(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.