Overview and Definitions

The University and the FDA wish to support a physician’s obligation to treat a seriously ill patient with all available modalities. The emergency use provision in federal regulations allows physicians restricted access to investigational treatments that would be otherwise off-limits [21 CFR 56.104(c) and 21 CFR 56.102(d)].

Contrary to common usage, the terms “emergency use” and “compassionate use” are not synonymous. Become aware of the specific, separate standards for emergency use and compassionate use/expanded use to avoid violating federal regulations and UCSF policy regarding the use of unapproved drugs, biologics and devices.

Different FDA regulations apply to the different types of test article use, and the terminology can be confusing. Use the following definitions:

Most administration/use of unapproved devices, drugs or biologics is part of a systematic clinical trial. All clinical investigations, including pilot studies, require prior IRB review and approval. Almost all clinical studies are conducted under an Investigational Device Exemption (IDE) or an Investigational New Drug (IND) exemption obtained from the FDA.

Use of an investigational drug, biological product, or medical device generally requires either an IND (for unapproved drugs and biologics) or an IDE (for unapproved devices).

However, the FDA's “emergency use” exemption allows 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.

A physician who treats a patient under emergency use provisions must justify the treatment according to strict criteria, consult with the IRB, and fulfill specific follow-up/reporting responsibilities in a timely manner, as described in detail below.

Note: Emergency use is emergency clinical care and does not meet the DHHS definition of research. IRB agreement that a particular case meets FDA criteria for emergency use applies to the treatment of one patient only and is not the same as IRB approval to conduct a research study.

Expanded access, sometimes called "compassionate use," is the use outside of a clinical trial of an investigational medical product. A patient may be able to receive the product (when appropriate) through expanded access when enrollment in a clinical trial is not possible, e.g., a patient is not eligible for any ongoing clinical trials, or there are no ongoing clinical trials. 

Such use of an investigational drug, biologic or device falls into one of the following expanded access treatment mechanisms. Prior IRB review and approval is required, even if only one patient is to be treated under the following mechanisms. In most circumstances, prior approval by the FDA is also required.

Expanded Access Treatment Mechanisms: 

Treatment INDs or Individual Patient Access to Investigational Drugs/Devices for Serious Diseases: These mechanisms are primarily intended to give seriously ill patients access to experimental drugs or devices where no comparable or satisfactory alternative treatment is available. Although the test article sponsor is expected to continue conventional clinical trials and pursue marketing approvals with due diligence, expanded access studies involve systematic use of experimental treatments, and, with very rare exceptions, require the same review and approval as research, including both IRB approval and FDA approval in the form of an IDE (medical device) or an IND (drug/biologic).

Open Protocols (Parallel Track, Open Label Protocol, Open Label IND) or Continued Access IDEs: These uncontrolled studies are typically used when controlled trials have ended and treatment is continued so the subjects may continue to receive the benefits of the test article until marketing approval is obtained. Informed consent and prior IRB approval are required.

 

Ethical Considerations of Emergency Use Provisions

Although treating a seriously ill patient under emergency use provisions is motivated by humaneness and compassion, there are several ethical issues to consider regarding the emergent use of an experimental treatment.

Although the FDA tracks test article emergency use, clinical data obtained from the use contributes little to the overall statistical evaluation of the treatment. The potential benefit is only to a single patient; there is little potential societal benefit from increasing scientific knowledge.

The physician should carefully consider that the standard is higher for emergency use informed consent than for routine clinical care. Given the life-threatening or potentially disabling condition of the patient, it is critical that the consent form clearly states that there is no guarantee of benefit from the emergency use procedure. Guidance on obtaining informed consent is provided below.

 

Emergency Use Criteria

The following criteria must be met to comply with federal regulations and University policy on emergency use of unapproved drugs, biologics and devices.

  1. The test article is used one time per institution to treat a single patient.
  2. The patient has a condition that is life-threatening or severely debilitating.
  3. No standard treatment is available.
  4. There is not sufficient time to obtain IRB review and approval.
  5. The emergency use is reported to the IRB within five working days; when possible, the treating physician should consult with the IRB prior to use.
  6. Consent will be sought and documented from the prospective participant or the participant’s legally authorized representative, unless the criteria for the exception to the requirement for consent.
  7. The treatment is not part of a systematic investigation designed to develop or contribute to generalizable knowledge (that is, treatment will not be incorporated into a project that meets the DHHS definition of research requiring IRB review).

Important Note: The FDA holds the institution to high standards when justifying emergency use. Past lessons tell us that it is very difficult to argue that there’s no acceptable alternative treatment and that there is “not sufficient time” to obtain prior IRB approval.

Emergency Use Request Requirements for Drug or Biologic

If the use of an unapproved drug, or biologic can be justified as emergency use, the physician must fulfill several time-sensitive requirements. 

1. Read the FDA's Emergency Use of an Investigational Drug or Biologic - Information Sheet

2. Contact the FDA to obtain an emergency IND (FDA contact numbers are listed on the above Information Sheet)

3. Once the emergency IND is obtained from the FDA, email the following to [email protected] with "Emergency Use Request" in the Subject line:

a. Request for Emergency Use Form

b. FDA approval correspondence or eIND if FDA approval was given over the phone

​Please note: If the FDA has issued an emergency IND and states that you may proceed, you may do so without IRB concurrence if waiting could jeopardize the patient’s well-being. Per the regulations, Emergency Use of an investigational drug or biologic is exempt from prospective IRB approval, provided the FDA has approved the emergency use request.

