take into account other data, including human data, available to the agency. FDA will rely on the evidence from studies in animals to provide substantial evidence of the effectiveness of these products only when:

(1) There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product;

(2) The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans;

(3) The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity; and

(4) The data or information on the kinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans, allows selection of an effective dose in humans.

(b) Approval under this subpart will be subject to three requirements:

(1) Postmarketing studies. The applicant must conduct postmarketing studies, such as field studies, to verify and describe the drug's clinical benefit and to assess its safety when used as indicated when such studies are feasible and ethical. Such postmarketing studies would not be feasible until an exigency arises. When such studies are feasible, the applicant must conduct such studies with due diligence. Applicants must include as part of their application a plan or approach to postmarketing study commitments in the event such studies become ethical and feasible.

(2) Approval with restrictions to ensure safe use. If FDA concludes that a drug product shown to be effective under this subpart can be safely used only if distribution or use is restricted, FDA will require such postmarketing restrictions as are needed to ensure safe use of the drug product, commensurate with the specific safety concerns presented by the drug product, such as:

(i) Distribution restricted to certain facilities or health care practitioners with special training or experience;

(ii) Distribution conditioned on the performance of specified medical procedures, including medical followup; and

(iii) Distribution conditioned on specified recordkeeping requirements.

(3) Information to be provided to patient recipients. For drug products or specific indications approved under this subpart, applicants must prepare, as part of their proposed labeling, labeling to be provided to patient recipients. The patient labeling must explain that, for ethical or feasibility reasons, the drug's approval was based on efficacy studies conducted in animals alone and must give the drug's indication(s), directions for use (dosage and administration), contraindications, a description of any reasonably foreseeable risks, adverse reactions, anticipated benefits, drug interactions, and any other relevant information required by FDA at the time of approval. The patient labeling must be available with the product to be provided to patients prior to administration or dispensing of the drug product for the use approved under this subpart, if possible.

(a) Reasons to withdraw approval. For new drugs approved under this subpart, FDA may withdraw approval, following a hearing as provided in part 15 of this chapter, as modified by this section, if:

(1) A postmarketing clinical study fails to verify clinical benefit;

(2) The applicant fails to perform the postmarketing study with due diligence;

(3) Use after marketing demonstrates that postmarketing restrictions are inadequate to ensure safe use of the drug product;

(4) The applicant fails to adhere to the postmarketing restrictions applied at the time of approval under this subpart;

(5) The promotional materials are false or misleading; or

(6) Other evidence demonstrates that the drug product is not shown to be safe or effective under its conditions of use.

(b) Notice of opportunity for a hearing. The Director of the Center for Drug Evaluation and Research (CDER) will give the applicant notice of an opportunity for a hearing on CDER's proposal to withdraw the approval of an application approved under this subpart. The notice, which will ordinarily be a letter, will state generally the reasons for the action and the proposed grounds for the order.

(c) Submission of data and information. (1) If the applicant fails to file a written request for a hearing within 15 days of receipt of the notice, the applicant waives the opportunity for a hearing.

(2) If the applicant files a timely request for a hearing, the agency will publish a notice of hearing in the Federal Register in accordance with §§ 12.32(e) and 15.20 of this chapter.

(3) An applicant who requests a hearing under this section must, within 30 days of receipt of the notice of opportunity for a hearing, submit the data and information upon which the applicant intends to rely at the hearing.

(d) Separation of functions. Separation of functions (as specified in § 10.55 of this chapter) will not apply at any point in withdrawal proceedings under this section.

(e) Procedures for hearings. Hearings held under this section will be conducted in accordance with the provisions of part 15 of this chapter, with the following modifications:

(1) An advisory committee duly constituted under part 14 of this chapter will be present at the hearing. The committee will be asked to review the issues involved and to provide advice and recommendations to the Commissioner of Food and Drugs.

(2) The presiding officer, the advisory committee members, up to three representatives of the applicant, and up to three representatives of CDER may question any person during or at the conclusion of the person's presentation. No other person attending the hearing may question a person making a presentation. The presiding officer may, as a matter of discretion, permit questions to be submitted to the presiding officer for response by a person making a presentation.

(f) Judicial review. The Commissioner of Food and Drugs' decision constitutes final agency action from which the applicant may petition for judicial review. Before requesting an order from a court for a stay of action pending review, an applicant must first submit a petition for a stay of action under § 10.35 of this chapter.

Drug products approved under this subpart are subject to the postmarketing recordkeeping and safety reporting requirements applicable to all approved drug products, as provided in §§ 314.80 and 314.81.

For drug products being considered for approval under this subpart, unless otherwise informed by the agency, applicants must submit to the agency for consideration during the preapproval review period copies of all promotional materials, including promotional labeling as well as advertisements, intended for dissemination or publication within 120 days following marketing approval. After 120 days following marketing approval, unless otherwise informed by the agency, the applicant must submit promotional materials at least 30 days prior to the intended time of initial dissemination of the labeling or initial publication of the advertisement.

If FDA determines after approval under this subpart that the requirements established in §§ 314.610(b)(2), 314.620, and 314.630 are no longer necessary for the safe and effective use of a drug product, FDA will so notify the applicant. Ordinarily, for drug products approved under § 314.610, these requirements will no longer apply when FDA determines that the postmarketing study verifies and describes the drug product's clinical benefit. For drug products approved under § 314.610, the restrictions would no longer apply when FDA determines that safe use of the drug product can be ensured through appropriate labeling. FDA also retains the discretion to remove specific postapproval requirements upon review of a petition submitted by the sponsor in accordance with § 10.30 of this chapter.

(a) This part implements sections 525, 526, 527, and 528 of the act and provides procedures to encourage and facilitate the development of drugs for rare diseases or conditions, including biological products and antibiotics. This part sets forth the procedures and requirements for:

(1) Submissions to FDA of:

(i) Requests for recommendations for investigations of drugs for rare diseases or conditions;

(ii) Requests for designation of a drug for a rare disease or condition; and

(iii) Requests for gaining exclusive approval for a drug for a rare disease or condition.

(2) Allowing a sponsor to provide an investigational drug under a treatment protocol to patients who need the drug for treatment of a rare disease or condition.

(b) This part does not apply to food, medical devices, or drugs for veterinary use.

(c) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21, unless otherwise noted.

The purpose of this part is to establish standards and procedures for determining eligibility for the benefits provided for in section 2 of the Orphan Drug Act, including written recommendations for investigations of orphan drugs, a 7-year period of exclusive marketing, and treatment use of investigational orphan drugs. This part is also intended to satisfy Congress' requirements that FDA promulgate procedures for the implementation of sections 525(a) and 526(a) of the act.

(a) The definitions and interpretations contained in section 201 of the act apply to those terms when used in this part.

(b) The following definitions of terms apply to this part:

(1) Act means the Federal Food, Drug, and Cosmetic Act as amended by section 2 of the Orphan Drug Act (sections 525-528 (21 U.S.C. 360aa-360dd)).

(2) Active moiety means the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.

(3) Clinically superior means that a drug is shown to provide a significant therapeutic advantage over and above that provided by an approved drug (that is otherwise the same drug) in one or more of the following ways:

(i) Greater effectiveness than an approved drug (as assessed by effect on a clinically meaningful endpoint in adequate and well controlled clinical trials). Generally, this would represent the same kind of evidence needed to support a comparative effectiveness claim for two different drugs; in most cases, direct comparative clinical trials would be necessary; or

(ii) Greater safety in a substantial portion of the target populations, for example, by the elimination of an ingredient or contaminant that is associated with relatively frequent adverse effects. In some cases, direct comparative clinical trials will be necessary; or

(iii) In unusual cases, where neither greater safety nor greater effectiveness has been shown, a demonstration that the drug otherwise makes a major contribution to patient care.

(4) Director means the Director of FDA's Office of Orphan Products Development.

(5) FDA means the Food and Drug Administration.

(6) Holder means the sponsor in whose name an orphan drug is designated and approved.

(7) IND means an investigational new drug application under part 312 of this chapter.

(8) Manufacturer means any person or agency engaged in the manufacture of a drug that is subject to investigation and approval under the act or the biologics provisions of the Public Health Service Act (42 U.S.C. 262-263).

(9) Marketing application means an application for approval of a new drug filed under section 505(b) of the act or an application for a biologics license submitted under section 351 of the Public Health Service Act (42 U.S.C. 262).

(10) Orphan drug means a drug intended for use in a rare disease or condition as defined in section 526 of the act.

(11) Orphan-drug designation means FDA's act of granting a request for designation under section 526 of the act.

(12) Orphan-drug exclusive approval or exclusive approval means that, effective on the date of FDA approval as stated in the approval letter of a marketing application for a sponsor of a designated orphan drug, no approval will be given to a subsequent sponsor of the same drug for the same use or indication for 7 years, except as otherwise provided by law or in this part. A designated drug will receive orphan-drug exclusive approval only if the same drug has not already been approved for the same use or indication.

(13) Orphan subset of a non-rare disease or condition (“orphan subset”) means that use of the drug in a subset of persons with a non-rare disease or condition may be appropriate but use of the drug outside of that subset (in the remaining persons with the non-rare disease or condition) would be inappropriate owing to some property(ies) of the drug, for example, drug toxicity, mechanism of action, or previous clinical experience with the drug.

(14) Same drug means:

(i) If it is a drug composed of small molecules, a drug that contains the same active moiety as a previously approved drug and is intended for the same use as the previously approved drug, even if the particular ester or salt (including a salt with hydrogen or coordination bonds) or other noncovalent derivative such as a complex, chelate or clathrate has not been previously approved, except that if the subsequent drug can be shown to be clinically superior to the first drug, it will not be considered to be the same drug.

(ii) If it is a drug composed of large molecules (macromolecules), a drug that contains the same principal molecular structural features (but not necessarily all of the same structural features) and is intended for the same use as a previously approved drug, except that, if the subsequent drug can be shown to be clinically superior, it will not be considered to be the same drug. This criterion will be applied as follows to different kinds of macromolecules:

(A) Two protein drugs would be considered the same if the only differences in structure between them were due to post-translational events or infidelity of translation or transcription or were minor differences in amino acid sequence; other potentially important differences, such as different glycosylation patterns or different tertiary structures, would not cause the drugs to be considered different unless the differences were shown to be clinically superior.

(B) Two polysaccharide drugs would be considered the same if they had identical saccharide repeating units, even if the number of units were to vary and even if there were postpolymerization modifications, unless the subsequent drug could be shown to be clinically superior.

(C) Two polynucleotide drugs consisting of two or more distinct nucleotides would be considered the same if they had an identical sequence of purine and pyrimidine bases (or their derivatives) bound to an identical sugar backbone (ribose, deoxyribose, or modifications of these sugars), unless the subsequent drug were shown to be clinically superior.

(D) Closely related, complex partly definable drugs with similar therapeutic intent, such as two live viral vaccines for the same indication, would be considered the same unless the subsequent drug was shown to be clinically superior.

(15) Sponsor means the entity that assumes responsibility for a clinical or nonclinical investigation of a drug, including the responsibility for compliance with applicable provisions of the act and regulations. A sponsor may be an individual, partnership, corporation, or Government agency and may be a manufacturer, scientific institution, or an investigator regularly and lawfully engaged in the investigation of drugs. For purposes of the Orphan Drug Act, FDA considers the real party or parties in interest to be a sponsor.

All correspondence and requests for FDA action under the provisions of this rule should be addressed as follows: Office of Orphan Products Development, Food and Drug Administration, Bldg. 32, Rm. 5271, 10903 New Hampshire Ave., Silver Spring, MD 20993.

(a) A sponsor's request for written recommendations from FDA concerning the nonclinical and clinical investigations necessary for approval of a marketing application shall be submitted in the form and contain the information required in this section. FDA may require the sponsor to submit information in addition to that specified in paragraph (b) of this section if FDA determines that the sponsor's initial request does not contain adequate information on which to base recommendations.

(b) A sponsor shall submit two copies of a completed, dated, and signed request for written recommendations that contains the following:

(1) The sponsor's name and address.

(2) A statement that the sponsor is requesting written recommendations on orphan-drug development under section 525 of the act.

(3) The name of the sponsor's primary contact person and/or resident agent, and the person's title, address, and telephone number.

(4) The generic name and trade name, if any, of the drug and a list of the drug product's components or description of the drug product's formulation, and chemical and physical properties.

(5) The proposed dosage form and route of administration.

(6) A description of the disease or condition for which the drug is proposed to be investigated and the proposed indication or indications for use for such disease or condition.

(7) Current regulatory and marketing status and history of the drug product, including:

(i) Whether the product is the subject of an IND or a marketing application (if the product is the subject of an IND or a marketing application, the IND or marketing application numbers should be stated and the investigational or approved indication or indications for use specified);

(ii) Known marketing experience or investigational status outside the United States;

(iii) So far as is known or can be determined, all indications previously or currently under investigation anywhere;

(iv) All adverse regulatory actions taken by the United States or foreign authorities.

(8) The basis for concluding that the drug is for a disease or condition that is rare in the United States, including the following:

(i) The size and other known demographic characteristics of the patient population affected and the source of this information.

(ii) For drugs intended for diseases or conditions affecting 200,000 or more people in the United States, or for a vaccine, diagnostic drug, or preventive drug that would be given to 200,000 or more persons per year, a summary of the sponsor's basis for believing that the disease or condition described in paragraph (b)(6) of this section occurs so infrequently that there is no reasonable expectation that the costs of drug development and marketing will be recovered in future sales of the drug in the United States. The estimated costs and sales data should be submitted as provided for in § 316.21(c).

(9) A summary and analysis of available data on the pharmacologic effects of the drug.

(10) A summary and analysis of available nonclinical and clinical data pertinent to the drug and the disease to be studied including copies of pertinent published reports. When a drug proposed for orphan drug designation is intended to treat a life-threatening or severely debilitating illness, especially where no satisfactory alternative therapy exists, the sponsor may wish voluntarily to provide this information. A sponsor of such a drug may be entitled to expeditious development, evaluation, and marketing under 21 CFR part 312, subpart E.

(11) An explanation of how the data summarized and analyzed under paragraphs (b)(9) and (b)(10) of this section support the rationale for use of the drug in the rare disease or condition.

(12) A definition of the population from which subjects will be identified for clinical trials, if known.

(13) A detailed outline of any protocols under which the drug has been or is being studied for the rare disease or condition and a summary and analysis of any available data from such studies.

(14) The sponsor's proposal as to the scope of nonclinical and clinical investigations needed to establish the safety and effectiveness of the drug.

(15) Detailed protocols for each proposed United States or foreign clinical investigation, if available.

(16) Specific questions to be addressed by FDA in its recommendations for nonclinical laboratory studies and clinical investigations.

(a) FDA will provide the sponsor with written recommendations concerning the nonclinical laboratory studies and clinical investigations necessary for approval of a marketing application if none of the reasons described in § 316.14 for refusing to do so applies.

(b) When a sponsor seeks written recommendations at a stage of drug development at which advice on any clinical investigations, or on particular investigations would be premature, FDA's response may be limited to written recommendations concerning only nonclinical laboratory studies, or only certain of the clinical studies (e.g., Phase 1 studies as described in § 312.21 of this chapter). Prior to providing written recommendations for the clinical investigations required to achieve marketing approval, FDA may require that the results of the nonclinical laboratory studies or completed early clinical studies be submitted to FDA for agency review.

(a) FDA may refuse to provide written recommendations concerning the nonclinical laboratory studies and clinical investigations necessary for approval of a marketing application for any of the following reasons:

(1) The information required to be submitted by § 316.10(b) has not been submitted, or the information submitted is incomplete.

(2) There is insufficient information about:

(i) The drug to identify the active moiety and its physical and chemical properties, if these characteristics can be determined; or

(ii) The disease or condition to determine that the disease or condition is rare in the United States; or

(iii) The reasons for believing that the drug may be useful for treating the rare disease or condition with that drug; or

(iv) The regulatory and marketing history of the drug to determine the scope and type of investigations that have already been conducted on the drug for the rare disease or condition; or

(v) The plan of study for establishing the safety and effectiveness of the drug for treatment of the rare disease or condition.

(3) The specific questions for which the sponsor seeks the advice of the agency are unclear or are not sufficiently specific.

(4) On the basis of the information submitted and on other information available to the agency, FDA determines that the disease or condition for which the drug is intended is not rare in the United States.

(5) On the basis of the information submitted and on other information available to the agency, FDA determines that there is an inadequate basis for permitting investigational use of the drug under part 312 of this chapter for the rare disease or condition.

(6) The request for information contains an untrue statement of material fact.

(b) A refusal to provide written recommendations will be in writing and will include a statement of the reason for FDA's refusal. Where practicable, FDA will describe the information or material it requires or the conditions the sponsor must meet for FDA to provide recommendations.

(c) Within 90 days after the date of a letter from FDA requesting additional information or material or setting forth the conditions that the sponsor is asked to meet, the sponsor shall either:

(1) Provide the information or material or amend the request for written recommendations to meet the conditions sought by FDA; or

(2) Withdraw the request for written recommendations. FDA will consider a sponsor's failure to respond within 90 days to an FDA letter requesting information or material or setting forth conditions to be met to be a withdrawal of the request for written recommendations.

(a) A sponsor that submits a request for orphan-drug designation of a drug for a specified rare disease or condition shall submit each request in the form and containing the information required in paragraph (b) of this section. A sponsor may request orphan-drug designation of a previously unapproved drug, or of a new use for an already marketed drug. In addition, a sponsor of a drug that is otherwise the same drug as an already approved drug may seek and obtain orphan-drug designation for the subsequent drug for the same rare disease or condition if it can present a plausible hypothesis that its drug may be clinically superior to the first drug. More than one sponsor may receive orphan-drug designation of the same drug for the same rare disease or condition, but each sponsor seeking orphan-drug designation must file a complete request for designation as provided in paragraph (b) of this section.

(b) A sponsor shall submit two copies of a completed, dated, and signed request for designation that contains the following:

(1) A statement that the sponsor requests orphan-drug designation for a rare disease or condition, which shall be identified with specificity.

(2) The name and address of the sponsor; the name of the sponsor's primary contact person and/or resident agent including title, address, telephone number, and email address; the generic and trade name, if any, of the drug, or, if neither is available, the chemical name or a meaningful descriptive name of the drug; and the name and address of the source of the drug if it is not manufactured by the sponsor.

(3) A description of the rare disease or condition for which the drug is being or will be investigated, the proposed use of the drug, and the reasons why such therapy is needed.

(4) A description of the drug, to include the identity of the active moiety if it is a drug composed of small molecules, or of the principal molecular structural features if it is composed of macromolecules; its physical and chemical properties, if these characteristics can be determined; and a discussion of the scientific rationale to establish a medically plausible basis for the use of the drug for the rare disease or condition, including all relevant data from in vitro laboratory studies, preclinical efficacy studies conducted in an animal model for the human disease or condition, and clinical experience with the drug in the rare disease or condition that are available to the sponsor, whether positive, negative, or inconclusive. Animal toxicology studies are generally not relevant to a request for orphan-drug designation. Copies of pertinent unpublished and published papers are also required.

(5) Where the sponsor of a drug that is otherwise the same drug as an already approved drug seeks orphan-drug designation for the subsequent drug for the same rare disease or condition, an explanation of why the proposed variation may be clinically superior to the first drug.

(6) Where a sponsor requests orphan-drug designation for a drug for only a subset of persons with a particular disease or condition that otherwise affects 200,000 or more people (“orphan subset”), a demonstration that, due to one or more properties of the drug, the remaining persons with such disease or condition would not be appropriate candidates for use of the drug.

(7) A summary of the regulatory status and marketing history of the drug in the United States and in foreign countries, e.g., IND and marketing application status and dispositions, what uses are under investigation and in what countries; for what indication is the drug approved in foreign countries; what adverse regulatory actions have been taken against the drug in any country.

(8) Documentation, with appended authoritative references, to demonstrate that:

(i) The disease or condition for which the drug is intended affects fewer than 200,000 people in the United States or, if the drug is a vaccine, diagnostic drug, or preventive drug, the persons to whom the drug will be administered in the United States are fewer than 200,000 per year as specified in § 316.21(b), or

(ii) For a drug intended for diseases or conditions affecting 200,000 or more people, or for a vaccine, diagnostic drug, or preventive drug to be administered to 200,000 or more persons per year in the United States, there is no reasonable expectation that costs of research and development of the drug for the indication can be recovered by sales of the drug in the United States as specified in § 316.21(c).

(c) Any of the information previously provided by the sponsor to FDA under subpart B of this part may be referenced by specific page or location if it duplicates information required elsewhere in this section.

(a) So that FDA can determine whether a drug qualifies for orphan-drug designation under section 526(a) of the act, the sponsor shall include in its request to FDA for orphan-drug designation under § 316.20 either:

(1) Documentation as described in paragraph (b) of this section that the number of people affected by the disease or condition for which the drug is to be developed is fewer than 200,000 persons; or

(2) Documentation as described in paragraph (c) of this section that demonstrates that there is no reasonable expectation that the sales of the drug will be sufficient to offset the costs of developing the drug for the U.S. market and the costs of making the drug available in the United States.

(b) For the purpose of documenting that the number of people affected by the disease or condition for which the drug is to be developed is less than 200,000 persons, “prevalence” is defined as the number of persons in the United States who have been diagnosed as having the disease or condition at the time of the submission of the request for orphan-drug designation. To document the number of persons in the United States who have the disease or condition for which the drug is to be developed, the sponsor shall submit to FDA evidence showing:

(1) The estimated prevalence of the disease or condition for which the drug is being developed, together with a list of the sources (including dates of information provided and literature citations) for the estimate;

(2) Upon request by FDA, the estimated prevalence of any other disease or condition for which the drug has already been approved or for which the drug is currently being developed, together with an explanation of the bases of these estimates; and

(3) The estimated number of people to whom the drug will be administered annually if the drug is a vaccine or is a drug intended for diagnosis or prevention of a rare disease or condition, together with an explanation of the bases of these estimates (including dates of information provided and literature citations).

(c) When submitting documentation that there is no reasonable expectation that costs of research and development of the drug for the disease or condition can be recovered by sales of the drug in the United States, the sponsor shall submit to FDA:

(1) Data on all costs that the sponsor has incurred in the course of developing the drug for the U.S. market. These costs shall include, but are not limited to, nonclinical laboratory studies, clinical studies, dosage form development, record and report maintenance, meetings with FDA, determination of patentability, preparation of designation request, IND/marketing application preparation, distribution of the drug under a “treatment” protocol, licensing costs, liability insurance, and overhead and depreciation. Furthermore, the sponsor shall demonstrate the reasonableness of the cost data. For example, if the sponsor has incurred costs for clinical investigations, the sponsor shall provide information on the number of investigations, the years in which they took place, and on the scope, duration, and number of patients that were involved in each investigation.

(2) If the drug was developed wholly or in part outside the United States, in addition to the documentation listed in paragraph (c)(1) of this section:

(i) Data on and justification for all costs that the sponsor has incurred outside of the United States in the course of developing the drug for the U.S. market. The justification, in addition to demonstrating the reasonableness of the cost data, must also explain the method that was used to determine which portion of the foreign development costs should be applied to the U.S. market, and what percent these costs are of total worldwide development costs. Any data submitted to foreign government authorities to support drug pricing determinations must be included with this information.

(ii) Data that show which foreign development costs were recovered through cost recovery procedures that are allowed during drug development in some foreign countries. For example, if the sponsor charged patients for the drug during clinical investigations, the revenues collected by the sponsor must be reported to FDA.

(3) In cases where the drug has already been approved for marketing for any indication or in cases where the drug is currently under investigation for one or more other indications (in addition to the indication for which orphan-drug designation is being sought), a clear explanation of and justification for the method that is used to apportion the development costs among the various indications.

(4) A statement of and justification for any development costs that the sponsor expects to incur after the submission of the designation request. In cases where the extent of these future development costs are not clear, the sponsor should request FDA's advice and assistance in estimating the scope of nonclinical laboratory studies and clinical investigations and other data that are needed to support marketing approval. Based on these recommendations, a cost estimate should be prepared.

(5) A statement of and justification for production and marketing costs that the sponsor has incurred in the past and expects to incur during the first 7 years that the drug is marketed.

(6) An estimate of and justification for the expected revenues from sales of the drug in the United States during its first 7 years of marketing. The justification should assume that the total market for the drug is equal to the prevalence of the disease or condition that the drug will be used to treat. The justification should include:

(i) An estimate of the expected market share of the drug in each of the first 7 years that it is marketed, together with an explanation of the basis for that estimate;

(ii) A projection of and justification for the price at which the drug will be sold; and

(iii) Comparisons with sales of similarly situated drugs, where available.

(7) The name of each country where the drug has already been approved for marketing for any indication, the dates of approval, the indication for which the drug is approved, and the annual sales and number of prescriptions in each country since the first approval date.

(8) A report of an independent certified public accountant in accordance with Statement on Standards for Attestation established by the American Institute of Certified Public Accountants on agreed upon procedures performed with respect to the data estimates and justifications submitted pursuant to this section. Cost data shall be determined in accordance with generally accepted accounting principles.

(d) A sponsor that is requesting orphan-drug designation for a drug designed to treat a disease or condition that affects 200,000 or more persons shall, at FDA's request, allow FDA or FDA-designated personnel to examine at reasonable times and in a reasonable manner all relevant financial records and sales data of the sponsor and manufacturer.

Every foreign sponsor that seeks orphan-drug designation shall name a permanent resident of the United States as the sponsor's agent upon whom service of all processes, notices, orders, decisions, requirements, and other communications may be made on behalf of the sponsor. Notifications of changes in such agents or changes of address of agents should preferably be provided in advance, but not later than 60 days after the effective date of such changes. The permanent-resident agent may be an individual, firm, or domestic corporation and may represent any number of sponsors. The name of the permanent-resident agent, address, telephone number, and email address shall be provided to: Office of Orphan Products Development, Food and Drug Administration, Bldg. 32, rm. 5271, 10903 New Hampshire Ave., Silver Spring, MD 20993.

(a) A sponsor may request orphan-drug designation at any time in its drug development process prior to the time that sponsor submits a marketing application for the drug for the same rare disease or condition.

(b) A sponsor may request orphan-drug designation of an already approved drug for an unapproved use without regard to whether the prior marketing approval was for a rare disease or condition.

(a) FDA will send a deficiency letter to the sponsor if the request for orphan-drug designation lacks information required under §§ 316.20 and 316.21, or contains inaccurate or incomplete information. FDA may consider a designation request voluntarily withdrawn if the sponsor fails to respond to the deficiency letter within 1 year of issuance of the deficiency letter, unless within that same timeframe the sponsor requests in writing an extension of time to respond. This request must include the reason(s) for the requested extension and the length of time of the requested extension. FDA will grant all reasonable requests for an extension. In the event FDA denies a request for an extension of time, FDA may consider the designation request voluntarily withdrawn. In the event FDA considers a designation request voluntarily withdrawn, FDA will so notify the sponsor in writing.

(b) FDA will grant the request for orphan-drug designation if none of the reasons described in § 316.25 for requiring or permitting refusal to grant such a request applies.

(c) When a request for orphan-drug designation is granted, FDA will notify the sponsor in writing and will publicize the orphan-drug designation in accordance with § 316.28.

(d) A sponsor may voluntarily withdraw an orphan-drug designation request or an orphan-drug designation at any time after the request is submitted or granted, respectively, by submitting a written request for withdrawal to FDA. FDA will acknowledge such withdrawal in a letter to the sponsor. Any benefits attendant to designation (such as orphan-exclusive approval) will cease once designation is voluntarily withdrawn, from the date of FDA's acknowledgement letter. If a sponsor voluntarily withdraws designation, FDA will publicize such withdrawal in accordance with § 316.28.

(a) FDA will refuse to grant a request for orphan-drug designation if any of the following reasons apply:

(1) The drug is not intended for a rare disease or condition because:

(i) There is insufficient evidence to support the estimate that the drug is intended for treatment of a disease or condition in fewer than 200,000 people in the United States, or that the drug is intended for use in prevention or in diagnosis in fewer than 200,000 people annually in the United States; or

(ii) Where the drug is intended for prevention, diagnosis, or treatment of a disease or condition affecting 200,000 or more people in the United States, the sponsor has failed to demonstrate that there is no reasonable expectation that development and production costs will be recovered from sales of the drug for such disease or condition in the United States. A sponsor's failure to comply with § 316.21 shall constitute a failure to make the demonstration required in this paragraph.

(2) There is insufficient information about the drug, or the disease or condition for which it is intended, to establish a medically plausible basis for expecting the drug to be effective in the prevention, diagnosis, or treatment of that disease or condition.

(3) The drug is otherwise the same drug as an already approved drug for the same rare disease or condition and the sponsor has not submitted a medically plausible hypothesis for the possible clinical superiority of the subsequent drug.

(b) FDA may refuse to grant a request for orphan-drug designation if the request for designation contains an untrue statement of material fact or omits material information or if the request is otherwise ineligible under this part.

(a) At any time prior to approval of a marketing application for a designated orphan drug, the sponsor holding designation may apply for an amendment to the designated use if the proposed change is due to new and unexpected findings in research on the drug, information arising from FDA recommendations, or unforeseen developments in treatment or diagnosis of the disease or condition.

(b) FDA will grant the amendment if it finds that the initial designation request was made in good faith and that the amendment is intended to conform the orphan-drug designation to the results of unanticipated research findings, to unforeseen developments in the treatment or diagnosis of the disease or condition, or to changes based on FDA recommendations, and that, as of the date of the submission of the amendment request, the amendment would not result in exceeding the prevalence or cost recovery thresholds in § 316.21(a)(1) or (a)(2) upon which the drug was originally designated.

