Single Patient Emergency Use

Expanded Access Guidance

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Purpose and Applicability

This webpage describes the IRB-related requirements and procedures for the mechanisms that allow expanded access to investigational drugs, devices, and biologics for clinical (not research) purposes before the items have been approved by the Food and Drug Administration (FDA) for use and marketing.

Expanded access is not the same as off-label use of an approved drug, device, or biologic.

Context

What is expanded access? Investigational (i.e., unapproved) items regulated by the FDA may normally be used with humans only through an approved clinical study in which the subjects meet certain criteria and the item is used only in accordance with the approved protocol by a clinical investigator participating in the trial. However, a health care provider may wish to use an investigational item to save the life of a patient or to help a patient suffering from a serious condition for which no effective alternative therapy exists. Access to the investigational items can be provided through one of several FDA mechanisms collectively called, expanded access.

Why is IRB review required? The FDA requires the clinician to obtain prior IRB review and approval for many expanded access mechanisms and to obtain informed consent that meets research consent requirements, even though the intended purpose of the use is clinical care rather than research. The FDA requires this because expanded access mechanisms involve use of an investigational item in a vulnerable population (i.e., seriously ill patients with no good alternative) which raises concerns sufficiently similar to those in clinical research such that IRB review and a research-like informed consent process are warranted. Prior IRB review and approval may not be required for Single Patient Emergency Uses (see WEBPAGE Single Patient Emergency or Compassionate Use).

Are other approvals needed? Clinicians are expected to comply with all applicable FDA regulations and UW Medicine policies and procedures. Those requirements are not listed in this guidance.

For uses at Fred Hutchinson Cancer Center (FHCC), contact RegulatoryAffairs@fredhutch.org to discuss institutional requirements. General guidance:

• Emergency uses at FHCC are reviewed by UW HSD (not the FHCC IRB).
• For non-emergency compassionate uses and other expanded access: select the same IRB you would select if the activity were research (see HSD guidance or FHCC guidance).

IRB Review Considerations

The IRB review requirements and procedures are generally the same for expanded access as they are for research clinical trials (FDA Regulated Research Guidance; SOP IRB Review). Expanded access mechanisms must be reviewed by the convened IRB (i.e., the expedited review process cannot be used), although single patient emergency or compassionate uses may be reviewed by the IRB Chair alone.

The FDA expects the IRB to be sensitive to the unique issues raised by expanded access activities, including the following:

• The activity is clinical care, not research
• The vulnerable nature of the patient population, who are typically seriously ill and have no other viable alternatives for treatment
• Ensuring full disclosure of risks
• Ensuring that the consent process adequately manages expectations about the possible benefits of the investigational treatment and makes clear what is unknown about the investigational item

If a clinician needs to report noncompliance with FDA regulations or HSD policy, they should use the instructions on the webpage, Report Events and New Information to submit a Report of New Information (RNI). If IRB noncompliance is being reported by HSD staff, refer to the SOP RNI Reporting by HSD Staff for instructions.

Expanded Access Use – Drugs

Expanded access drug mechanisms may be used when the FDA determines that the following criteria are met [21 CFR 312.305]:

• The patient(s) has 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;
• The potential benefit justifies the potential risks, and those potential risks are not unreasonable in the context of the disease or condition
• Providing the drug will not interfere with the initiation, conduct, or completion of clinical trials that could support marketing approval of the expanded access use or otherwise compromise the potential development of the expanded access use (i.e., these mechanisms may not be used as a substitute for the normal drug development process)

Types of Expanded Access for Drugs

Individual Patient. This mechanism is intended for use with a single patient at a given institution and may or may not occur in an emergency situation.  The FDA must approve the use under an Investigational New Drug (IND) approval before the drug or biologic is administered to the patient. When used in an emergency situation, this may be called an Emergency IND.

Emergency use. Prospective IRB approval is not required if there is insufficient time to obtain it, but the IRB must be notified within 5 business days of the use. See the HSD webpage Single Patient Emergency or Compassionate Use and the APPLICATION Notification of Emergency Use, Drug or Biologic for details and instructions.

