FDA Guidance for Institutional Review Boards and Clinical Investigators
1998 Update

Drugs and Biologics

Emergency Use of an Investigational Drug or Biologic

• Obtaining an Emergency IND
• Emergency Exemption from Prospective IRB Approval
• Exception From Informed Consent Requirement
• Planned Emergency Research, Informed Consent Exception

Treatment Use of Investigational Drugs
Waiver of IRB Requirements
Drug Study Designs
Evaluation of Gender Differences

Emergency Use of an Investigation Drug or Biologic

The emergency use of test articles frequently prompts questions from Institutional Review Boards (IRBs) and investigators. This information sheet addresses three areas of concern: emergency Investigational New Drug (IND) requirements; IRB procedures; and informed consent requirements.

The emergency use of an unapproved investigational drug or biologic requires an IND. If the intended subject does not meet the 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 company'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. In such a case, FDA may authorize shipment of the test article in advance of the IND submission. Requests for such authorization may be made by telephone or other rapid communication means [21 CFR 312.36].

Emergency Exemption from Prospective IRB Approval

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)]. 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.

Life-threatening, for the purposes of section 56.102(d), includes the scope of both life-threatening and severely debilitating, as defined below.

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.
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.

Institutional procedures may require that the IRB be notified prior to such use, however, this notification should not be construed as an IRB approval. Notification should be used by the IRB to initiate tracking to ensure that the investigator files a report within the five day time-frame required by 21 CFR 56.104(c). The FDA regulations do not provide for expedited IRB approval in emergency situations. Therefore, "interim," "compassionate," "temporary" or other terms for an expedited approval process are not authorized. An IRB must either convene and give "full board" approval of the emergency use or, if the conditions of 21 CFR 56.102(d) are met and it is not possible to convene a quorum within the time available, the use may proceed without any IRB approval.

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, some IRBs have sent to 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.

This policy is undergoing review and is subject to change.

Exception From Informed Consent Requirement

Even for an emergency use, the investigator is required to obtain informed consent of the subject or the subject's legally authorized representative unless both the investigator and a physician who is not otherwise participating in the clinical investigation 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 suhigh demand.

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Are all investigational drugs available through an expanded access or special exception mechanism?

No. The drug company or sponsor decides whether to provide an investigational drug outside the clinical trials setting. Availability may be limited in part by drug supply, patient demand, or other factors.

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What is the NCI's role in providing access to investigational drugs?

The NCI acts as the sponsor for many, but not all, investigational drugs. When acting as sponsor, the NCI provides the investigational drug to the physicians who are participating in clinical trials of the drug. A physician who wishes to treat a patient with the investigational drug as a special exception must request the drug from the NCI. The request must include the patient's age, sex, diagnosis, date of diagnosis, previous cancer therapy, current clinical status, intended dose and schedule of the requested drug, any proposed concomitant cancer drugs or other therapies, and pertinent laboratory data. These requests are reviewed on a case-by-case basis.

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Who can provide access to investigational drugs being developed by pharmaceutical companies?

In the case of investigational drugs sponsored by a drug company, the drug company in collaboration with the FDA provides access to the drug. The process is similar to that described above.

A request to treat a patient with an investigational drug outside a clinical trial must be made to the drug company and to the FDA. The request to the FDA is sent as general correspondence to the appropriate reviewing division where the IND application is filed. The drug company can provide the name of the appropriate reviewing division. (FDA reviewing divisions are prohibited from divulging proprietary information such as whether a sponsor has filed an IND or the status of an IND.)

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Are there specific criteria used to determine whether patients can receive an investigational drug outside the clinical trial setting?

Generally, patients must meet the following criteria to be considered for treatment with an investigational drug outside the clinical trial setting; they must:

• have undergone standard treatment that has not been successful;
• be ineligible for any ongoing clinical trials; and
• have a cancer diagnosis for which an investigational drug has demonstrated activity and is being studied in ongoing Phase 2 or Phase 3 protocols

The potential benefits of receiving the drug should outweigh the risks involved.

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What should patients do if they are interested in receiving an investigational drug through a special exception or expanded access mechanism?

Patients interested in gaining access to investigational drugs should talk to their physician about available options. Physicians can make requests for special exceptions by contacting the study sponsor. Physicians will be required to follow strict guidelines, including gaining approval from their Institutional Review Board and obtaining "informed consent" from the patient. Informed consent is a process that includes a document to be signed by the patient that outlines the known risks and benefits of the treatment, as well as the rights and responsibilities of the patient.

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What are the costs involved in receiving an investigational drug?

In general, the drug is provided free of charge. However, there may be other costs associated with the treatment. Patients should check with their insurer about coverage of these costs prior to beginning treatment.

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What are some of the potential drawbacks to receiving an investigational drug?

There are some potential drawbacks to receiving an investigational drug. It is not known whether an investigational drug is better than standard therapy for treating a disease, and a patient who is receiving an investigational drug may not receive any benefit from it. Side effects (both long-term and short-term) from the drug may not be fully understood, especially if the drug is in early phases of testing. Finally, a patient's health insurance company may not pay expenses associated with receiving the investigational drug.

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How can patients find out more information about a specific investigational drug?

Patients can find out more about a specific drug by contacting the drug company that is developing the drug. Information may also be available from the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

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What other resources are available on this topic?

The following list of resources may be helpful:

1. NCI's cancerTrials Web site has a feature titled Understanding the Approval Process for New Cancer Drugs.
   
   
2. FDA Center for Drug Evaluation and Research Web site has Oncology Tools, which contains a variety of information related to cancer including a section on access to unapproved drugs.
   
   
3. CTEP (the Cancer Therapy Evaluation Program at NCI) has a feature titled Developing Cancer Therapies.