(a) A sponsor may transfer ownership of or any beneficial interest in the orphan-drug designation of a drug to a new sponsor. At the time of the transfer, the new and former owners are required to submit the following information to FDA:

(1) The former owner or assignor of rights shall submit a letter or other document that states that all or some rights to the orphan-drug designation of the drug have been transferred to the new owner or assignee and that a complete copy of the request for orphan-drug designation, including any amendments to the request, supplements to the granted request, and correspondence relevant to the orphan-drug designation, has been provided to the new owner or assignee.

(2) The new owner or assignee of rights shall submit a statement accepting orphan-drug designation and a letter or other document containing the following:

(i) The date that the change in ownership or assignment of rights is effective;

(ii) A statement that the new owner has a complete copy of the request for orphan-drug designation including any amendments to the request, supplements to the granted request, and correspondence relevant to the orphan-drug designation; and

(iii) A specific description of the rights that have been assigned and those that have been reserved. This may be satisfied by the submission of either a list of rights assigned and reserved or copies of all relevant agreements between assignors and assignees; and

(iv) The name and address of a new primary contact person or resident agent.

(b) No sponsor may relieve itself of responsibilities under the Orphan Drug Act or under this part by assigning rights to another person without:

(1) Assuring that the sponsor or the assignee will carry out such responsibilities; or

(2) Obtaining prior permission from FDA.

Each month FDA will update a publicly available cumulative posting of all drugs designated as orphan drugs. These postings will contain the following information:

(a) The name and address of the sponsor;

(b) The generic name and trade name, if any, or, if neither is available, the chemical name or a meaningful descriptive name of the drug;

(c) The date of the granting of orphan-drug designation;

(d) The designated use in the rare disease or condition; and

(e) If the drug loses designation after August 12, 2013, the date of it no longer having designation.

(a) FDA may revoke orphan-drug designation for any drug if the agency finds that:

(1) The request for designation contained an untrue statement of material fact; or

(2) The request for designation omitted material information required by this part; or

(3) FDA subsequently finds that the drug in fact had not been eligible for orphan-drug designation at the time of submission of the request therefor.

(b) For an approved drug, revocation of orphan-drug designation also suspends or withdraws the sponsor's exclusive marketing rights for the drug but not the approval of the drug's marketing application.

(c) Where a drug has been designated as an orphan drug because the prevalence of a disease or condition (or, in the case of vaccines, diagnostic drugs, or preventive drugs, the target population) is under 200,000 in the United States at the time of designation, its designation will not be revoked on the ground that the prevalence of the disease or condition (or the target population) becomes more than 200,000 persons.

(d) If FDA revokes orphan-drug designation, FDA will publicize that the drug is no longer designated in accordance with § 316.28(e).

Within 14 months after the date on which a drug was designated as an orphan drug and annually thereafter until marketing approval, the sponsor of a designated drug shall submit a brief progress report to the FDA Office of Orphan Products Development on the drug that includes:

(a) A short account of the progress of drug development including a review of preclinical and clinical studies initiated, ongoing, and completed and a short summary of the status or results of such studies.

(b) A description of the investigational plan for the coming year, as well as any anticipated difficulties in development, testing, and marketing; and

(c) A brief discussion of any changes that may affect the orphan-drug status of the product. For example, for products nearing the end of the approval process, sponsors should discuss any disparity between the probable marketing indication and the designated indication as related to the need for an amendment to the orphan-drug designation pursuant to § 316.26.

(a) FDA may approve a sponsor's marketing application for a designated orphan drug for use in the rare disease or condition for which the drug was designated, or for select indication(s) or use(s) within the rare disease or condition for which the drug was designated. Unless FDA previously approved the same drug for the same use or indication, FDA will not approve another sponsor's marketing application for the same drug for the same use or indication before the expiration of 7 years from the date of such approval as stated in the approval letter from FDA, except that such a marketing application can be approved sooner if, and at such time as, any of the following occurs:

(1) Withdrawal of exclusive approval or revocation of orphan-drug designation by FDA under any provision of this part; or

(2) Withdrawal for any reason of the marketing application for the drug in question; or

(3) Consent by the holder of exclusive approval to permit another marketing application to gain approval; or

(4) Failure of the holder of exclusive approval to assure a sufficient quantity of the drug under section 527 of the act and § 316.36.

(b) Orphan-drug exclusive approval protects only the approved indication or use of a designated drug. If such approval is limited to only particular indication(s) or uses(s) within the rare disease or condition for which the drug was designated, FDA may later approve the drug for additional indication(s) or uses(s) within the rare disease or condition not protected by the exclusive approval. If the sponsor who obtains approval for these new indication(s) or uses(s) has orphan-drug designation for the drug for the rare disease or condition, FDA will recognize a new orphan-drug exclusive approval for these new (not previously approved) indication(s) or use(s) from the date of approval of the drug for such new indication(s) or use(s).

(c) If a sponsor's marketing application for a drug product is determined not to be approvable because approval is barred under section 527 of the Federal Food, Drug, and Cosmetic Act until the expiration of the period of exclusive marketing of another drug, FDA will so notify the sponsor in writing.

(a) FDA will send the sponsor (or, the permanent-resident agent, if applicable) timely written notice recognizing exclusive approval once the marketing application for a designated orphan-drug product has been approved, if the same drug has not already been approved for the same use or indication. The written notice will inform the sponsor of the requirements for maintaining orphan-drug exclusive approval for the full 7-year term of exclusive approval.

(b) When a marketing application is approved under section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) for a designated orphan drug that qualifies for exclusive approval, FDA will publish in its publication entitled “Approved Drug Products With Therapeutic Equivalence Evaluations” information identifying the sponsor, the drug, and the date of termination of the orphan-drug exclusive approval. A subscription to this publication and its monthly cumulative supplements is available from the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325, and is also available online at http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm.

(c) If a drug is otherwise the same drug as a previously approved drug for the same use or indication, FDA will not recognize orphan-drug exclusive approval if the sponsor fails to demonstrate upon approval that the drug is clinically superior to the previously approved drug.

(a) Under section 527 of the act, whenever the Director has reason to believe that the holder of exclusive approval cannot assure the availability of sufficient quantities of an orphan drug to meet the needs of patients with the disease or condition for which the drug was designated, the Director will so notify the holder of this possible insufficiency and will offer the holder one of the following options, which must be exercised by a time that the Director specifies:

(1) Provide the Director in writing, or orally, or both, at the Director's discretion, views and data as to how the holder can assure the availability of sufficient quantities of the orphan drug within a reasonable time to meet the needs of patients with the disease or condition for which the drug was designated; or

(2) Provide the Director in writing the holder's consent for the approval of other marketing applications for the same drug before the expiration of the 7-year period of exclusive approval.

(b) If, within the time that the Director specifies, the holder fails to consent to the approval of other marketing applications and if the Director finds that the holder has not shown that it can assure the availability of sufficient quantities of the orphan drug to meet the needs of patients with the disease or condition for which the drug was designated, the Director will issue a written order withdrawing the drug product's exclusive approval. This order will embody the Director's findings and conclusions and will constitute final agency action. An order withdrawing the sponsor's exclusive marketing rights may issue whether or not there are other sponsors that can assure the availability of alternative sources of supply. Once withdrawn under this section, exclusive approval may not be reinstated for that drug.

Prospective investigators seeking to obtain treatment use of designated orphan drugs may do so as provided in subpart I of this chapter.

FDA's Office of Orphan Products Development will maintain and make publicly available a list of guidance documents that apply to the regulations in this part. The list is maintained on the Internet and is published annually in the Federal Register. A request for a copy of the list should be directed to the Office of Orphan Products Development, Food and Drug Administration, Bldg. 32, rm. 5271, 10903 New Hampshire Ave., Silver Spring, MD 20993.

(a) FDA will not publicly disclose the existence of a request for orphan-drug designation under section 526 of the act prior to final FDA action on the request unless the existence of the request has been previously publicly disclosed or acknowledged.

(b) Whether or not the existence of a pending request for designation has been publicly disclosed or acknowledged, no data or information in the request are available for public disclosure prior to final FDA action on the request.

(c) Upon final FDA action on a request for designation, FDA will determine the public availability of data and information in the request in accordance with part 20 and § 314.430 of this chapter and other applicable statutes and regulations.

(d) In accordance with § 316.28, FDA will make a cumulative list of all orphan drug designations available to the public and update such list monthly.

(e) FDA will not publicly disclose the existence of a pending marketing application for a designated orphan drug for the use for which the drug was designated unless the existence of the application has been previously publicly disclosed or acknowledged.

(f) FDA will determine the public availability of data and information contained in pending and approved marketing applications for a designated orphan drug for the use for which the drug was designated in accordance with part 20 and § 314.430 of this chapter and other applicable statutes and regulations.

The definitions contained in § 314.3 of this chapter apply to those terms when used in this part.

(a) Any person submitting a full new drug application to the Food and Drug Administration (FDA) shall include in the application either:

(1) Evidence measuring the in vivo bioavailability of the drug product that is the subject of the application; or

(2) Information to permit FDA to waive the submission of evidence measuring in vivo bioavailability.

(b) Any person submitting an abbreviated new drug application to FDA shall include in the application either:

(1) Evidence demonstrating that the drug product that is the subject of the abbreviated new drug application is bioequivalent to the reference listed drug (defined in § 314.3(b) of this chapter). A complete study report must be submitted for the bioequivalence study upon which the applicant relies for approval. For all other bioequivalence studies conducted on the same drug product formulation, the applicant must submit either a complete or summary report. If a summary report of a bioequivalence study is submitted and FDA determines that there may be bioequivalence issues or concerns with the product, FDA may require that the applicant submit a complete report of the bioequivalence study to FDA; or

(2) Information to show that the drug product is bioequivalent to the reference listed drug which would permit FDA to waive the submission of evidence demonstrating in vivo bioequivalence as provided in paragraph (f) of this section.

(c) Any person submitting a supplemental application to FDA shall include in the supplemental application the evidence or information set forth in paragraphs (a) and (b) of this section if the supplemental application proposes any of the following changes:

(1) A change in the manufacturing site or a change in the manufacturing process, including a change in product formulation or dosage strength, beyond the variations provided for in the approved application.

(2) A change in the labeling to provide for a new indication for use of the drug product, if clinical studies are required to support the new indication for use.

(3) A change in the labeling to provide for a new dosage regimen or for an additional dosage regimen for a special patient population, e.g., infants, if clinical studies are required to support the new or additional dosage regimen.

(d) FDA may approve a full new drug application, or a supplemental application proposing any of the changes set forth in paragraph (c) of this section, that does not contain evidence of in vivo bioavailability or information to permit waiver of the requirement for in vivo bioavailability data, if all of the following conditions are met.

(1) The application is otherwise approvable.

(2) The application agrees to submit, within the time specified by FDA, either:

(i) Evidence measuring the in vivo bioavailability and demonstrating the in vivo bioequivalence of the drug product that is the subject of the application; or

(ii) Information to permit FDA to waive measurement of in vivo bioavailability.

(e) Evidence measuring the in vivo bioavailability and demonstrating the in vivo bioequivalence of a drug product shall be obtained using one of the approaches for determining bioavailability set forth in § 320.24.

(f) Information to permit FDA to waive the submission of evidence measuring the in vivo bioavailability or demonstrating the in vivo bioequivalence shall meet the criteria set forth in § 320.22.

(g) Any person holding an approved full or abbreviated new drug application shall submit to FDA a supplemental application containing new evidence measuring the in vivo bioavailability or demonstrating the in vivo bioequivalence of the drug product that is the subject of the application if notified by FDA that:

(1) There are data demonstrating that the dosage regimen in the labeling is based on incorrect assumptions or facts regarding the pharmacokinetics of the drug product and that following this dosage regimen could potentially result in subtherapeutic or toxic levels; or

(2) There are data measuring significant intra-batch and batch-to-batch variability, e.g., plus or minus 25 percent, in the bioavailability of the drug product.

(h) The requirements of this section regarding the submission of evidence measuring the in vivo bioavailability or demonstrating the in vivo bioequivalence apply only to a full or abbreviated new drug application or a supplemental application for a finished dosage formulation.

(a) Any person submitting a full or abbreviated new drug application, or a supplemental application proposing any of the changes set forth in § 320.21(c), may request FDA to waive the requirement for the submission of evidence measuring the in vivo bioavailability or demonstrating the in vivo bioequivalence of the drug product that is the subject of the application. An applicant shall submit a request for waiver with the application. Except as provided in paragraph (f) of this section, FDA shall waive the requirement for the submission of evidence of in vivo bioavailability or bioequivalence if the drug product meets any of the provisions of paragraphs (b), (c), (d), or (e) of this section.

(b) For certain drug products, the in vivo bioavailability or bioequivalence of the drug product may be self-evident. FDA shall waive the requirement for the submission of evidence obtained in vivo measuring the bioavailability or demonstrating the bioequivalence of these drug products. A drug product's in vivo bioavailability or bioequivalence may be considered self-evident based on other data in the application if the product meets one of the following criteria:

(1) The drug product:

(i) Is a parenteral solution intended solely for administration by injection, or an ophthalmic or otic solution; and

(ii) Contains the same active and inactive ingredients in the same concentration as a drug product that is the subject of an approved full new drug application or abbreviated new drug application.

(2) The drug product:

(i) Is administered by inhalation as a gas, e.g., a medicinal or an inhalation anesthetic; and

(ii) Contains an active ingredient in the same dosage form as a drug product that is the subject of an approved full new drug application or abbreviated new drug application.

(3) The drug product:

(i) Is a solution for application to the skin, an oral solution, elixir, syrup, tincture, a solution for aerosolization or nebulization, a nasal solution, or similar other solubilized form; and

(ii) Contains an active drug ingredient in the same concentration and dosage form as a drug product that is the subject of an approved full new drug application or abbreviated new drug application; and

(iii) Contains no inactive ingredient or other change in formulation from the drug product that is the subject of the approved full new drug application or abbreviated new drug application that may significantly affect absorption of the active drug ingredient or active moiety for products that are systemically absorbed, or that may significantly affect systemic or local availability for products intended to act locally.

(c) FDA shall waive the requirement for the submission of evidence measuring the in vivo bioavailability or demonstrating the in vivo bioequivalence of a solid oral dosage form (other than a delayed release or extended release dosage form) of a drug product determined to be effective for at least one indication in a Drug Efficacy Study Implementation notice or which is identical, related, or similar to such a drug product under § 310.6 of this chapter unless FDA has evaluated the drug product under the criteria set forth in § 320.33, included the drug product in the Approved Drug Products with Therapeutic Equivalence Evaluations List, and rated the drug product as having a known or potential bioequivalence problem. A drug product so rated reflects a determination by FDA that an in vivo bioequivalence study is required.

(d) For certain drug products, bioavailability may be measured or bioequivalence may be demonstrated by evidence obtained in vitro in lieu of in vivo data. FDA shall waive the requirement for the submission of evidence obtained in vivo measuring the bioavailability or demonstrating the bioequivalence of the drug product if the drug product meets one of the following criteria:

(1) [Reserved]

(2) The drug product is in the same dosage form, but in a different strength, and is proportionally similar in its active and inactive ingredients to another drug product for which the same manufacturer has obtained approval and the conditions in paragraphs (d)(2)(i) through (d)(2)(iii) of this section are met:

(i) The bioavailability of this other drug product has been measured;

(ii) Both drug products meet an appropriate in vitro test approved by FDA; and

(iii) The applicant submits evidence showing that both drug products are proportionally similar in their active and inactive ingredients.

(iv) Paragraph (d) of this section does not apply to delayed release or extended release products.

(3) The drug product is, on the basis of scientific evidence submitted in the application, shown to meet an in vitro test that has been correlated with in vivo data.

(4) The drug product is a reformulated product that is identical, except for a different color, flavor, or preservative that could not affect the bioavailability of the reformulated product, to another drug product for which the same manufacturer has obtained approval and the following conditions are met:

(i) The bioavailability of the other product has been measured; and

(ii) Both drug products meet an appropriate in vitro test approved by FDA.

(e) FDA, for good cause, may waive a requirement for the submission of evidence of in vivo bioavailability or bioequivalence if waiver is compatible with the protection of the public health. For full new drug applications, FDA may defer a requirement for the submission of evidence of in vivo bioavailability if deferral is compatible with the protection of the public health.

(f) FDA, for good cause, may require evidence of in vivo bioavailability or bioequivalence for any drug product if the agency determines that any difference between the drug product and a listed drug may affect the bioavailability or bioequivalence of the drug product.

(a)(1) The in vivo bioavailability of a drug product is measured if the product's rate and extent of absorption, as determined by comparison of measured parameters, e.g., concentration of the active drug ingredient in the blood, urinary excretion rates, or pharmacological effects, do not indicate a significant difference from the reference material's rate and extent of absorption. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by scientifically valid measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.

(2) Statistical techniques used must be of sufficient sensitivity to detect differences in rate and extent of absorption that are not attributable to subject variability.

(3) A drug product that differs from the reference material in its rate of absorption, but not in its extent of absorption, may be considered to be bioavailable if the difference in the rate of absorption is intentional, is appropriately reflected in the labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug product.

(b)(1) Two drug products will be considered bioequivalent drug products if they are pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose of the active moiety under similar experimental conditions, either single dose or multiple dose. Some pharmaceutical equivalents or pharmaceutical alternatives may be equivalent in the extent of their absorption but not in their rate of absorption and yet may be considered bioequivalent because such differences in the rate of absorption are intentional and are reflected in the labeling, are not essential to the attainment of effective body drug concentrations on chronic use, and are considered medically insignificant for the particular drug product studied.

(2) For drug products that are not intended to be absorbed into the bloodstream, bioequivalence may be demonstrated by scientifically valid methods that are expected to detect a significant difference between the drug and the listed drug in safety and therapeutic effect.

(a) Bioavailability may be measured or bioequivalence may be demonstrated by several in vivo and in vitro methods. FDA may require in vivo or in vitro testing, or both, to measure the bioavailability of a drug product or establish the bioequivalence of specific drug products. Information on bioequivalence requirements for specific products is included in the current edition of FDA's publication “Approved Drug Products with Therapeutic Equivalence Evaluations” and any current supplement to the publication. The selection of the method used to meet an in vivo or in vitro testing requirement depends upon the purpose of the study, the analytical methods available, and the nature of the drug product. Applicants shall conduct bioavailability and bioequivalence testing using the most accurate, sensitive, and reproducible approach available among those set forth in paragraph (b) of this section. The method used must be capable of measuring bioavailability or establishing bioequivalence, as appropriate, for the product being tested.

(b) The following in vivo and in vitro approaches, in descending order of accuracy, sensitivity, and reproducibility, are acceptable for determining the bioavailability or bioequivalence of a drug product.

(1)(i) An in vivo test in humans in which the concentration of the active ingredient or active moiety, and, when appropriate, its active metabolite(s), in whole blood, plasma, serum, or other appropriate biological fluid is measured as a function of time. This approach is particularly applicable to dosage forms intended to deliver the active moiety to the bloodstream for systemic distribution within the body; or

(ii) An in vitro test that has been correlated with and is predictive of human in vivo bioavailability data; or

(2) An in vivo test in humans in which the urinary excretion of the active moiety, and, when appropriate, its active metabolite(s), are measured as a function of time. The intervals at which measurements are taken should ordinarily be as short as possible so that the measure of the rate of elimination is as accurate as possible. Depending on the nature of the drug product, this approach may be applicable to the category of dosage forms described in paragraph (b)(1)(i) of this section. This method is not appropriate where urinary excretion is not a significant mechanism of elimination.

(3) An in vivo test in humans in which an appropriate acute pharmacological effect of the active moiety, and, when appropriate, its active metabolite(s), are measured as a function of time if such effect can be measured with sufficient accuracy, sensitivity, and reproducibility. This approach is applicable to the category of dosage forms described in paragraph (b)(1)(i) of this section only when appropriate methods are not available for measurement of the concentration of the moiety, and, when appropriate, its active metabolite(s), in biological fluids or excretory products but a method is available for the measurement of an appropriate acute pharmacological effect. This approach may be particularly applicable to dosage forms that are not intended to deliver the active moiety to the bloodstream for systemic distribution.

(4) Well-controlled clinical trials that establish the safety and effectiveness of the drug product, for purposes of measuring bioavailability, or appropriately designed comparative clinical trials, for purposes of demonstrating bioequivalence. This approach is the least accurate, sensitive, and reproducible of the general approaches for measuring bioavailability or demonstrating bioequivalence. For dosage forms intended to deliver the active moiety to the bloodstream for systemic distribution, this approach may be considered acceptable only when analytical methods cannot be developed to permit use of one of the approaches outlined in paragraphs (b)(1)(i) and (b)(2) of this section, when the approaches described in paragraphs (b)(1)(ii), (b)(1)(iii), and (b)(3) of this section are not available. This approach may also be considered sufficiently accurate for measuring bioavailability or demonstrating bioequivalence of dosage forms intended to deliver the active moiety locally, e.g., topical preparations for the skin, eye, and mucous membranes; oral dosage forms not intended to be absorbed, e.g., an antacid or radiopaque medium; and bronchodilators administered by inhalation if the onset and duration of pharmacological activity are defined.

(5) A currently available in vitro test acceptable to FDA (usually a dissolution rate test) that ensures human in vivo bioavailability.

(6) Any other approach deemed adequate by FDA to measure bioavailability or establish bioequivalence.

(c) FDA may, notwithstanding prior requirements for measuring bioavailability or establishing bioequivalence, require in vivo testing in humans of a product at any time if the agency has evidence that the product:

(1) May not produce therapeutic effects comparable to a pharmaceutical equivalent or alternative with which it is intended to be used interchangeably;

(2) May not be bioequivalent to a pharmaceutical equivalent or alternative with which it is intended to be used interchangeably; or

(3) Has greater than anticipated potential toxicity related to pharmacokinetic or other characteristics.

(a) Guiding principles. (1) The basic principle in an in vivo bioavailability study is that no unnecessary human research should be done.

(2) An in vivo bioavailability study is generally done in a normal adult population under standardized conditions. In some situations, an in vivo bioavailability study in humans may preferably and more properly be done in suitable patients. Critically ill patients shall not be included in an in vivo bioavailability study unless the attending physician determines that there is a potential benefit to the patient.

(b) Basic design. The basic design of an in vivo bioavailability study is determined by the following:

(1) The scientific questions to be answered.

(2) The nature of the reference material and the dosage form to be tested.

(3) The availability of analytical methods.

(4) Benefit-risk considerations in regard to testing in humans.

(c) Comparison to a reference material. In vivo bioavailability testing of a drug product shall be in comparison to an appropriate reference material unless some other approach is more appropriate for valid scientific reasons.

(d) Previously unmarketed active drug ingredients or therapeutic moieties. (1) An in vivo bioavailability study involving a drug product containing an active drug ingredient or therapeutic moiety that has not been approved for marketing can be used to measure the following pharmacokinetic data:

(i) The bioavailability of the formulation proposed for marketing; and

(ii) The essential pharmacokinetic characteristics of the active drug ingredient or therapeutic moiety, such as the rate of absorption, the extent of absorption, the half-life of the therapeutic moiety in vivo, and the rate of excretion and/or metabolism. Dose proportionality of the active drug ingredient or the therapeutic moiety needs to be established after single-dose administration and in certain instances after multiple-dose administration. This characterization is a necessary part of the investigation of the drug to support drug labeling.

(2) The reference material in such a bioavailability study should be a solution or suspension containing the same quantity of the active drug ingredient or therapeutic moiety as the formulation proposed for marketing.

(3) The reference material should be administered by the same route as the formulation proposed for marketing unless an alternative or additional route is necessary to answer the scientific question under study. For example, in the case of an active drug ingredient or therapeutic moiety that is poorly absorbed after oral administration, it may be necessary to compare the oral dosage form proposed for marketing with the active drug ingredient or therapeutic moiety administered in solution both orally and intravenously.

(e) New formulations of active drug ingredients or therapeutic moieties approved for marketing. (1) An in vivo bioavailability study involving a drug product that is a new dosage form, or a new salt or ester of an active drug ingredient or therapeutic moiety that has been approved for marketing can be used to:

(i) Measure the bioavailability of the new formulation, new dosage form, or new salt or ester relative to an appropriate reference material; and

(ii) Define the pharmacokinetic parameters of the new formulation, new dosage form, or new salt or ester to establish dosage recommendation.

(2) The selection of the reference material(s) in such a bioavailability study depends upon the scientific questions to be answered, the data needed to establish comparability to a currently marketed drug product, and the data needed to establish dosage recommendations.

(3) The reference material should be taken from a current batch of a drug product that is the subject of an approved new drug application and that contains the same active drug ingredient or therapeutic moiety, if the new formulation, new dosage form, or new salt or ester is intended to be comparable to or to meet any comparative labeling claims made in relation to the drug product that is the subject of an approved new drug application.

(f) Extended release formulations. (1) The purpose of an in vivo bioavailability study involving a drug product for which an extended release claim is made is to determine if all of the following conditions are met:

(i) The drug product meets the extended release claims made for it.

(ii) The bioavailability profile established for the drug product rules out the occurrence of any dose dumping.

(iii) The drug product's steady-state performance is equivalent to a currently marketed nonextended release or extended release drug product that contains the same active drug ingredient or therapeutic moiety and that is subject to an approved full new drug application.

(iv) The drug product's formulation provides consistent pharmacokinetic performance between individual dosage units.

(2) The reference material(s) for such a bioavailability study shall be chosen to permit an appropriate scientific evaluation of the extended release claims made for the drug product. The reference material shall be one of the following or any combination thereof:

(i) A solution or suspension of the active drug ingredient or therapeutic moiety.

(ii) A currently marketed noncontrolled release drug product containing the same active drug ingredient or therapeutic moiety and administered according to the dosage recommendations in the labeling of the noncontrolled release drug product.

(iii) A currently marketed extended release drug product subject to an approved full new drug application containing the same active drug ingredient or therapeutic moiety and administered according to the dosage recommendations in the labeling proposed for the extended release drug product.

(iv) A reference material other than one set forth in paragraph (f)(2) (i), (ii) or (iii) of this section that is appropriate for valid scientific reasons.

(g) Combination drug products. (1) Generally, the purpose of an in vivo bioavailability study involving a combination drug product is to determine if the rate and extent of absorption of each active drug ingredient or therapeutic moiety in the combination drug product is equivalent to the rate and extent of absorption of each active drug ingredient or therapeutic moiety administered concurrently in separate single-ingredient preparations.

(2) The reference material in such a bioavailability study should be two or more currently marketed, single-ingredient drug products each of which contains one of the active drug ingredients or therapeutic moieties in the combination drug product. The Food and Drug Administration may, for valid scientific reasons, specify that the reference material shall be a combination drug product that is the subject of an approved new drug application.

(3) The Food and Drug Administration may permit a bioavailability study involving a combination drug product to determine the rate and extent of absorption of selected, but not all, active drug ingredients or therapeutic moieties in the combination drug product. The Food and Drug Administration may permit this determination if the pharmacokinetics and the interactions of the active drug ingredients or therapeutic moieties in the combination drug product are well known and the therapeutic activity of the combination drug product is generally recognized to reside in only one of the active drug ingredients or therapeutic moieties, e.g., ampicillin in an ampicillin-probenecid combination drug product.

(h) Use of a placebo as the reference material. Where appropriate or where necessary to demonstrate the sensitivity of the test, the reference material in a bioavailability study may be a placebo if:

(1) The study measures the therapeutic or acute pharmacological effect of the active drug ingredient or therapeutic moiety; or

(2) The study is a clinical trial to establish the safety and effectiveness of the drug product.

(i) Standards for test drug product and reference material. (1) Both the drug product to be tested and the reference material, if it is another drug product, shall be shown to meet all compendial or other applicable standards of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and dissolution rates.

(2) Samples of the drug product to be tested shall be manufactured using the same equipment and under the same conditions as those used for full-scale production.

(a) Basic principles. (1) An in vivo bioavailability or bioequivalence study should be a single-dose comparison of the drug product to be tested and the appropriate reference material conducted in normal adults.

(2) The test product and the reference material should be administered to subjects in the fasting state, unless some other approach is more appropriate for valid scientific reasons.

(b) Study design. (1) A single-dose study should be crossover in design, unless a parallel design or other design is more appropriate for valid scientific reasons, and should provide for a drug elimination period.

(2) Unless some other approach is appropriate for valid scientific reasons, the drug elimination period should be either:

(i) At least three times the half-life of the active drug ingredient or therapeutic moiety, or its metabolite(s), measured in the blood or urine; or

(ii) At least three times the half-life of decay of the acute pharmacological effect.

(c) Collection of blood samples. (1) When comparison of the test product and the reference material is to be based on blood concentration time curves, unless some other approach is more appropriate for valid scientific reasons, blood samples should be taken with sufficient frequency to permit an estimate of both:

(i) The peak concentration in the blood of the active drug ingredient or therapeutic moiety, or its metabolite(s), measured; and

(ii) The total area under the curve for a time period at least three times the half-life of the active drug ingredient or therapeutic moiety, or its metabolite(s), measured.

(2) In a study comparing oral dosage forms, the sampling times should be identical.

(3) In a study comparing an intravenous dosage form and an oral dosage form, the sampling times should be those needed to describe both:

(i) The distribution and elimination phase of the intravenous dosage form; and

(ii) The absorption and elimination phase of the oral dosage form.

(4) In a study comparing drug delivery systems other than oral or intravenous dosage forms with an appropriate reference standard, the sampling times should be based on valid scientific reasons.

(d) Collection of urine samples. When comparison of the test product and the reference material is to be based on cumulative urinary excretion-time curves, unless some other approach is more appropriate for valid scientific reasons, samples of the urine should be collected with sufficient frequency to permit an estimate of the rate and extent of urinary excretion of the active drug ingredient or therapeutic moiety, or its metabolite(s), measured.

(e) Measurement of an acute pharmacological effect. (1) When comparison of the test product and the reference material is to be based on acute pharmacological effect-time curves, measurements of this effect should be made with sufficient frequency to permit a reasonable estimate of the total area under the curve for a time period at least three times the half-life of decay of the pharmacological effect, unless some other approach is more appropriate for valid scientific reasons.

