115. FDA Regulations for Treatment or Emergency Uses of Investigational Drugs
Updated July 26, 2021
The Food and Drug Administration's Expanded Access Program allows for drugs that are investigational (i.e., not FDA approved) to be used for treatment use outside of a clinical trial. Sometimes this is referred to as compassionate use. Treatment use is not considered a clinical investigation. However, FDA submission and IRB review are necessary. The criteria for Expanded Access are largely determined by (1) the seriousness of a patient's condition, (2) other available FDA-approved treatment options, (3) patient population size needing treatment, and (4) drug status.
FDA allows flexibility in the expanded use of investigational drugs for treatment for persons with serious or life-threatening diseases or conditions (Subpart I) and for persons with life-threatening and severely debilitating illnesses (Subpart E). See IRB policy on overview of FDA regulations, information sheets and guidance for a listing of relevant references, including the FDA Information Sheet Guidance for IRBs and Clinical Investigators: Emergency Use of an Investigational Drug or Biologic.
IMPORTANT NOTE: Currently, neither the University nor its Affiliate sites actively conduct or manage planned emergency research; therefore, the University does not have policies in place for such research. Investigators interested in conducting planned emergency research must contact Research Integrity to discuss the possibility of engaging in this type of research. As warranted, the IRB will develop and publish policy for planned emergency research.
Expanded Access (Treatment) Uses of Investigational Drugs
Subpart I of FDA regulations describes the requirements for the use of investigational and approved drugs where availability is limited by a risk evaluation and mitigation strategy when the primary purpose of the use is to diagnose, monitor, or treat a patient's disease or condition (i.e., expanded access uses). By authorizing such expanded access uses, FDA aims to facilitate the availability of such drugs to patients with serious or life-threatening diseases or conditions when there is no comparable or satisfactory alternative therapy.
General Requirements for Expanded Access Uses
Step 1: Evaluate the seriousness of the patient's or patients' condition using the FDA's criteria
All the following criteria must be met, as described in 21 CFR 312.305(a):
- 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;
- 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
- 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 Step development of the expanded access use.
Step 2: Determine the patient population size that requires treatment use and evaluate the drug status using the FDA's criteria
Single Patient Emergency Use
- Definition: 21CFR 56.102 (d); the patient is in an immediately life-threatening situation
- Criteria: 21 CFR 312.310 (a)
- Drug status: The patient cannot obtain the drug under another IND or protocol (21 CFR 312.310 (a)).
Single Patient Non-Emergency Use
- Criteria: 21 CFR 312.310 (a); the patient has a serious condition and is not in an immediately life-threatening situation
- Drug status: The patient cannot obtain the drug under another IND or protocol (21 CFR 312.310 (a)).
Intermediate-Size Patient Population
- Definition: 21 CFR 312.315; the investigational use of a drug for the treatment of a patient population smaller than that typical of a treatment IND or treatment protocol
- Criteria: 21 CFR 312.315(b)
- Drug status: 21 CFR 312.315(a)
Large Patient Population, i.e., Treatment IND or Treatment Protocol
- Criteria and drug status: 21 CFR 312.320(a)
An IND is required for all Expanded Access. An individual physician may apply to the FDA for an IND or may function under an existing IND held by another physician or the drug manufacturer. Some IND holders will not allow for Expanded Access to be amended to their existing IND; in this case, the physician must apply for a new IND. Consult with the IND holder to determine if an existing IND can be amended.
Step 4: Submit an Expanded Access submission to the FDA
Use the instructions provided in 21 CFR 312.305(b) for the Expanded Access submission. These instructions must be followed for both new IND submissions and amendment submissions to existing INDs.
Step 5: Submit an application for IRB Review
The application must include the following:
- IND documentation from the FDA/drug manufacturer
- Drug information via an Investigator's Brochure or a package insert
- An informed consent document
In non-emergency situations, treatment may not begin until the IRB has approved the Expanded Access protocol.
Step 6: After initiating the treatment, ensure that all case histories and adverse events are properly recorded and reported
21 CFR 312.300 describes the safeguards and records that must be in place to ensure appropriate monitoring of patient safety. The requirements are different for the type of Expanded Access approved, based on patient population size. Treating physicians should ensure they are familiar with these requirements and can maintain appropriate records and oversight for Expanded Access protocols.
