Expanded Access to Unapproved Drugs or Biologics
The Food and Drug Administration (FDA) allows for two options for treating patients with an unapproved drug, biologic or test article outside of a clinical trial.
One option is Expanded Access.
The other option is Right to Try.
- The IRB must prospectively approve Expanded Access and Right to Try requests.
- The only exception is Single Patient - Emergency Use, a type of Expanded Access.
- In all cases, a UCI IRB submission is required for prospective review or, in the case of Emergency Use, notification.
Expanded Access Overview
Under FDA regulations (21 CFR 312.300), expanded access allows for the use of unapproved drugs and biologics outside of a clinical trial for patients with serious diseases or conditions when there is no satisfactory alternative therapy to treat the patient’s disease or condition. While expanded access is not considered a clinical investigation, FDA submission and IRB review are required.
Key Definitions:
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.
Criteria for Expanded Access of an Unapproved Drug, Biologic or Test Article
The FDA must determine that:
- 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 development of the expanded access use.
Three Types of Expanded Access: Single Patient, Intermediate and Large Patient Group
Under FDA’s current regulations, there are three categories of expanded access as shown in the diagram below.
Expanded Access - Single Patient (Non-Emergency Use)
In addition to the criteria for all expanded access uses, the following must also be met:
- 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
- FDA must determine that the patient cannot obtain the drug under another IND or protocol.
If the drug is the subject of an existing IND, the expanded access IND submission to the FDA may be made by the sponsor or by a licensed physician.
IRB submission of Expanded Access - Single Patient (Non-Emergency Use)
To streamline the submission process for individual patient expanded access INDs, the FDA has developed Form FDA 3926. In lieu of approval by a convened IRB, FDA guidance allows for review and approval of Form FDA 3926 by an IRB chair or by a designated IRB member, before the treatment use begins.
NOTE: Box 10b MUST be checked; otherwise the request will have to wait for convened board review.
Physicians may use this form to request expanded access to an investigational drug outside of a clinical investigation, or to an approved drug where availability is limited by a risk evaluation and mitigation strategy (REMS). FDA generally intends to accept submission of a completed Form FDA 3926 to comply with the IND submission requirements. Form FDA 3926 may also be used for certain follow-up submissions to an individual patient expanded access IND. The FDA provides guidance on How to Request Single Patient Expanded Access.
Expanded Access - Single Patient (Emergency Use)
In an emergency situation that requires the patient to be treated before a written submission can be made, the request to use the investigational drug for individual patient expanded access may be made by telephone (or other rapid means of communication) to the appropriate FDA review division. Authorization of the emergency use may be given by an FDA official by telephone, provided the physician explains how the expanded access use will meet the FDA requirements of 21 CFR 312.305 and 312.310 and agrees to submit an expanded access application within 15 business days of FDA’s initial authorization of the expanded access use.
According to FDA regulations (21 CFR 56.102(d)), emergency use is the use of a test article on a human subject in a life-threatening situation in which no standard acceptable treatment is available, and in which there is not sufficient time to obtain IRB approval. Life-threatening, for the purposes of section 56.102(d), includes the scope of both life-threatening and severely debilitating, as defined below.
- Life-threatening means diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted and diseases or conditions with potentially fatal outcomes, where the end point of clinical trial analysis is survival. The criteria for life-threatening do not require the condition to be immediately life-threatening or to immediately result in death. Rather, the patients must be in a life-threatening situation requiring intervention before review at a convened meeting of the IRB is feasible.
- Severely debilitating means diseases or conditions that cause major irreversible morbidity. Examples of severely debilitating conditions include blindness, loss of arm, leg, hand or foot, loss of hearing, paralysis or stroke.
The FDA emergency use provision is an exemption from prospective IRB review and approval for one emergency use (i.e., one use refers to one treatment which may include multiple cycles or applications, as applicable) of a drug or biologic. FDA regulations require that any subsequent use of the investigational product at the institution have prospective IRB review and approval. However, in guidance documents, FDA acknowledges 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 protocol.
IRB Submission of Expanded Access - Single Patient (Emergency Use)
The FDA provides an Emergency IND Timeline for Submission of Single Patient Application for Emergency Use. The UCI IRB requests that, when possible, the IRB be notified in advance of the proposed emergency use of an unapproved drug or biologic by completing the KRP Application for Emergency Use. There are two parts to this application. First, a new protocol application in KRP must be completed prior to the emergency use of the unapproved drug or biologic. The IRB Chair or Vice Chair will review and acknowledge the emergency use. Secondly, submit an amendment for the same protocol with a follow up to the IRB within five business days after the emergency use. Note that acknowledgment of the emergency use by the IRB Chair or Vice Chair should not be construed as IRB approval. IRBs are informed of Emergency Use situations during convened IRB meetings.