(2) The use of an acute pharmacological effect to determine bioavailability may further require demonstration of dose-related response. In such a case, bioavailability may be determined by comparison of the dose-response curves as well as the total area under the acute pharmacological effect-time curves for any given dose.

(a) Basic principles. (1) In selected circumstances it may be necessary for the test product and the reference material to be compared after repeated administration to determine steady-state levels of the active drug ingredient or therapeutic moiety in the body.

(2) The test product and the reference material should be administered to subjects in the fasting or nonfasting state, depending upon the conditions reflected in the proposed labeling of the test product.

(3) A multiple-dose study may be required to determine the bioavailability of a drug product in the following circumstances:

(i) There is a difference in the rate of absorption but not in the extent of absorption.

(ii) There is excessive variability in bioavailability from subject to subject.

(iii) The concentration of the active drug ingredient or therapeutic moiety, or its metabolite(s), in the blood resulting from a single dose is too low for accurate determination by the analytical method.

(iv) The drug product is an extended release dosage form.

(b) Study design. (1) A multiple-dose study should be crossover in design, unless a parallel design or other design is more appropriate for valid scientific reasons, and should provide for a drug elimination period if steady-state conditions are not achieved.

(2) A multiple-dose study is not required to be of crossover design if the study is to establish dose proportionality under a multiple-dose regimen or to establish the pharmacokinetic profile of a new drug product, a new drug delivery system, or an extended release dosage form.

(3) If a drug elimination period is required, unless some other approach is more appropriate for valid scientific reasons, the drug elimination period should be either:

(i) At least five times the half-life of the active drug ingredient or therapeutic moiety, or its active metabolite(s), measured in the blood or urine; or

(ii) At least five times the half-life of decay of the acute pharmacological effect.

(c) Achievement of steady-state conditions. Whenever a multiple-dose study is conducted, unless some other approach is more appropriate for valid scientific reasons, sufficient doses of the test product and reference material should be administered in accordance with the labeling to achieve steady-state conditions.

(d) Collection of blood or urine samples. (1) Whenever comparison of the test product and the reference material is to be based on blood concentration-time curves at steady state, appropriate dosage administration and sampling should be carried out to document attainment of steady state.

(2) Whenever comparison of the test product and the reference material is to be based on cumulative urinary excretion-time curves at steady state, appropriate dosage administration and sampling should be carried out to document attainment of steady state.

(3) A more complete characterization of the blood concentration or urinary excretion rate during the absorption and elimination phases of a single dose administered at steady-state is encouraged to permit estimation of the total area under concentration-time curves or cumulative urinary excretion-time curves and to obtain pharmacokinetic information, e.g., half-life or blood clearance, that is essential in preparing adequate labeling for the drug product.

(e) Steady-state parameters. (1) In certain instances, e.g., in a study involving a new drug entity, blood clearances at steady-state obtained in a multiple-dose study should be compared to blood clearances obtained in a single-dose study to support adequate dosage recommendations.

(2) In a linear system, the area under the blood concentration-time curve during a dosing interval in a multiple-dose steady-state study is directly proportional to the fraction of the dose absorbed and is equal to the corresponding “zero to infinity” area under the curve for a single-dose study. Therefore, when steady-state conditions are achieved, a comparison of blood concentrations during a dosing interval may be used to define the fraction of the active drug ingredient or therapeutic moiety absorbed.

(3) Other methods based on valid scientific reasons should be used to determine the bioavailability of a drug product having dose-dependent kinetics (non-linear system).

(f) Measurement of an acute pharmacological effect. When comparison of the test product and the reference material is to be based on acute pharmacological effect-time curves, measurements of this effect should be made with sufficient frequency to demonstrate a maximum effect and a lack of significant difference between the test product and the reference material.

Correlation of in vivo bioavailability data with an acute pharmacological effect or clinical evidence of safety and effectiveness may be required if needed to establish the clinical significance of a special claim, e.g., in the case of an extended release preparation.

(a) The analytical method used in an in vivo bioavailability or bioequivalence study to measure the concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s), in body fluids or excretory products, or the method used to measure an acute pharmacological effect shall be demonstrated to be accurate and of sufficient sensitivity to measure, with appropriate precision, the actual concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s), achieved in the body.

(b) When the analytical method is not sensitive enough to measure accurately the concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s), in body fluids or excretory products produced by a single dose of the test product, two or more single doses may be given together to produce higher concentration if the requirements of § 320.31 are met.

(a) The Commissioner of Food and Drugs strongly recommends that, to avoid the conduct of an improper study and unnecessary human research, any person planning to conduct a bioavailability or bioequivalence study submit the proposed protocol for the study to FDA for review prior to the initiation of the study.

(b) FDA may review a proposed protocol for a bioavailability or bioequivalence study and will offer advice with respect to whether the following conditions are met:

(1) The design of the proposed bioavailability or bioequivalence study is appropriate.

(2) The reference material to be used in the bioavailability or bioequivalence study is appropriate.

(3) The proposed chemical and statistical analytical methods are adequate.

(c)(1) General inquiries relating to in vivo bioavailability requirements and methodology shall be submitted to the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Clinical Pharmacology, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002.

(2) General inquiries relating to bioequivalence requirements and methodology shall be submitted to the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Bioequivalence (HFD-650), 7500 Standish Pl., Rockville, MD 20855-2773.

(a) Any person planning to conduct an in vivo bioavailability or bioequivalence study in humans shall submit an “Investigational New Drug Application” (IND) if:

(1) The test product contains a new chemical entity as defined in § 314.108(a) of this chapter; or

(2) The study involves a radioactively labeled drug product; or

(3) The study involves a cytotoxic drug product.

(b) Any person planning to conduct a bioavailability or bioequivalence study in humans using a drug product that contains an already approved, non-new chemical entity shall submit an IND if the study is one of the following:

(1) A single-dose study in normal subjects or patients where either the maximum single or total daily dose exceeds that specified in the labeling of the drug product that is the subject of an approved new drug application or abbreviated new drug application.

(2) A multiple-dose study in normal subjects or patients where either the single or total daily dose exceeds that specified in the labeling of the drug product that is the subject of an approved new drug application or abbreviated new drug application.

(3) A multiple-dose study on an extended release product on which no single-dose study has been completed.

(c) The provisions of parts 50, 56, and 312 of this chapter are applicable to any bioavailability or bioequivalence study in humans conducted under an IND.

(d) A bioavailability or bioequivalence study in humans other than one described in paragraphs (a) through (c) of this section is exempt from the requirements of part 312 of this chapter if the following conditions are satisfied:

(1) If the study is one described under § 320.38(b) or § 320.63, the person conducting the study, including any contract research organization, must retain reserve samples of any test article and reference standard used in the study and release the reserve samples to FDA upon request, in accordance with, and for the period specified in, § 320.38;

(2) An in vivo bioavailability or bioequivalence study in humans must be conducted in compliance with the requirements for institutional review set forth in part 56 of this chapter, and informed consent set forth in part 50 of this chapter; and

(3) The person conducting the study, including any contract research organization, must notify FDA and all participating investigators of any serious adverse event, as defined in § 312.32(a), observed during the conduct of the study as soon as possible but in no case later than 15 calendar days after becoming aware of its occurrence. Each report must be submitted on FDA Form 3500A or in an electronic format that FDA can process, review, and archive. FDA will periodically issue guidance on how to provide the electronic submission (e.g., method of transmission, media, file formats, preparation and organization of files). Each report must bear prominent identification of its contents, i.e., “bioavailability/bioequivalence safety report.” The person conducting the study, including any contract research organization, must also notify FDA of any fatal or life-threatening adverse event from the study as soon as possible but in no case later than 7 calendar days after becoming aware of its occurrence. Each notification under this paragraph must be submitted to the Director, Office of Generic Drugs in the Center for Drug Evaluation and Research at FDA. Relevant followup information to a bioavailability/bioequivalence safety report must be submitted as soon as the information is available and must be identified as such, i.e., “Followup bioavailability/bioequivalence safety report.” Upon request from FDA, the person conducting the study, including any contract research organization, must submit to FDA any additional data or information that the agency deems necessary, as soon as possible, but in no case later than 15 calendar days after receiving the request.

(a) The Food and Drug Administration, on its own initiative or in response to a petition by an interested person, may propose and promulgate a regulation to establish a bioequivalence requirement for a product not subject to section 505(j) of the act if it finds there is well-documented evidence that specific pharmaceutical equivalents or pharmaceutical alternatives intended to be used interchangeably for the same therapeutic effect:

(1) Are not bioequivalent drug products; or

(2) May not be bioequivalent drug products based on the criteria set forth in § 320.33; or

(3) May not be bioequivalent drug products because they are members of a class of drug products that have close structural similarity and similar physicochemical or pharmacokinetic properties to other drug products in the same class that FDA finds are not bioequivalent drug products.

(b) FDA shall include in a proposed rule to establish a bioequivalence requirement the evidence and criteria set forth in § 320.33 that are to be considered in determining whether to issue the proposal. If the rulemaking is proposed in response to a petition, FDA shall include in the proposal a summary and analysis of the relevant information that was submitted in the petition as well as other available information to support the establishment of a bioequivalence requirement.

(c) FDA, on its own initiative or in response to a petition by an interested person, may propose and promulgate an amendment to a bioequivalence requirement established under this subpart.

The Commissioner of Food and Drugs shall consider the following factors, when supported by well-documented evidence, to identify specific pharmaceutical equivalents and pharmaceutical alternatives that are not or may not be bioequivalent drug products.

(a) Evidence from well-controlled clinical trials or controlled observations in patients that such drug products do not give comparable therapeutic effects.

(b) Evidence from well-controlled bioequivalence studies that such products are not bioequivalent drug products.

(c) Evidence that the drug products exhibit a narrow therapeutic ratio, e.g., there is less than a 2-fold difference in median lethal dose (LD50) and median effective dose (ED50) values, or have less than a 2-fold difference in the minimum toxic concentrations and minimum effective concentrations in the blood, and safe and effective use of the drug products requires careful dosage titration and patient monitoring.

(d) Competent medical determination that a lack of bioequivalence would have a serious adverse effect in the treatment or prevention of a serious disease or condition.

(e) Physicochemical evidence that:

(1) The active drug ingredient has a low solubility in water, e.g., less than 5 milligrams per 1 milliliter, or, if dissolution in the stomach is critical to absorption, the volume of gastric fluids required to dissolve the recommended dose far exceeds the volume of fluids present in the stomach (taken to be 100 milliliters for adults and prorated for infants and children).

(2) The dissolution rate of one or more such products is slow, e.g., less than 50 percent in 30 minutes when tested using either a general method specified in an official compendium or a paddle method at 50 revolutions per minute in 900 milliliters of distilled or deionized water at 37 °C, or differs significantly from that of an appropriate reference material such as an identical drug product that is the subject of an approved full new drug application.

(3) The particle size and/or surface area of the active drug ingredient is critical in determining its bioavailability.

(4) Certain physical structural characteristics of the active drug ingredient, e.g., polymorphic forms, conforms, solvates, complexes, and crystal modifications, dissolve poorly and this poor dissolution may affect absorption.

(5) Such drug products have a high ratio of excipients to active ingredients, e.g., greater than 5 to 1.

(6) Specific inactive ingredients, e.g., hydrophilic or hydrophobic excipients and lubricants, either may be required for absorption of the active drug ingredient or therapeutic moiety or, alternatively, if present, may interfere with such absorption.

(f) Pharmacokinetic evidence that:

(1) The active drug ingredient, therapeutic moiety, or its precursor is absorbed in large part in a particular segment of the gastrointestinal tract or is absorbed from a localized site.

(2) The degree of absorption of the active drug ingredient, therapeutic moiety, or its precursor is poor, e.g., less than 50 percent, ordinarily in comparison to an intravenous dose, even when it is administered in pure form, e.g., in solution.

(3) There is rapid metabolism of the therapeutic moiety in the intestinal wall or liver during the process of absorption (first-pass metabolism) so the therapeutic effect and/or toxicity of such drug product is determined by the rate as well as the degree of absorption.

(4) The therapeutic moiety is rapidly metabolized or excreted so that rapid dissolution and absorption are required for effectiveness.

(5) The active drug ingredient or therapeutic moiety is unstable in specific portions of the gastrointestinal tract and requires special coatings or formulations, e.g., buffers, enteric coatings, and film coatings, to assure adequate absorption.

(6) The drug product is subject to dose dependent kinetics in or near the therapeutic range, and the rate and extent of absorption are important to bioequivalence.

(a) If the Commissioner determines that individual batch testing by the Food and Drug Administration is necessary to assure that all batches of the same drug product meet an appropriate in vitro test, he shall include in the bioequivalence requirement a requirement for manufacturers to submit samples of each batch to the Food and Drug Administration and to withhold distribution of the batch until notified by the Food and Drug Administration that the batch may be introduced into interstate commerce.

(b) The Commissioner will ordinarily terminate a requirement for a manufacturer to submit samples for batch testing on a finding that the manufacturer has produced four consecutive batches that were tested by the Food and Drug Administration and found to meet the bioequivalence requirement, unless the public health requires that batch testing be extended to additional batches.

If a bioequivalence requirement specifies a currently available in vitro test or an in vitro bioequivalence standard comparing the drug product to a reference standard, the manufacturer shall conduct the test on a sample of each batch of the drug product to assure batch-to-batch uniformity.

(a) All records of in vivo or in vitro tests conducted on any marketed batch of a drug product to assure that the product meets a bioequivalence requirement shall be maintained by the manufacturer for at least 2 years after the expiration date of the batch and submitted to the Food and Drug Administration on request.

(b) Any person who contracts with another party to conduct a bioequivalence study from which the data are intended to be submitted to FDA as part of an application submitted under part 314 of this chapter shall obtain from the person conducting the study sufficient accurate financial information to allow the submission of complete and accurate financial certifications or disclosure statements required under part 54 of this chapter and shall maintain that information and all records relating to the compensation given for that study and all other financial interest information required under part 54 of this chapter for 2 years after the date of approval of the application. The person maintaining these records shall, upon request for any properly authorized officer or employee of the Food and Drug Administration, at reasonable time, permit such officer or employee to have access to and copy and verify these records.

(a) The applicant of an application or supplemental application submitted under section 505 of the Federal Food, Drug, and Cosmetic Act, or, if bioavailability testing was performed under contract, the contract research organization shall retain an appropriately identified reserve sample of the drug product for which the applicant is seeking approval (test article) and of the reference standard used to perform an in vivo bioavailability study in accordance with and for the studies described in paragraph (b) of this section that is representative of each sample of the test article and reference standard provided by the applicant for the testing.

(b) Reserve samples shall be retained for the following test articles and reference standards and for the studies described:

(1) If the formulation of the test article is the same as the formulation(s) used in the clinical studies demonstrating substantial evidence of safety and effectiveness for the test article's claimed indications, a reserve sample of the test article used to conduct an in vivo bioavailability study comparing the test article to a reference oral solution, suspension, or injection.

(2) If the formulation of the test article differs from the formulation(s) used in the clinical studies demonstrating substantial evidence of safety and effectiveness for the test article's claimed indications, a reserve sample of the test article and of the reference standard used to conduct an in vivo bioequivalence study comparing the test article to the formulation(s) (reference standard) used in the clinical studies.

(3) For a new formulation, new dosage form, or a new salt or ester of an active drug ingredient or therapeutic moiety that has been approved for marketing, a reserve sample of the test article and of the reference standard used to conduct an in vivo bioequivalence study comparing the test article to a marketed product (reference standard) that contains the same active drug ingredient or therapeutic moiety.

(c) Each reserve sample shall consist of a sufficient quantity to permit FDA to perform five times all of the release tests required in the application or supplemental application.

(d) Each reserve sample shall be adequately identified so that the reserve sample can be positively identified as having come from the same sample as used in the specific bioavailability study.

(e) Each reserve sample shall be stored under conditions consistent with product labeling and in an area segregated from the area where testing is conducted and with access limited to authorized personnel. Each reserve sample shall be retained for a period of at least 5 years following the date on which the application or supplemental application is approved, or, if such application or supplemental application is not approved, at least 5 years following the date of completion of the bioavailability study in which the sample from which the reserve sample was obtained was used.

(f) Authorized FDA personnel will ordinarily collect reserve samples directly from the applicant or contract research organization at the storage site during a preapproval inspection. If authorized FDA personnel are unable to collect samples, FDA may require the applicant or contract research organization to submit the reserve samples to the place identified in the agency's request. If FDA has not collected or requested delivery of a reserve sample, or if FDA has not collected or requested delivery of any portion of a reserve sample, the applicant or contract research organization shall retain the sample or remaining sample for the 5-year period specified in paragraph (e) of this section.

(g) Upon release of the reserve samples to FDA, the applicant or contract research organization shall provide a written assurance that, to the best knowledge and belief of the individual executing the assurance, the reserve samples came from the same samples as used in the specific bioavailability or bioequivalence study identified by the agency. The assurance shall be executed by an individual authorized to act for the applicant or contract research organization in releasing the reserve samples to FDA.

(h) A contract research organization may contract with an appropriate, independent third party to provide storage of reserve samples provided that the sponsor of the study has been notified in writing of the name and address of the facility at which the reserve samples will be stored.

(i) If a contract research organization conducting a bioavailability or bioequivalence study that requires reserve sample retention under this section or § 320.63 goes out of business, it shall transfer its reserve samples to an appropriate, independent third party, and shall notify in writing the sponsor of the study of the transfer and provide the study sponsor with the name and address of the facility to which the reserve samples have been transferred.

The applicant of an abbreviated application or a supplemental application submitted under section 505 of the Federal Food, Drug, and Cosmetic Act, or, if bioequivalence testing was performed under contract, the contract research organization shall retain reserve samples of any test article and reference standard used in conducting an in vivo or in vitro bioequivalence study required for approval of the abbreviated application or supplemental application. The applicant or contract research organization shall retain the reserve samples in accordance with, and for the period specified in, § 320.38 and shall release the reserve samples to FDA upon request in accordance with § 320.38.

Reference in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.

As used in this part:

(a) Alcohol means the substance known as ethanol, ethyl alcohol, or Alcohol, USP.

(b) Inactive ingredient means any component of a product other than an active ingredient as defined in § 210.3(b)(7) of this chapter.

(a) Any over-the-counter (OTC) drug product intended for oral ingestion shall not contain alcohol as an inactive ingredient in concentrations that exceed those established in this part, unless a specific exemption, as provided in paragraph (e) or (f) of this section, has been approved.

(b) For any OTC drug product intended for oral ingestion and labeled for use by adults and children 12 years of age and over, the amount of alcohol in the product shall not exceed 10 percent.

(c) For any OTC drug product intended for oral ingestion and labeled for use by children 6 to under 12 years of age, the amount of alcohol in the product shall not exceed 5 percent.

(d) For any OTC drug product intended for oral ingestion and labeled for use by children under 6 years of age, the amount of alcohol in the product shall not exceed 0.5 percent.

(e) The Food and Drug Administration will grant an exemption from paragraphs (b), (c), and (d) of this section where appropriate, upon petition under the provisions of § 10.30 of this chapter. Appropriate cause, such as a specific solubility or manufacturing problem, must be adequately documented in the petition. Decisions with respect to requests for exemption shall be maintained in a permanent file for public review by the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

(f) Ipecac syrup is exempt from the provisions of paragraph (d) of this section.

(g) The following drugs are temporarily exempt from the provisions of paragraphs (b), (c), and (d) of this section:

(1) Aromatic Cascara Fluidextract.

(2) Cascara Sagrada Fluidextract.

(3) Orally ingested homeopathic drug products.

(a) The amount (percentage) of alcohol present in a product shall be stated in terms of percent volume of absolute alcohol at 60 °F (15.56 °C) in accordance with § 201.10(d)(2) of this chapter.

(b) A statement expressing the amount (percentage) of alcohol present in a product shall appear prominently and conspicuously on the “principal display panel,” as defined in § 201.60 of this chapter. For products whose principal display panel is on the immediate container label and that are not marketed in another retail package (e.g., an outer box), the statement of the percentage of alcohol present in the product shall appear prominently and conspicuously on the “principal display panel” of the immediate container label.

(c) For products whose principal display panel is on the retail package and the retail package is not the immediate container, the statement of the percentage of alcohol present in the product shall also appear on the immediate container label; it may appear anywhere on that label in accord with section 502(e) of the Federal Food, Drug, and Cosmetic Act.

(d) The statement expressing the amount (percentage) of alcohol present in the product shall be in a size reasonably related to the most prominent printed matter on the panel or label on which it appears, and shall be in lines generally parallel to the base on which the package rests as it is designed to be displayed.

(e) For a product to state in its labeling that it is “alcohol free,” it must contain no alcohol (0 percent).

(f) For any OTC drug product intended for oral ingestion containing over 5 percent alcohol and labeled for use by adults and children 12 years of age and over, the labeling shall contain the following statement in the directions section: “Consult a physician for use in children under 12 years of age.”

(g) For any OTC drug product intended for oral ingestion containing over 0.5 percent alcohol and labeled for use by children ages 6 to under 12 years of age, the labeling shall contain the following statement in the directions section: “Consult a physician for use in children under 6 years of age.”

(h) When the direction regarding age in paragraph (e) or (f) of this section differs from an age-limiting direction contained in any OTC drug monograph in this chapter, the direction containing the more stringent age limitation shall be used.

An over-the-counter (OTC) drug listed in this subchapter is generally recognized as safe and effective and is not misbranded if it meets each of the conditions contained in this part and each of the conditions contained in any applicable monograph. Any product which fails to conform to each of the conditions contained in this part and in an applicable monograph is liable to regulatory action.

(a) The product is manufactured in compliance with current good manufacturing practices, as established by parts 210 and 211 of this chapter.

(b) The establishment(s) in which the drug product is manufactured is registered, and the drug product is listed, in compliance with part 207 of this chapter. It is requested but not required that the number assigned to the product pursuant to part 207 of this chapter appear on all drug labels and in all drug labeling. If this number is used, it shall be placed in the manner set forth in part 207 of this chapter.

(c)(1) The product is labeled in compliance with chapter V of the Federal Food, Drug, and Cosmetic Act (the act) and subchapter C et seq. of this chapter, including the format and content requirements in § 201.66 of this chapter. An OTC drug product that is not in compliance with chapter V and subchapter C, including § 201.66 of this chapter, is subject to regulatory action. For purposes of § 201.61(b) of this chapter, the statement of identity of the product shall be the term or phrase used in the applicable OTC drug monograph established in this part.

(2) The “Uses” section of the label and labeling of the product shall contain the labeling describing the “Indications” that have been established in an applicable OTC drug monograph or alternative truthful and nonmisleading statements describing only those indications for use that have been established in an applicable monograph, subject to the provisions of section 502 of the act relating to misbranding and the prohibition in section 301(d) of the act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the act. Any other labeling under this subchapter and subchapter C et seq. of this chapter shall be stated in the exact language where exact language has been established and identified by quotation marks in an applicable OTC drug monograph or by regulation (e.g., § 201.63 of this chapter), except as provided in paragraphs (i) and (j) of this section.

(d) The advertising for the product prescribes, recommends, or suggests its use only under the conditions stated in the labeling.

(e) The product contains only suitable inactive ingredients which are safe in the amounts administered and do not interfere with the effectiveness of the preparation or with suitable tests or assays to determine if the product meets its professed standards of identity, strength, quality, and purity. Color additives may be used only in accordance with section 721 of the act and subchapter A of this chapter.

(f) The product container and container components meet the requirements of § 211.94 of this chapter.

(g) The labeling for all drugs contains the general warning: “Keep out of reach of children.” [highlighted in bold type]. The labeling of drugs shall also state as follows: For drugs used by oral administration, “In case of overdose, get medical help or contact a Poison Control Center right away”; for drugs used topically, rectally, or vaginally and not intended for oral ingestion, “If swallowed, get medical help or contact a Poison Control Center right away”; and for drugs used topically and intended for oral use, “If more than used for” (insert intended use, e.g., pain) “is accidentally swallowed, get medical help or contact a Poison Control Center right away.” The Food and Drug Administration will grant an exemption from these general warnings where appropriate upon petition, which shall be maintained in a permanent file for public review by the Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

(h) Where no maximum daily dosage limit for an active ingredient is established in this part, it is used in a product at a level that does not exceed the amount reasonably required to achieve its intended effect.

(i) The following terms may be used interchangeably in the labeling of OTC drug products, provided such use does not alter the meaning of the labeling that has been established and identified in an applicable monograph or by regulation. The following terms shall not be used to change in any way the title, headings, and subheadings required under § 201.66(c)(1) through (c)(9) of this chapter:

(1) “Abdominal” or “stomach” (in context only).

(2) “Administer” or “give”.

(3) “Aggravate(s)” or “make(s) worse”.

(4) “Application of this product” or “applying”.

(5) “Are uncertain” or “do not know”.

(6) “Ask” or “consult” or “contact”.

(7) “Asking” or “consulting”.

(8) “Assistance” or “help” or “aid”.

(9) “Associated with” or “due to” or “caused by”.

(10) “Avoid contact with eyes” or “do not get into eyes”.

(11) “Avoid inhaling” or “do not inhale”.

(12) “Before a doctor is consulted” or “without first consulting your doctor” or “consult your doctor before”.

(13) “Beverages” or “drinks”.

(14) “Clean” or “cleanse”.

(15) “Consulting” or “advising”.

(16) “Continue(s)” or “persist(s)” or “is persistent” or “do(es) not go away” or “last(s)”.

(17) “Daily” or “every day”.

(18) “Develop(s)” or “begin(s)” or “occur(s)”.

(19) “Difficulty” or “trouble”.

(20) “Difficulty in urination” or “trouble urinating”.

(21) “Discard” or “throw away”.

(22) “Discontinue” or “stop” or “quit”.

(23) “Doctor” or “physician”.

(24) “Drowsiness” or “the drowsiness effect”.

(25) “Drowsiness may occur” or “you may get drowsy”.

(26) “Enlargement of the” or “an enlarged”.

(27) “Especially in children” or especially children”.

(28) “Exceed” or “use more than” or “go beyond”.

(29) “Exceed recommended dosage” or “use more than directed”.

(30) “Excessive” or “too much”.

(31) “Excitability may occur” or “you may get excited”.

(32) “Experience” or “feel”.

(33) “For relief of” or “relieves”.

(34) “For temporary reduction of” or “temporarily reduces”.

(35) “For the temporary relief of” or “temporarily relieves”.

(36) “For the treatment of” or “treats”.

(37) “Frequently” or “often”.

(38) “Give to” or “use in”.

(39) “Immediately” or “right away” or “directly”.

(40) “Immediately” or “as soon as”.

(41) “Immediately following” or “right after”.

(42) “Improve(s)” or “get(s) better” or “make(s) better”.

(43) “Increased” or “more”.

(44) “Increase your risk of” or “cause”.

(45) “Indication(s)” or “Use(s)”.

(46) “Inhalation” or “puff”.

(47) “In persons who” or “if you” or “if the child”.

(48) “Instill” or “put”.

(49) “Is (are) accompanied by” or “you also have” (in context only) or “(optional: that) occur(s) with”.

(50) “Longer” or “more”.

(51) “Lung” or “pulmonary”.

(52) “Medication(s)” or “medicine(s)” or “drug(s)”.

(53) “Nervousness, dizziness, or sleeplessness occurs” or “you get nervous, dizzy, or sleepless”.

(54) “Not to exceed” or “do not exceed” or “not more than”.

(55) “Obtain(s)” or “get(s)”.

(56) “Passages” or “passageways” or “tubes”.

(57) “Perforation of” or “hole in”.

(58) “Persistent” or “that does not go away” or “that continues” or “that lasts”.

(59) “Per day” or “daily”.

(60) “Presently” or “now”.

(61) “Produce(s)” or “cause(s)”.

(62) “Prompt(ly)” or “quick(ly)” or “right away”.

(63) “Reduce” or “minimize”.

(64) “Referred to as” or “of”.

(65) “Sensation” or “feeling”.

(66) “Solution” or “liquid”.

(67) “Specifically” or “definitely”.

(68) “Take” or “use” or “give”.

(69) “Tend(s) to recur” or “reoccur(s)” or “return(s)” or “come(s) back”.

(70) “To avoid contamination” or “avoid contamination” or “do not contaminate”.

(71) “To help” or “helps”.

(72) “Unless directed by a doctor” or “except under the advice of a doctor” or “unless told to do so by a doctor”.

(73) “Use caution” or “be careful”.

(74) “Usually” or “generally” (in context only).

(75) “You” (“Your”) or “the child” (“the child's”).

(76) “You also have” or “occurs with”.

(77) “When practical” or “if possible”.

(78) “Whether” or “if”.

(79) “Worsen(s)” or “get(s) worse” or “make(s) worse”.

(j) The following connecting terms may be deleted from the labeling of OTC drug products, provided such deletion does not alter the meaning of the labeling that has been established and identified in an applicable monograph or by regulation. The following terms shall not be used to change in any way the specific title, headings, and subheadings required under § 201.66(c)(1) through (c)(9) of this chapter:

(l) “And”.

(2) “As may occur with”.

(3) “Associated” or “to be associated”.

(4) “Consult a doctor”.

(5) “Discontinue use”.

(6) “Drug Interaction Precaution”.

(7) “Due to”.

(8) “Except under the advice and supervision of a physician”.

(9) “If this occurs”.

(10) “In case of”.

(11) “Notice”.

(12) “Or”.

(13) “Occurring with”.

(14) “Or as directed by a doctor”.

(15) “Such as”.

(16) “Such as occurs with”.

(17) “Tends to”.

(18) “This product”.

(19) “Unless directed by a doctor”.

(20) “While taking this product” or “before taking this product”.

(21) “Within”.

A pregnancy-nursing warning for OTC drugs is set forth under § 201.63 of this chapter.

A requirement to imprint an identification code on solid oral dosage form drug products is set forth under part 206 of this chapter.

