Expanded Access to Unapproved Drugs or Biologics

What is Expanded Access?

The Food and Drug Administration (FDA) allows for the following options when treating patients with an unapproved drug or biologic outside of a clinical trial:

Single Patient (Emergency Use, Non-Emergency Use)
Medium or Intermediate Population
Large Patient Group
Right to Try

Expanded access is for patients with an immediately life threatening condition or serious diseases or conditions where there is no satisfactory alternative therapy to treat their disease or condition.

This page focuses on drugs and biologics. Expanded access also applies to unapproved medical devices. Refer to this HRP page for information on devices.

Is prospective Institutional Review Board (IRB) approval required?

Yes! A convened IRB review is required with two exceptions:

Single patient (non-emergency use) may be reviewed by an IRB Chair or designee IRB Member with a completed FDA Form 3926
Emergency Use does not require prospective IRB approval

FDA Expanded Access Request Form

A web-based tool that enables physicians to complete, sign, and submit non-emergency Expanded Access (EA) requests to FDA

Use This Tool

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.

FDA Reference

Criteria for Expanded Access of an Unapproved Drug, Biological or Test Article Expanded Access - Single Patient (Non-Emergency Use) Expanded Access - Single Patient (Emergency Use) Expanded Access - Medium or Intermediate Populations Expanded Access - Large Populations Right to Try an Investigational Drug

Criteria for Expanded Access of an Unapproved Drug, Biological 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.

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.

IRB Submission Process:

Researchers should submit a new study application in ZOT IRB.
Complete PI WORKSHEET - Expanded Access
Also include a completed HRP-506 CONSENT - Expanded Access
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.

Expanded Access - Single Patient (Emergency 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.

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 Process Overview:

The FDA provides an Emergency IND Timeline for Submission of Single Patient Application for Emergency Use.

Aligning with the federal regulations, the UCI IRB does not require approval prior to emergency use. Some Principal Investigators (PI) may still want to submit an application for IRB Chair review. In those cases, the PI may submit an application in ZOT IRB via the Reportable New Information module.

The UCI IRB does require a follow up report within five business days after the emergency use. The PI must submit an application in ZOT IRB via the Reportable New Information module.

Informed consent of the patient or their legally authorized representative is required. Consent may be waived in the following situation.

Independent Physician Attestation:

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 their determination by a physician not participating in the emergency treatment.

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.

IRB Submission: Step by Step Instructions:

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 A Administrator India: 949-824-1082 or IRB B Administrator Cheree: 949-824-3711. Physicians may also reach out to the IRB Chairs. IRB A Chair: Tahseen Mozaffar, MD. IRB B Chair: Kenneth Linden, MD, PhD.
Contact the Manufacturer to Use IND: 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.
Contact the FDA for Approval: 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.
Optional Initial Submission to the IRB: The PI may submit an application in ZOT IRB via the Reportable New Information module. This is not required however if submitted, include the following. Note: All documents are available in the HRP Toolkit:
1. The PI Worksheet for Emergency Use: HRP-322 PI WORKSHEET - Emergency Use
2. An Expanded Access Consent form (this will be used to consent the patient regardless if IRB review occurs prospectively): HRP-506 CONSENT - Expanded Access
  1. If consent cannot be obtained provide the physician attestation.
3. Sponsor Letter of Authorization for the use of the IND (if applicable) and
4. FDA Authorization
If the investigator is unable to prospectively obtain informed consent, the investigator should obtain an Emergency Use Independent Physician Attestation. This is available in the PI Worksheet for Emergency Use: HRP-322 PI WORKSHEET - Emergency Use
Upon receipt of the IRB 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.
Required IRB Submission: Within five working days of the emergency use, the investigator must provide the IRB with follow-up information and documentation regarding the emergency use. The PI must submit an application in ZOT IRB via the Reportable New Information module.This is a federal requirement.
If an initial IRB submission was not made, provide all documents as noted in 4.1, 4.2, 4.3, 4.4 above. If an initial IRB submission was made, provide any requisite materials not already submitted.
The IRB will review the Emergency use of the test article and the follow up report at a Committee 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 Principal Investigator. The investigator should work with their sponsor and FDA contacts to determine their reporting responsibilities.

Expanded Access - Medium or Intermediate 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 protocols for intermediate patient populations must be submitted per usual IRB process and require full IRB review and approval under FDA regulations.

Expanded Access - Large 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.

Expanded access protocols for large patient populations must be submitted per usual IRB process and require Committee IRB review and approval under FDA regulations.

Right to Try an Investigational Drug

In May 2018, the Federal Right to Try (RTT) Act was signed into law, creating a federal framework for patients to access investigational new drugs and biologics outside of clinical trials and outside of the U.S. Food and Drug Administration’s (FDA) expanded access program. The federal law enables manufacturers and physicians to provide investigational drugs to eligible patients without risk of liability. It follows California’s passage of the State’s Right to Try Act, signed into law in 2016. Similar to the federal law, the California law enables manufacturers and physicians to provide investigational products to eligible patients without risk of liability under state law. The state law also prohibits California medical boards from taking disciplinary action against physicians.

Given the stricter California law requirements for using an investigational drug without FDA approval and the additional protection the California law affords to physicians regarding licensure, UCI will comply with California’s RTT law requirements.

Because the federal RTT law does not address the use of investigational devices UCI will not provide investigational devices to patients outside of the FDA’s expanded access program.

Both the federal and state RTT laws enable patients meeting certain criteria under each law to receive access to investigational test articles without FDA oversight. However, the laws differ in fundamental ways that should be considered before providing an investigational product to a patient without FDA authorization.