Criteria for FDA Exceptions from General Requirements for Informed Consent for Emergency Use
FDA regulations describe exceptions to general requirements for informed consent. The following two exceptions are relevant to emergency uses of test articles. The required documentation for both requirements must be submitted to the IRB within 5 working days after the use of the test article.
FDA Exception per §50.23, item (a): Informed consent is deemed feasible unless before use of the test article, both the investigator and a physician who is not otherwise participating in the clinical investigation certify (in writing) all the following are true:
- The human participant is confronted by a life-threatening situation necessitating the use of the test article.
- Informed consent cannot be obtained from the participant because of an inability to communicate with, or obtain legally effective consent from, the subject.
- Time is not sufficient to obtain consent from the participant's legal representative.
- No alternative method of approved or generally recognized therapy is available that provides an equal or greater likelihood of saving the life of the participant.
FDA Exception per §50.23, item (b): If it is the opinion of a clinical investigator that immediate use of the test article is required to preserve the life of the subject, and time is not sufficient to obtain the determination of an independent physician as described above prior to using the test article, the article may be used if within 5 working days after the use of the article, the clinical investigator's determinations are reviewed and evaluated in writing by a physician who is not participating in the clinical investigation.
FDA Exemption from Requirement for Prior IRB Review and Approval for Emergency Use
The need for an investigational drug or biologic may arise in an emergency situation that does not allow time for submission of an IND. The FDA can authorize shipment of the test article (drug, biologic or device) in advance of the IND submission. FDA regulations describe exceptions to general requirements for informed consent. The FDA requirements and regulations for an emergency IND for the use of an investigational drug or biologic are slightly different than for an emergency use of a device. In both situations, FDA must conclude that the use is for a "serious or life-threatening disease or condition and there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition."
On October 3, 2017, the FDA issued new guidance regarding individual patient expanded access INDs. The new pathway still involves a submission to the IRB, but the IRB can now provide concurrence by the chair or another IRB member (rather than review and approval by the convened board). To use this pathway, the sponsor-investigator needs to request 'Authorization to Use Alternative IRB Review Procedures' from the FDA. This can be done either on form FDA 3926 (section 10.b.), or, if submitting using a 1571, by a separate attachment to the FDA. Note: This pathway is only available when a physician sponsor-investigator will hold the IND; it is not available when the pharmaceutical sponsor will hold the IND.
The required documentation must be submitted to the IRB within 5 working days after the use of the test article. FDA regulations do not provide for expedited IRB approval in emergency situations. There are three possible ways to proceed:
- the IRB can provide concurrence by the chair or another IRB member for the emergency use (see above), provided the FDA has granted a waiver under §56.105 of the requirements in § 56.108(c), which relate to IRB review by the convened board;
- the IRB must convene and give full board approval for the emergency use (e.g., if the sponsor is a pharmaceutical company and not a physician sponsor-investigator, or the FDA has concluded that a waiver of the requirement for review and approval by a convened board is not appropriate); or,
- if the conditions of 21 CFR 56.102(d) are met (see information box to the right) and it is not possible to convene a quorum/chair concurrence within the time available, the use may proceed without any IRB approval/chair concurrence. This latter option is also known as an Emergency Exemption from prospective IRB review.
FDA regulations at §56.104, item (c) exempt emergency use of an FDA-regulated test article from requirements for prior IRB review and approval if:
- the use meets all requirements for the expanded access use (see above); and
- the physician using the test article reports the emergency use to the University IRB within 5 working days.
NOTE: Any subsequent use of the test article at the University is subject to IRB review.
Investigator and Sponsor Responsibilities for Expanded Access Uses
Investigators’ and sponsors' responsibilities (Subpart D of FDA regulations) apply as follows to the extent the requirements are relevant to the expanded access use:
- A licensed physician who administers an investigational drug for an expanded access use is considered an investigator (i.e., physician-investigator) and must comply with the responsibilities for investigators as itemized below.
- An individual or entity that submits an expanded access IND or protocol under Subpart I is considered a sponsor and must comply with the responsibilities for sponsors as itemized below.
- A licensed physician who submits an IND for expanded access use under is considered a sponsor-investigator and must comply with the responsibilities for sponsors and investigators.
Responsibilities of Physician-Investigators
Physician-investigators must obtain prior IRB approval for any expanded access use unless following three conditions are true:
- The use of the test article is for a human subject in a life-threatening situation, no standard acceptable treatment is available, and time is insufficient to obtain prior IRB approval (see definition of "emergency use" at §56.102, item (d)).
- The emergency use is reported to the IRB within 5 working days (per §56.104, item (c)).