Monographs promulgated pursuant to the provisions of this part shall be established in this part 330 and following parts and shall cover the following designated categories:

(a) Antacids.

(b) Laxatives.

(c) Antidiarrheal products.

(d) Emetics.

(e) Antiemetics.

(f) Antiperspirants.

(g) Sunburn prevention and treatment products.

(h) Vitamin-mineral products.

(i) Antimicrobial products.

(j) Dandruff products.

(k) Oral hygiene aids.

(l) Hemorrhoidal products.

(m) Hematinics.

(n) Bronchodilator and antiasthmatic products.

(o) Analgesics.

(p) Sedatives and sleep aids.

(q) Stimulants.

(r) Antitussives.

(s) Allergy treatment products.

(t) Cold remedies.

(u) Antirheumatic products.

(v) Ophthalmic products.

(w) Contraceptive products.

(x) Miscellaneous dermatologic products.

(y) Dentifrices and dental products such as analgesics, antiseptics, etc.

(z) Miscellaneous (all other OTC drugs not falling within one of the above therapeutic categories).

For purposes of classifying over-the-counter (OTC) drugs as drugs generally recognized among qualified experts as safe and effective for use and as not misbranded drugs, the following regulations shall apply:

(a) Procedure for establishing OTC drug monographs - (1) Advisory review panels. The Commissioner shall appoint advisory review panels of qualified experts to evaluate the safety and effectiveness of OTC drugs, to review OTC drug labeling, and to advise him on the promulgation of monographs establishing conditions under which OTC drugs are generally recognized as safe and effective and not misbranded. A single advisory review panel shall be established for each designated category of OTC drugs and every OTC drug category will be considered by a panel. The members of a panel shall be qualified experts (appointed by the Commissioner) and may include persons from lists submitted by organizations representing professional, consumer, and industry interests. The Commissioner shall designate the chairman of each panel. Summary minutes of all meetings shall be made.

(2) Request for data and views. The Commissioner will publish a notice in the Federal Register requesting interested persons to submit, for review and evaluation by an advisory review panel, published and unpublished data and information pertinent to a designated category of OTC drugs. Data and information submitted pursuant to a published notice, and falling within the confidentiality provisions of 18 U.S.C. 1905, 5 U.S.C. 552(b), or 21 U.S.C. 331(j), shall be handled by the advisory review panel and the Food and Drug Administration as confidential until publication of a proposed monograph and the full report(s) of the panel or until the Commissioner places the panel's recommendations on public display at the office of the Division of Dockets Management. Thirty days thereafter such data and information shall be made publicly available and may be viewed at the office of the Division of Dockets Management of the Food and Drug Administration, except to the extent that the person submitting it demonstrates that it still falls within the confidentiality provisions of one or more of those statutes. To be considered, eight copies of the data and/or views on any marketed drug within the class must be submitted, preferably bound, indexed, and on standard sized paper (approximately 8 1/2 × 11 inches). When requested, abbreviated submissions should be sent. All submissions must be in the following format:

(3) Deliberations of an advisory review panel. An advisory review panel will meet as often and for as long as is appropriate to review the data submitted to it and to prepare a report containing its conclusions and recommendations to the Commissioner with respect to the safety and effectiveness of the drugs in a designated category of OTC drugs. A panel may consult any individual or group. Any interested person may request an opportunity to present oral views to the panel; such request may be granted or denied by the panel. Such requests for oral presentations should be in written form including a summarization of the data to be presented to the panel. Any interested person may present written data and views which shall be considered by the panel. This information shall be presented to the panel in the format set forth in paragraph (a)(2) of this section and within the time period established for the drug category in the notice for review by a panel.

(4) Standards for safety, effectiveness, and labeling. The advisory review panel, in reviewing the data submitted to it and preparing its conclusions and recommendations, and the Commissioner, in reviewing the conclusions and recommendations of the panel and the published proposed, tentative, and the final monographs, shall apply the following standards to determine general recognition that a category of OTC drugs is safe and effective and not misbranded:

(i) Safety means a low incidence of adverse reactions or significant side effects under adequate directions for use and warnings against unsafe use as well as low potential for harm which may result from abuse under conditions of widespread availability. Proof of safety shall consist of adequate tests by methods reasonably applicable to show the drug is safe under the prescribed, recommended, or suggested conditions of use. This proof shall include results of significant human experience during marketing. General recognition of safety shall ordinarily be based upon published studies which may be corroborated by unpublished studies and other data.

(ii) Effectiveness means a reasonable expectation that, in a significant proportion of the target population, the pharmacological effect of the drug, when used under adequate directions for use and warnings against unsafe use, will provide clinically significant relief of the type claimed. Proof of effectiveness shall consist of controlled clinical investigations as defined in § 314.126(b) of this chapter, unless this requirement is waived on the basis of a showing that it is not reasonably applicable to the drug or essential to the validity of the investigation and that an alternative method of investigation is adequate to substantiate effectiveness. Investigations may be corroborated by partially controlled or uncontrolled studies, documented clinical studies by qualified experts, and reports of significant human experience during marketing. Isolated case reports, random experience, and reports lacking the details which permit scientific evaluation will not be considered. General recognition of effectiveness shall ordinarily be based upon published studies which may be corroborated by unpublished studies and other data.

(iii) The benefit-to-risk ratio of a drug shall be considered in determining safety and effectiveness.

(iv) An OTC drug may combine two or more safe and effective active ingredients and may be generally recognized as safe and effective when each active ingredient makes a contribution to the claimed effect(s); when combining of the active ingredients does not decrease the safety or effectiveness of any of the individual active ingredients; and when the combination, when used under adequate directions for use and warnings against unsafe use, provides rational concurrent therapy for a significant proportion of the target population.

(v) Labeling shall be clear and truthful in all respects and may not be false or misleading in any particular. It shall state the intended uses and results of the product; adequate directions for proper use; and warnings against unsafe use, side effects, and adverse reactions in such terms as to render them likely to be read and understood by the ordinary individual, including individuals of low comprehension, under customary conditions of purchase and use.

(vi) A drug shall be permitted for OTC sale and use by the laity unless, because of its toxicity or other potential for harmful effect or because of the method or collateral measures necessary to its use, it may safely be sold and used only under the supervision of a practitioner licensed by law to administer such drugs.

(5) Advisory review panel report to the Commissioner. An advisory review panel may submit to the Commissioner a report containing its conclusions and recommendations with respect to the conditions under which OTC drugs falling within the category covered by the panel are generally recognized as safe and effective and not misbranded. Included within this report shall be:

(i) A recommended monograph or monographs covering the category of OTC drugs and establishing conditions under which the drugs involved are generally recognized as safe and effective and not misbranded (Category I). This monograph may include any conditions relating to active ingredients, labeling indications, warnings and adequate directions for use, prescription or OTC status, and any other conditions necessary and appropriate for the safety and effectiveness of drugs covered by the monograph.

(ii) A statement of active ingredients, labeling claims or other statements, or other conditions reviewed and excluded from the monograph on the basis of the panel's determination that they would result in the drug's not being generally recognized as safe and effective or would result in misbranding (Category II).

(iii) A statement of active ingredients, labeling claims or other statements, or other conditions reviewed and excluded from the monograph on the basis of the panel's determination that the available data are insufficient to classify such condition under either paragraph (a)(5) (i) or (ii) of this section and for which further testing is therefore required (Category III). The report may recommend the type of further testing required and the time period within which it might reasonably be concluded.

(6) Proposed monograph. After reviewing the conclusions and recommendations of the advisory review panel, the Commissioner shall publish in the Federal Register a proposed order containing:

(i) A monograph or monographs establishing conditions under which a category of OTC drugs or a specific or specific OTC drugs are generally recognized as safe and effective and not misbranded (Category I).

(ii) A statement of the conditions excluded from the monograph on the basis of the Commissioner's determination that they would result in the drug's not being generally recognized as safe and effective or would result in misbranding (Category II).

(iii) A statement of the conditions excluded from the monograph on the basis of the Commissioner's determination that the available data are insufficient to classify such conditions under either paragraph (a)(6)(i) or (ii) of this section (Category III).

(iv) The full report(s) of the panel to the Commissioner. The proposed order shall specify a reasonable period of time within which conditions falling within paragraph (a)(6)(iii) of this section may be continued in marketed products while the data necessary to support them are being obtained for evaluation by the Food and Drug Administration. The summary minutes of the panel meetings shall be made available to interested persons upon request. Any interested person may, within 90 days after publication of the proposed order in the Federal Register, file with the Division of Dockets Management of the Food and Drug Administration written comments in triplicate. Comments may be accompanied by a memorandum or brief in support thereof. All comments may be reviewed at the office of the Division of Dockets Management between the hours of 9 a.m. and 4 p.m., Monday through Friday. Within 30 days after the final day for submission of comments, reply comments may be filed with the Division of Dockets Management; these comments shall be utilized to reply to comments made by other interested persons and not to reiterate a position. The Commissioner may satisfy this requirement by publishing in the Federal Register a proposed order summarizing the full report of the advisory review panel, containing its conclusions and recommendations, to obtain full public comment before undertaking his own evaluation and decision on the matters involved.

(7) Tentative final monograph. (i) After reviewing all comments, reply comments, and any new data and information or, alternatively, after reviewing a panel's recommendations, the Commissioner shall publish in the Federal Register a tentative order containing a monograph establishing conditions under which a category of OTC drugs or specific OTC drugs are generally recognized as safe and effective and not misbranded. Within 90 days, any interested person may file with the Division of Dockets Management, Food and Drug Administration, written comments or written objections specifying with particularity the omissions or additions requested. These objections are to be supported by a brief statement of the grounds therefor. A request for an oral hearing may accompany such objections.

(ii) The Commissioner may also publish in the Federal Register a separate tentative order containing a statement of those active ingredients reviewed and proposed to be excluded from the monograph on the basis of the Commissioner's determination that they would result in a drug product not being generally recognized as safe and effective or would result in misbranding. This order may be published when no substantive comments in opposition to the panel report or new data and information were received by the Food and Drug Administration under paragraph (a)(6)(iv) of this section or when the Commissioner has evaluated and concurs with a panel's recommendation that a condition be excluded from the monograph. Within 90 days, any interested person may file with the Division of Dockets Management, Food and Drug Administration, written objections specifying with particularity the provision of the tentative order to which objection is made. These objections are to be supported by a brief statement of the grounds therefor. A request for an oral hearing may accompany such objections.

(iii) Within 12 months after publishing a tentative order pursuant to paragraph (a)(7)(i) of this section, any interested person may file with the Division of Dockets Management, Food and Drug Administration, new data and information to support a condition excluded from the monograph in the tentative order.

(iv) Within 60 days after the final day for submission of new data and information, comments on the new data and information may be filed with the Division of Dockets Management, Food and Drug Administration.

(v) New data and information submitted after the time specified in this paragraph but prior to the establishment of a final monograph will be considered as a petition to amend the monograph and will be considered by the Commissioner only after a final monograph has been published in the Federal Register unless the Commisisoner finds that good cause has been shown that warrants earlier consideration.

(8) Oral hearing before the Commissioner. After reviewing objections filed in response to the tentative final monograph, the Commissioner, if he finds reasonable grounds in support thereof, shall by notice in the Federal Register schedule an oral hearing. The notice scheduling an oral hearing shall specify the length of the hearing and how the time shall be divided among the parties requesting the hearing. The hearing shall be conducted by the Commissioner and may not be delegated.

(9) Final monograph. After reviewing the objections, the entire administrative record including all new data and information and comments, and considering the arguments made at any oral hearing, the Commissioner shall publish in the Federal Register a final order containing a monograph establishing conditions under which a category of OTC drugs or a specific or specific OTC drugs are generally recognized as safe and effective and not misbranded. The monograph shall become effective as specified in the order.

(10) Administrative record. (i) All data and information to be considered in any proceeding pursuant to this section shall be submitted in response to the request for data and views pursuant to paragraph (a)(2) of this section, in response to any other notice published in the Federal Register, or accepted by the panel during its deliberations pursuant to paragraph (a)(3) of this section or submitted to the Division of Dockets Management as part of the comments during the 90-day period and 30-day rebuttal comment period permitted pursuant to paragraph (a)(6) of this section or submitted to the Division of Dockets Management during the 12-month period or as part of the comments during the 60-day period permitted pursuant to paragraph (a)(7) of this section.

(ii) The Commissioner shall make all decisions and issue all orders pursuant to this section solely on the basis of the administrative record, and shall not consider data or information not included as part of the administrative record.

(iii) The administrative record shall consist solely of the following material: All notices and orders published in the Federal Register, all data and views submitted in response to the request published pursuant to paragraph (a)(2) of this section, in response to any other notice published in the Federal Register, or accepted by the panel during its deliberations pursuant to paragraph (a)(3) of this section, all minutes of panel meetings, the panel report(s), all comments and rebuttal comments submitted on the proposed monograph and all new data and information submitted pursuant to paragraph (a)(6) of this section, all objections submitted on the tentative final monograph and all new data and information and comments submitted pursuant to paragraph (a)(7) of this section, the complete record of any oral public hearing conducted pursuant to paragraph (a)(8) of this section, all other comments requested at any time by the Commissioner, all data and information for which the Commissioner has reopened the administrative record, and all other material that the Commissioner includes in the administrative record as part of the basis for the Commissioner's decision.

(11) Court appeal. The monograph contained in the final order constitutes final agency action from which appeal lies to the courts. The Food and Drug Administration will request consolidation of all appeals in a single court. Upon court appeal, the Commissioner may, at his discretion, stay the effective date for part or all of the monograph pending appeal and final court adjudication.

(12) Amendment of monographs. (i) The Commissioner may propose on the Commissioner's own initiative to amend or repeal any monograph established pursuant to this section. Any interested person may petition the Commissioner for such proposal pursuant to § 10.30 of this chapter. The Commissioner may deny the petition if the Commissioner finds a lack of safety or effectiveness employing the standards in paragraph (a)(4) of this section (in which case the appeal provisions of paragraph (a)(11) of this section shall apply), or the Commissioner may publish a proposed amendment or repeal in the Federal Register if the Commissioner finds general recognition of safety and effectiveness employing the standards in paragraph (a)(4) of this section. Any interested person may, within 90 days after publication of the proposed order in the Federal Register, file with the Division of Dockets Management, Food and Drug Administration, written comments in triplicate. Comments may be accompanied by a memorandum or brief in support thereof. All comments may be reviewed in the Division of Dockets Management between the hours of 9 a.m. and 4 p.m., Monday through Friday. After reviewing the comments, the Commissioner shall publish a final order amending the monograph established under the provisions of paragraph (a)(9) of this section or withdraw the proposal if comments opposing the amendment are persuasive. A new drug application may be submitted in lieu of, or in addition to, a petition under this paragraph.

(ii) A new drug application may be submitted in lieu of a petition to amend the OTC drug monograh only if the drug product with the condition that is the subject of the new drug application has not been marketed on an interim basis (such as under the provisions of paragraph (a)(6)(iii) of this section), all clinical testing has been conducted pursuant to a new drug application plan, and no marketing of the product with the condition for which approval is sought is undertaken prior to approval of the new drug application. The Food and Drug Administration shall handle a new drug application as a petition for amendment of a monograph, and shall review it on that basis, if the provisions of this paragraph preclude approval of a new drug application but permit the granting of such a petition.

(b) Regulatory action. Any product which fails to conform to an applicable monograph after its effective date is liable to regulatory action.

(c) Information and data submitted under this section shall include, with respect to each nonclinical laboratory study contained in the application, either a statement that the study was conducted in compliance with the good laboratory practice regulations set forth in part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance.

(d) [Reserved]

(e) Institutional review and informed consent. Information and data submitted under this section after July 27, 1981, shall include statements regarding each clinical investigation involving human subjects, from which the information and data are derived, that it either was conducted in compliance with the requirements for institutional review set forth in part 56 of this chapter, or was not subject to such requirements in accordance with §§ 56.104 or 56.105, and that it was conducted in compliance with the requirements for informed consent set forth in part 50 of this chapter.

(f) Financial certification or disclosure statement. Any clinical data submitted under this section must be accompanied by financial certifications or disclosure statements or both as required by part 54 of this chapter.

A new drug application requesting approval of an OTC drug deviating in any respect from a monograph that has become final shall be in the form required by § 314.50 of this chapter, but shall include a statement that the product meets all conditions of the applicable monograph except for the deviation for which approval is requested and may omit all information except that pertinent to the deviation.

(a) There were 420 OTC drugs reviewed in the Drug Efficacy Study (a review of drugs introduced to the market through new drug procedures between 1938 and 1962). A careful review has been made of the reports on these drugs to determine those drugs for which implementation may be deferred without significant risk to the public health, pending review by appropriate OTC drug advisory review panels and promulgation of a monograph.

(b) On and after April 20, 1972, a number of notices were published in the Federal Register concerning previously unpublished OTC drugs reviewed by the National Academy of Sciences-National Research Council Drug Efficacy Study Group. Only the evaluations and comments of the panels were published, with no conclusions of the Commissioner of Food and Drugs. Those publications were for the purpose of giving interested persons the benefit of the Academy's opinions. For those products, and also for OTC drug products previously published with the Commissioner's conclusions (except for the products listed in paragraphs (b) (1) and (2) of this section, all requests for data, revised labeling, requests for new drug applications, abbreviated new drug applications, updating supplements, data to support less than effective claims, if any, etc., are deferred, and such OTC drug products are instead subject to the OTC drug review in their appropriate classes pursuant to the procedures established in this subpart.

(1) The requirements of the following DESI announcements are not deferred (the reference document may also pertain to prescription drugs):

(i) Certain Surgical Sutures (DESI 4725), published in the Federal Register of November 11, 1971 (36 FR 21612).

(ii) Absorbable Dusting Powder (DESI 6264), published in the Federal Register of May 25, 1971 (36 FR 9475).

(iii) Certain Insulin Preparations (DESI 4286), published in the Federal Register of April 9, 1971 (36 FR 6842).

(iv) Sulfo-Van Ointment (DESI 2230), published in the Federal Register of October 8, 1970 (35 FR 15860).

(v) Antiperspirants and Deodorants Containing Neomycin Sulfate (DESI 11048) for which an order revoking provisions for certification or release was published in the Federal Register of December 5, 1972 (37 FR 25820) and has been stayed by the filing of objections.

(vi) Thorexin Cough Medicine (DESI 11160) for which a notice of opportunity for hearing was published in the Federal Register of February 2, 1973 (38 FR 3210).

(vii) Antibiotic susceptibility discs (DESI 90235) for which an order providing for certain discs to be certified and removing provisions for certification of other discs was published in the Federal Register of September 30, 1972 (37 FR 20525) and has been stayed by the filing of objections notice of which was published in the Federal Register of March 15, 1973 (38 FR 7007).

(2) Deferral of requirements is not appropriate when an announcement has been published and has been followed by a final order classifying a drug either as lacking substantial evidence of effectiveness or as not shown to be safe. These products will be removed from the market, if they have not already been removed. Regulatory action will also be undertaken against identical, similar and related products (21 CFR 310.6). Deferral of requirements is not appropriate for the following (the referenced document may also pertain to prescription drugs):

(i) Certain Sulfonamide-Decongestant Nasal Preparation (DESI 4850), for which notice of withdrawal of approval of new drug applications was published in the Federal Register of October 24, 1970 (35 FR 16605, 16606).

(ii) Eskay's Theranates, containing strychnine, sodium, and calcium glycerophosphates, thiamine hydrochloride, alcohol, and phosphoric acid (DESI 2220), for which notice of withdrawal of approval of the new drug application was published in the Federal Register of February 18, 1971 (36 FR 3152).

(iii) The following topical drugs (DESI 1726), for which notice of withdrawal of new drug applications was published in the Federal Register of August 28, 1971 (36 FR 17368):

(a) Rhulitol Solution, containing tannic acid, chlorobutanol, phenol, camphor, alum, and isopropyl alcohol.

(b) Zirnox Topical Lotion, containing phenyitoloxamine citrate and zirconium oxide.

(iv) Menacyl Tablets, containing aspirin, menadione, and ascorbic acid (DESI 6363), for which notice of withdrawal of approval of the new drug application was published in the Federal Register of July 23, 1970 (35 FR 11827).

(v) Curad Medicated Adhesive Bandage containing sulfathiazole (DESI 4964), for which notice of withdrawal of approval of the new drug application was published in the Federal Register of December 31, 1969 (34 FR 20441).

(vi) Drugs Containing Rutin, Quercetin, Hesperidin, or any Bioflavonoids (DESI 5960), for which notice of withdrawal of approval of new drug applications was published in the Federal Register of July 3, 1970 (35 FR 10872, 10873) and October 17, 1970 (35 FR 16332). A further notice of opportunity for hearing with respect to the drugs covered by the October 17, 1970 Federal Register notice will be published at a later date.

(vii) Antibiotics in Combination with Other Drugs for Nasal Use (DESI 7561), for which an order revoking provision for certification was published in the Federal Register of August 6, 1971 (36 FR 14469) and confirmed in the Federal Register of October 28, 1971 (36 FR 20686).

(viii) Antibiotic Troches (DESI 8328), for which an order revoking provision for certification was published in the Federal Register of July 14, 1971 (36 FR 13089) and confirmed in the Federal Register of October 9, 1971 (36 FR 19695).

(ix) Certain Drugs Containing Oxyphenisatin or Oxyphenisatin Acetate (DESI 10732), for which notices of withdrawal of approval of new drug applications were published in the Federal Register of February 1, 1972 (37 FR 2460), and March 9, 1973 (38 FR 6419).

(x) Curad Medicated Adhesive Bandage containing tyrothricin-nitrofurazone (DESI 6898), for which an order revoking provision for certification was published March 14, 1972 (37 FR 5294), and confirmed in the Federal Register of July 6, 1972 (37 FR 13254).

(xi) Candette Cough Gel (DESI 11562), for which notice of withdrawal of approval of the new drug application was published in the Federal Register of November 19, 1972 (37 FR 25249).

(xii) Certain OTC Multiple-Vitamin Preparations for Oral Use containing excessive amounts of vitamin D and/or vitamin A (DESI 97), for which notice of withdrawal of approval of the new drug applications was published in the Federal Register of November 29, 1972 (37 FR 25249).

(xiii) Certain Sulfonamide-Containing Preparations for Topical Ophthalmic or Otic Use (DESI 368, for which a notice of withdrawal of approval was published in the Federal Register of February 2, 1973 (38 FR 3208).

(xiv) Those parts of the publication entitled “Certain Mouthwash and Gargle Preparations” (DESI 2855) pertaining to Tyrolaris Mouthwash, containing tyrothricin, panthenol, and alcohol, for which an order revoking provision for certification was published in the Federal Register of February 2, 1967 (32 FR 1172) prior to the drug efficacy study implementation.

(c) Manufacturers and distributors should take notice that the information on OTC drugs provided by the Drug Efficacy Study review is valuable information as to the deficiencies in the data available to support indications for use. They are encouraged to perform studies to obtain adequate evidence of effectiveness for the review of OTC drugs which is already in progress. In the interim it is in the public interest that manufacturers and distributors of all OTC drugs effect changes in their formulations and/or labeling to bring the products into conformity with current medical knowledge and experience.

(d) Manufacturers and distributors of OTC drugs may be reluctant to make appropriate formulation and/or labeling changes for fear of losing the protection of the so-called “grandfather” provisions of the 1938 Federal Food, Drug, and Cosmetic Act (sec. 201(p)(1)) and the 1962 amendments to the act (sec. 107(c) of those amendments). To encourage and facilitate prompt changes, the Food and Drug Administration will not take legal action against any OTC drug, other than those not deferred, based on a charge that the product is a new drug and not grandfathered under the act as a result of the changes if the changes in formulation and/or labeling are of the following kind:

(1) The addition to the labeling of warning, contraindications, side effects, and/or precaution information.

(2) The deletion from the labeling of false, misleading, or unsupported indications for use or claims of effectiveness.

(3) Changes in the components or composition of the drug that will give increased assurance that the drug will have its intended effect, yet not raise or contribute any added safety questions.

(4) Changes in the components or composition of the drug which may reasonably be concluded to improve the safety of the drug, without diminishing its effectiveness.

(e) The forbearance from legal action for lack of grandfather protection is an interim procedure designed to encourage appropriate change in formulation and/or labeling during the time period required to review the various classes of OTC drugs. At such time as an applicable OTC drug monograph becomes effective, the interim procedure will automatically be terminated and any appropriate regulatory action will be initiated.

(a) Before the publication in the Federal Register of an applicable proposed monograph, an OTC drug product that contains: (1) An active ingredient limited, on or after May 11, 1972, to prescription use for the indication and route of administration under consideration by an OTC advisory review panel, and not thereafter exempted from such limitation pursuant to § 310.200 of this chapter, or

(2) An active ingredient at a dosage level higher than that available in an OTC drug product on December 4, 1975, shall be regarded as a new drug within the meaning of section 201(p) of the act for which an approved new drug application is required.

(b)(1) An OTC drug product that contains: (i) An active ingredient limited, on or after May 11, 1972, to prescription use for the indication and route of administration under consideration by an OTC advisory review panel, and not thereafter exempted from such limitation pursuant to § 310.200 of this chapter, or

(ii) An active ingredient at a dosage level higher than that available in an OTC drug product on December 4, 1975, which ingredient and/or dosage level is classified by the panel in category I (conditions subject to § 330.10(a)(6)(i)) shall be regarded as a new drug within the meaning of section 201(p) of the act for which an approved new drug application is required if marketed for OTC use prior to the date of publication in the Federal Register of a proposed monograph.

(2) An OTC drug product covered by paragraph (b)(1) of this section which is marketed after the date of publication in the Federal Register of a proposed monograph but prior to the effective date of a final monograph shall be subject to the risk that the Commissioner may not accept the panel's recommendation and may instead adopt a different position that may require relabeling, recall, or other regulatory action. The Commissioner may state such position at any time by notice in the Federal Register, either separately or as part of another document; appropriate regulatory action will commence immediately and will not await publication of a final monograph. Marketing of such a product with a formulation or labeling not in accord with a proposed monograph or tentative final monograph also may result in regulatory action against the product, the marketer, or both.

(c) An OTC drug product that contains: (1) An active ingredient limited, on or after May 11, 1972, to prescription use for the indication and route of administration under consideration by an OTC advisory review panel, and not thereafter exempted from such limitation pursuant to § 310.200 of this chapter, or

(2) An active ingredient at a dosage level higher than that available in any OTC drug product on December 4, 1975, which ingredient and/or dosage level is classified by the panel in category II (conditions subject to § 330.10(a)(6)(ii)), may be marketed only after:

(i) The Center for Drug Evaluation and Research or the Commissioner tentatively determines that the ingredient is generally recognized as safe and effective, and the Commissioner states by notice in the Federal Register (separately or as part of another document) that marketing under specified conditions will be permitted;

(ii) The ingredient is determined by the Commissioner to be generally recognized as safe and effective and is included in the appropriate published OTC drug final monograph; or

(iii) A new drug application for the product has been approved.

(d) An OTC drug product that contains: (1) An active ingredient limited, on or after May 11, 1972, to prescription use for the indication and route of administration under consideration by an OTC advisory review panel, and not thereafter exempted from such limitation pursuant to § 310.200 of this chapter, or

(2) An active ingredient at a dosage level higher than that available in any OTC drug product on December 4, 1975, which ingredient and/or dosage level is classified by the panel in category III (conditions subject to § 330.10(a)(6)(iii)), may be marketed only after:

(i) The Center for Drug Evaluation and Research or the Commissioner tentatively determines that the ingredient is generally recognized as safe and effective, and the Commissioner states by notice in the Federal Register (separately or as part of another document) that marketing under specified conditions will be permitted;

(ii) The ingredient is determined by the Commissioner to be generally recognized as safe and effective and is included in the appropriate published OTC drug final monograph; or

(iii) A new drug application for the product has been approved.

(e) This section applies only to conditions under consideration as part of the OTC drug review initiated on May 11, 1972, and evaluated under the procedures set forth in § 330.10. Section 330.14(h) applies to the marketing of all conditions under consideration and evaluated using the criteria and procedures set forth in § 330.14.

This section sets forth additional criteria and procedures by which over-the-counter (OTC) drugs initially marketed in the United States after the OTC drug review began in 1972 and OTC drugs without any U.S. marketing experience can be considered in the OTC drug monograph system. This section also addresses conditions regulated as a cosmetic or dietary supplement in a foreign country that would be regulated as OTC drugs in the United States. Section 330.15 sets forth timelines for FDA review and action.

(a) Definitions. The definitions and interpretations contained in section 201 of the Federal Food, Drug, and Cosmetic Act and the following definitions of terms apply to this section and to § 330.15.

(1) Botanical drug substance means a drug substance derived from one or more plants, algae, or macroscopic fungi, but does not include a highly purified or chemically modified substance derived from such a source.

(2) Condition means an active ingredient or botanical drug substance (or a combination of active ingredients or botanical drug substances), dosage form, dosage strength, or route of administration, marketed for a specific OTC use, except as excluded in paragraph (b)(2) of this section.

(3) Date of filing means the date of the notice from FDA stating that FDA has made a threshold determination that the safety and effectiveness data submission is sufficiently complete to permit a substantive review; or, if the submission is filed over protest in accordance with paragraph (j)(3) of this section, the date of filing is the date of the notice from FDA stating that FDA has filed the submission over protest (this date will be no later than 30 days after the request that FDA file the submission over protest).

(4) Feedback letter means a letter issued by the agency in accordance with paragraph (g)(4) of this section that informs the sponsor and other interested persons who have submitted data under paragraph (f) of this section that a condition is initially determined not to be generally recognized as safe and effective (GRASE).

(5) Safety and effectiveness data submission means a data package submitted by a sponsor or other interested person that includes safety and effectiveness data and information under paragraph (f) of this section and that is represented by the submitter as being a complete submission.

(6) Sponsor means the person that submitted a time and extent application (TEA) under paragraph (c) of this section.

