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Emergency Test Article Use

Regulations pertaining to emergency use of a test article (FDA-exempted investigational drug, biologic, or device) are those of the US Food & Drug Administration (FDA), published as part of the Code of Federal Regulations (CFR) 21 CFR 50 and 21 CFR 56. This "Report of Emergency Use of a Test Article" form is designed to facilitate the submission of complete information needed for the IRB to fulfill its monitoring function.

Please note: this is not an application for approval of a research project. Emergency use of a test article in a life-threatening condition is not considered research; nevertheless, it is under the purview of the IRB, because the use of an investigational test article not yet approved by the FDA is involved.

The investigational drug, biologic, or device must have received an IND (investigational new drug) exemption or IDE (investigational device exemption) from the FDA for clinical testing, to be eligible for use in an emergency setting. Usually, IND exemption or IDE is expended by the manufacturer. If IND or IDE authorization by the FDA is not available, the investigator must contact the FDA on an emergency basis. Call 301-827-1501 for drugs; 800-835-4709 for biologics; 301-594-1190 for devices; and 202-857-8400 on nights and weekends.

Emergency Use Criteria

For emergency use of a test article, all of the following criteria must be met:

  1. The subject is facing a life-threatening condition, for which there is no conventional treatment, or for which conventional treatments have failed.
  2. The physician has access to a test article; and believes that there is a reasonable likelihood that the article will help save the subject's life and that no approved treatment has an equal or greater likelihood of helping the subject.
  3. Comprehensive written informed consent has been executed prior to initiation of the administration of the test article. The rules governing informed consent, as defined in the IRB polices and procedures apply.

Certain emergency circumstances may not permit the execution of the standard informed consent process prior to administration of the test article. FDA regulations provide an exemption from the informed consent requirement, if the subject is unable to provide effective consent, and there is insufficient time in which to obtain consent from the subject's legal representative. Under these circumstances, the opinion of another impartial physician on the expected benefit from the use of the test article is required. Please refer to the "Definitions and Interpretations of the Federal Rules on Emergency Use of a Test article, prepared by the Office for Human Research Protection (OHRP) of the US Department of Health and Human Services" provided in the Specific Information section below.

The test article is expected to be administered to a single subject as a single course (may involve multiple dosing to achieve maximal efficacy), by a physician licensed to practice medicine in the State of Ohio. The subject to receive the test article should not be enrolled in a research study related to the test article. If subsequent use of the test article is contemplated in the same subject or in others, a new protocol application to the IRB is required in advance of that use.

The use of a test article in an investigation designed to be conducted under emergency conditions (e.g. emergency room research) usually does not qualify for the emergency use exemption.

For quick reference while preparing this application, please find below the following information derived from Federal agencies regarding:

  1. Trial Phases of Research Involving Drugs and Biologics
  2. Significant Risk and Nonsignificant Risk Investigational Medical Devices
  3. Definitions and Interpretations of the Federal Rules on Emergency Use of A Test Article, prepared by the Office of Human Research Protection (OHRP) of the US Department of Health and Human Services

Trial Phases of Research Involving Investigational Drugs & Biologics

Phase 1 Drug Trial

Phase 1 trials include the initial introduction of an investigational new drug into humans. These studies are typically conducted with healthy volunteers; however, when the drug is intended for use in patients with a particular disease, such patients may sometimes participate as subjects. Phase 1 trials are designed to determine the metabolic and pharmacological actions of the drug in humans, to uncover the side effects associated with increasing doses (to establish a safe dose range), and, if possible, to gain early evidence of effectiveness. Typically, Phase I trials are closely monitored.

The ultimate goal of a Phase 1 trial is to obtain sufficient information about the drug's pharmacokinetics and pharmacological effects to permit the design of well-controlled, sufficiently valid Phase 2 studies. Other examples of Phase 1 studies include studies of drug metabolism, structure-activity relationships, and mechanisms of actions in humans, as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes. The total number of subjects involved in Phase 1 investigations is generally between 20 and 80.

Phase 2 Drug Trial

Phase 2 trials include controlled clinical studies conducted to evaluate the drug's effectiveness for a particular indication in patients with the disease or condition under study, and to determine the common short-term side effects and risks associated with the drug. These studies are typically well-controlled, closely monitored, and conducted with a relatively small number of patients, usually involving no more than several hundred subjects.

Phase 3 Drug Trial

Phase 3 trials involve the administration of a new drug to a larger number of patients in different clinical settings to determine its safety, effectiveness, and appropriate dosage. They are performed after preliminary evidence of effectiveness has been obtained, and are intended to gather necessary additional information about effectiveness and safety for evaluating the overall benefit-risk relationship of the drug, and to provide an adequate basis for physician labeling. In Phase 3 studies, the drug is used the way it would be administered when marketed. When these studies are completed and the sponsor believes that the drug is safe and effective under specific conditions, the sponsor applies to the FDA for approval to market the drug. Phase 3 trials usually involve several hundred to several thousand patient-subjects.

Phase 4 Drug Trial

Concurrent with marketing approval, the FDA may seek agreement from the sponsor to conduct certain post-marketing (Phase 4) studies to delineate additional information about the drug's risks, benefits, and optimal use. These studies could include, but would not be limited to, studying different doses or schedules of administration than were used in Phase 2 studies, use of the drug in other patient populations or other stages of the disease, or use of the drug over a longer period of time [21 CFR - 312.85].