In the event of a waiver of informed consent for an emergency use, the IRB Chair or Vice Chair will confirm that both the physician holding the emergency IND and a physician who is not otherwise participating in the emergency use have certified in writing all of the following:
- the patient is confronted by a life-threatening situation necessitating use of the test article;
- informed consent cannot be obtained because of an inability to communicate with, or obtain legally effective consent from, the patient;
- time is not sufficient to obtain consent from the patient’s legal representative;
- no alternative method of approved or generally recognized therapy is available that provides an equal or greater likelihood of saving the patient’s life;
If, in the physician’s opinion, there is not sufficient time to obtain an independent physician’s determination that the four criteria are met, the physician holding the emergency IND should make the determination and subsequently obtain (i.e., within five business days) a review of his/her determination by a physician not participating in the emergency treatment. An independent physician's attestation form is attached to the IRB forms page for the independent physician to complete.
Other Treating Physician Responsibilities:
- Consult with Clinical Trials Team in Sponsored Projects Administration to determine whether an agreement is necessary with the sponsor/manufacturer.
- Consult with UCI Health Research Revenue Integrity (RRI) to determine billing implications.
- Consult with Investigational Drug Services (IDS) pharmacy to determine drug requirements.
- Register the patient in OnCore, as determined by RRI.
Step by Step Instructions for Investigators: Emergency Use of a Test Article
- At any stage in the following process, for assistance in determining whether an emergency use of a test article in a life threatening situation meets the criteria for use, contact the UCI Human Research Protection staff at one of the following numbers (during business hours (M-F, 8-5)): IRB Administrators: 949-824-5622 or 949-824-2576.
- Check the List of Previous Emergency Uses of Test Articles at UCI.
- If the drug or biological product is not listed, contact the manufacturer to determine if the product can be made available (for one, specific patient) under the company’s IND; or if the company declines or cannot be reached, contact the FDA for an emergency IND. In either case, the appropriate division at FDA must be contacted to authorize the use.
- Prior to Emergency Use, complete and submit the IRB application for Emergency Use via KRP. Ensure to attach the required documents - Expanded Access Consent form (this will be used to consent the patient); Sponsor Letter of Authorization for the use of the IND (if applicable); FDA Authorization; and Form 3926 (if this was submitted to the FDA)
- If unable to obtain prospective informed consent from the patient, the investigator should prospectively confirm with the IRB Chair that the waiver of consent is appropriate. In addition, as part of completing the KRP New Protocol application for Emergency Use, if the investigator is unable to prospectively obtain informed consent, the investigator should obtain an Emergency Use Independent Physician Attestation and attach it to the application. A physician not involved in the care of the patient must confirm (via signature) that the criterion for a waiver of informed consent has been met. The current biomedical IRB Chairs are Dr. Tahseen Mozaffar and Dr. Kenneth Linden.
- Upon receipt of the KRP application of Emergency Use for the single patient, HRP Staff will notify the IRB (i.e., the IRB Chair or a designee not involved in the patient's care). The IRB will review the documentation to determine whether the circumstances will follow regulatory or legal requirements for use of a test article. Note: Clearance from UCIMC Health Services Administration may also be necessary.
- The IRB will monitor the emergency use of test articles at UCI to ensure that continued use does not occur (as this constitutes research which would require prospective IRB review and approval).
- Within five working days of the emergency use, the investigator must provide the IRB with follow-up information and documentation regarding the emergency use. This is a federal requirement. To fulfill this requirement, complete and submit an amendment in KRP to the existing Emergency Use KRP protocol application. Also, if not already done so, provide written verification of approval from the IND/IDE holder authorizing release of the test article. This may have been authorized verbally, but written confirmation should be provided.
- The IRB will review the Emergency use of the test article and the follow up report at a convened meeting to determine whether the circumstances follow regulatory requirements for the emergency use of a test article, consent was obtained in accordance with FDA regulations, or the circumstances met the exception to the requirement for consent.
- The investigator should maintain copies of all paperwork involved in the emergency use.
- There will be additional paperwork and report filing as required by sponsors, drug companies, and the FDA (such as follow up/ annual reporting requirements). This is the responsibility of the UCI investigator. The investigator should work with their sponsor and FDA contacts to determine their reporting responsibilities
Expanded Access for Intermediate Size Populations
FDA may permit an investigational drug to be used for treatment of a patient population smaller than that typical of a treatment IND or treatment protocol. In cases where FDA has received a significant number of requests for individual patient expanded access for the same use, a sponsor may be asked to consolidate expanded access under this category.
In addition to the criteria listed at the beginning of this section for all expanded access, the FDA must also determine that there is enough evidence that the drug is safe at the proposed dose and duration and there is at least preliminary evidence of effectiveness of the drug as a therapeutic option in the patient population. For more information about FDA requirements, please see 21 CFR 312.315.
Expanded Access for Large Patient Populations
Expanded access protocols for large patient populations are also referred to as treatment IND or treatment protocols. This category is used for widespread treatment use of an investigational drug. In addition to the criteria listed at the beginning of this section for all expanded access, the FDA must also determine: that the drug is being investigated in a controlled trial under an IND to support a marketing application for the expanded access, or all clinical trials of the drug have been completed; the sponsor is actively pursuing marketing for approval of the expanded access; and there is sufficient data supporting safety and effectiveness of the drug for the expanded access.
IRB Submission of Expanded Access - Intermediate and Large PatientPopulations
Expanded access protocols for intermediate and large patient populations must be submitted per usual IRB process and require full IRB review and approval under FDA regulations.