- Any subsequent use of the test article at the institution is subject to prior IRB review.
Physician-investigators must obtain legally effective informed consent as required by the IRB (unless an FDA exception for informed consent at CFR 50.23 (a) or (b) applies) (as described above).
Physician-investigators must report adverse drug events to the sponsor.
Physician-investigators must maintain and retain accurate records that include a case history of the patient and the disposition of the drug as required.
Responsibilities of Sponsors
Sponsor responsibilities are beyond the scope of this policy. Information about sponsor (and investigator) responsibilities are codified at §312 Subpart D.
Investigator-Sponsor Requirements for Expanded Access Uses
- ensure physician-investigators are qualified to administer the investigational drug for the expanded access use;
- provide the physician-investigator with the information needed to minimize risk and maximize the potential benefits of the investigational drug (e.g., Investigator's Brochure);
- maintain an effective IND for the expanded access use;
- maintain and retain adequate drug disposition records in accordance with FDA and institutional requirements; and
- comply with FDA requirements for submission of IND safety and annual reports.
- communicate to the IRB within 10 work days using the Unanticipated Problem form in IRBNet any problem (including any adverse) that occurred as a result of the use of the drug/device.
Types of Expanded Access Uses of Investigational Drugs
Single Patient Treatment Use of an Investigational Drug by a Licensed Physician
FDA regulations at §312.310 specify the two criteria under which a licensed physician may administer or dispense an investigational drug for treatment use, including emergency use, for an individual patient.
- A licensed physician determined the probable risk to the person from the investigational drug is not greater than the probable risk from the disease or condition.
- FDA determined that the patient cannot obtain the drug under another IND or protocol.
Requires prospective IRB approval and informed consent unless the use is for emergency treatment and the relevant conditions have been met for expanded, emergency use and/or exception from general requirements for informed consent.
NOTE: The IRB may determine it would be inappropriate to deny emergency treatment to a second individual if the only obstacle is that the IRB has not had sufficient time to convene a meeting to review this use of the test drug.
If the drug is the subject of an existing IND, the expanded access submission may be made by the sponsor, or a licensed physician as follows:
- The sponsor amends an existing IND to include a protocol for expanded access for an individual patient.
- A licensed physician submitting an expanded access obtains permission from the sponsor for FDA to refer to any information in the IND that would be needed to support the expanded access request and provides any other required information not contained in the IND (e.g., information specific to the individual patient).
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. The licensed physician or sponsor must provide FDA with an expanded access submission within 15 business days of FDA's authorization of the use.
Treatment use for a single patient is generally limited to a single course of therapy for a specified duration unless FDA authorizes multiple courses or chronic therapy.
At the end 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.
FDA may require the sponsor to monitor expanded access uses of extended duration.
NOTE: Under DHHS regulations, emergency use of an investigational drug is not considered research. Patients receiving the drug are not considered research participants and the outcome of emergency use of an investigational drug cannot be included in any report of a research activity subject to DHHS regulations. Under FDA regulations, the emergency use of an investigational drug is a clinical investigation, the patient is a participant, and the FDA may require data from an emergency use to be reported in a marketing application.
Treatment Use of an Investigational Drug by a Licensed Physician in an Intermediate-sized Population
Under specific conditions (see §312.315), FDA allows use of an investigational drug for the treatment of more than one patient when the population is smaller than that typical of a treatment IND or treatment protocol (as described below). For example, when a significant number of requests arise for individual patient expanded access to an investigational drug for the same use, FDA may ask a sponsor to consolidate the expanded access uses.
Requires prospective IRB approval and informed consent.
Treatment uses for intermediate populations may arise when a drug:
- is not being developed (e.g., rareness of disease/condition restricts recruitment);
- is being studied in a clinical trial but patients requesting use of the drug are unable to participate in the trial; or
- is approved but is no longer marketed for safety reasons or is otherwise unavailable through marketing.
In addition to the criteria for all expanded uses (above), expanded uses in intermediate-sized populations require there is:
- enough evidence that the drug is safe at the dose and duration proposed for the 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
- 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.
(See §312.315 for more information about submission requirements, and safeguards for this type of expanded access use.)
Wide-spread Treatment Use of an Investigational Drug by a Licensed Physician
In addition to provisions for expanded access use for treatment of an individual patient and intermediate-sized populations, FDA regulations at §312.83 and §312.320 allow for wide-spread treatment use of an investigational drug via a treatment protocol or Treatment IND.
