The COVID-19 pandemic has brought up questions regarding the emergency use of drugs, devices, and/or biologics. What issues must investigators understand prior to submission of a study to the Institutional Review Board (IRB) for review? Below is a brief description of the regulations and IRB requirements. Please refer to the Code of Federal Regulations and/or FDA guidance for additional information (please see below for applicable regulations).
Emergency Use: Background and Regulations
The FDA regulates the use of all investigational drugs and devices, including emergency uses.
The FDA defines “emergency use” as the use of a test article on a human subject in a life-threatening (see definition below) situation in which no standard acceptable treatment is available, and in which there is not sufficient time to obtain IRB approval [21CFR 56.102 (d)]. The IRB must be notified of all emergency use, even though it is not considered research.
Often, the term “emergency use” creates confusion because there are three different areas of concern:
- Requirements for the test article: These requirements deal with how the FDA allows the shipment and distribution of investigational drugs and devices in emergency situations. If an emergency IND or IDE (or Emergency Use Authorization (EUA)) is obtained, it does not necessarily qualify a protocol for the exemption from prospective IRB review or an exemption from informed consent.
- IRB requirements: IRB approval is required for the use of a test article on a human subject unless there is not enough time to obtain approval at a convened board – even if the use/study is for only one (1) patient.
- Informed consent requirements: Informed consent must be obtained from a subject. A consent form must be prepared for use and submitted to the IRB. Regulations allow for an exception from informed consent or “after treatment consent” in certain emergency situations.
What Does “Life-Threatening” Mean?
Life-threatening, for the purposes of the above section [21 CFR 56.102(d)] includes the scope of both life-threatening and severely debilitating as defined below:
- FDA definition of “life-threatening“: 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, subjects must be in a life-threatening situation requiring intervention before review at a convened IRB meeting is feasible.
- FDA definition of “severely debilitating“: Diseases or conditions that cause major irreversible morbidity. Examples of severely debilitating conditions include blindness, loss of arm, leg or hand, loss of hearing, paralysis or stroke.
Emergency Use Authorizations
During a public health emergency, the FDA can use its EUA authority to allow the use of unapproved medical products, or unapproved uses of approved medical products, to diagnose, treat, or prevent serious or life-threatening diseases when certain criteria are met, if there are no adequate, approved, and available alternatives. EUA candidate products include medical products and uses that are not approved, cleared, or licensed under sections 505, 510(k), and 515 of the FD&C Act or section 351 of the PHS Act. Please see the applicable guidance document and sections 564(f) and 564(g)(2) of the Act for additional information.
Before the FDA can issue an EUA, the Secretary of Health and Human Services must make a declaration of emergency or threat justifying authorization of emergency use for a product. When the emergency is over, the EUA declaration is terminated, and all EUAs issued based on that declaration will no longer remain in effect.
Emergency Use of an Investigational Drug or Biologic
This type of use is not dependent on the existence of a public health emergency. The emergency use of an unapproved investigational drug or biologic requires an Investigational New Drug (IND) number. An IND number is also needed for submission of the use into Mentor. For more information, please refer directly to the Emergency Use of an Investigational Drug or Biologic – Information Sheet found on the FDA website.
Obtaining access to an IND number can be accomplished in two ways:
- Contact the manufacturer or sponsor (or IND holder) of the product to determine if the drug or biologic can be made available for the emergency use under the existing IND. There may or may not be an existing, approved study (at any of the manufacturer’s study sites) using the IND. The manufacturer may be required to contact the FDA to obtain permission for the emergency use to occur using the existing IND.
- A treating physician may request an emergency IND from the FDA specific to the emergency use case. An emergency use IND number is not associated with another clinical trial or another emergency use case. In some cases, the need for an investigational drug or biologic may be a situation that does not allow time for a submission of an emergency IND and the FDA may authorize shipment of the test article in advance of the IND submission. In such cases, the submission must occur within X days of dosing or treatment.
Emergency Use of an Unapproved Device
This use is not dependent on the existence of a public health emergency. The FDA provides guidance that defines an unapproved medical device as a device that is utilized for a purpose, condition, or use for which the device requires, but does not have, an approved application for premarket approval under section 515 of the Federal Food, Drug, & Cosmetic Act (21 U.S.C. 360e) (the act) or an approved IDE under section 520(g) of the act (21 U.S.C. 360j(g)).