Federal Right to Try Act:

The Federal Right to Act enables a patient with a “life-threatening” disease or condition to access investigational drugs and biologics that have completed Phase 1 testing under an FDA-approved clinical trial and which are either being actively developed or produced by the manufacturer or not placed on clinical hold. Importantly, the federal law does not address the use of investigational devices.

In order to receive an investigational drug or biologic under the federal RTT Act, the patient must:

Have a life-threatening disease or condition;
Have exhausted treatment options, as certified by the physician;
Be unable to participate in a clinical trial involving the investigational drug, as certified by the physician; and
Have given his or her written informed consent (or consent of a legally authorized representative) to the treating physician regarding use of the investigational drug.

Use of an investigational drug under the RTT is exempt from FDA requirements for review and authorization, so long as the sponsor or manufacturer of the drug is in compliance with FDA requirements applicable to investigational drugs. Note that the law does not limit compliance to the specific investigational drug that is the subject of the use.

The RTT act does require sponsors and manufacturers who have made their investigational drugs available under RTT to annually report to the FDA the number of doses supplied, the number of patients treated, the uses for which the drug was made available, and any known serious adverse events. In turn, the FDA must make this information publicly available on its website.

Patients may be charged the direct costs of making the investigational drug available for their use. The federal RTT does incentivizes sponsors and manufacturers to make their investigational drugs available by protecting them against liability with respect to acts and omissions regarding the investigational drug. The Act also protects prescribers, dispensers, and other individuals from liability, unless the act or omission constitutes reckless or willful misconduct, gross negligence, or an international tort under state law. Finally, the Act expressly protects against liability to any person for not providing access to an investigational drug under the Act.

California Right to Try Act:

The California Right to Try (RTT) Act is similar to the federal Act, though there are notable differences.

In one respect, the California law is broader than the federal right to try law as it applies to use of investigational drugs, biologics and devices that have successfully completed an FDA-regulated Phase 1 trial and remain under active investigation by the FDA. The federal law does not include devices.

In most instances, the California law imposes more requirements to obtain access to an investigational drug outside of a clinical trial.

The state RTT limits access to patients with an “immediately life-threatening disease or condition”, whereas the federal law only requires patients have a “life-threatening disease or condition.” Thus, under state law, the patient must be in a stage of disease in which there is a reasonable likelihood death will occur in a matter of months.
The treating physician and a second consulting physician must both recommend that the patient receive the investigational product, attest to this recommendation, and attest that the patient meets the criteria of the state law.
Specific informed consent requirements must be met. Like the federal law, a surrogate may consent on behalf of the patient consistent with California law requirements. However, the consent form must contain the information from the California Health and Safety Code - Section 111548.1(h)(1), and also must meet the requirements set forth in the California Protection of Human Subjects in Medical Experimentation Act.
An IRB must review and approve the protocol and consent form.

Reporting requirements between the federal and California RTT Acts also differ. While federal law requires that the sponsor or manufacturer make information available to the FDA (which the FDA must publicly post), the California law imposes an obligation upon the IRB of record to biannually report information regarding the number of requests made to the IRB for an investigational product, the status of each request, the duration of treatment, the costs of treatment paid by patients, the success or failure of the investigational product in treatment, and adverse events.

Similar to federal law, California RTT does not impose an obligation upon manufacturers to make an investigational product available to a patient. California RTT also provides that a manufacturer may recover the costs of the manufacture of the product. However, the law removes any liability upon the patient’s heirs or the patient’s health benefit plan, for any outstanding debt related to the treatment using the investigational product.

In addition, the CA RTT specifically prohibits the Medical Board of California and the Osteopathic Medical Board of California from taking any disciplinary action against a physician’s license to practice medicine based solely upon the physician’s recommendation to treat or treatment of a patient with an investigational product, so long as the protocol was approved by an IRB. The Act also provides that any actions taken pursuant to the state law by a manufacturer or any other person or entity involved in caring for the patient cannot serve as the basis for any civil, criminal or disciplinary claim or cause of action under state law.

Procedure for IRB submission:

Right to Try protocols must be submitted as a new study application in ZOT IRB and requires prospective IRB review and approval.

Provide the following information (without patient identifiers):
• The Treatment Plan, include the cost of treatment
• Draft a Consent Form: HRP-502d CONSENT - Right to Try
• A signed Consulting Physician Attestation

Provide a copy of the signed attestation to the IRB within 5 days from the beginning of treatment (as part of the new study submission to the IRB). Please see the HRP Toolkit for all forms.

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 pharmacy to determine drug requirements.
Ensure patient understands financial and health care considerations outlined in consent form.
Register the patient in OnCore, as determined by RRI.

Additional References

Regulations

FDA: Emergency Use Definition: 21 CFR 56.102(d)
FDA: IRB Reporting: 21 CFR 56.104(c)
FDA: Consent Exception: 21 CFR 50.23
FDA: Physician Care: 21 CFR 50.25(e)
FDA Information Sheet: Emergency Use of an Investigational Drug or Biologic
FDA Information Sheet: Expanded Access to Investigational Drugs for Treatment Use Questions and Answers

Resources for Expanded Access

Individual Patient Expanded Access Applications: Form FDA 3926 (PDF - 356KB)
Federal Regulation on Expanded Access
- Registration (page 335)
- Updates (page 1651)
Timeline for registration and updating an Expanded Access Record
Who should submit an Expanded Access record

FDA "Project Facilitate"

- A new pilot program to assist oncology health care professionals in requesting access to unapproved therapies for patients with cancer
- "Project Facilitate" helps treating physicians submit an Expanded Access request for an individual patient