Section XVI:

FDA - Regulated Products

WPP #: XVI-3

Title 3:

Emergency Use of an Investigational Drug, Device, or Biologic

Effective Date:

08-12-14

Revision History:

06-20-00; 06-07-04; 06-21-06; 02-05-07

Objective

To describe the process for emergency use of investigational drugs, devices, or biologics.

Description

Emergency use of unapproved drugs or biologics is research under the FDA regulations. As such, the emergency use of a test article, other than a medical device, is considered a clinical investigation by the FDA and the patient is a participant. The FDA may require data from an emergency use to be reported in a marketing application.

Conversely, DHHS regulations stipulate that patients receiving a test article in an emergency use situation may not be considered a research participant. Thus, this activity is not considered research at VCU that is subject to prior IRB review and approval. As the activity is not research, the outcome of such treatment may not be included in any report of research activity subject to DHHS regulations. However, comprehensive records must be retained regarding the administration and monitoring of this unapproved article. Standard IRB reporting requirements and deadlines apply as well as any sponsor-requirements for monitoring and sharing safety information. Emergency use of a test article may not be used to circumvent the general requirement for prior IRB review and approval.

  1. Definitions:
    1. Emergency use is defined as the use of an investigational drug or biological product with 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 [21 CFR 56.102(d)]. Every effort should be made to attempt to obtain prior IRB review and approval (where possible). However, the FDA regulations do not provide for expedited IRB review in emergency situations. Therefore, "interim," "compassionate," "temporary" or other terms for an expedited approval process are not applicable.
    2. An unapproved medical device is defined as a device that is used for a purpose or condition for which the device requires, but does not have, an approved application for premarket approval under section 515 of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 360(e)]. An unapproved device may be used in human subjects only if it is approved for clinical testing under an approved application for an Investigational Device Exemption (IDE) under section 520(g) of the Act [21 U.S.C. 360(j)(g)] and 21 CFR part 812. Medical devices that have not received marketing clearance under section 510(k) of the FD&C Act are also considered unapproved devices which require an IDE. The Food and Drug Administration (FDA) recognizes that emergencies arise where an unapproved device may offer the only possible life-saving alternative, but an IDE for the device does not exist, or the proposed use is not approved under an existing IDE, or the physician or institution is not approved under the IDE. In these instances, justification to the FDA, that the emergency existed, is subsequently required.
    3. Life-threatening, for the purposes of section 56.102(d), includes the scope of both life-threatening and severely debilitating, as defined below.
      1. 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 subjects must be in a life-threatening situation requiring intervention before review at a convened meeting of the IRB is feasible.
      2. 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.
    4. Emergency Use Provision: The "Emergency Use Provision" in the FDA regulations [21 CFR 56.104(c)] is an exemption from prior review and approval by the IRB. The exemption, which may not be used unless all of the conditions described in 21 CFR 56.102(d) exist, allows for one emergency use of a test article without prospective IRB review. FDA regulations require that any subsequent use of the investigational product at the institution have prospective IRB review and approval. FDA acknowledges, however, 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 issue.
  2. Conditions for the Emergency Use Provision (Exemption from Prior Review):
    1. Prospective IRB Review Not Possible: If full board VCU IRB review and approval is possible, the responsible individual (medical professional) should pursue the prospective IRB review. ONLY IF treatment of a life-threatening condition is necessary before the IRB approval is made, does the Emergency Use Provision (Exemption from Prior IRB Review and Approval) apply.
    2. IND Required for Drugs/Biologics: The emergency use of an unapproved investigational drug or biologic requires an IND. If the intended subject does not meet the inclusion criteria of an existing study protocol, or if an approved study protocol does not exist, the usual procedure is to contact the manufacturer and determine if the drug or biologic can be made available for the emergency use under the manufacturer’s IND.

      The need for an investigational drug or biologic may arise in an emergency situation that does not allow time for submission of an IND or amendment of the manufacturer’s IND. In such a case, only the FDA may authorize shipment of the test article in advance of the IND submission (or amendment). Requests for such authorization may be made by telephone or other rapid communication means to the FDA [21 CFR 312.36].