An unapproved device should normally only be used in human subjects if it is approved for clinical testing under an IDE and if it is used by an investigator for the sponsor in accordance with the terms and conditions of the application. Emergency use of an unapproved device, however, may also occur when: (i) an IDE for the device does not exist, (ii) when a physician wants to use the device in a way not approved under the IDE, or (iii) when a physician is not an investigator under the IDE.
A physician who intends to treat a patient with an unapproved medical device in an emergency situation should conclude that:
- The patient has a life-threatening condition that needs immediate treatment.
- No generally acceptable alternative treatment for the condition exists; and,
- Because of the immediate need to use the device, there is no time to use existing procedures to get FDA approval for the use.
FDA expects the physician to make the determination that the patient’s circumstances meet the above criteria, to assess the potential for benefit from the use of the unapproved device, and to have substantial reason to believe that benefits will exist.
The emergency use of an investigational device must be reported to the FDA by the IDE sponsor within 5 working days. If no IDE exists, the physician should follow the above procedures and report the emergency use to CDRH or CBER. For additional information on the procedures physicians should follow in an emergency situation, see the guidance entitled IDE Policies and Procedures on the FDA website.
IRB Requirements
The FDA provides an emergency use provision in the regulations [21 CFR 56.104(c)] which allows an exception from prospective review by the IRB. Emergency use of a test article as defined above does not require review by a convened IRB Panel, but the use must be reported to the IRB. The IRB Chair or Co-Chair will determine whether the use complies with the regulatory requirements.
The treating physician must notify the IRB before the emergency use of the test article using the Mentor system. If immediate use of the test article is required to save the life of the participant and there is not sufficient time to contact the IRB, the treating physician may proceed with the emergency use. In this case, the use of the test article must be reported to the IRB using the Mentor system as soon as possible and absolutely no later than 5 working days from the time the procedure is conducted or drug is administered.
Notifying the IRB of the emergency use (either before or after the procedure or drug administration) should not be construed as IRB approval. A letter will be issued from the IRB Chair or Co-Chair stating whether the use complies with the regulatory requirements.
If the IRB can reasonably hold a convened meeting to review all prepared emergency use materials prior to the use of the test article, it is not considered exempt from prospective review by the IRB. The IRB should be contacted as soon as possible to facilitate review at the convened meeting.
Is the emergency use of a test article considered “research?”
Emergency use of a test article (21 CFR 56.104(c)) is considered by FDA to be human research. It meets the FDA definition of clinical investigation and requires regulation under the Food, Drug & Cosmetic Act. It also involves the administration of a test article to a human, so it involves human subjects. Therefore, under FDA regulations, it is human research.
The research must not be subject to OHRP regulation since DHHS has no corresponding exemption from prospective IRB review. The activity must not meet the DHHS definition of “research” and involve “subjects” as defined by DHHS regulations. In other words, the data from an emergency use may not be reported in a way that implies that the activity was a prospectively planned systematic investigation designed to develop or contribute to generalizable knowledge.
Informed Consent
Even for emergency use, the treating physician is required to obtain informed consent of the subject or the subject’s legally authorized representative. An informed consent must be submitted to the IRB. A research consent template may be used to create a consent form for emergency use situations. Language in the consent form must reflect that the treatment is not FDA-approved and the treatment is an option for treating the patient’s life-threatening condition. The consent form must state that the patient is not receiving treatment as part of research.
Additionally, the FDA provides an exception from the requirements of informed consent [21 CFR 50.23] as follows:
Before the use of the test article, both the treating physician and a physician who is not otherwise participating in the clinical investigation must certify all of the following:
- The human subject is confronted by a life-threatening situation necessitating use of test article.
- Consent cannot be obtained because of an inability to communicate with or obtain consent from the subject.
- Time is not sufficient to obtain consent from subject’s legal representative.
- No alternative generally approved method is available.
- If immediate use of the test article is required to save the life of the subject and time is not sufficient to obtain independent determination by another physician, a determination by the treating physician shall be made. This determination is to be reviewed and evaluated in writing by a physician who is not participating in the investigation within 5 days after use of article. Submit the completed certifications with the Report of Emergency Use in the Mentor system.
The documentation described above must be submitted to the IRB within 5 working days after the use of a test article.