Requires prospective IRB approval and informed consent.
Requirements for FDA Approval of a Treatment IND
- Trial status. The drug must be under investigation in a controlled clinical trial under an IND designed to support a marketing application for the expanded access use or all clinical trials of the drug have been completed.
- Marketing status. The sponsor of the IND supporting marketing must be actively pursuing marketing approval of the drug for the expanded access use with due diligence.
- Evidence. Sufficient clinical evidence must be available to provide a reasonable basis for concluding the investigational drug may be effective for the expanded access use without exposing patients to an unreasonable and significant risk of illness or injury.
The sponsor is responsible for monitoring the treatment protocol to ensure that licensed physicians comply with the protocol and the regulations applicable to investigators.
Open Label Protocol or Open Protocol IND
When a controlled trial has ended, treatment may be continued to allow participants to continue to receive the benefits of the investigational drug until marketing approval is obtained. These are considered uncontrolled studies that are carried out to obtain additional safety data (Phase 3 studies).
Requires prospective IRB approval and informed consent.
Group C Treatment IND
FDA established the "Group C" treatment IND as an agreement between FDA and the National Cancer Institute (NCI). The Group C program allows distribution of investigational agents to oncologists for the treatment of cancer under protocols outside the controlled clinical trial. Group C drugs are distributed only by the National Institutes of Health under NCI protocols.
Treatment is the primary objective. Patients treated under Group C guidelines are not part of a clinical trial. The University likely would accept the FDA waiver from the requirement for approval for Group C drugs but recognizes the University IRB may opt to review the project under its policies/procedures. Investigators wishing to provide treatment under a Group C IND must submit the "Guideline Protocol" for the use of the Group C drug and the FDA-approved informed consent document.
Through its Parallel Track policy, FDA permits wider access to promising new drugs for AIDS/HIV related diseases under a separate "expanded access" protocol that "parallels" the controlled clinical trials that are essential to establish the safety and effectiveness of new drugs. It provides an administrative system that expands the availability of drugs for treating AIDS/HIV.
These studies require prospective IRB review and informed consent.
Emergency Use IND
The need for an investigational drug may arise in an emergency situation that does not allow time for submission of an IND in the usual manner. In such cases, FDA may authorize shipment of the drug for a specified use with the requirement for the sponsor to file an appropriate application as soon as practicable.
Prospective IRB review is required unless:
- all the conditions for "emergency use" described above and at §56.102, (d) are met; and
- all the conditions are met for an FDA exemption at §56.104, (c).
FDA regulations require that any subsequent use of the investigational product at the institution have prospective IRB review and approval.
FDA and the University IRB acknowledges, however, that it would be inappropriate to deny emergency treatment to a second individual if the only obstacle is that the IRB has not had sufficient time to convene a meeting to review the issue.
Informed consent must be obtained unless the conditions for exception from general requirements for informed consent at §50.23 are met.
Drugs for Treatment Uses for Persons with Life-Threatening and Severely Debilitating Illnesses
Subpart E of FDA regulations for Investigational New Drug Applications (IND), describes procedures 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. (See life-threatening and severely debilitating in the HRPP online Policy Manual Definitions.) The decision to allow treatment or expanded uses of drugs for life-threatening and severely debilitating illnesses for a single participant or a group of participants is based on the following considerations:
- When no satisfactory alternative treatment exists, participants are generally willing to accept greater risks from test articles that may treat life-threatening and debilitating illnesses.
- Benefits of a drug should be evaluated considering the severity of the disease being treated.
See Subpart E for the scope, and procedures and requirements (including requirement for early consultation of sponsor with FDA) for drugs intended to treat life-threatening and severely debilitating illnesses. Contact Research Integrity for information about submitting a request to use an investigational drug for a person with life-threatening and severely debilitating illnesses.
- How to submit an expanded access request (form) provides step-by-step instructions for expanded access submissions for investigational drugs and biologics
- Form FDA 3926 and instructions for requests for individual patient expanded access to investigational drugs and biologics, including those for emergency use. It can also be used for certain submissions to FDA after the initial request is filed. (You may need to open this form in a different browser (Internet Explorer) or save the form to your desktop.)
- Quick guide on how to complete Form FDA 1571 and 1572.
- Forms FDA 1571 and 1572 are required for other expanded access submissions (e.g., intermediate access or treatment INDs) and for IND submissions by industry.
- Database for Registered IRBs