    3. Informed Consent Required: Even for an emergency use, the physician is required to obtain informed consent of the patient or the patient's legally authorized representative unless both the treatment physician and a physician who is not otherwise participating in the patient’s care certify in writing all of the following [21 CFR 50.23(a)]:
      1. The subject is confronted by a life-threatening situation necessitating the use of the test article.
      2. Informed consent cannot be obtained because of an inability to communicate with, or obtain legally effective consent from, the subject.
      3. Time is not sufficient to obtain consent from the subject's legal representative.
      4. No alternative method of approved or generally recognized therapy is available that provides an equal or greater likelihood of saving the subject's life.
    4. PROMPT IRB Reporting Required: If, in the physician's opinion, immediate use of the test article is required to preserve the subject's life, and if time is not sufficient to obtain an independent physician's determination that the four conditions above apply, the clinical investigator should make the determination and, within 5 working days after the use of the article, have the determination reviewed and evaluated in writing by a physician who is not participating in the clinical investigation. The physician must notify the IRB within 5 working days after the use of the test article [21 CFR 50.23(c)].
  3. VCU IRB Required Reporting/Review Procedures:

    In order to exercise the Emergency Use Provision (for Exemption from Prior IRB Review), the following procedures must be followed:

    1. Pre-Emergency Use Notification: The physician seeking to provide life-saving treatment with an investigational drug, device, or biologic should notify the VCU IRB that he or she is prepared to exercise the "Emergency Use Provision" (where possible, using any available means, such as fax, phone, email, or other method). This notification should not be construed as an IRB approval. Rather, the VCU IRB uses the prior notification to initiate tracking to ensure that the investigator files a report within the five day time-frame required by 21 CFR 56.104(c).
    2. Pre-Emergency Use Research Participant Protections: VCU requires that the physician authorizing the use of the device follow as many subject protection procedures as possible, including:
      • obtaining an independent assessment by an uninvolved physician;
      • obtaining informed consent from the patient or a legal representative;
      • notifying institutional officials as specified by clinical/institutional policies;
      • notifying the VCU Institutional Review Board (IRB); AND
      • obtaining authorization from the IND/IDE holder (as appropriate).
    3. Post-Emergency Use Report: Following the treatment of an individual under the "Emergency Use Provision" the treating physician must justify the "Emergency Use", as follows:
      • Describe how the individual treated was in a life-threatening situation in which no standard acceptable treatment was available and in which there was not sufficient time to obtain VCU IRB approval;
      • Document when contact was made to the IRB and what information was transmitted;
      • Justify why prospective IRB review was not possible;
      • Identify how the requirements for an IND were met (if applicable - see several options, above); and
      • Identify the informed consent process used (see options, above).
    4. Subsequent Use: Any subsequent use of the test article is subject to prospective VCU IRB review.
    5. IRB Chairperson Review: The IRB chairperson ( or knowledgeable designee) will review reports of "Emergency Use" both prospective reports and retrospective reports) to determine whether the circumstances meet the regulatory requirement and to determine whether informed consent was obtained or waived in accordance with FDA regulations.
    6. Concerns: If the Chairperson has concerns regarding failure to follow regulations, the matter will be referred to the OECO in accordance with the VCU IRB WPP#: VI-3.
  4. Special Issues:
    1. The FDA notes that in the event that a device is to be used in circumstances meeting the criteria listed above, the device developer must notify the Center for Devices and Radiological Health (CDRH), Program Operation Staff by telephone (301-594-1190) immediately after shipment is made. [Note: an unapproved device may not be shipped in anticipation of an emergency.] Nights and weekends, contact the Division of Emergency and Epidemiological Operations (202-857-8400).
    2. Some manufacturers will agree to allow the use of the test article, but their policy requires "an IRB approval letter" before the test article will be shipped. If it is not possible to convene a quorum of the IRB within the time available, the VCU IRB may send the sponsor a written statement that the IRB is aware of the proposed use and considers the use to meet the requirements of 21 CFR 56.104(c). Although, this is not an "IRB approval," the acknowledgment letter has been acceptable to manufacturers and has allowed the shipment to proceed.

Responsibility

It is the responsibility of the treating physician/practitioner to determine if emergency use of an unapproved drug, device, or biologic is of medical necessity and to take the pre-use and post-use actions described above, including reporting the use to the IRB within 5 working days.

References

Emergency Use of an Investigational Drug or Biologic (FDA Information Sheet)
21 CFR §312.36
Emergency Use of an Unapproved Medical Devices