(7) Time and extent application (TEA) means a submission by a sponsor under paragraph (c) of this section, which will be evaluated by the agency to determine eligibility of a condition for consideration in the OTC drug monograph system.

(b) Criteria. To be considered for inclusion in the OTC drug monograph system, the condition must meet the following criteria:

(1) The condition must be marketed for OTC purchase by consumers. If the condition is marketed in another country in a class of OTC drug products that may be sold only in a pharmacy, with or without the personal involvement of a pharmacist, it must be established that this marketing restriction does not indicate safety concerns about the condition's toxicity or other potentiality for harmful effect, the method of its use, or the collateral measures necessary to its use.

(2) The condition must have been marketed OTC for a minimum of 5 continuous years in the same country and in sufficient quantity, as determined in paragraphs (c)(2)(ii), (c)(2)(iii), and (c)(2)(iv) of this section. Depending on the condition's extent of marketing in only one country with 5 continuous years of marketing, marketing in more than one country may be necessary.

(c) Time and extent application. Certain information must be provided when requesting that a condition subject to this section be considered for inclusion in the OTC drug monograph system. The following information must be provided in the format of a time and extent application (TEA):

(1) Basic information about the condition that includes a description of the active ingredient(s) or botanical drug substance(s), pharmacologic class(es), intended OTC use(s), OTC strength(s) and dosage form(s), route(s) of administration, directions for use, and the applicable existing OTC drug monograph(s) under which the condition would be marketed or the request and rationale for creation of a new OTC drug monograph(s).

(i) A detailed chemical description of the active ingredient(s) that includes a full description of the drug substance, including its physical and chemical characteristics, the method of synthesis (or isolation) and purification of the drug substance, and any specifications and analytical methods necessary to ensure the identity, strength, quality, and purity of the drug substance.

(ii) For a botanical drug substance(s), a detailed description of the botanical ingredient (including proper identification of the plant, plant part(s), alga, or macroscopic fungus used; a certificate of authenticity; and information on the grower/supplier, growing conditions, harvest location and harvest time); a qualitative description (including the name, appearance, physical/chemical properties, chemical constituents, active constituent(s) (if known), and biological activity (if known)); a quantitative description of the chemical constituents, including the active constituent(s) or other chemical marker(s) (if known and measurable); the type of manufacturing process (e.g., aqueous extraction, pulverization); and information on any further processing of the botanical substance (e.g., addition of excipients or blending).

(iii) Reference to the current edition of the U.S. Pharmacopeia (USP)-National Formulary (NF) or foreign compendiums may help satisfy the requirements in this section.

(2) A list of all countries in which the condition has been marketed. Include the following information for each country. (For a condition that has been marketed OTC in 5 or more countries with a minimum of 5 continuous years of marketing in at least one country, the sponsor may submit information in accordance with paragraph (c)(4) of this section):

(i) How the condition has been marketed (e.g., OTC general sales direct-to-consumer; sold only in a pharmacy, with or without the personal involvement of a pharmacist; dietary supplement; or cosmetic). If the condition has been marketed as a nonprescription pharmacy-only product, establish that this marketing restriction does not indicate safety concerns about its toxicity or other potentiality for harmful effect, the method of its use, or the collateral measures necessary to its use.

(ii) The cumulative total number of dosage units (e.g., tablets, capsules, ounces) sold for each dosage form of the condition. Manufacturers or suppliers of OTC active ingredients may provide dosage unit information as the total weight of active ingredient sold. List the various package sizes for each dosage form in which the condition is marketed OTC. Provide an estimate of the minimum number of potential consumer exposures to the condition using one of the following calculations:

(A) Divide the total number of dosage units sold by the number of dosage units in the largest package size marketed, or

(B) Divide the total weight of the active ingredient sold by the total weight of the active ingredient in the largest package size marketed.

(iii) A description of the population demographics (percentage of various racial/ethnic groups) and the source(s) from which this information has been compiled, to ensure that the condition's use(s) can be reasonably extrapolated to the U.S. population.

(iv) If the use pattern (i.e., how often it is to be used (according to the label) and for how long) varies between countries based on the condition's packaging and labeling, or changes in use pattern have occurred over time in one or more countries, describe the use pattern for each country and explain why there are differences or changes.

(v) A description of the country's system for identifying adverse drug experiences, especially those found in OTC marketing experience, including method of collection if applicable.

(3) A statement of how long the condition has been marketed in each country and how long the current product labeling has been in use, accompanied by a copy of the current product labeling. All labeling that is not in English must be translated to English in accordance with § 10.20(c)(2) of this chapter. State whether the current product labeling has or has not been authorized, accepted, or approved by a regulatory body in each country where the condition is marketed.

(4) For a condition that has been marketed OTC in five or more countries with a minimum of 5 continuous years of marketing in at least one country, the sponsor may select at least five of these countries from which to submit information in accord with paragraphs (c)(2)(i) through (c)(2)(iv) of this section. Selected countries must include the country with a minimum of 5 continuous years of OTC marketing, countries that have the longest duration of marketing, and countries having the most support for extent of marketing, i.e., a large volume of sales with cultural diversity among users of the product. If the condition meets these criteria in countries listed in section 802(b)(1)(A) of the Federal Food, Drug, and Cosmetic Act, some of these countries should be included among the five selected. Sponsors should provide information from more than five countries if they believe that it is needed to support eligibility. Sponsors should explain the basis for the countries selected in the TEA.

(5) A list of all countries where the condition is marketed only as a prescription drug and the reasons why its marketing is restricted to prescription in these countries.

(6) A list of all countries in which the condition has been withdrawn from marketing or in which an application for OTC marketing approval has been denied. Include the reasons for such withdrawal or application denial.

(7) The information requested in paragraphs (c)(2), (c)(2)(i) through (c)(2)(iv), and (c)(3) of this section must be provided in a table format. The labeling required by paragraph (c)(3) of this section must be attached to the table.

(8) For OTC drugs that have been marketed for more than 5 years in the United States under a new drug application, the information requested in paragraphs (c)(2)(i), (c)(2)(iii), (c)(2)(v), (c)(3), and (c)(5) of this section need not be provided.

(d) Submission of information; confidentiality. The sponsor must submit three copies of the TEA to the Central Document Room, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. The Food and Drug Administration will handle the TEA as confidential until such time as a decision is made on the eligibility of the condition for consideration in the OTC drug monograph system. If the condition is found eligible, the TEA will be placed on public display in the Division of Dockets Management after deletion of information deemed confidential under 18 U.S.C. 1905, 5 U.S.C. 552(b), or 21 U.S.C. 331(j). Sponsors must identify information that is considered confidential under these statutory provisions. If the condition is not found eligible, the TEA will not be placed on public display, but a letter from the agency to the sponsor stating why the condition was not found acceptable will be placed on public display in the Division of Dockets Management.

(e) Notice of eligibility. If the condition is found eligible, the agency will publish a notice of eligibility in the Federal Register and provide the sponsor and other interested parties an opportunity to submit data to demonstrate safety and effectiveness. When the notice of eligibility is published, the agency will place the TEA on public display in the Division of Dockets Management.

(f) Safety and effectiveness data submission. The notice of eligibility will request a safety and effectiveness data submission that includes published and unpublished data to demonstrate the safety and effectiveness of the condition for its intended OTC use(s), as well as the submission of any other relevant data and views. These data will be submitted to a docket established in the Division of Dockets Management and will be publicly available for viewing at that office, except data deemed confidential under 18 U.S.C. 1905, 5 U.S.C. 552(b), or 21 U.S.C. 331(j). Data considered confidential under these provisions must be clearly identified. Any proposed compendial standards for the condition will not be considered confidential. The safety and effectiveness data submission must be sufficiently complete to be filed by the agency under paragraph (j)(2) of this section. Safety and effectiveness data and other information submitted under this paragraph are subject to the requirements in § 330.10(c), (e), and (f). The safety and effectiveness data submission must include the following:

(1) All data and information listed in § 330.10(a)(2) under the outline “OTC Drug Review Information,” items III through VII.

(2) All serious adverse drug experiences as defined in §§ 310.305 and 314.80 of this chapter, from each country where the condition has been or is currently marketed as a prescription drug or as an OTC drug or product. Provide individual adverse drug experience reports (FDA Form 3500A or equivalent) along with a summary of all serious adverse drug experiences and expected or frequently reported side effects for the condition. Individual reports that are not in English must be translated to English in accordance with § 10.20(c)(2) of this chapter.

(g) Administrative procedures. The agency may use an advisory review panel to evaluate the safety and effectiveness data in accord with the provisions of § 330.10(a)(3). Alternatively, the agency may evaluate the data in conjunction with the advisory review panel or on its own without using an advisory review panel. The agency will use the safety, effectiveness, and labeling standards in § 330.10(a)(4)(i) through (a)(4)(vi) in evaluating the data.

(1) If the agency uses an advisory review panel to evaluate the data, the panel may submit its recommendations in its official minutes of meeting(s) or by a report under the provisions of § 330.10(a)(5).

(2) The agency may act on an advisory review panel's recommendations using the procedures in §§ 330.10(a)(2) and 330.10(a)(6) through (a)(10).

(3) If the condition is initially determined to be generally recognized as safe and effective for OTC use in the United States, the agency will propose to include it in an appropriate OTC drug monograph(s), either by amending an existing monograph(s) or establishing a new monograph(s), if necessary.

(4) If the condition is initially determined not to be GRASE for OTC use in the United States, the agency will inform the sponsor and other interested persons who have submitted data of its determination by feedback letter, a copy of which will be placed on public display in the docket established in the Division of Dockets Management. The agency will publish a notice of proposed rulemaking to include the condition in § 310.502 of this chapter.

(5) Interested parties will have an opportunity to submit comments and new data. The agency will subsequently publish a final rule (or reproposal if necessary) in the Federal Register.

(h) Marketing. A condition submitted under this section for consideration in the OTC drug monograph system may be marketed in accordance with an applicable final OTC drug monograph(s) only after the agency determines that the condition is generally recognized as safe and effective and includes it in the appropriate OTC drug final monograph(s), and the condition complies with paragraph (i) of this section. When an OTC drug monograph has not been finalized and finalization is not imminent, after the agency has evaluated the comments to a proposed rule to include a new condition in a tentative final monograph as generally recognized as safe and effective and the agency has not changed its position as a result of the comments, and the condition complies with paragraph (i) of this section, the agency may publish a notice of enforcement policy that allows marketing to begin pending completion of the final monograph subject to the risk that the agency may, prior to or in the final monograph, adopt a different position that could require relabeling, recall, or other regulatory action.

(i) Compendial monograph. Any active ingredient or botanical drug substance included in a final OTC drug monograph or the subject of an enforcement notice described in paragraph (h) of this section must be recognized in an official USP-NF drug monograph that sets forth its standards of identity, strength, quality, and purity. Sponsors must include an official or proposed compendial monograph as part of the safety and effectiveness data submission listed in § 330.10(a)(2) under item VII of the outline entitled “OTC DRUG REVIEW INFORMATION.”

(j) Filing determination. (1) After FDA receives a safety and effectiveness data submission, the agency will determine whether the submission may be filed. The filing of a submission means that FDA has made a threshold determination that the submission is sufficiently complete to permit a substantive review.

(2) If FDA finds that none of the reasons in paragraph (j)(4) of this section for refusing to file the safety and effectiveness data submission apply, the agency will file the submission and notify the submitter in writing. FDA will post a copy of the notice to the docket. The date of filing begins the FDA timelines described in § 330.15(c)(3) and (4). Data submitted after the date of filing will be considered before the issuance of a notice of proposed rulemaking if there is adequate time for review; otherwise, the data will be considered as comments to the proposed rule after issuance of a notice of proposed rulemaking.

(3) If FDA refuses to file the safety and effectiveness data submission, the agency will notify the submitter in writing and state the reason(s) under paragraph (j)(4) of this section for the refusal. The submitter may request in writing, within 30 days of the date of the agency's notification, a meeting with the agency about whether the agency should file the submission, and FDA will convene the meeting within 30 days of the request. If, within 120 days after the meeting, the submitter requests that FDA file the submission (with or without correcting the deficiencies), the agency will file the safety and effectiveness data submission over protest under paragraph (j)(2) of this section, notify the submitter in writing and post a copy to the docket, and review the submission as filed. The submitter must have a meeting before requesting that FDA file the submission over protest but need not resubmit a copy of a safety and effectiveness data submission that is filed over protest. A safety and effectiveness data submission and the corresponding TEA-eligible condition are both not deemed under consideration if FDA refuses to file the safety and effectiveness data submission, and it is not filed over protest; the condition remains eligible for consideration and the sponsor or any interested person can pursue consideration of the condition in the future by submitting a new safety and effectiveness data submission.

(4) FDA may refuse to file a safety and effectiveness data submission if any of the following applies:

(i) The submission is incomplete because it does not contain information required under paragraph (f) of this section. If the submission does not contain required information because such information or data are not relevant to the condition, the submission must clearly identify and provide an explanation for the omission.

(ii) The submission is not organized or formatted in a manner to enable the agency to readily determine whether it is sufficiently complete to permit a substantive review.

(iii) The submission does not contain a signed statement that the submission represents a complete safety and effectiveness data submission and that the submission includes all the safety and effectiveness data and information available to the submitter at the time of the submission, whether positive or negative.

(iv) The submission does not contain an analysis and summary of the data and other supporting information, organized by clinical or nonclinical area, such as clinical efficacy data, clinical safety data, clinical pharmacology, adverse event reports, animal toxicology, chemistry data, and compendial status.

(v) The submission does not contain a supporting document summarizing the strategy used for literature searches, including search terms, sources, dates accessed, and years reviewed.

(vi) The submission does not contain a reference list of supporting information, such as published literature, unpublished information, abstracts and case reports, and a copy of the supporting information.

(vii) The submission includes data or information relevant for making a GRASE determination marked as confidential without a statement that the information may be released to the public.

(viii) The submission does not contain a complete environmental assessment under § 25.40 of this chapter or fails to provide sufficient information to establish that the requested action is subject to categorical exclusion under § 25.30 or § 25.31 of this chapter.

(ix) The submission does not contain a statement for each nonclinical laboratory study that the study was conducted in compliance with the requirements set forth in part 58 of this chapter, or, if it was not conducted in compliance with part 58 of this chapter, a brief statement of the reason for the noncompliance.

(x) The submission does not contain a statement for each clinical investigation involving human subjects that the investigation was conducted in compliance with the institutional review board regulations in part 56 of this chapter, or was not subject to those regulations, and that the investigation was conducted in compliance with the informed consent regulations in part 50 of this chapter.

(xi) The submission does not include financial certification or disclosure statements, or both, as required by part 54 of this chapter, accompanying any clinical data submitted.

(k) Withdrawal of consideration. (1) Notwithstanding paragraph (g) of this section, FDA may withdraw consideration of a TEA submission or a safety and effectiveness data submission if:

(i) The person that submitted the submission requests that its submission be withdrawn from consideration; or

(ii) FDA deems the submission to be withdrawn from consideration due to the submitter's failure to respond to communications from FDA.

(2) Before FDA deems a submission withdrawn under paragraph (k)(1)(ii) of this section, FDA will notify the person that submitted the submission. If, within 90 days from the date of the notice from FDA, the submitter requests that FDA not withdraw consideration of the submission, FDA will not deem the submission to be withdrawn.

(3) If FDA withdraws consideration of a submission under paragraph (k)(1) of this section, FDA will post a notice of withdrawal to the docket, except in the case of a TEA submission that is withdrawn from consideration before issuance of a notice of eligibility, in which case, the notice of withdrawal will only be provided to the sponsor. Information that has been posted to the public docket for the condition at the time of the withdrawal (such as a notice of eligibility or a safety and effectiveness data submission that has been accepted for filing and posted to the docket) will remain in the public docket. If the condition has been found eligible through issuance of a notice of eligibility, the condition remains eligible for consideration and the sponsor or any interested person can pursue consideration of the condition in the future by submitting a new safety and effectiveness data submission.

(4) If FDA withdraws consideration of a submission under paragraph (k)(1) of this section, the timelines under § 330.15(c) will no longer apply as of the date of withdrawal, and the submission will not be included in the metrics under § 330.15(b).

(a) Applicability. This section applies to the review of a condition in a time and extent application (TEA) submitted under § 330.14 for consideration in the over-the-counter (OTC) drug monograph system. This section does not apply to:

(1) A sunscreen active ingredient or combination of sunscreen active ingredients, and other conditions for such ingredients; or

(2) A non-sunscreen active ingredient or combination of non-sunscreen active ingredients, and other conditions for such ingredients submitted in a TEA under § 330.14 before November 27, 2014, subject to section 586F(a)(1)(C) of the Federal Food, Drug, and Cosmetic Act.

(b) Metrics. FDA will maintain and update annually, a publicly available posting of metrics for the review of TEAs and safety and effectiveness data submissions that are subject to the timelines in this section. The posting will contain the following information for tracking the extent to which the timelines set forth in paragraph (c) of this section were met during the previous calendar year.

(1) Number and percent of eligibility notices or ineligibility letters issued within 180 days of submission of a TEA;

(2) Number and percent of filing determinations issued within 90 days of submission of a safety and effectiveness data submission;

(3) If applicable, number and percent of feedback letters issued within 730 days from the date of filing;

(4) Number and percent of notices for proposed rulemaking issued within 1,095 days from the date of filing;

(5) Number and percent of final rules issued within 912 days of closing of the docket of the proposed rulemaking; and

(6) Total number of TEAs submitted under § 330.14.

(c) Timelines for FDA review and action. FDA will review and take an action within the following timelines:

(1) Within 180 days of submission of a TEA under § 330.14(c), FDA will issue a notice of eligibility or post to the docket a letter of ineligibility, in accordance with § 330.14(d) and (e).

(2) Within 90 days of submission of a safety and effectiveness data submission, in accordance with § 330.14(j), FDA will issue a filing determination. The date of filing begins the FDA timelines in paragraphs (c)(3) and (4) of this section.

(3) Within 730 days from the date of filing, if the condition is initially determined not to be GRASE for OTC use in the United States, FDA will inform the sponsor and other interested persons who have submitted data of its determination by feedback letter in accordance with § 330.14(g)(4).

(4) Within 1,095 days from the date of filing of a safety and effectiveness data submission, FDA will issue a notice of proposed rulemaking to either:

(i) Include the condition in an appropriate OTC monograph(s), either by amending an existing monograph(s) or establishing a new monograph(s), if necessary; or

(ii) Include the condition in § 310.502 of this chapter.

(5) Within 912 days of the closing of the docket of the proposed rulemaking under paragraph (c)(4) of this section, FDA will issue a final rule.

An over-the-counter antacid product in a form suitable for oral administration is generally recognized as safe and effective and is not misbranded if it meets each of the following conditions and each of the general conditions established in § 330.1 of this chapter.

(a) The active antacid ingredients of the product consist of one or more of the ingredients permitted in § 331.11 within any maximum daily dosage limit established, each ingredient is included at a level that contributes at least 25 percent of the total acid neutralizing capacity of the product, and the finished product contains at least 5 meq of acid neutralizing capacity as measured by the procedure provided in the United States Pharmacopeia 23/National Formulary 18. The method established in § 331.20 shall be used to determine the percent contribution of each antacid active ingredient.

(b) This section does not apply to an antacid ingredient specifically added as a corrective to prevent a laxative or constipating effect.

(a) Aluminum-containing active ingredients:

(1) Basic aluminum carbonate gel.

(2) Aluminum hydroxide (or as aluminum hydroxide-hexitol stabilized polymer, aluminum hydroxide-magnesium carbonate codried gel, aluminum hydroxide-magnesium trisilicate codried gel, aluminum-hydroxide sucrose powder hydrated).

(3) Dihydroxyaluminum aminoacetate and dihydroxyaluminum aminoacetic acid.

(4) Aluminum phosphate gel when used as part of an antacid combination product and contributing at least 25 percent of the total acid neutralizing capacity; maximum daily dosage limit is 8 grams.

(5) Dihydroxyaluminum sodium carbonate.

(b) Bicarbonate-containing active ingredients: Bicarbonate ion; maximum daily dosage limit 200 mEq. for persons up to 60 years old and 100 mEq. for persons 60 years or older.

(c) Bismuth-containing active ingredients:

(1) Bismuth aluminate.

(2) Bismuth carbonate.

(3) Bismuth subcarbonate.

(4) Bismuth subgallate.

(5) Bismuth subnitrate.

(d) Calcium-containing active ingredients: Calcium, as carbonate or phosphate; maximum daily dosage limit 160 mEq. calcium (e.g., 8 grams calcium carbonate).

(e) Citrate-containing active ingredients: Citrate ion, as citric acid or salt; maximum daily dosage limit 8 grams.

(f) Glycine (aminoacetic acid).

(g) Magnesium-containing active ingredients:

(1) Hydrate magnesium aluminate activated sulfate.

(2) Magaldrate.

(3) Magnesium aluminosilicates.

(4) Magnesium carbonate.

(5) Magnesium glycinate.

(6) Magnesium hydroxide.

(7) Magnesium oxide.

(8) Magnesium trisilicate.

(h) Milk solids, dried.

(i) Phosphate-containing active ingredients:

(1) Aluminum phosphate; maximum daily dosage limit 8 grams.

(2) Mono or dibasic calcium salt; maximum daily dosage limit 2 grams.

(3) Tricalcium phosphate; maximum daily dosage limit 24 grams.

(j) Potassium-containing active ingredients:

(1) Potassium bicarbonate (or carbonate when used as a component of an effervescent preparation); maximum daily dosage limit 200 mEq. of bicarbonate ion for persons up to 60 years old and 100 mEq. of bicarbonate ion for persons 60 years or older.

(2) Sodium potassium tartrate.

(k) Sodium-containing active ingredients:

(1) Sodium bicarbonate (or carbonate when used as a component of an effervescent preparation); maximum daily dosage limit 200 mEq. of sodium for persons up to 60 years old and 100 mEq. of sodium for persons 60 years or older, and 200 mEq. of bicarbonate ion for persons up to 60 years old and 100 mEq. of bicarbonate ion for persons 60 years or older. That part of the warning required by § 330.1(g), which states, “Keep this and all drugs out of the reach of children” is not required on a product which contains only sodium bicarbonate powder and which is intended primarily for other than drug uses.

(2) Sodium potassium tartrate.

(l) Silicates:

(1) Magnesium aluminosilicates.

(2) Magnesium trisilicate.

(m) Tartrate-containing active ingredients. Tartaric acid or its salts; maximum daily dosage limit 200 mEq. (15 grams) of tartrate.

(a) An antacid may contain any generally recognized as safe and effective nonantacid laxative ingredient to correct for constipation caused by the antacid. No labeling claim of the laxative effect may be used for such a product.

(b) An antacid may contain any generally recognized as safe and effective analgesic ingredient(s), if it is indicated for use solely for the concurrent symptoms involved, e.g., headache and acid indigestion, and is marketed in a form intended for ingestion as a solution.

(c) An antacid may contain any generally recognized as safe and effective antiflatulent ingredient if it is indicated for use solely for the concurrent symptoms of gas associated with heartburn, sour stomach or acid indigestion.

To determine the percent contribution of an antacid active ingredient, place an accurately weighed amount of the antacid active ingredient equal to the amount present in a unit dose of the product into a 250-milliliter (mL) beaker. If wetting is desired, add not more than 5 mL of alcohol (neutralized to an apparent pH of 3.5), and mix to wet the sample thoroughly. Add 70 mL of water, and mix on a magnetic stirrer at 300 ±30 r.p.m. for 1 minute. Analyze the acid neutralizing capacity of the sample according to the procedure provided in the United States Pharmacopeia 23/National Formulary 18 and calculate the percent contribution of the antacid active ingredient in the total product as follows:

Percent contribution = (Total mEq. Antacid Active Ingredient × 100)/(Total mEq. Antacid Product).

The formulation or mode of administration of certain products may require a modification of the United States Pharmacopeia 23/National Formulary 18 acid neutralizing capacity test. Any proposed modification and the data to support it shall be submitted as a petition under the rules established in § 10.30 of this chapter. All information submitted will be subject to the disclosure rules in part 20 of this chapter.

(a) Statement of identity. The labeling of the product contains the established name of the drug, if any, and identifies the product as an “antacid.”

(b) Indications. The labeling of the product states, under the heading “Indications,” the following: “For the relief of” (optional, any or all of the following:) “heartburn,” “sour stomach,” and/or “acid indigestion” (which may be followed by the optional statement:) “and upset stomach associated with” (optional, as appropriate) “this symptom” or “these symptoms.” Other truthful and nonmisleading statements, describing only the indications for use that have been established and listed in this paragraph (b), may also be used, as provided in § 330.1(c)(2) of this chapter, subject to the provisions of section 502 of the act relating to misbranding and the prohibition in section 301(d) of the act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the act.

(c) Warnings. The labeling of the product contains the following warnings, under the heading “Warnings”, which may be combined but not rearranged to eliminate duplicative words or phrases if the resulting warning is clear and understandable:

(1) “Do not take more than (maximum recommended daily dosage, broken down by age groups if appropriate, expressed in units such as tablets or teaspoonfuls) in a 24-hour period, or use the maximum dosage of this product for more than 2 weeks, except under the advice and supervision of a physician.”

(2) For products which cause constipation in 5 percent or more of persons who take the maximum recommended dosage: “May cause constipation.”

(3) For products which cause laxation in 5 percent or more of persons who take the maximum recommended dosage: “May have laxative effect.”

(4) For products containing more than 5 gm per day lactose in a maximum daily dosage: “Do not use this product except under advice and supervision of a physician if you are allergic to milk or milk products.”

(d) Drug interaction precaution. The labeling of the product contains the following statement “Ask a doctor or pharmacist before use if you are [bullet] 1 presently taking a prescription drug. Antacids may interact with certain prescription drugs.”

(e) Directions for use. The labeling of the product contains the recommended dosage, under the heading “Directions”, per time interval (e.g., every 4 hours) or time period (e.g., 4 times a day) broken down by age groups if appropriate, followed by “or as directed by a physician.”

(f) Exemption from the general accidental overdose warning. The labeling for antacid drug products containing the active ingredients identified in § 331.11(a), (b), and (d) through (m); permitted combinations of these ingredients provided for in § 331.10; and any of these ingredients or combinations of these ingredients in combination with simethicone (identified in § 332.10 of this chapter and provided for in § 331.15(c)), are exempt from the requirement in § 330.1(g) of this chapter that the labeling bear the general warning statement “In case of accidental overdose, seek professional assistance or contact a poison control center immediately.” With the exception of sodium bicarbonate powder products identified in § 331.11(k)(1), the labeling must continue to bear the first part of the general warning in § 330.1(g) of this chapter, which states, “Keep this and all drugs out of the reach of children.”

(g) [Reserved]

(h) The word “doctor” may be substituted for the word “physician” in any of the labeling statements in this section.

(a) The labeling of the product provided to health professionals (but not to the general public):

(1) Shall contain the neutralizing capacity of the product as calculated using the procedure set forth in United States Pharmacopeia 23/National Formulary 18 expressed in terms of the dosage recommended per minimum time interval or, if the labeling recommends more than one dosage, in terms of the minimum dosage recommended per minimum time interval.

(2) May contain an indication for the symptomatic relief of hyperacidity associated with the diagnosis of peptic ulcer, gastritis, peptic esophagitis, gastric hyperacidity, and hiatal hernia.

(3) For products containing basic aluminum carbonate gel identified in § 331.11(a)(1) - Indication. “For the treatment, control, or management of hyperphosphatemia, or for use with a low phosphate diet to prevent formation of phosphate urinary stones, through the reduction of phosphates in the serum and urine.”

(4) For products containing aluminum identified in § 331.11(a) - Warnings. (i) Prolonged use of aluminum-containing antacids in patients with renal failure may result in or worsen dialysis osteomalacia. Elevated tissue aluminum levels contribute to the development of the dialysis encephalopathy and osteomalacia syndromes. Small amounts of aluminum are absorbed from the gastrointestinal tract and renal excretion of aluminum is impaired in renal failure. Aluminum is not well removed by dialysis because it is bound to albumin and transferrin, which do not cross dialysis membranes. As a result, aluminum is deposited in bone, and dialysis osteomalacia may develop when large amounts of aluminum are ingested orally by patients with impaired renal function.

(ii) Aluminum forms insoluble complexes with phosphate in the gastrointestinal tract, thus decreasing phosphate absorption. Prolonged use of aluminum-containing antacids by normophosphatemic patients may result in hypophosphatemia if phosphate intake is not adequate. In its more severe forms, hypophosphatemia can lead to anorexia, malaise, muscle weakness, and osteomalacia.

(b) Professional labeling for an antacid-antiflatulent combination may contain the information allowed for health professionals for antacids and antiflatulents.

An over-the-counter antiflatulent product in a form suitable for oral administration is generally recognized as safe and effective and is not misbranded if it meets each of the following conditions and each of the general conditions established in § 330.1 of this chapter.

As used in this part:

Antigas. A term that may be used interchangeably with the term antiflatulent. Neither term should be considered as describing the mechanism of action of the active ingredient contained in the product.

Simethicone; maximum daily dose 500 mg. There is no dosage limitation at this time for professional labeling.

An antiflatulent may contain any generally recognized as safe and effective antacid ingredient(s) if it is indicated for use solely for the concurrent symptoms of gas associated with heartburn, sour stomach or acid indigestion.

(a) Statement of identity. The labeling of the product contains the established name of the drug, if any, and identifies the product as an “antiflatulent,” “antigas,” or “antiflatulent (antigas).”

(b) Indications. The labeling of the product states, under the heading “Indications,” one or more of the phrases listed in this paragraph (b), as appropriate. Other truthful and nonmisleading statements, describing only the indications for use that have been established and listed in this paragraph (b), may also be used, as provided in § 330.1(c)(2) of this chapter, subject to the provisions of section 502 of the Federal Food, Drug, and Cosmetic Act (the act) relating to misbranding and the prohibition in section 301(d) of the act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the act.