Non-emergency use. Prospective IRB approval is required. Follow the procedures outlined in the FDA Guidance, Investigational Review Board (IRB) Review of Individual Patient Expanded Access Requests for Investigational Drugs and Biological Products During the COVID-19 Public Health Emergency

Intermediate-Sized Patient Populations. This is for treatment of a patient population smaller than that typical of a Treatment IND. This commonly occurs when the FDA asks a sponsor to consolidate expanded access under this mechanism because the FDA has received a significant number of individual patient requests for the same use/purpose. It typically addresses the following situations:

• The drug is not being developed. For example, the disease or condition may be so rare that the sponsor is unable to recruit patients for a clinical trial.
• The drug is under development but patients requesting the drug are unable to participate in the trial because, for example: (1) they have a different disease or stage of disease than the one being studied; (2) they do not meet enrollment criteria; (3) trial enrollment is closed; or (4) the trial site is not geographically accessible.
• The drug is approved but not being marketed because: (1) it is no longer marketed for safety reasons or is unavailable through marketing due to failure to meet the conditions of the approved marketing application; or (2) the drug contains the same active ingredient as an approved drug that is unavailable through marketing due to a drug shortage or a failure to meet the conditions of the approved marketing application.

Treatment IND or Treatment Protocol. This mechanism allows an investigational drug to be used for widespread treatment use, usually after much of the formal drug development process has been completed.

Group C Treatment IND. Group C drugs are Phase III cancer drugs that have shown evidence of reproducible efficacy. These drugs are distributed by the National Institutes of Health (NIH) under National Cancer Institute (NCI) protocols. Treatment is a primary objective, but safety and effectiveness data are still collected. FDA generally grants a waiver from the IRB review requirements. This mechanism is seldom encountered by the UW IRB because almost all UW oncology protocols are managed and reviewed by Fred Hutchinson Cancer Center (FHCC).

Treatment Use of a Designated Orphan Drug. The FDA has formally designated some drugs as orphan drugs, because they are primarily used to treat a rare disease or condition [21 CFR 316]. Orphan drugs may be used for clinical treatment under the same mechanisms as investigational drugs.

Open Label Protocol or Open Protocol IND. These protocols are usually uncontrolled studies, carried out to obtain additional safety data (Phase 3 studies). They are typically used when the controlled trial has ended and treatment is continued to enable the subjects and the controls to continue to receive the benefits of the investigational drug until marketing approval is obtained from the FDA. These studies require prospective IRB approval.

Parallel Track. The FDA’s Parallel Track [policy 57 FR 13250] 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 establishing the safety and effectiveness of new drugs. It does so by providing an administrative system that expands the availability of drugs for treating AIDS/HIV. These studies require prospective IRB approval.

Expanded Access Use – Devices

Types of Expanded Access for Devices

Emergency Use. This mechanism is intended for use with a single patient at a given institution. This mechanism may be used when: (1) an individual patient has a life-threatening condition that needs immediate treatment; (2) no acceptable alternative treatments exist; and (3) there is no time to use existing procedures to get FDA approval for the use. If these three criteria are met, prior FDA approval is not required, but the FDA must be notified after the use. Prospective IRB approval is not required if there is insufficient time to obtain it, but the IRB must be notified within 5 business days of the use. “Insufficient time” is defined by HSD as situations in which the drug must be used within 7 business days. See the HSD webpage Single Patient Emergency or Compassionate Use and the APPLICATION Notification of Emergency Use, Device for full details and instructions.

Compassionate Use. This mechanism allows access to an investigational device to treat or diagnose individuals patients (or, less often, a small group of patients) at a given institution with a serious disease or condition when there are no available alternative options. This mechanism may be used for patients who do not meet the requirements for inclusion in a clinical trial but for whom the treating physician believes the device may provide a benefit in treating and/or diagnosing their disease or condition. This mechanism may be used when: (1) the patient has a serious or life-threatening disease or condition; (2) there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition; and (3) the potential benefit justifies the potential risks of the investigational device. Prior FDA approval is required before compassionate use occurs. Prior IRB approval or concurrence is not required, but the IRB should be notified within 5 business days of the compassionate use. See the HSD webpage Single Patient Emergency or Compassionate Use and the APPLICATION Notification of Compassionate Use, Device for full details and instructions.

Treatment Investigational Device Exemption (IDE). An IDE for a clinical trial specifies the maximum number of clinical sites and the maximum number of human subjects that may be enrolled in the study. During the course of the clinical trial, if the data suggests that the device is effective, then the trial may be expanded to include additional patients with life-threatening or serious diseases or conditions. This purpose of the Treatment IDE mechanism is to facilitate the availability of promising new devices to desperately ill patients as early in the device development process as possible, before the final action on the marketing application to the FDA, and to obtain additional data on the device’s safety and effectiveness. This mechanism may be used when: (1) the device is intended to treat or diagnose a serious or life-threatening disease or condition; (2) there is no comparable or satisfactory alternative treatment; (3)* the device is under investigation in a controlled clinical trial for the same use under an approved IDE, or all clinical trials have been completed; and (4) the sponsor of the controlled clinical trial is pursuing marketing approval or clearance of the investigational device. Prior FDA approval and IRB approval are required.