Significant Risk and Nonsignificant Risk Investigational Medical Devices

A Significant Risk Device (SR) study is defined [21 CFR 812.3(m)] as a study of a device that presents a potential for serious risk to the health, safety, or welfare of a subject and (1) is an implant; (2) is used in supporting or sustaining human life; (3) is of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise prevents impairment of human health; or, (4) otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.

A Nonsignificant Risk Device (NSR) investigation is one that does not meet the definition for a significant risk study. However, NSR device studies should not be confused with the concept of "minimal risk," a term used in the Institutional Review Board (IRB) regulations [21 CFR part 56] to identify certain studies that may be approved through an "expedited review" procedure.

For both SR and NSR device studies, IRB approval prior to conducting clinical trials and continuing review by the IRB are required. In addition, informed consent must be obtained for either type of study [21 CFR part 50].

Distinguishing Between SR and NSR Device Studies

The effect of the SR versus NSR decision is very important to research sponsors and investigators. SR device studies are governed by the IDE regulations [21 CFR part 812]. NSR device studies have fewer regulatory controls than SR studies and are governed by the abbreviated requirements [21 CFR 812.2(b)]. The major differences are in the approval process and in the record-keeping and reporting requirements. The SR versus NSR decision is also important to the FDA because the IRB serves, in a sense, as the Agency's surrogate with respect to review and approval of NSR studies. The FDA is usually not apprised of the existence of approved NSR studies, because sponsors and IRBs are not required to report NSR device study approvals to the FDA.

If an investigator or a sponsor proposes the initiation of a claimed NSR investigation to an IRB, and if the IRB agrees that the device study is NSR and approves the study, the investigation may begin at that institution immediately, without submission of an IDE application to the FDA. If an IRB believes that a device study is SR, the investigation may not begin until both the IRB and the FDA approves the investigation. To help in the determination of the risk status of the device, IRBs should review information such as reports of prior investigations conducted with the device, the proposed investigational plan, a description of subject selection criteria, and monitoring procedures. The sponsor should provide the IRB with a risk assessment and the rationale used in making its risk determination [21 CFR 812.150(b)(10)].

Definitions and Interpretations

The Office for Human Research Protection (OHRP) of the US Department of Health and Human Services prepared federal rules on "Emergency Use of a Test Article."

Emergency use is defined as 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 for the use. The Investigator is still required to obtain informed consent under these circumstances.

The IRB requires the Investigator to submit, within 24 hours, a letter describing the nature of the situation as well as requesting approval for use of the test article. The Chairperson must be contacted prior to Emergency/Compassionate use of the test article to determine whether or not the request meets the emergent use criteria. The Chairperson has the option to convene an Ad Hoc committee to review the merit of the request; as well as, the option to decide whether the test article may be used prior to full IRB committee review.

Subsequent use of the test article is subject to IRB review [21 CFR 50.23; 21 CFR 56.104(c)]. "Subsequent use" means any use of the test article that occurs after its initial emergency use. When an IRB receives a report by a clinical Investigator of an emergency use, the IRB must examine each case to assure itself and the institution that the emergency use was justified.

Although 21 CFR 56.104 is designed to permit only a single emergency use of a test article for the treatment of one patient by one physician within an institution, the regulation is not intended to limit the authority of a physician to provide emergency care in a life-threatening situation. Should a situation arise which would require the emergency use of the test article for a second patient, either by the same or a second physician, subsequent emergency use should not be withheld for the purpose of gaining IRB approval. If it appears probable that similar emergencies will require subsequent use of the test article at the institution, every effort should be made either to sign on to the sponsor's protocol or to develop a protocol for future emergency use of the article at the institution. Either of these protocols would need to be prospectively reviewed and approved by the IRB for future use of the test article.

Informed Consent Exemption

In emergency circumstances, it may not be feasible to obtain informed consent prior to using the test article. The regulations therefore provide an exemption from the informed consent requirement for such situations. Emergencies qualifying for this exemption are defined as:

  1. Life-threatening situations necessitating use of the test article
  2. Where the subject is unable to provide effective consent
  3. There is insufficient time in which to obtain consent from the subject's legal representative
  4. No available alternative approved or generally recognized therapy has an equal or greater likelihood of saving the subject's life [21 CFR 50.23(a)(1)-(4)].

Special procedures for documenting the unfeasibility of obtaining consent apply as follows:

  1. The Investigator, and a physician who is not participating in the clinical investigation, must certify in writing to the existence of all four of the above conditions before using the test article [21 CFR 50.23(a)].
  2. If, in the investigator's opinion,
    • immediate use of the test article is necessary to save the life of the subject
      AND
    • there is insufficient time to obtain the independent determination required by - 50.23(a) before using the test article
      THEN
    • the Investigator is to make his/her own written determination, then obtain the written review
      and independent evaluation of a physician who is not participating in the clinical investigation
      within 5 working days after the use of the test article [21 CFR 50.23(b)].

The documentation required by either 21 CFR 50.23(a) or 50.23(b) must be submitted to the IRB within 5 working days after the use of the test article [21 CFR 50.23(c)].

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