(1) (Select one of the following: “Alleviates or Relieves”) “the symptoms referred to as gas.”

(2) (Select one of the following: “Alleviates” or “Relieves”) (select one or more of the following: “bloating,” “pressure,” “fullness,” or “stuffed feeling”) “commonly referred to as gas.”

(c) Exemption from the general accidental overdose warning. The labeling for antiflatulent drug products containing simethicone identified in § 332.10 and antacid/antiflatulent combination drug products provided for in § 332.15, containing the active ingredients identified in § 331.11(a), (b), and (d) through (m) of this chapter are exempt from the requirement in § 330.1(g) of this chapter that the labeling bear the general warning statement “In case of accidental overdose, seek professional assistance or contact a poison control center immediately.” The labeling must continue to bear the first part of the general warning in § 330.1(g) of this chapter, which states, “Keep this and all drugs out of the reach of children.”

(a) The labeling of the product provided to health professionals (but not to the general public) may contain as additional indications postoperative gas pain or for use in endoscopic examination.

(b) Professional labeling for an antiflatulent-antacid combination may contain information allowed for health professionals for antacids and antiflatulents.

(a) An over-the-counter first aid antibiotic drug product in a form suitable for topical administration is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this subpart and each of the general conditions established in § 330.1.

(b) References in this subpart to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.

As used in this subpart:

First aid antibiotic. An antibiotic-containing drug product applied topically to the skin to help prevent infection in minor cuts, scrapes, and burns.

The product consists of any of the following active ingredients within the specified concentration established for each ingredient and in the specified dosage form:

(a) Bacitracin ointment containing, in each gram, 500 units of bacitracin in a suitable ointment base.

(b) Bacitracin zinc ointment containing, in each gram, 500 units of bacitracin zinc in a suitable ointment base.

(c) Chlortetracycline hydrochloride ointment containing, in each gram, 30 milligrams of chlortetracycline hydrochloride in a suitable ointment base.

(d) Neomycin sulfate ointment containing, in each gram, 3.5 milligrams of neomycin in a suitable water soluble or oleaginous ointment base.

(e) Neomycin sulfate cream containing, in each gram, 3.5 milligrams of neomycin in a suitable cream base.

(f) Tetracycline hydrochloride ointment containing, in each gram, 30 milligrams of tetracycline hydrochloride in a suitable ointment base.

The following combinations are permitted provided each active ingredient is present within the established concentration and in the specified dosage form, and the product is labeled in accordance with § 333.160.

(a) Combinations of antibiotic active ingredients. (1) Bacitracin-neomycin sulfate ointment containing, in each gram, 500 units of bacitracin and 3.5 milligrams of neomycin in a suitable ointment base.

(2) Bacitracin-neomycin sulfate-polymyxin B sulfate ointment containing, in each gram, in a suitable ointment base the following:

(i) 500 units of bacitracin, 3.5 milligrams of neomycin, and 5,000 units of polymyxin B; or

(ii) 400 units of bacitracin, 3.5 milligrams of neomycin, and 5,000 units of polymyxin B;

(3) Bacitracin-polymyxin B sulfate topical aerosol containing, in each gram, 500 units of bacitracin and 5,000 units of polymyxin B in a suitable vehicle, packaged in a pressurized container with suitable inert gases.

(4) Bacitracin zinc-neomycin sulfate ointment containing, in each gram, 500 units of bacitracin and 3.5 milligrams of neomycin in a suitable ointment base.

(5) Bacitracin zinc-neomycin sulfate-polymyxin B sulfate ointment containing, in each gram, in a suitable ointment base the following:

(i) 400 units of bacitracin, 3 milligrams of neomycin, and 8,000 units of polymyxin B; or

(ii) 400 units of bacitracin, 3.5 milligrams of neomycin, and 5,000 units of polymyxin B; or

(iii) 500 units of bacitracin, 3.5 milligrams of neomycin, and 5,000 units of polymyxin B; or

(iv) 500 units of bacitracin, 3.5 milligrams of neomycin, and 10,000 units of polymyxin B;

(6) Bacitracin zinc-polymyxin B sulfate ointment containing, in each gram, 500 units of bacitracin and 10,000 units of polymyxin B in a suitable ointment base.

(7) Bacitracin zinc-polymyxin B sulfate topical aerosol containing, in each gram, 120 units of bacitracin and 2,350 units of polymyxin B in a suitable vehicle, packaged in a pressurized container with suitable inert gases.

(8) Bacitracin zinc-polymyxin B sulfate topical powder containing, in each gram, 500 units of bacitracin and 10,000 units of polymyxin B in a suitable base.

(9) Neomycin sulfate-polymyxin B sulfate ointment containing, in each gram, 3.5 milligrams of neomycin and 5,000 units of polymyxin B in a suitable water miscible base.

(10) Neomycin sulfate-polymyxin B sulfate cream containing, in each gram, 3.5 milligrams of neomycin and 10,000 units of polymyxin B in a suitable vehicle.

(11) Oxytetracycline hydrochloride-polymyxin B sulfate ointment containing, in each gram, 30 milligrams of oxytetracycline and 10,000 units of polymyxin B in a suitable ointment base.

(12) Oxytetracycline hydrochloride-polymyxin B sulfate topical powder containing, in each gram, 30 milligrams of oxytetracycline and 10,000 units of polymyxin B with a suitable filler.

(b) Combinations of first aid antibiotic active ingredients and local anesthetic active ingredients. (1) Bacitracin ointment containing, in each gram, 500 units of bacitracin and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient in a suitable ointment base.

(2) Bacitracin-neomycin sulfate-polymyxin B sulfate ointment containing, in each gram, in a suitable ointment base the following:

(i) 500 units of bacitracin, 3.5 milligrams of neomycin, 5,000 units of polymyxin B, and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient; or

(ii) 400 units of bacitracin, 3.5 milligrams of neomycin, 5,000 units of polymyxin B, and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient.

(3) Bacitracin-polymyxin B sulfate topical aerosol containing, in each gram, 500 units of bacitracin and 5,000 units of polymyxin B and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient in a suitable vehicle, packaged in a pressurized container with suitable inert gases.

(4) Bacitracin zinc-neomycin sulfate-polymyxin B sulfate ointment containing, in each gram, in a suitable ointment base the following:

(i) 400 units of bacitracin, 3 milligrams of neomycin, 8,000 units of polymyxin B, and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient; or

(ii) 400 units of bacitracin, 3.5 milligrams of neomycin, 5,000 units of polymyxin B, and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient; or

(iii) 500 units of bacitracin, 3.5 milligrams of neomycin, 5,000 units of polymyxin B, and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient; or

(iv) 500 units of bacitracin, 3.5 milligrams of neomycin, 10,000 units of polymyxin B, and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient;

(5) Bacitracin zinc-polymyxin B sulfate ointment containing, in each gram, 500 units of bacitracin, 10,000 units of polymyxin B, and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient in a suitable ointment base.

(6) Neomycin sulfate-polymyxin B sulfate cream containing, in each gram, 3.5 milligrams of neomycin, 10,000 units of polymyxin B, and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient in a suitable vehicle.

(a) Statement of identity. The labeling of the product contains the established name of the drug, if any, and identifies the product as a “first aid antibiotic.”

(b) Indications. The labeling of the product states, under the heading “Indications,” the following: “First aid to help” [select one of the following: “prevent,” (“decrease” (“the risk of” or “the chance of”)), (“reduce” (“the risk of” or “the chance of”)), “guard against,” or “protect against”] [select one of the following: “infection,” “bacterial contamination,” or “skin infection”] “in minor cuts, scrapes, and burns.” Other truthful and nonmisleading statements describing only the indications for use that have been established and listed in this paragraph (b), may also be used, as provided in § 330.1(c)(2), subject to the provisions of section 502 of the act relating to misbranding and the prohibition in section 301(d) of the act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the act.

(c) Warnings. The labeling of the product contains the following warnings under the heading “Warnings”:

(1) “For external use only. Do not use in the eyes or apply over large areas of the body. In case of deep or puncture wounds, animal bites, or serious burns, consult a doctor.”

(2) For products containing chlortetracycline hydrochloride or tetracycline hydrochloride.“Stop use and consult a doctor if the condition persists or gets worse. Do not use longer than 1 week unless directed by doctor.”

(3) For any product containing bacitracin, bacitracin zinc, neomycin, neomycin sulfate, polymyxin B, and/or polymyxin B sulfate. “Stop use and consult a doctor if the condition persists or gets worse, or if a rash or other allergic reaction develops. Do not use if you are allergic to any of the ingredients. Do not use longer than 1 week unless directed by a doctor.”

(d) Directions. The labeling of the product contains the following statements under the heading “Directions”: (1) For ointment and cream products. “Clean the affected area. Apply a small amount of this product (an amount equal to the surface area of the tip of a finger) on the area 1 to 3 times daily. May be covered with a sterile bandage.”

(2) For powder products. “Clean the affected area. Apply a light dusting of the powder on the area 1 to 3 times daily. May be covered with a sterile bandage.”

(3) For aerosol products. “Clean the affected area. Spray a small amount of this product on the area 1 to 3 times daily. May be covered with a sterile bandage.”

(e) The word “doctor” may be substituted for the word “physician” in any of the labeling statements in this subpart.

Statements of identity, indications, warnings, and directions for use, respectively, applicable to each ingredient in the product may be combined to eliminate duplicative words or phrases so that the resulting information is clear and understandable.

(a) Statement of identity. For a combination drug product that has an established name, the labeling of the product states the established name of the combination drug product, followed by the statement of identity for each ingredient in the combination, as established in the statement of identity sections of the applicable OTC drug monographs. For a combination drug product that does not have an established name, the labeling of the product states the statement of identity for each ingredient in the combination, as established in the statement of identity sections of the applicable OTC drug monographs.

(b) Indications. The labeling of the product states, under the heading “Indications,” the indication(s) for each ingredient in the combination, as established in the “Indications” sections of the applicable OTC drug monographs, unless otherwise stated in this paragraph. Other truthful and nonmisleading statements, describing only the indications for use that have been established and listed in this paragraph (b), may also be used, as provided in § 330.1(c)(2), subject to the provisions of section 502 of the act relating to misbranding and the prohibition in section 301(d) of the act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the act.

(1) For permitted combinations identified in § 333.120(a). The indications in § 333.150 should be used.

(2) For permitted combinations identified in § 333.120(b). In addition to the required indication identified in § 333.150, the labeling of the product may state, under the heading “Indications,” the following additional indication: “First aid for the temporary relief of” (select one of the following: “pain,” “discomfort,” “pain or discomfort” or “pain and itching”) “in minor cuts, scrapes, and burns.”

(c) Warnings. The labeling of the product states, under the heading “Warnings,” the warning(s) for each ingredient in the combination, as established in the warnings sections of the applicable OTC drug monographs.

(d) Directions. The labeling of the product states, under the heading “Directions,” directions that conform to the directions established for each ingredient in the directions sections of the applicable OTC drug monographs. When the time intervals or age limitations for administrations of the individual ingredients differ, the directions for the combination product may not exceed any maximum dosage limits established for the individual ingredients in the applicable OTC drug monograph.

(a) An over-the-counter antifungal drug product in a form suitable for topical administration is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this subpart and each general condition established in § 330.1 of this chapter.

(b) Reference in this subpart to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.

As used in this subpart:

(a) Antifungal. A drug which inhibits the growth and reproduction of fungal cells and decreases the number of fungi present.

(b) Athlete's foot. An infection of the feet caused by certain dermatophytic fungi.

(c) Dermatophyte. A fungus that invades and lives upon the skin or in the hair or nails.

(d) Fungus. Any of a large division of plants, including dermatophytes, yeasts, and molds, characterized by a simple cell structure and the absence of chlorophyll.

(e) Jock itch. A chronic and recurrent infection caused by certain dermatophytic fungi; affects the upper, inner thighs and sometimes extends to the groin and the pubic area; the condition most frequently occurs in men, but may also occur in women.

(f) Ringworm. A skin infection caused by certain dermatophytic fungi.

The active ingredient of the product consists of any one of the following within the specified concentration established for each ingredient:

(a) Clioquinol 3 percent.

(b) Haloprogin 1 percent.

(c) Miconazole nitrate 2 percent.

(d) Povidone-iodine 10 percent.

(e) Tolnaftate 1 percent.

(f) Undecylenic acid, calcium undecylenate, copper undecylenate, and zinc undecylenate may be used individually or in any ratio that provides a total undecylenate concentration of 10 to 25 percent.

(g) Clotrimazole 1 percent.

(a) Statement of identity. The labeling of the product contains the established name of the drug, if any, and identifies the product as an “antifungal.”

(b) Indications. The labeling of the product states, under the heading “Indications,” the phrase listed in paragraph (b)(1)(i) of this section and may contain the additional phrase listed in paragraph (b)(1)(ii) of this section. Other truthful and nonmisleading statements, describing only the indications for use that have been established in paragraph (b) of this section, may also be used, as provided in § 330.1(c)(2) of this chapter, subject to the provisions of section 502 of the Federal Food, Drug, and Cosmetic Act (the act) relating to misbranding and the prohibition in section 301(d) of the act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the act.

(1) For products containing any ingredient identified in § 333.210 labeled for the treatment of athlete's foot, jock itch, and ringworm. (i) (Select one of the following: “Treats,” “For the treatment of,” “For effective treatment of,” “Cures,” “For the cure of,” “Clears up,” or “Proven clinically effective in the treatment of”) “most” (select one condition from any one or more of the following groups of conditions:

(A) “Athlete's foot,” athlete's foot (dermatophytosis),” “athlete's foot (tinea pedis),” or “tinea pedis (athlete's foot)”;

(B) “Jock itch,” “jock itch (tinea cruris),” or “tinea cruris (jock itch)”; or

(C) “Ringworm,” “ringworm (tinea corporis),” or “tinea corporis (ringworm).”)

(ii) In addition to the information identified in paragraph (b)(1)(i) of this section, the labeling of the product may contain the following statement: (Select one of the following: “Relieves,” “For relief of,” “For effective relief of,” or “Soothes,”) (select one or more of the following: “Itching,” “scaling,” “cracking,” “burning,” “redness,” “soreness,” “irritation,” “discomfort,” “chafing associated with jock itch,” “itchy, scaly skin between the toes,” or “itching, burning feet”).

(2) For products containing the ingredient identified in § 333.210(e) labeled for the prevention of athlete's foot. (i) (Select one of the following: “Clinically proven to prevent,” “Prevents,” “Proven effective in the prevention of,” “Helps prevent,” “For the prevention of,” “For the prophylaxis (prevention) of,” “Guards against,” or “Prevents the recurrence of”) “most” (select one of the following: “Athlete's foot,” “athlete's foot (dermatophytosis),” “athlete's foot (tinea pedis),” or “tinea pedis (athlete's foot)”) “with daily use.”

(ii) In addition to the information identified in paragraph (b)(2)(i) of this section, the labeling of the product may contain the following statement: “Clears up most athlete's foot infection and with daily use helps keep it from coming back.”

(c) Warnings. The labeling of the product contains the following warnings under the heading “Warnings”:

(1) For products containing any ingredient identified in § 330.210. (i) “Do not use on children under 2 years of age unless directed by a doctor.”

(ii) “For external use only.”

(iii) “Avoid contact with the eyes.”

(2) For products labeled according to paragraph (b)(1) of this section for the treatment of athlete's foot and ringworm. “If irritation occurs or if there is no improvement within 4 weeks, discontinue use and consult a doctor.”

(3) For products labeled according to paragraph (b)(1) of this section for the treatment of jock itch. “If irritation occurs or if there is no improvement within 2 weeks, discontinue use and consult a doctor.”

(4) For products labeled according to paragraph (b)(2) of this section for the prevention of athlete's foot. “If irritation occurs, discontinue use and consult a doctor.”

(5) For products containing the ingredient identified in § 333.210(a) labeled according to paragraph (b)(1) of this section. The following statements must appear in boldface type as the first warnings under the “Warnings” heading. (i) “Do not use on children under 2 years of age.” (This warning is to be used in place of the warning in paragraph (c)(1)(i) of this section.)

(ii) “Do not use for diaper rash.”

(d) Directions. The labeling of the product contains the following statements under the heading “Directions”:

(1) For products labeled according to paragraph (b)(1) of this section for the treatment of athlete's foot, jock itch, and ringworm. [Select one of the following: “Clean” or “Wash”] “the affected area and dry thoroughly. Apply” (the word “spray” may be used to replace the word “apply” for aerosol products) “a thin layer of the product over affected area twice daily (morning and night) or as directed by a doctor. Supervise children in the use of this product. For athlete's foot: Pay special attention to spaces between the toes; wear well-fitting, ventilated shoes, and change shoes and socks at least once daily. For athlete's foot and ringworm, use daily for 4 weeks; for jock itch, use daily for 2 weeks. If condition persists longer, consult a doctor. This product is not effective on the scalp or nails.”

(2) For products labeled according to paragraph (b)(2) of this section for the prevention of athlete's foot. “To prevent athlete's foot,” (select one of the following: “clean” or “wash”) “the feet and dry thoroughly. Apply” (the word “spray” may be used to replace the word “apply” for aerosol products) “a thin layer of the product to the feet once or twice daily (morning and/or night). Supervise children in the use of this product. Pay special attention to spaces between the toes; wear well-fitting, ventilated shoes, and change shoes and socks at least once daily.”

(e) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this section.

The labeling provided to health professionals (but not to the general public) may contain the following additional indication:

(a) For products containing haloprogin or miconazole nitrate identified in § 333.210 (a) and (c). “For the treatment of superficial skin infections caused by yeast (Candida albicans).”

(b) [Reserved]

(a) An over-the-counter acne drug product in a form suitable for topical application is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this subpart and each general condition established in § 330.1 of this chapter.

(b) References in this subpart to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.

As used in this subpart:

(a) Acne. A disease involving the oil glands and hair follicles of the skin which is manifested by blackheads, whiteheads, acne pimples, and acne blemishes.

(b) Acne blemish. A flaw in the skin resulting from acne.

(c) Acne drug product. A drug product used to reduce the number of acne blemishes, acne pimples, blackheads, and whiteheads.

(d) Acne pimple. A small, prominent, inflamed elevation of the skin resulting from acne.

(e) Blackhead. A condition of the skin that occurs in acne and is characterized by a black tip.

(f) Whitehead. A condition of the skin that occurs in acne and is characterized by a small, firm, whitish elevation of the skin.

The active ingredient of the product consists of any of the following:

(a) Benzoyl peroxide, 2.5 to 10 percent.

(b) Resorcinol, 2 percent, when combined with sulfur in accordance with § 333.320(a).

(c) Resorcinol monoacetate, 3 percent, when combined with sulfur in accordance with § 333.320(b).

(d) Salicylic acid, 0.5 to 2 percent.

(e) Sulfur, 3 to 10 percent.

(f) Sulfur, 3 to 8 percent, when combined with resorcinol or resorcinol monoacetate in accordance with § 333.320.

(a) Resorcinol identified in § 333.310(b) may be combined with sulfur identified in § 333.310(f).

(b) Resorcinol monoacetate identified in § 333.310(c) may be combined with sulfur identified in § 333.310(f).

(a) Statement of identity. The labeling of the product contains the established name of the drug, if any, and identifies the product as an “acne medication,” “acne treatment,” “acne medication” (insert dosage form, e.g., “cream,” “gel,” “lotion,” or “ointment”), or “acne treatment” (insert dosage form, e.g., “cream,” “gel,” “lotion,” or “ointment”).

(b) Indications. The labeling of the product states, under the heading “Indications,” the phrase listed in paragraph (b)(1) of this section and may contain any of the additional phrases listed in paragraph (b)(2) of this section. Other truthful and nonmisleading statements, describing only the indications for use that have been established and listed in paragraph (b) of this section, may also be used, as provided in § 330.1(c)(2) of this chapter, subject to the provisions of section 502 of the Federal Food, Drug, and Cosmetic Act (the act) relating to misbranding and the prohibition in section 301(d) of the act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the act.

(1) “For the” (select one of the following: “management” or “treatment”) “of acne.”

(2) In addition to the information identified in paragraph (b)(1) of this section, the labeling of the product may contain any one or more of the following statements:

(i) (Select one of the following: “Clears,” “Clears up,” “Clears up most,” “Dries,” “Dries up,” “Dries and clears,” “Helps clear,” “Helps clear up,” “Reduces the number of,” or “Reduces the severity of”) (select one or more of the following: “acne blemishes,” “acne pimples,” “blackheads,” or “whiteheads”) which may be followed by “and allows skin to heal.”

(ii) “Penetrates pores to” (select one of the following: “eliminate most,” “control,” “clear most,” or “reduce the number of”) (select one or more of the following: “acne blemishes,” “acne pimples,” “blackheads,” or “whiteheads”).

(iii) “Helps keep skin clear of new” (select one or more of the following: “acne blemishes,” “acne pimples,” “blackheads,” or “whiteheads”).

(iv) “Helps prevent new” (select one or more of the following: “acne blemishes,” “acne pimples,” “blackheads,” or “whiteheads”) which may be followed by “from forming.”

(v) “Helps prevent the development of new” (select one or more of the following: “acne blemishes,” “acne pimples,” “blackheads,” or “whiteheads”).

(c) Warnings. The labeling of the product contains the following warnings under the heading “Warnings”:

(1) For products containing any ingredients identified in § 330.310.

(i) The labeling states “For external use only.”

(ii) The labeling states “When using this product [bullet] skin irritation and dryness is more likely to occur if you use another topical acne medication at the same time. If irritation occurs, only use one topical acne medication at a time.”

(2) For products containing sulfur identified in § 333.310(e) and (f).

(i) The labeling states “Do not use on [bullet] broken skin [bullet] large areas of the skin.”

(ii) The labeling states “When using this product [bullet] apply only to areas with acne.”

(3) For products containing any combination identified in § 333.320. (i) The labeling states “When using this product [bullet] rinse right away with water if it gets in eyes.”

(ii) The labeling states “Stop use and ask a doctor [bullet] if skin irritation occurs or gets worse.”

(4) For products containing benzoyl peroxide identified in § 333.310(a).

(i) The labeling states “Do not use if you [bullet] have very sensitive skin [bullet] are sensitive to benzoyl peroxide.”

(ii) The labeling states “When using this product [bullet] avoid unnecessary sun exposure and use a sunscreen [bullet] avoid contact with the eyes, lips, and mouth [bullet] avoid contact with hair and dyed fabrics, which may be bleached by this product [bullet] skin irritation may occur, characterized by redness, burning, itching, peeling, or possibly swelling. Irritation may be reduced by using the product less frequently or in a lower concentration.”

(iii) The labeling states “Stop use and ask a doctor if [bullet] irritation becomes severe.”

(d) Directions. The labeling of the product contains the following information under the heading “Directions”:

(1) For products applied containing any ingredient identified in § 333.310. The labeling states “[bullet] clean the skin thoroughly before applying this product [bullet] cover the entire affected area with a thin layer one to three times daily [bullet] because excessive drying of the skin may occur, start with one application daily, then gradually increase to two or three times daily if needed or as directed by a doctor [bullet] if bothersome dryness or peeling occurs, reduce application to once a day or every other day.”

(2) For products applied and left on the skin containing benzoyl peroxide identified in § 333.310(a).

(i) The labeling states the directions in paragraph (d)(1) of this section.

(ii) The labeling states “[bullet] if going outside, apply sunscreen after using this product. If irritation or sensitivity develops, stop use of both products and ask a doctor.”

(3) For products applied and removed from the skin containing any ingredient identified in § 333.310. Products, such as soaps and masks, may be applied and removed and should include appropriate directions. All products containing benzoyl peroxide should include the directions in paragraph (d)(2)(ii) of this section.

(4) Optional directions. In addition to the required directions in paragraphs (d)(1) and (d)(2) of this section, the product may contain the following optional labeling: “Sensitivity Test for a New User. Apply product sparingly to one or two small affected areas during the first 3 days. If no discomfort occurs, follow the directions stated (select one of the following: ‘elsewhere on this label,’ ‘above,’ or ‘below’).”

(a) An over-the-counter antidiarrheal drug product in a form suitable for oral administration is generally recognized as safe and effective and is not misbranded if it meets each condition in this part and each general condition established in § 330.1 of this chapter.

(b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.

As used in this part:

(a) Antidiarrheal. A drug that can be shown by objective measurement to treat or control (stop) the symptoms of diarrhea.

(b) Diarrhea. A condition characterized by increased frequency of loose, watery stools (three or more daily) during a limited period (24 to 48 hours), usually with no identifiable cause.

(c) Travelers' diarrhea. A subset of diarrhea occurring in travelers that is most commonly caused by an infectious agent.

The active ingredient of the product consists of any one of the following when used within the dosage limits established for each ingredient in § 335.50(d):

(a) Bismuth subsalicylate.

(b) Kaolin.

(a) Statement of identity. The labeling of the product contains the established name of the drug, if any, and identifies the product either as an “antidiarrheal” or “for diarrhea.”

(b) Indications. The labeling of the product states, under the heading “Use,” one or more of the phrases listed in this paragraph (b), as appropriate. Other truthful and nonmisleading statements, describing only the indications for use that have been established and listed in this paragraph (b) may also be used, as provided in § 330.1(c)(2) of this chapter, subject to the provisions of section 502 of the Federal Food, Drug, and Cosmetic Act (the act) relating to misbranding and the prohibition in section 301(d) of the act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the act.

(1) For products containing bismuth subsalicylate identified in § 335.10(a). The labeling states [select one of the following: “controls” or “relieves”] [select one or both of the following: “diarrhea” or “travelers' diarrhea”]. If both “diarrhea” and “travelers' diarrhea” are selected, each shall be preceded by a bullet in accordance with § 201.66(b)(4) and (d)(4) of this chapter and the heading “Uses” shall be used.

(2) For products containing kaolin identified in § 335.10(b). The labeling states “helps firm stool within 24 to 48 hours”.

(3) Additional indications - (i) When any additional indications are used, the heading “Uses” shall be used and each listed use shall be preceded by a bullet in accord with § 201.66(b)(4) of this chapter.

(ii) In addition to the indication in paragraph (b)(1) of this section, one or both of the following may be used for products containing bismuth subsalicylate in § 335.10(a): “[bullet] reduces number of bowel movements” “[bullet] helps firm stool”.

(c) Warnings. The labeling of the product contains the following warnings under the heading “Warnings”:

(1) For products containing any ingredient identified in § 335.10. (i) “Do not use if you have [bullet] bloody or black stool”.

(ii) “Ask a doctor before use if you have [bullet] fever [bullet] mucus in the stool”.

(2) For products containing bismuth subsalicylate identified in § 335.10(a). (i) The following shall appear in accordance with § 201.66(c)(5)(ii) of this chapter.

(A) The Reye's syndrome warning in § 201.314(h) of this chapter.

(B) “Allergy alert: Contains salicylate. Do not take if you are [bullet] allergic to salicylates (including aspirin), [bullet] taking other salicylate products”.

(ii) “Do not use if you have [bullet] an ulcer [bullet] a bleeding problem”.

(iii) “Ask a doctor or pharmacist before use if you are taking any drug for [bullet] anticoagulation (thinning the blood) [bullet] diabetes [bullet] gout [bullet] arthritis”.

(iv) “When using this product a temporary, but harmless, darkening of the stool and/or tongue may occur”.

(v) “Stop use and ask a doctor if [bullet] symptoms get worse [bullet] ringing in the ears or loss of hearing occurs [bullet] diarrhea lasts more than 2 days”.

(3) For products containing kaolin identified in § 335.10(b). (i) “Ask a doctor or pharmacist before use if you are taking any other drugs. Try to use at least 3 hours before or after taking any other drugs.”

(ii) “Stop use and ask a doctor if [bullet] symptoms get worse [bullet] diarrhea lasts more than 2 days”.

(d) Directions. The labeling of the product contains the following information under the heading “Directions”:

(1) For products containing any ingredient identified in § 335.10. The labeling states “[bullet] drink plenty of clear fluids to help prevent dehydration caused by diarrhea”.

(2) For products containing bismuth subsalicylate identified in § 335.10(a). The labeling states “[bullet] adults and children 12 years and over:” 525 milligrams “every 1/2 to 1 hour, or” 1,050 milligrams “every hour as needed [bullet] do not exceed” 4,200 milligrams “in 24 hours [bullet] use until diarrhea stops but not more than 2 days [bullet] children under 12 years: ask a doctor”.

(3) For products containing kaolin identified in § 335.10(b). The labeling states “[bullet] adults and children 12 years and over:” 26.2 grams “after each loose stool [bullet] continue to take every 6 hours until stool is firm but not more than 2 days [bullet] do not exceed” [262 grams] “in 24 hours [bullet] children under 12 years of age: ask a doctor”.

(e) Products that meet the criteria established in § 201.66(d)(10) of this chapter. The information described in § 201.66(c) of this chapter shall be printed in accordance with the following specifications.

(1) The labeling shall meet the requirements of § 201.66(c) of this chapter except that the information in § 201.66(c)(3) of this chapter may be omitted, and the information in § 201.66(c)(5) and (c)(6) of this chapter may be presented as follows:

(i) The words “Contains salicylate.” may be omitted from the warning in § 335.50(c)(2)(i)(B).

(ii) The subheading “When using this product” in § 335.50(c)(2)(iv) may be omitted.

(iii) The words “continue to” may be omitted from the directions in § 335.50(d)(3).

(2) The labeling shall be printed in accordance with the requirements of § 201.66(d) of this chapter except that any requirements related to § 201.66(c)(3) of this chapter and the bullet in the warning in § 335.50(c)(1)(i) may be omitted.

(a) An over-the-counter antiemetic drug product in a form suitable for oral administration is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this part and each of the general conditions established in § 330.1.

(b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.

As used in this part:

Antiemetic. An agent that prevents or treats nausea and vomiting.