* The timeframe during which this mechanism can be used is determined by the patient condition. For immediately life-threating disease or conditions, the use may occur prior to the completion of all clinical trials. For serious diseases or conditions, the use may occur after all clinical trials have been completed but before the FDA has approved a marketing application.

Continued Access/Extended Investigation. The FDA may allow continued enrollment of subjects after a clinical trial with an IDE has been completed, in order to allow access to the investigational device while the marketing application is being prepared by the sponsor or reviewed by the FDA. There is significant overlap between the Treatment IDE mechanism and the Continued Access mechanism as both are intended to provide additional access to an unapproved device once preliminary evidence about safety and effectiveness is available. Treatment IDEs differ in that they: (1) can be obtained earlier in the device development process; and (2) have a more narrow application than Continued Access which can be used with any clinical investigation (i.e., the disease/condition does not have to be serious or life-threatening). Prior FDA approval and IRB approval are required.

The Continued Access mechanism can be used after all pre-marketing clinical trials are completed and the marketing application to the FDA must be under preparation by the sponsor or under review by the FDA.

Humanitarian Use Device (HUD). Use of this special category of devices is not considered an expanded access mechanism because the FDA has granted a type of approval for the devices. See the HSD webpage, GUIDANCE Humanitarian Use Device.

Applying for IRB Review

Single patient emergency use and compassionate use. In many cases, there is insufficient time for a clinician to obtain IRB approval prior to the single patient emergency use of a drug or device or compassionate use of a device. In these cases, clinicians should submit the APPLICATION Notification of Emergency Use, Drug, APPLICATION Notification of Emergency Use, Device or APPLICATION Notification of Compassionate Use, Device to the IRB within 5 business days of the use. Use the TEMPLATE Consent Form, Emergency or Compassionate Use and attach an unsigned copy of the consent form with the application.

For all other expanded access mechanisms for which prior IRB approval is required:

• Obtain the applicable approval from the FDA (typically as a type of IND or IDE)
• Identify the correct IRB. Most expanded access protocols are reviewed by the UW IRB, however some, such as industry-initiated or oncology-related should be reviewed by non-UW IRBs. Contact hsdrely@uw.edu if you need guidance.
  • If submitting to the UW IRB, submit a standard IRB application, with these additional instructions:
    • In the Purpose section of the application, include the information that the application is for an expanded access use. Name the type of expanded access mechanism.
    • In the Consent Process section, include a description of how you ensure that the patients have an accurate understanding of the risks, likelihood of personal benefit, and other alternatives
    • Attach documentation of FDA approval
    • Attach a consent form for the expanded access use. Use a UW research consent form, adapting as needed. Required elements of consent are listed in the WORKSHEET Consent Requirements and Waivers. Omit the normally-required statement about registration of the activity at the federal ClinicalTrials.gov.
  • If submitting to a non-UW IRB, submit a reliance request to HSD prior to submitting to the non-UW IRB, according to their instructions.

Related Materials

APPLICATION Notification of Compassionate Use, Device
APPLICATION Notification of Emergency Use, Device
APPLICATION Notification of Emergency Use, Drug or Biologic
GLOSSARY off-label use
SOP IRB Review
SOP RNI Reporting by HSD Staff [HSD staff access only]
TEMPLATE Consent Form, Emergency or Compassionate Use
UW Consent Templates
WEBPAGE Apply for Review
FDA Regulated Research Guidance
WEBPAGE How to Ask for a Non-UW IRB
WEBPAGE Report Events and New Information
WEBPAGE Single Patient Emergency or Compassionate Use
WORKSHEET Consent Requirements and Waivers

Regulatory References

• 21 CFR 50
• 21 CFR 56
• 21 CFR 312, Subpart I (expanded access to investigational drugs)
• 21 CFR 316, Orphan Drug
• 21 CFR 812 Investigational Devices
• FDA Guidance for Industry. “Expanded Access to Investigational Drugs for Treatment Use – Questions and Answers”, 2016
• FDA Guidance for IRBs and Clinical Investigators. “Institutional Review Board (IRB) Review of Individual Patient Expanded Access Requests for Investigational Drugs and Biological Products During the COVID-19 Public Health Emergency”, 2020
• FDA Information Sheet, “Emergency Use of an Investigational Drug or Biologic: Guidance for IRBs and Clinical Investigators”, 1998
• FDA Information Sheet, “Expanded Access for Medical Devices”
• FDA Instructions for physicians on how to request an emergency IND

Version Information

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Keywords: Expanded access; FDA