Also note: Emergency Use is not the same as a non-emergency Single Patient IND. The physician should discuss with the FDA if there are questions about whether a case is emergency use or non-emergency.

Per FDA, the following conditions must apply for Emergency Use:

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 obtaining FDA approval.

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.

Before the emergency use, every effort should be made to obtain informed consent signed by the patient or the patient’s surrogate (legally authorized representative). If written informed consent is not possible, there are special provisions for an informed consent waiver.

Whether the physician writes the consent or uses a template consent from another source (e.g. the sponsor/manufacturer of the test article), the emergency use consent should contain the elements of informed consent found in the UCSF template, but need not follow the UCSF format and wording. It must be stated clearly that:

  • the patient is not part of a UCSF-approved research study,
  • the treatment is experimental and not approved by the FDA, and
  • there is no guarantee of benefit.

Because the FDA exempts emergency use from requirements for IRB review, prior IRB approval of the consent form is not needed. A signed copy of the informed consent must be included in the Emergency Use Post-use Report Form

Waiver of Consent:

If prior consent is not possible, federal regulations [21 CFR 50.23] allow a waiver under the following conditions:

  • If at all possible, before the emergency use the treating physician and a physician not involved in clinical investigation of the test article certify in writing that:
  1. The patient is confronted with a life-threatening situation.
  2. The physician cannot communicate with the patient.
  3. Time is not sufficient to obtain consent from the patient’s surrogate (legally authorized representative).
  4. No alternative method of approved or generally recognized therapy is available that provides equal or greater likelihood of saving the patient’s life.
  • If immediate use of the test article is needed to preserve the patient’s life, and there is not sufficient time to secure an independent physician’s determination that the four conditions described above apply, the treating physician must have the written determination reviewed and signed by an independent physician within five working days after the emergency use of the test article.
  • Include a copy of the written determination with the post-use written report.

The FDA requires the treating physician to document the emergency use in writing and submit the report to the IRB within five (5) working days of emergency use initiation. The physician must use the Emergency Use Post-use Report Form.

 

Consequences of Noncompliance with Federal Regulations

If the strict emergency use requirements are not met, both the physician and the institution may suffer strong sanctions.

  • Physician noncompliance may result in termination or suspension from treating patients in any and all FDA-regulated studies.
  • If the institution fails to provide guidance to physicians and to establish clear procedures, the institution's ability to conduct FDA-regulated research may be restricted.

IRB Oversight

  • To help physicians comply with emergency use regulations, the IRB determines whether each use complies. Most often, this is done when the physician discusses the proposed use with an IRB Chair or Vice Chair before the patient is treated. When prior consultation is not possible, a Chair will review the post-use written report. If the post-use written report indicates consent was waived, the IRB Chair or Vice Chair also will review the waiver to determine if it complies with FDA requirements.
  • For both the emergency use itself and for a waiver of consent (if applicable), the IRB will issue a letter certifying compliance or informing the physician of noncompliance. In the case of noncompliance, the IRB will follow its usual procedure to determine whether the noncompliance is a serious or continuing problem requiring additional action.

Expanded Access - Individual Patient (SPIND)

In 2017, the FDA began allowing “Alternative IRB Review Procedures” for Individual Patient Expanded Access (sometimes referred to as Single Patient IND). Prior to this FDA decision, Individual Patient Expanded Access requests were required to be reviewed by a convened IRB committee. Note: “Alternative IRB Review Procedures” can only be requested for Individual Patient Expanded Access, not for Expanded Access involving groups.

The UCSF IRB has determined that IRB Chair review is appropriate provided FDA does not decline the physicians request for “Alternative IRB Review Procedures.” If the physician would like to request “Alternative IRB Review Procedures” from FDA, here are the instructions:

  • Read the FDA guidance
  • When submitting to FDA, use FDA Form 3926 -- Individual Patient Expanded Access Investigational New Drug Application (IND); In June 2021, FDA released a new tool: Expanded Access eRequest, which is a web-based tool that enables physicians to complete, sign, and submit non-emergency Expanded Access (EA) requests to FDA.
  • FDA Form 3926 will have a box (Question 10b.) request “Alternative IRB Review Procedures.” 

  • Once you’ve received the FDA May Proceed Letter, here are the instructions for submitting to the IRB:
    • Individual Patient Expanded Access requests are reviewed in iRIS using the same IRB application as a research study.
    • Complete the IRB application as completely as possible. Some sections may not apply given your type of submission.
    • FDA May Proceed Letter, FDA Form 3926 that you submitted to FDA, Informed Consent Form (IRB template), HIPAA Form, Investigator’s Brochure, any other relevant documents that will assist the IRB Chairperson in the review.
    • In the title of the IRB submission, include “Individual Patient Expanded Access” so the submission can be quickly identified by IRB staff.

Forms

Last updated: August 25, 2021