The active ingredient of the product consists of any of the following when used within the dosage limits established for each ingredient in § 336.50(d):

(a) Cyclizine hydrochloride.

(b) Dimenhydrinate.

(c) Diphenhydramine hydrochloride.

(d) Meclizine hydrochloride.

(a) Statement of identity. The labeling of the product contains the established name of the drug, if any, and identifies the product as an “antiemetic.”

(b) Indications. The labeling of the product states the following under the heading “Indications,” “For the prevention and treatment of the nausea, vomiting, or dizziness associated with motion sickness.” Other truthful and nonmisleading statements, describing only the indications for use that have been established and listed in this paragraph (b), may also be used, as provided in § 330.1(c)(2), subject to the provisions of section 502 of the act relating to misbranding and the prohibition in section 301(d) of the act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the act.

(c) Warnings. The labeling of the product contains the following warnings under the heading “Warnings:”

(1) For products containing any ingredient identified in § 336.10 - (i) When labeled for use in adults and for those products that can be and are labeled for use in children under 12 years of age. “Do not take this product, unless directed by a doctor, if you have a breathing problem such as emphysema or chronic bronchitis, or if you have glaucoma or difficulty in urination due to enlargement of the prostate gland.”

(ii) For those products that can be and are labeled only for children under 12 years of age. “Do not give this product to children who have a breathing problem such as chronic bronchitis or who have glaucoma, without first consulting the child's doctor.”

(2) For products containing cyclizine hydrochloride identified in § 336.10(a). “Do not give to children under 6 years of age unless directed by a doctor.”

(3) For products containing dimenhydrinate identified in § 336.10(b). “Do not give to children under 2 years of age unless directed by a doctor.”

(4) For products containing diphenhydramine hydrochloride identified in § 336.10(c). “Do not give to children under 6 years of age unless directed by a doctor.”

(5) For products containing meclizine hydrochloride identified in § 336.10(d). “Do not give to children under 12 years of age unless directed by a doctor.”

(6) For products containing cyclizine hydrochloride identified in § 336.10(a) or meclizine hydrochloride identified in § 330.10(d). “May cause drowsiness; alcohol, sedatives, and tranquilizers may increase the drowsiness effect. Avoid alcoholic beverages while taking this product. Do not take this product if you are taking sedatives or tranquilizers, without first consulting your doctor. Use caution when driving a motor vehicle or operating machinery.”

(7) For products containing dimenhydrinate identified in § 336.10(b) or diphenhydramine hydrochloride identified in § 336.10(c). “May cause marked drowsiness; alcohol, sedatives, and tranquilizers may increase the drowsiness effect. Avoid alcoholic beverages while taking this product. Do not take this product if you are taking sedatives or tranquilizers, without first consulting your doctor. Use caution when driving a motor vehicle or operating machinery.”

(8) For products containing diphenhydramine hydrochloride identified in § 336.10(c). “Do not use [bullet] 1 with any other product containing diphenhydramine, including one used on skin”.

(d) Directions. The labeling of the product contains the following information under the heading “Directions”:

(1) For products containing cyclizine hydrochloride identified in § 336.10(a). Adults and children 12 years of age and over: Oral dosage is 50 milligrams every 4 to 6 hours, not to exceed 200 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: Oral dosage is 25 milligrams every 6 to 8 hours, not to exceed 75 milligrams in 24 hours, or as directed by a doctor.

(2) For products containing dimenhydrinate identified in § 336.10(b). Adults and children 12 years of age and over: Oral dosage is 50 to 100 milligrams every 4 to 6 hours, not to exceed 400 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: Oral dosage is 25 to 50 milligrams every 6 to 8 hours, not to exceed 150 milligrams in 24 hours, or as directed by a doctor. Children 2 to under 6 years of age: Oral dosage is 12.5 to 25 milligrams every 6 to 8 hours, not to exceed 75 milligrams in 24 hours, or as directed by a doctor.

(3) For products containing diphenhydramine hydrochloride identified in § 336.10(c). Adults and children 12 years of age and over: Oral dosage is 25 to 50 milligrams every 4 to 6 hours, not to exceed 300 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: Oral dosage is 12.5 to 25 milligrams every 4 to 6 hours, not to exceed 150 milligrams in 24 hours, or as directed by a doctor.

(4) For products containing meclizine hydrochloride identified in § 336.10(d). Adults and children 12 years of age and over: Oral dosage is 25 to 50 milligrams once daily, or as directed by a doctor.

(e) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this section.

The labeling provided to health professionals (but not to the general public) may contain the following additional indications.

(a) For products containing cyclizine hydrochloride, dimenhydrinate, and diphenhydramine hydrochloride identified in § 336.10 (a), (b), and (c). “For the treatment of vertigo of motion sickness.”

(b) For products containing meclizine hydrochloride identified in § 336.10(d). “For the treatment of vertigo.”

(a) An over-the-counter nighttime sleep-aid drug product in a form suitable for oral administration is generally recognized as safe and effective and is not misbranded if it meets each condition in this part and each general condition established in § 330.1 of this chapter.

(b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.

As used in this part:

Nighttime sleep-aid. A drug that is useful for the relief of occasional sleeplessness by individuals who have difficulty falling asleep.

The active ingredient of the product consists of any of the following when used within the dosage limits established for each ingredient in § 338.50(d):

(a) Diphenhydramine hydrochloride.

(b) Diphenhydramine citrate.

(a) Statement of identity. The labeling of the product contains the established name of the drug, if any, and identifies the product as a “nighttime sleep-aid.”

(b) Indications. The labeling of the product states, under the heading “Indications,” one or more of the phrases listed in this paragraph. Other truthful and nonmisleading statements, describing only the indications for use that have been established and listed in this paragraph (b), may also be used, as provided in § 330.1(c)(2) of this chapter, subject to the provisions of section 502 of the act relating to misbranding and the prohibition in section 301(d) of the act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the act.

(1) (“Helps you” or “Reduces time to”) “fall asleep if you have difficulty falling asleep.”

(2) “For relief of occasional sleeplessness.”

(3) “Helps to reduce difficulty falling asleep.”

(c) Warnings. The labeling of the product contains the following warnings under the heading “Warnings”:

(1) “Do not give to children under 12 years of age.”

(2) “If sleeplessness persists continuously for more than 2 weeks, consult your doctor. Insomnia may be a symptom of serious underlying medical illness.”

(3) “Do not take this product, unless directed by a doctor, if you have a breathing problem such as emphysema or chronic bronchitis, or if you have glaucoma or difficulty in urination due to enlargement of the prostate gland.”

(4) “Avoid alcoholic beverages while taking this product. Do not take this product if you are taking sedatives or tranquilizers, without first consulting your doctor.”

(5) “Do not use [bullet] 1 with any other product containing diphenhydramine, even one used on skin”.

(d) Directions. The labeling of the product contains the following information under the heading “Directions”:

(1) For products containing diphenhydramine hydrochloride identified in § 338.10(a). Adults and children 12 years of age and over: Oral dosage is 50 milligrams at bedtime if needed, or as directed by a doctor.

(2) For products containing diphenhydramine citrate identified in § 338.10(b). Adults and children 12 years of age and over: Oral dosage is 76 milligrams at bedtime if needed, or as directed by a doctor.

(e) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this section.

(a) An over-the-counter stimulant drug product in a form suitable for oral administration is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this part and each of the general conditions established in § 330.1.

(b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.

As used in this part:

Stimulant. A drug which helps restore mental alertness or wakefulness during fatigue or drowsiness.

The active ingredient of the product consists of caffeine when used within the dosage limits established in § 340.50(d).

(a) Statement of identity. The labeling of the product contains the established name of the drug, if any, and identifies the product as an “altertness aid” or a “stimulant.”

(b) Indications. The labeling of the product states, under the heading “Indications,” the following: “Helps restore mental alertness or wakefulness when experiencing fatigue or drowsiness.” Other truthful and nonmisleading statements, describing only the indications for use that have been established and listed in this paragraph (b), may also be used, as provided in § 330.1(c)(2), subject to the provisions of section 502 of the Act relating to misbranding and the prohibition in section 301(d) of the Act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the Act.

(c) Warnings. The labeling of the product contains the following warnings under the heading “Warnings”:

(1) “The recommended dose of this product contains about as much caffeine as a cup of coffee. Limit the use of caffeine-containing medications, foods, or beverages while taking this product because too much caffeine may cause nervousness, irritability, sleeplessness, and, occasionally, rapid heart beat.”

(2) “For occasional use only. Not intended for use as a substitute for sleep. If fatigue or drowsiness persists or continues to recur, consult a” (select one of the following: “physician” or “doctor”).

(3) “Do not give to children under 12 years of age.”

(d) Directions. The labeling of the product contains the following information under the heading “Directions”: Adults and children 12 years of age and over: Oral dosage is 100 to 200 milligrams not more often than every 3 to 4 hours.

(a) An over-the-counter cold, cough, allergy, bronchodilator, or antiasthmatic drug product in a form suitable for oral, inhalant, or topical administration is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this part and each of the general conditions established in § 330.1.

(b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.

As used in this part:

(a) Bronchodilator drug. A drug used to overcome spasms that cause narrowing of the bronchial air tubes, such as in the symptomatic treatment of the wheezing and shortness of breath of asthma.

(b) Oral antitussive drug. A drug that either is taken by mouth or is dissolved in the mouth in the form of a lozenge and acts systemically to relieve cough.

(c) Topical antitussive drug. A drug that relieves cough when inhaled after being applied topically to the throat or chest in the form of an ointment or from a steam vaporizer, or when dissolved in the mouth in the form of a lozenge for a local effect.

(d) Expectorant drug. A drug taken orally to promote or facilitate the removal of secretions from the respiratory airways.

(e) Antihistamine drug. A drug used for the relief of the symptoms of hay fever and upper respiratory allergies (allergic rhinitis).

(f) Oral nasal decongestant drug. A drug that is taken by mouth and acts systemically to reduce nasal congestion caused by acute or chronic rhinitis.

(g) Topical nasal decongestant drug. A drug that when applied topically inside the nose, in the form of drops, jellies, or sprays, or when inhaled intranasally reduces nasal congestion caused by acute or chronic rhinitis.

(h) Calibrated dropper. A dropper calibrated such that the volume error incurred in measuring any liquid does not exceed 15 percent under normal use conditions.

(i) Effervescent dosage form. A dosage form intended to be dissolved in water before administration. It contains, in addition to the active ingredient(s), mixtures of acids (citric acid, tartaric acid) and sodium bicarbonate, which release carbon dioxide when dissolved in water.

The active ingredient of the product consists of any of the following when used within the dosage limits established for each ingredient:

(a) Brompheniramine maleate.

(b) Chlorcyclizine hydrochloride.

(c) Chlorpheniramine maleate.

(d) Dexbrompheniramine maleate.

(e) Dexchlorpheniramine maleate.

(f) Diphenhydramine citrate.

(g) Diphenhydramine hydrochloride.

(h) Doxylamine succinate.

(i) Phenindamine tartrate.

(j) Pheniramine maleate.

(k) Pyrilamine maleate.

(l) Thonzylamine hydrochloride.

(m) Triprolidine hydrochloride.

The active ingredients of the product consist of any of the following when used within the dosage limits and in the dosage forms established for each ingredient in § 341.74(d):

(a) Oral antitussives. (1) Chlophedianol hydrochloride.

(2) Codeine ingredients. The following ingredients may be used only in combination in accordance with § 290.2 and 21 CFR 1308.15(c).

(i) Codeine.

(ii) Codeine phosphate.

(iii) Codeine sulfate.

(3) Dextromethorphan.

(4) Dextromethorphan hydrobromide.

(5) Diphenhydramine citrate.

(6) Diphenhydramine hydrochloride.

(b) Topical antitussives. (1) Camphor.

(2) Menthol.

The active ingredients of the product consist of any of the following when used within the dosage limits established for each ingredient:

(a) Ephedrine.

(b) Ephedrine hydrochloride.

(c) Ephedrine sulfate.

(d) Epinephrine.

(e) Epinephrine bitartrate.

(f) Racephedrine hydrochloride.

(g) Racepinephrine hydrochloride.

The active ingredient of the product is guaifenesin when used within the dosage limits established in § 341.78(d).

The active ingredient of the product consists of any of the following when used within the dosage limits and in the dosage forms established for each ingredient:

(a) Oral nasal decongestants. (1) Phenylephrine hydrochloride.

(2) Pseudoephedrine hydrochloride.

(3) Pseudoephedrine sulfate.

(4) Phenylephrine bitartrate in an effervescent dosage form.

(b) Topical nasal decongestants. (1) Levmetamfetamine.

(2) Ephedrine.

(3) Ephedrine hydrochloride.

(4) Ephedrine sulfate.

(5) [Reserved]

(6) Naphazoline hydrochloride.

(7) Oxymetazoline hydrochloride.

(8) Phenylephrine hydrochloride.

(9) Propylhexedrine.

(10) Xylometazoline hydrochloride.

The following combinations are permitted provided each active ingredient is present within the dosage limits established in parts 341, 343, and 356 of this chapter and the product is labeled in accordance with §§ 341.70 or 341.85:

(a) Any single antihistamine active ingredient identified in § 341.12 may be combined with any generally recognized as safe and effective single analgesic-antipyretic active ingredient, or any combination of acetaminophen with other analgesic-antipyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to § 341.85.

(b) Any single antihistamine active ingredient identified in § 341.12 may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) provided that the product is labeled according to § 341.85.

(c) Any single antihistamine active ingredient identified in § 341.12 may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) and any generally recognized as safe and effective single analgesic-antipyretic active ingredient, or any combination of acetaminophen with other analgesic-antipyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to § 341.85.

(d) Any single antihistamine active ingredient identified in § 341.12(a) through (e) and (h) through (m) may be combined with any single oral antitussive active ingredient identified in § 341.14(a)(1) through (a)(4) provided that the product is labeled according to § 341.85(c)(4). Diphenhydramine citrate in §§ 341.12(f) and 341.14(a)(5) or diphenhydramine hydrochloride in §§ 341.12(g) and 341.14(a)(6) may be both the antihistamine and the antitussive active ingredient provided that the product is labeled according to § 341.70(a).

(e) Any single antihistamine active ingredient identified in § 341.12(a) through (e) and (h) through (m) may be combined with any single oral antitussive active ingredient identified in § 341.14(a)(1) through (a)(4) and any single oral nasal decongestant active ingredient identified in § 341.20(a) provided that the product is labeled according to § 341.85(c)(4). Diphenhydramine citrate in §§ 341.12(f) and 341.14(a)(5) or diphenhydramine hydrochloride in §§ 341.12(g) and 341.14(a)(6) may be both the antihistamine and the antitussive active ingredient provided that the product is labeled according to § 341.70(a).

(f) Any single antihistamine active ingredient identified in § 341.12(a) through (e) and (h) through (m) may be combined with any single oral antitussive active ingredient identified in § 341.14(a)(1) through (a)(4) and any generally recognized as safe and effective single analgesic-antipyretic active ingredient, or any combination of acetaminophen with other analgesic-antipyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to § 341.85(c)(4). Diphenhydramine citrate in §§ 341.12(f) and 341.14(a)(5) or diphenhydramine hydrochloride in §§ 341.12(g) and 341.14(a)(6) may be both the antihistamine and the antitussive active ingredient provided that the product is labeled according to § 341.70(a).

(g) Any single antihistamine active ingredient identified in § 341.12(a) through (e) and (h) through (m) may be combined with any single oral antitussive active ingredient identified in § 341.14(a)(1) through (a)(4) and any single oral nasal decongestant active ingredient identified in § 341.20(a) and any generally recognized as safe and effective single analgesic-antipyretic active ingredient, or any combination of acetaminophen with other analgesic-antipyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to § 341.85(c)(4). Diphenhydramine citrate in §§ 341.12(f) and 341.14(a)(5) or diphenhydramine hydrochloride in §§ 341.12(g) and 341.14(a)(6) may be both the antihistamine and the antitussive active ingredient provided that the product is labeled according to § 341.70(a).

(h) Any single oral antitussive active ingredient identified in § 341.14(a)(1) through (a)(4) may be combined with any single expectorant active ingredient identified in § 341.18 provided that the product is labeled according to § 341.85.

(i) Any single oral antitussive active ingredient identified in § 341.14(a) may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) provided that the product is labeled according to § 341.85.

(j) Any single oral antitussive active ingredient identified in § 341.14(a)(1) through (a)(4) may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) and any single expectorant active ingredient identified in § 341.18 provided that the product is labeled according to § 341.85.

(k) Any single antitussive active ingredient identified in § 341.14(a) or (b)(2) may be combined with any generally recognized as safe and effective single oral anesthetic/analgesic active ingredient, or any combination of anesthetic/analgesic active ingredients provided that the product is available in either a liquid (to be swallowed) or a solid dosage form (to be dissolved in the mouth and swallowed) and provided that the product is labeled according to § 341.85. If the combination contains a topical antitussive, the product must be formulated in a solid dosage form to be dissolved in the mouth. Menthol in § 341.14(b)(2) and part 356 of this chapter may be both the antitussive and the anesthetic/analgesic active ingredient provided that the product is labeled according to § 341.70(b).

(l) Any single oral antitussive active ingredient identified in § 341.14(a) may be combined with any generally recognized as safe and effective single analgesic-antipyretic active ingredient, or any combination of acetaminophen with other analgesic-antipyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to § 341.85.

(m) Any single oral antitussive active ingredient identified in § 341.14(a) may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) and any generally recognized as safe and effective single analgesic-antipyretic active ingredient, or any combination of acetaminophen with other analgesic-antipyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to § 341.85.

(n) Any single oral antitussive active ingredient identified in § 341.14(a)(1) through (a)(4) may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) and any single expectorant active ingredient identified in § 341.18 and any generally recognized as safe and effective single analgesic-antipyretic active ingredient, or any combination of acetaminophen with other analgesic-antipyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to § 341.85.

(o) Any single expectorant active ingredient identified in § 341.18 may be combined with any generally recognized as safe and effective single analgesic-antipyretic active ingredient, or any combination of acetaminophen with other analgesic-antipyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to § 341.85.

(p) Any single expectorant active ingredient identified in § 341.18 may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) provided that the product is labeled according to § 341.85.

(q) Any single expectorant active ingredient identified in § 341.18 may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) and any generally recognized as safe and effective single analgesic-antipyretic active ingredient, or any combination of acetaminophen with other analgesic-antipyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to § 341.85.

(r) Any single oral nasal decongestant active ingredient identified in § 341.20(a) may be combined with any generally recognized as safe and effective single analgesic-antipyretic active ingredient, or any combination of acetaminophen with other analgesic-antipyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to § 341.85.

(s) Any single oral nasal decongestant active ingredient identified in § 341.20(a) may be combined with any generally recognized as safe and effective single oral anesthetic/analgesic active ingredient identified, or any combination of anesthetic/analgesic active ingredients provided that the product is available in either a liquid (to be swallowed) or a solid dosage form (to be dissolved in the mouth and swallowed) and provided that the product is labeled according to § 341.85.

(t) Any single oral nasal decongestant active ingredient identified in § 341.20(a) may be combined with any single antitussive active ingredient identified in § 341.14(a) or (b)(2) and any generally recognized as safe and effective single oral anesthetic/analgesic active ingredient, or any combination of anesthetic/analgesic active ingredients provided that the product is available in either a liquid (to be swallowed) or a solid dosage form (to be dissolved in the mouth and swallowed) and provided that the product is labeled according to § 341.85. If the combination contains a topical antitussive, the product must be formulated in a solid dosage form to be dissolved in the mouth.

(u) Camphor identified in § 341.14(b)(1) may be combined with menthol identified in § 341.14(b)(2) and eucalyptus oil (1.2 to 1.3 percent) provided that the product is available only in a suitable ointment vehicle and provided that the product is labeled according to § 341.85.

(v) Levmetamfetamine identified in § 341.20(b)(1) may be combined with aromatics (camphor (54 milligrams (mg)), menthol (80 mg), methyl salicylate (11 mg), and lavender oil (4 mg)) provided that the product is available only as a nasal inhaler and provided that the product is labeled according to § 341.85.

(w) Any single antitussive active ingredient identified in § 341.14(a) or (b)(2) may be combined with any generally recognized as safe and effective single oral demulcent active ingredient provided that the product is available in either a liquid (to be swallowed) or a solid dosage form (to be dissolved in the mouth and swallowed) and provided that the product is labeled according to § 341.85. If the combination contains a topical antitussive, the product must be formulated in a solid dosage form to be dissolved in the mouth.

(x) Any single oral nasal decongestant active ingredient identified in § 341.20(a) may be combined with any generally recognized as safe and effective single oral demulcent active ingredient provided that the product is available in either a liquid (to be swallowed) or a solid dosage form (to be dissolved in the mouth and swallowed) and provided that the product is labeled according to § 341.85.

(y) Any single antitussive active ingredient identified in § 341.14(a) or (b)(2) may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) and any generally recognized as safe and effective single oral demulcent active ingredient provided that the product is available in either a liquid (to be swallowed) or a solid dosage form (to be dissolved in the mouth and swallowed) and provided that the product is labeled according to § 341.85. If the combination contains a topical antitussive, the product must be formulated in a solid dosage form to be dissolved in the mouth.

(z) Any single antitussive active ingredient identified in § 341.14(a) or (b)(2) may be combined with any generally recognized as safe and effective single oral anesthetic/analgesic active ingredient or any combination of anesthetic/analgesic active ingredients and any generally recognized as safe and effective single oral demulcent active ingredient provided that the product is available in either a liquid (to be swallowed) or a solid dosage form (to be dissolved in the mouth and swallowed) and provided that the product is labeled according to § 341.85. If the combination contains a topical antitussive, the product must be formulated in a solid dosage form to be dissolved in the mouth.

(aa) Any single oral nasal decongestant active ingredient identified in § 341.20(a) may be combined with any generally recognized as safe and effective single oral anesthetic/analgesic active ingredient or any combination of oral anesthetic/analgesic active ingredients and any generally recognized as safe and effective single oral demulcent active ingredient provided that the product is available in either a liquid (to be swallowed) or a solid dosage form (to be dissolved in the mouth and swallowed) and provided that the product is labeled according to § 341.85.

(bb) Any single antitussive active ingredient identified in § 341.14(a) or (b)(2) may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) and any generally recognized as safe and effective single oral anesthetic/analgesic active ingredient identified or any combination of anesthetic/analgesic active ingredients and any generally recognized as safe and effective single oral demulcent active ingredient provided that the product is available in either a liquid (to be swallowed) or a solid dosage form (to be dissolved in the mouth and swallowed) and provided that the product is labeled according to § 341.85. If the combination contains a topical antitussive, the product must be formulated in a solid dosage form to be dissolved in the mouth.

The statements of identity, indications, warnings, and directions for use, respectively, applicable to each ingredient in the product may be combined to eliminate duplicative words or phrases so that the resulting information is clear and understandable.

(a) For products containing diphenhydramine citrate and diphenhydramine hydrochloride identified in § 341.14(a)(5) and (a)(6). The labeling of the product contains the established name of the drug, if any, and identifies the product as an “antihistamine/cough suppressant” or “antihistamine/antitussive (cough suppressant).” The indications shall be combined from §§ 341.72(b) and 341.74(b). The warnings shall be combined from §§ 341.72(c)(1), (c)(2), (c)(4), and (c)(6) and 341.74(c)(1), (c)(2), (c)(3), and (c)(4). Alternatively, all of the warnings in § 341.74(c) shall be used. The directions for OTC labeling shall follow §§ 341.74(d)(1)(iv) or (d)(1)(v), as applicable. The directions for professional labeling shall follow § 341.90(j) or (k), as applicable.

(b) For products containing menthol identified in §§ 341.14(b)(2) and 356.12(f) of this chapter. The product contains 5 to 10 milligrams menthol. The labeling of the product contains the established name of the drug, if any, and identifies the product as a “cough suppressant/oral anesthetic” or “antitussive (cough suppressant)/oral anesthetic.” The indications shall be combined from § 341.74(b) and part 356 of this chapter. The warnings shall be combined from § 341.74(c)(1), (c)(2), and (c)(3) and part 356 of this chapter. The directions shall be: “Directions [in bold type] [bullet] 1 adults and children 2 years and over: dissolve lozenge slowly in the mouth. Repeat every 2 hours as needed or as directed by a doctor. [bullet] children under 2 years of age: ask a doctor”.

(a) Statement of identity. The labeling of the product contains the established name of the drug, if any, and identifies the product as an “antihistamine.”

(b) Indications. The labeling of the product states, under the heading “Indications,” any of the phrases listed in paragraph (b) of this section, as appropriate. Other truthful and nonmisleading statements, describing only the indications for use that have been established and listed in this paragraph, may also be used, as provided in § 330.1(c)(2) of this chapter, subject to the provisions of section 502 of the Federal Food, Drug, and Cosmetic Act (the act) relating to misbranding and the prohibition in section 301(d) of the act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the act.

(1) “Temporarily” (select one of the following: “relieves,” “alleviates,” “decreases,” “reduces,” or “dries”) “runny nose and” (select one of the following: “relieves,” “alleviates,” “decreases,” or “reduces”) “sneezing, itching of the nose or throat, and itchy, watery eyes due to hay fever” (which may be followed by one or both of the following: “or other upper respiratory allergies” or “(allergic rhinitis)”).

(2) “For the temporary relief of runny nose, sneezing, itching of the nose or throat, and itchy, watery eyes due to hay fever” (which may be followed by one or both of the following: “or other upper respiratory allergies” or “(allergic rhinitis)”).

(c) Warnings. The labeling of the product contains the following warnings, under the heading “Warnings”:

(1) “May cause excitability especially in children.”

(2) “Do not take this product, unless directed by a doctor, if you have a breathing problem such as emphysema or chronic bronchitis, or if you have glaucoma or difficulty in urination due to enlargement of the prostate gland.”

(3) For products containing brompheniramine maleate, chlorcyclizine hydrochloride, chlorpheniramine maleate, dexbrompheniramine maleate, dexchlorpheniramine maleate, phenindamine tartrate, pheniramine maleate, pyrilamine maleate, thonzylamine hydrochloride, or triprolidine hydrochloride identified in § 341.12(a), (b), (c), (d), (e), (i), (j), (k), (l), and (m). “May cause drowsiness; alcohol, sedatives, and tranquilizers may increase the drowsiness effect. Avoid alcoholic beverages while taking this product. Do not take this product if you are taking sedatives or tranquilizers, without first consulting your doctor. Use caution when driving a motor vehicle or operating machinery.”

(4) For products containing diphenhydramine citrate, diphenhydramine hydrochloride, or doxylamine succinate identified in § 341.12(f), (g), and (h). “May cause marked drowsiness; alcohol, sedatives, and tranquilizers may increase the drowsiness effect. Avoid alcoholic beverages while taking this product. Do not take this product if you are taking sedatives or tranquilizers, without first consulting your doctor. Use caution when driving a motor vehicle or operating machinery.”

(5) For products containing phenindamine tartrate identified in § 341.12(i). “May cause nervousness and insomnia in some individuals.”

(6) For products that are labeled only for use by children under 12 years of age. The labeling of the product contains only the warnings identified in paragraphs (c)(1) and (c)(5) of this section as well as the following:

(i) “Do not give this product to children who have a breathing problem such as chronic bronchitis, or who have glaucoma, without first consulting the child's doctor.”

(ii) For products containing brompheniramine maleate, chlorpheniramine maleate, dexbrompheniramine maleate, dexchlorpheniramine maleate, phenindamine tartrate, pheniramine maleate, pyrilamine maleate, thonzylamine hydrochloride, or triprolidine hydrochloride identified in § 341.12(a), (c), (d), (e), (i), (j), (k), (l), and (m). “May cause drowsiness. Sedatives and tranquilizers may increase the drowsiness effect. Do not give this product to children who are taking sedatives or tranquilizers, without first consulting the child's doctor.”

(iii) For products containing diphenhydramine citrate, diphenhydramine hydrochloride, or doxylamine succinate identified in § 341.12(f), (g), and (h). “May cause marked drowsiness. Sedatives and tranquilizers may increase the drowsiness effect. Do not give this product to children who are taking sedatives or tranquilizers, without first consulting the child's doctor.”

(iv) For products containing diphenhydramine citrate or diphenhydramine hydrochloride identified in § 341.12(f) and (g). “Do not use [bullet] 1 with any other product containing diphenhydramine, even one used on skin”.

(7) For products containing diphenhydramine citrate or diphenhydramine hydrochloride identified in § 341.12(f) and (g). “Do not use [bullet] with any other product containing diphenhydramine, even one used on skin”.

(d) Directions. The labeling of the product contains the following information under the heading “Directions”:

(1) For products containing brompheniramine maleate identified in § 341.12(a). Adults and children 12 years of age and over: oral dosage is 4 milligrams every 4 to 6 hours, not to exceed 24 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: oral dosage is 2 milligrams every 4 to 6 hours, not to exceed 12 milligrams in 24 hours, or as directed by a doctor. Children under 6 years of age: consult a doctor.

(2) For products containing chlorcyclizine hydrochloride identified in § 341.12(b). Adults and children 12 years of age and over: oral dosage is 25 milligrams every 6 to 8 hours, not to exceed 75 milligrams in 24 hours, or as directed by a doctor. Children under 12 years of age: consult a doctor.

(3) For products containing chlorpheniramine maleate identified in § 341.12(c). Adults and children 12 years of age and over: oral dosage is 4 milligrams every 4 to 6 hours, not to exceed 24 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: oral dosage is 2 milligrams every 4 to 6 hours, not to exceed 12 milligrams in 24 hours, or as directed by a doctor. Children under 6 years of age: consult a doctor.

(4) For products containing dexbrompheniramine maleate identified in § 341.12(d). Adults and children 12 years of age and over: oral dosage is 2 milligrams every 4 to 6 hours, not to exceed 12 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: oral dosage is 1 milligram every 4 to 6 hours, not to exceed 6 milligrams in 24 hours, or as directed by a doctor. Children under 6 years of age: consult a doctor.

(5) For products containing dexchlorpheniramine maleate identified in § 341.12(e). Adults and children 12 years of age and over: oral dosage is 2 milligrams every 4 to 6 hours, not to exceed 12 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: oral dosage is 1 milligram every 4 to 6 hours, not to exceed 6 milligrams in 24 hours, or as directed by a doctor. Children under 6 years of age: consult a doctor.

(6) For products containing diphenhydramine citrate identified in § 341.12(f). Adults and children 12 years of age and over: oral dosage is 38 to 76 milligrams every 4 to 6 hours, not to exceed 456 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: oral dosage is 19 to 38 milligrams every 4 to 6 hours, not to exceed 228 milligrams in 24 hours, or as directed by a doctor. Children under 6 years of age: consult a doctor.

(7) For products containing diphenhydramine hydrochloride identified in § 341.12(g). Adults and children 12 years of age and over: oral dosage is 25 to 50 milligrams every 4 to 6 hours, not to exceed 300 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: oral dosage is 12.5 to 25 milligrams every 4 to 6 hours, not to exceed 150 milligrams in 24 hours, or as directed by a doctor. Children under 6 years of age: consult a doctor.

(8) For products containing doxylamine succinate identified in § 341.12(h). Adults and children 12 years of age and over: oral dosage is 7.5 to 12.5 milligrams every 4 to 6 hours, not to exceed 75 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: oral dosage is 3.75 to 6.25 milligrams every 4 to 6 hours, not to exceed 37.5 milligrams in 24 hours, or as directed by a doctor. Children under 6 years of age: consult a doctor.

(9) For products containing phenindamine tartrate identified in § 341.12(i). Adults and children 12 years of age and over: oral dosage is 25 milligrams every 4 to 6 hours, not to exceed 150 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: oral dosage is 12.5 milligrams every 4 to 6 hours, not to exceed 75 milligrams in 24 hours, or as directed by a doctor. Children under 6 years of age: consult a doctor.

(10) For products containing pheniramine maleate identified in § 341.12(j). Adults and children 12 years of age and over: oral dosage is 12.5 to 25 milligrams every 4 to 6 hours, not to exceed 150 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: oral dosage is 6.25 to 12.5 milligrams every 4 to 6 hours, not to exceed 75 milligrams in 24 hours, or as directed by a doctor. Children under 6 years of age: consult a doctor.

(11) For products containing pyrilamine maleate identified in § 341.12(k). Adults and children 12 years of age and over: oral dosage is 25 to 50 milligrams every 6 to 8 hours, not to exceed 200 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: oral dosage is 12.5 to 25 milligrams every 6 to 8 hours, not to exceed 100 milligrams in 24 hours, or as directed by a doctor. Children under 6 years of age: consult a doctor.

(12) For products containing thonzylamine hydrochloride identified in § 341.12(l). Adults and children 12 years of age and over: oral dosage is 50 to 100 milligrams every 4 to 6 hours, not to exceed 600 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: oral dosage is 25 to 50 milligrams every 4 to 6 hours, not to exceed 300 milligrams in 24 hours, or as directed by a doctor. Children under 6 years of age: consult a doctor.

(13) For products containing triprolidine hydrochloride identified in § 341.12(m). Adults and children 12 years of age and over: oral dosage is 2.5 milligrams every 4 to 6 hours, not to exceed 10 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: oral dosage is 1.25 milligrams every 4 to 6 hours, not to exceed 5 milligrams in 24 hours, or as directed by a doctor. Children under 6 years of age: consult a doctor.

(e) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this section.

(a) Statement of identity. The labeling of the product contains the established name of the drug, if any, and identifies the product as a “cough suppressant” or an “antitussive (cough suppressant).”

(b) Indications. The labeling of the product states, under the heading “Indications,” any of the phrases listed in this paragraph (b), as appropriate. Other truthful and nonmisleading statements, describing only the indications for use that have been established and listed in this paragraph, may also be used, as provided in § 330.1(c)(2), subject to the provisions of section 502 of the act relating to misbranding and the prohibition in section 301(d) of the act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the act.

(1) “Temporarily” (select one of the following: “alleviates,” “calms,” “controls,” “decreases,” “quiets,” “reduces,” “relieves,” or “suppresses”) “cough due to” (select one of the following: “minor bronchial irritation” or “minor throat and bronchial irritation”) (select one of the following: “as may occur with,” “associated with,” or “occurring with”) (select one of the following: “A cold” or “the common cold”) “or inhaled irritants.”

(2) “Temporarily” (select one of the following: “alleviates,” “calms,” “controls,” “decreases,” “quiets,” “reduces,” “relieves,” or “suppresses”) “cough” (select one of the following: “as may occur with,” “associated with,” or “occurring with”) (select one of the following: “A cold,” “the common cold,” or “inhaled irritants”).

(3) In addition to the required information identified in paragraphs (b) (1) and (2) of this section, the labeling of the product may contain any (one or more) of the following statements:

(i) “Cough suppressant which temporarily” (select one of the following: “Alleviates,” “controls,” “decreases,” “reduces,” “relieves,” or “suppresses”) “the impulse to cough.”

(ii) “Temporarily helps you cough less.”

(iii) “Temporarily helps to” (select one of the following: “Alleviate,” “control,” “decrease,” “reduce,” “relieve,” or “suppress”) “the cough reflex that causes coughing.”

(iv) “Temporarily” (select one of the following: “Alleviates,” “controls,” “decreases,” “reduces,” “relieves,” or “suppresses”) “the intensity of coughing.”

(v) (Select one of the following: “Alleviates,” “Controls,” “Decreases,” “Reduces,” “Relieves,” or “Suppresses”) (select one of the following: “Cough,” “the impulse to cough,” or “your cough”) “to help you” (select one of the following: “Get to sleep,” “sleep,” or “rest”).

(vi) For products containing chlophedianol hydrochloride, codeine ingredients, dextromethorphan, or dextromethorphan hydrobromide identified in § 341.14(a) (1), (2), (3), and (4). “Calms the cough control center and relieves coughing.”

(vii) For products containing chlophedianol hydrochloride, dextromethorphan, dextromethorphan hydrobromide, camphor, or menthol identified in § 341.14(a) (1), (3), (4) and (b) (1) and (2). (a) “Nonnarcotic cough suppressant for the temporary” (select one of the following: “alleviation,” “control,” “decrease,” “reduction,” “relief,” or “suppression”) “of cough.”

(b) (Select one of the following: “Alleviates,” “Controls,” “Decreases,” “Reduces,” “Relieves,” or “Suppresses”) “cough impulses without narcotics.”

(c) Warnings. The labeling of the product contains the following warnings under the heading “Warnings”:

(1) For oral and topical antitussives. “A persistent cough may be a sign of a serious condition. If cough persists for more than 1 week, tends to recur, or is accompanied by fever, rash, or persistent headache, consult a doctor.”

(2) For oral and topical antitussives labeled for adults or for adults and children under 12 years of age. “Do not take this product for persistent or chronic cough such as occurs with smoking, asthma, or emphysema, or if cough is accompanied by excessive phlegm (mucus) unless directed by a doctor.”

(3) For oral and topical antitussives labeled only for children under 12 years of age. “Do not give this product for persistent or chronic cough such as occurs with asthma or if cough is accompanied by excessive phlegm (mucus) unless directed by a doctor.”

(4) Oral antitussives - (i) For products containing codeine ingredients identified in § 341.14(a)(2). “May cause or aggravate constipation.”

(ii) For products containing codeine ingredients identified in § 341.14(a)(2) when labeled only for adults. “Do not take this product if you have a chronic pulmonary disease or shortness of breath unless directed by a doctor.”

(iii) For products containing codeine ingredients identified in § 341.14(a)(2) when labeled only for children under 12 years of age. “Do not give this product to children who have a chronic pulmonary disease, shortness of breath, or who are taking other drugs unless directed by a doctor.”

(iv) For products containing codeine ingredients identified in § 341.14(a)(2) when labeled for use in adults and children under 12 years of age. “Adults and children who have a chronic pulmonary disease or shortness of breath, or children who are taking other drugs, should not take this product unless directed by a doctor.”

(v) For products containing dextromethorphan or dextromethorphan hydrobromide as identified in § 341.14 (a)(3) and (a)(4) when labeled for adults or for adults and children under 12 years of age. Drug interaction precaution. “Do not use if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.”

(vi) For products containing dextromethorphan or dextromethorphan hydrobromide as identified in § 341.14 (a)(3) and (a)(4) when labeled only for children under 12 years of age. Drug interaction precaution. “Do not use in a child who is taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your child's prescription drug contains an MAOI, ask a doctor or pharmacist before giving this product.”

(vii) For products containing diphenhydramine citrate or diphenhydramine hydrochloride identified in § 341.14 (a)(5) and (a)(6). “May cause excitability especially in children.”

(viii) For products containing diphenhydramine citrate or diphenhydramine hydrochloride identified in § 341.14 (a)(5) and (a)(6) when labeled only for children under 12 years of age - (A) “Do not give this product to children who have a breathing problem such as chronic bronchitis, or who have glaucoma, without first consulting the child's doctor.”

(B) “May cause marked drowsiness. Sedatives and tranquilizers may increase the drowsiness effect. Do not give this product to children who are taking sedatives or tranquilizers, without first consulting the child's doctor.”

(C) “Do not use [bullet] 1 with any other product containing diphenhydramine, even one used on skin”.

(ix) For products containing diphenhydramine citrate or diphenhydramine hydrochloride identified in § 341.14 (a)(5) and (a)(6) when labeled for use in adults and children under 12 years of age - (A) “Do not take this product, unless directed by a doctor, if you have a breathing problem such as emphysema or chronic bronchitis, or if you have glaucoma or difficulty in urination due to enlargement of the prostate gland.”

(B) “May cause marked drowsiness; alcohol, sedatives, and tranquilizers may increase the drowsiness effect. Avoid alcoholic beverages while taking this product. Do not take this product if you are taking sedatives or tranquilizers, without first consulting your doctor. Use caution when driving a motor vehicle or operating machinery.”

(C) “Do not use [bullet] with any other product containing diphenhydramine, even one used on skin”.

(5) Topical antitussives - (i) For products containing camphor or menthol identified in § 341.14 (b) (1) and (2) in a suitable ointment vehicle. “For external use only. Do not take by mouth or place in nostrils.”

(ii) For products containing camphor or menthol identified in § 341.14(b) (1) and (2) for steam inhalation use. “For steam inhalation only. Do not take by mouth.”

(iii) For any product containing camphor or menthol in a suitable ointment vehicle or for steam inhalation use and meets the definition of one of the signal words (“extremely flammable,” “flammable,” “combustible”) as described in 16 CFR 1500.3(b)(10). The labeling contains the appropriate flammability signal word(s) followed by a colon and the statement “Keep away from fire or flame.”

(iv) For any product containing camphor or menthol in a suitable ointment vehicle and that does not contain a flammability signal word as described in 16 CFR 1500.3(b)(10). “When using this product, do not [bullet] 1 heat [bullet] microwave [bullet] add to hot water or any container where heating water. May cause splattering and result in burns.” [Information highlighted in bold type.]

(v) For any product containing camphor or menthol in a suitable ointment vehicle and that contains a flammability signal word as described in 16 CFR 1500.3(b)(10). “When using this product, do not [bullet] heat [bullet] microwave [bullet] use near an open flame [bullet] add to hot water or any container where heating water. May cause splattering and result in burns.” [Information highlighted in bold type.]

(vi) For any product containing camphor or menthol for steam inhalation use. “When using this product, do not [bullet] heat [bullet] microwave [bullet] use near an open flame [bullet] add to hot water or any container where heating water except when adding to cold water only in a hot steam vaporizer. May cause splattering and result in burns.” [Information highlighted in bold type.]

(vii) For any product formulated in a volatile vehicle. The labeling contains the following statement under the heading “Other information”: “Close container tightly and store at room temperature away from heat.”

(d) Directions. The labeling of the product contains the following information under the heading “Directions”:

(1) Oral antitussives - (i) For products containing chlophedianol hydrochloride identified in § 341.14(a)(1). Adults and children 12 years of age and over: Oral dosage is 25 milligrams every 6 to 8 hours, not to exceed 100 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: Oral dosage is 12.5 milligrams every 6 to 8 hours, not to exceed 50 milligrams in 24 hours, or as directed by a doctor. Children under 6 years of age: Consult a doctor.

(ii) For products containing codeine ingredients identified in § 341.14(a)(2). Adults and children 12 years of age and over: Oral dosage is 10 to 20 milligrams every 4 to 6 hours, not to exceed 120 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: Oral dosage is 5 to 10 milligrams every 4 to 6 hours, not to exceed 60 milligrams in 24 hours, or as directed by a doctor. Children under 6 years of age: Consult a doctor. A special measuring device should be used to give an accurate dose of this product to children under 6 years of age. Giving a higher dose than recommended by a doctor could result in serious side effects for your child.

(iii) For products containing dextromethorphan or dextromethorphan hydrobromide identified in § 341.14(a) (3) and (4). The dosage is equivalent to dextromethorphan hydrobromide. Adults and children 12 years of age and over: Oral dosage is 10 to 20 milligrams every 4 hours or 30 milligrams every 6 to 8 hours, not to exceed 120 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: Oral dosage is 5 to 10 milligrams every 4 hours or 15 milligrams every 6 to 8 hours, not to exceed 60 milligrams in 24 hours, or as directed by a doctor. Children 2 to under 6 years of age: Oral dosage is 2.5 to 5 milligrams every 4 hours or 7.5 milligrams every 6 to 8 hours, not to exceed 30 milligrams in 24 hours, or as directed by a doctor. Children under 2 years of age: Consult a doctor.

(iv) For products containing diphenhydramine citrate identified in § 341.14(a)(5). Adults and children 12 years of age and over: oral dosage is 38 milligrams every 4 hours, not to exceed 228 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: oral dosage is 19 milligrams every 4 hours, not to exceed 114 milligrams in 24 hours, or as directed by a doctor. Children under 6 years of age: consult a doctor.

(v) For products containing diphenhydramine hydrochloride identified in § 341.14(a)(6). Adults and children 12 years of age and over: oral dosage is 25 milligrams every 4 hours, not to exceed 150 milligrams in 24 hours, or as directed by a doctor. Children 6 to under 12 years of age: oral dosage is 12.5 milligrams every 4 hours, not to exceed 75 milligrams in 24 hours, or as directed by a doctor. Children under 6 years of age: consult a doctor.

(2) Topical antitussives - (i) For products containing camphor identified in § 341.14(b)(1) in a suitable ointment vehicle. The product contains 4.7 to 5.3 percent camphor. “[bullet] see important warnings under ‘When using this product’ [appears as the first statement under the heading “Directions” and is highlighted in bold type] [bullet] adults and children 2 years and older: [bullet] rub on the throat and chest in a thick layer [bullet] cover with a warm, dry cloth if desired [bullet] clothing should be loose about throat and chest to help vapors reach the nose and mouth [bullet] use up to three times daily or as directed by a doctor [bullet] children under 2 years of age: Ask a doctor.

(ii) For products containing menthol identified in § 341.14(b)(2) in a suitable ointment vehicle. The product contains 2.6 to 2.8 percent menthol. “[bullet] see important warnings under 'When using this product' ” [appears as the first statement under the heading “Directions” and is highlighted in bold type] [bullet] adults and children 2 years and older: [bullet] rub on the throat and chest in a thick layer [bullet] cover with a warm, dry cloth if desired [bullet] clothing should be loose about throat and chest to help vapors reach the nose and mouth [bullet] use up to three times daily or as directed by a doctor [bullet] children under 2 years of age: Ask a doctor.

(iii) For products containing menthol identified in § 341.14(b)(2) in a lozenge. The product contains 5 to 10 milligrams menthol. Adults and children 2 to under 12 years of age: Allow lozenge to dissolve slowly in the mouth. May be repeated every hour as needed or as directed by a doctor. Children under 2 years of age: Consult a doctor.

(iv) For products containing camphor identified in § 341.14(b)(1) for steam inhalation use. The product contains 6.2 percent camphor. “[bullet] see important warnings under ‘When using this product’ ” [appears as the first statement under the heading “Directions” and is highlighted in bold type] [bullet] adults and children 2 years and older: (select one of the following, as appropriate: For products formulated to be added directly to cold water inside a hot steam vaporizer. [bullet] use 1 tablespoonful of solution for each quart of water or 1 1/2 teaspoonsful of solution for each pint of water [bullet] add solution directly to cold water only in a hot steam vaporizer [bullet] follow manufacturer's directions for using vaporizer or For products formulated to be placed in the medication chamber of a hot steam vaporizer. [bullet] place water in the vaporizer and follow manufacturer's directions for using vaporizer [bullet] place solution in the medication chamber only) [bullet] breathe in the medicated vapors [bullet] use up to three times daily or as directed by a doctor [bullet] children under 2 years of age: Ask a doctor.

(v) For products containing menthol identified in § 341.14(b)(2) for steam inhalation use. The product contains 3.2 percent menthol. “[bullet] see important warnings under ‘When using this product’ ”[appears as the first statement under the heading “Directions” and is highlighted in bold type] [bullet] adults and children 2 years and older: (select one of the following, as appropriate: For products formulated to be added directly to cold water inside a hot steam vaporizer. [bullet] use 1 tablespoonful of solution for each quart of water or 1 1/2 teaspoonsful of solution for each pint of water [bullet] add solution directly to cold water only in a hot steam vaporizer [bullet] follow manufacturer's directions for using vaporizer or For products formulated to be placed in the medication chamber of a hot steam vaporizer. [bullet] place water in the vaporizer and follow manufacturer's directions for using vaporizer [bullet] place solution in the medication chamber only) [bullet] breathe in the medicated vapors [bullet] use up to three times daily or as directed by a doctor [bullet] children under 2 years of age: Ask a doctor.

(e) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this section.

(f) Exemption from the general accidental overdose warning. The labeling for antitussive drug products containing the active ingredient identified in § 341.14(b)(2) marketed in accordance with § 341.74(d)(2)(iii) is exempt from the requirement in § 330.1(g) of this chapter that the labeling bear the general warning statement “In case of accidental overdose, seek professional assistance or contact a poison control center immediately.” The labeling must continue to bear the first part of the general warning in § 330.1(g) of this chapter, which states, “Keep this and all drugs out of the reach of children.”

(a) Statement of identity. The labeling of the product contains the established name of the drug, if any, and identifies the product as a “bronchodilator.”

(b) Indication. The labeling of the product states the following under the heading “Use”: “for temporary relief of mild symptoms of intermittent asthma: [bullet] 1 wheezing [bullet] tightness of chest [bullet] shortness of breath”. Other truthful and nonmisleading statements, describing only the indication for use that has been established and listed in this paragraph (b) may also be used, as provided in § 330.1(c)(2) of this chapter, subject to the provisions of section 502 of the Federal Food, Drug, and Cosmetic Act relating to misbranding and the prohibition in section 301(d) of the Federal Food, Drug, and Cosmetic Act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the Federal Food, Drug, and Cosmetic Act.

(c) Warnings. The labeling of the product contains the following warnings under the heading “Warnings”:

(1) The following statements shall appear after the subheading “Do not use” [in bold type]:

(i) “[Bullet] unless a doctor said you have asthma”.

(ii) “[Bullet] if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs taken for depression, psychiatric or emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.”

(2) The following information shall appear after the subheading “Ask a doctor before use if you have” [in bold type]: “[bullet] ever been hospitalized for asthma [bullet] heart disease [bullet] high blood pressure [bullet] diabetes [bullet] thyroid disease [bullet] seizures [bullet] narrow angle glaucoma [bullet] a psychiatric or emotional condition [bullet] trouble urinating due to an enlarged prostate gland”.

(3) The following information shall appear after the subheading “Ask a doctor or pharmacist before use if you are” [in bold type]:

(i) “[Bullet] taking prescription drugs for asthma, obesity, weight control, depression, or psychiatric or emotional conditions”.

(ii) “[Bullet] taking any drug that contains phenylephrine, pseudoephedrine, ephedrine, or caffeine (such as for allergy, cough-cold, or pain)”.

(4) The following information shall appear after the subheading “When using this product” [in bold type]:

(i) “[Bullet] your blood pressure or heart rate may go up. This could increase your risk of heart attack or stroke, which may cause death.” [in bold type]

(ii) “[Bullet] your risk of heart attack or stroke increases if you: [Bullet] have a history of high blood pressure or heart disease [Bullet] take this product more frequently or take more than the recommended dose”. [in bold type]

(iii) “[Bullet] avoid foods or beverages that contain caffeine”.

(iv) “[Bullet] avoid dietary supplements containing ingredients reported or claimed to have a stimulant effect”.

(5) For products containing ephedrine, ephedrine hydrochloride, ephedrine sulfate, or racephedrine hydrochloride identified in § 341.16(a), (b), (c), and (f). (i) The following information shall appear after the subheading “Asthma alert: Because asthma may be life threatening, see a doctor if you” [in bold type]:

(A) “[Bullet] are not better in 60 minutes”.

(B) “[Bullet] get worse”.

(C) “[Bullet] need more than [insert total number of dosage units that equals 150 milligrams] in 24 hours”.

(D) “[Bullet] use more than [insert total number of dosage units that equals 100 milligrams] in 24 hours for 3 or more days a week”.

(E) “[Bullet] have more than 2 asthma attacks in a week”.

(F) “These may be signs that your asthma is getting worse.”

(G) “[Bullet] This product will not give you asthma relief as quickly as an inhaled bronchodilator.”

(ii) This “Asthma alert” shall appear on any labeling that contains warnings and shall be the first warning statement under the heading “Warnings”.

(6) For products containing epinephrine, epinephrine bitartrate, or racepinephrine hydrochloride identified in § 341.16(d), (e), and (g). (i) The following information shall appear after the subheading “Asthma alert: Because asthma may be life threatening, see a doctor if you” [in bold type]:

(A) “[Bullet] are not better in 20 minutes”.

(B) “[Bullet] get worse”.

(C) “[Bullet] need more than 12 inhalations in 24 hours”.

(D) “[Bullet] use more than 9 inhalations in 24 hours for 3 or more days a week”.

(E) “[Bullet] have more than 2 asthma attacks in a week”.

(F) “These may be signs that your asthma is getting worse.”

(ii) This “Asthma alert” shall appear on any labeling that contains warnings and shall be the first warning statement under the heading “Warnings.”

(iii) For products intended for use in a hand-held rubber bulb nebulizer. The following statement shall also appear after the subheading “Do not use” along with the other information in paragraph (c)(1) of this section: “[bullet] if product is brown in color or cloudy”.

(7) The following information shall appear after the subheading “Stop use and ask a doctor if” [in bold type]:

(i) “[Bullet] your asthma is getting worse (see Asthma alert)”.

(ii) “[Bullet] you have difficulty sleeping”.

(iii) “[Bullet] you have a rapid heart beat”.

(iv) “[Bullet] you have tremors, nervousness, or seizure”.

(d) Directions. The labeling of the product contains the following information under the heading “Directions”:

(1) For products containing ephedrine, ephedrine hydrochloride, ephedrine sulfate, or racephedrine hydrochloride identified in § 341.16(a), (b), (c), and (f): (i) “[Bullet] do not take more than directed” [sentence appears as first bulleted statement under “Directions” and in bold type]

(ii) “[Bullet] adults and children 12 years of age and over: oral dose is 12.5 to 25 milligrams every 4 hours as needed. Do not take more than 150 milligrams in 24 hours”.

(iii) “[Bullet] children under 12 years of age: ask a doctor”.

(2) For products containing epinephrine, epinephrine bitartrate, and racepinephrine hydrochloride identified in § 341.16(d), (e), and (g) for use in a hand-held rubber bulb nebulizer. The ingredient is used in an aqueous solution at a concentration equivalent to 1-percent epinephrine:

(i) “[Bullet] do not use more than directed” [appears as first bulleted statement under “Directions” and in bold type].

(ii) “[Bullet] adults and children 4 years of age and over: 1 to 3 inhalations not more often than every 3 hours. Do not use more than 12 inhalations in 24 hours. The use of this product by children should be supervised by an adult.”

(iii) “[Bullet] children under 4 years of age: ask a doctor”.

(a) Statement of identity. The labeling of the product contains the established name of the drug, if any, and identifies the product as an “expectorant.”

(b) Indications. The labeling of the product states, under the heading “Indications,” the following: “Helps loosen phlegm (mucus) and thin bronchial secretions to” (select one or more of the following: “rid the bronchial passageways of bothersome mucus,” “drain bronchial tubes,” and “make coughs more productive”). Other truthful and nonmisleading statements, describing only the indications for use that have been established and listed in this paragraph (b), may also be used, as provided in § 330.1(c)(2) of this chapter, subject to the provisions of section 502 of the act relating to misbranding and the prohibition in section 301(d) of the act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the act.

(c) Warnings. The labeling of the product contains the following warnings, under the heading “Warnings”:

(1) “A persistent cough may be a sign of a serious condition. If cough persists for more than 1 week, tends to recur, or is accompanied by a fever, rash, or persistent headache, consult a doctor.”

(2) For expectorant drug products labeled for adults or for adults and children under 12 years of age. “Do not take this product for persistent or chronic cough such as occurs with smoking, asthma, chronic bronchitis, or emphysema, or where cough is accompanied by excessive phlegm (mucus) unless directed by a doctor.”

(3) For expectorant drug products labeled only for children under 12 years of age. “Do not give this product for persistent or chronic cough such as occurs with asthma or if cough is accompanied by excessive phlegm (mucus) unless directed by a doctor.”

(d) Directions. The labeling of the product contains the following information under the heading “Directions” for products containing guaifenesin identified in § 341.18: Adults and children 12 years of age and over: oral dosage is 200 to 400 milligrams every 4 hours not to exceed 2,400 milligrams in 24 hours. Children 6 to under 12 years of age: oral dosage is 100 to 200 milligrams every 4 hours not to exceed 1,200 milligrams in 24 hours. Children 2 to under 6 years of age: oral dosage is 50 to 100 milligrams every 4 hours not to exceed 600 milligrams in 24 hours. Children under 2 years of age: consult a doctor.

(e) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this section.

(a) Statement of identity. The labeling of the product contains the established name of the drug, if any, and identifies the product as a “nasal decongestant.”

(b) Indications. The labeling of the product states, under the heading “Indications,” the phrase listed in paragraph (b)(1) of this section, as appropriate, and may contain any additional phrases listed in paragraph (b)(2) of this section. Other truthful and nonmisleading statements, describing only the indications for use that have been established and listed in paragraphs (b)(1) and (b)(2) of this section, may also be used, as provided in § 330.1(c)(2) of this chapter, subject to the provisions of section 502 of the Federal Food, Drug, and Cosmetic Act (the act) relating to misbranding and the prohibition in section 301(d) of the act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the act.

(1) (Select one of the following: “For the temporary relief of nasal congestion” or “Temporarily relieves nasal congestion”) (which may be followed by any of the following in paragraphs (b)(1) (i), (ii), and (iii) of this section):

(i) “due to” (select one of the following: “the common cold” or “a cold”).

(ii) “due to” (select one of the following: “hay fever,” “hay fever (allergic rhinitis),” “hay fever or other upper respiratory allergies,” or “hay fever or other upper respiratory allergies (allergic rhinitis)”).

(2) In addition to the information identified in paragraph (b)(1) of this section, the labeling of the product may contain any (one or more) of the following statements:

(i) (Select one of the following: “For the temporary relief of” or “Temporarily relieves”) (select one of the following: “stuffy nose,” “stopped up nose,” “nasal stuffiness,” or “clogged up nose.”)

(ii) (Select one of the following: “Reduces swelling of,” “Decongests,” or “Helps clear”) “nasal passages; shrinks swollen membranes.”

(iii) “Temporarily restores freer breathing through the nose.”

(iv) “Helps decongest sinus openings and passages; temporarily relieves sinus congestion and pressure.”

(v) “Promotes nasal and/or sinus drainage; temporarily relieves sinus congestion and pressure.”

(c) Warnings. The labeling of the product contains the following warnings under the heading “Warnings”:

(1) Oral nasal decongestants - (i) For products containing phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, or phenylephrine bitartrate identified in § 341.20 (a)(1) through (a)(4) when labeled for adults. (A) “Do not exceed recommended dosage. [first sentence in boldface type] If nervousness, dizziness, or sleeplessness occur, discontinue use and consult a doctor.”

(B) “If symptoms do not improve within 7 days or are accompanied by fever, consult a doctor.”

(C) “Do not take this product if you have heart disease, high blood pressure, thyroid disease, diabetes, or difficulty in urination due to enlargement of the prostate gland unless directed by a doctor.”

(D) Drug interaction precaution. “Do not use if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.”

(ii) For products containing phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, or phenylephrine bitartrate identified in § 341.20 (a)(1) through (a)(4) when labeled for children under 12 years of age. (A) “Do not exceed recommended dosage. [first sentence in boldface type] If nervousness, dizziness, or sleeplessness occur, discontinue use and consult a doctor.”

(B) “If symptoms do not improve within 7 days or are accompanied by fever, consult a doctor.”

(C) “Do not give this product to a child who has heart disease, high blood pressure, thyroid disease, or diabetes unless directed by a doctor.”

(D) Drug interaction precaution. “Do not use in a child who is taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your child's prescription drug contains an MAOI, ask a doctor or pharmacist before giving this product.”

(iii) For oral nasal decongestant products labeled for both adults and children under 12 years of age. The labeling of the product contains the warnings identified in paragraph (c)(1)(i) of this section.

(2) Topical nasal decongestants - (i) For products containing any topical nasal decongestant identified in § 341.20(b) when labeled for adults. (A) “Do not exceed recommended dosage.” [sentence in boldface type]

(B) “This product may cause temporary discomfort such as burning, stinging, sneezing, or an increase in nasal discharge.”

(C) “The use of this container by more than one person may spread infection.”