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THE COMMITTEE ON HUMAN RESEARCH

UCSF GUIDANCE ON RESEARCH TOPICS AND ISSUES

Emergency Use and Compassionate Use of Experimental Drugs and Devices (August 2004, revised August 2005)

•	Brief Overview
•	Terms and Definitions
	•	Research Use
	•	Emergency Use
	•	Compassionate Use
	•	Research in Emergency Medicine
	•	Innovative Treatment (Off-Label Use)
	•	Humanitarian Device Exemption
•	Ethical Considerations
•	Emergency Use Requirements
	•	Meeting the Criteria
	•	Contacting the CHR
	•	Obtaining Informed Consent
	•	Notifying the FDA
	•	Submitting a Post-Use Written Report
•	Obtaining Informed Consent
•	Notifying the FDA
•	Submitting a Post-Use Written Report
•	Consequences of Noncompliance with Federal Regulations
•	Forms
	•	Emergency Use Compliance Checklist
	•	Emergency Use Written Report Form
•	Resources

Brief Overview

The University and the Food and Drug Administration (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 [21 CFR 56.104(c)] allows physicians restricted access to experimental treatments that would be otherwise off-limits. This guidance aims to support physicians by clarifying the strict emergency use requirements, and, by outlining the necessary procedures, to help ensure physicians are in full compliance with those requirements.

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

A physician who treats a patient under emergency use provisions must justify the treatment according to strict criteria, consult with the Committee on Human Research (CHR), and fulfill specific follow-up responsibilities in a timely manner.

Separate rules govern what is often called “compassionate use” of investigational drugs, biologics and devices. These are described below.

Terms and Definitions

The Food and Drug Administration (FDA) strictly regulates all use of drugs, biologics, and devices that have not been approved for marketing by the FDA. Different regulations apply to the different types of test article use, and the terminology can be confusing.

•	Research Use: Most administration/use of unapproved devices, drugs, or biologics is part of a systematic clinical trial or other clinical investigation designed to test the safety and/or efficacy of the test article. All such clinical investigations, including pilot studies, require prior CHR review and approval. In addition, almost all clinical studies are conducted under an Investigational Device Exemption (IDE) or an Investigational New Drug (IND) exemption obtained from the FDA, which require that research protocols be filed with the FDA prior to study commencement.
•	Emergency Use: Emergency use of an unapproved device, drug or biologic is intended to benefit a single patient who is not eligible for a study approved at the treating institution. Generally, emergency use of a test article requires either an IND (for unapproved drugs and biologics) or an IDE (for unapproved devices). FDA regulations [21 CFR 56.104(c) and 21 CFR 56.102(d)] provide an “emergency use” exemption from rules requiring prior CHR review and approval. However, reporting the use to the CHR is required by the FDA, and UCSF requires consultation with the CHR prior to use if possible. The following five criteria must be met to comply with federal regulations and University policy:
	1)	The test article is used one time per institution to treat a single patient, and
	2)	The patient has a condition that is life-threatening or severely debilitating, and
	3)	No standard treatment is available, and
	4)	There is not sufficient time to obtain CHR review and approval, and
	5)	The emergency use is reported to the CHR within five working days; when possible, the treating physician should consult with the CHR prior to use. IMPORTANT NOTES:
		•	There are strict requirements for consulting with and reporting to the CHR, the sponsor/manufacturer of the test article, and the FDA. See Emergency Use Requirements below.
		•	Emergency use is emergency clinical care and does not meet the DHHS definition of research. {45 CFR 46.102(d), although the FDA considers it research but allows an exemption from CHR review. CHR 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 CHR approval to conduct a research study under DHHS rules.
•	Compassionate Use: Physicians tend to use “compassionate use” to refer to the treatment of a seriously ill patient using an unapproved test article where no other available treatments are satisfactory. Such use of an investigational drug, biologic, or device actually falls into one of the following treatment mechanisms and is allowed only after prior review and approval by the CHR, and in most circumstances prior approval by the FDA as well. Prior CHR approval is needed even if only one patient is to be treated under the following mechanisms:
		Expanded Access
		•	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 CHR 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: Uncontrolled studies, 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 CHR approval are required.
•	Enrollment Exception to the Inclusion/Exclusion Criteria of an Approved Protocol: In order to allow treatment of a single patient who does not meet the entry criteria of a CHR-approved protocol, the Principal Investigator should submit a written request for a one-time, one-patient enrollment exception as a modification request to the CHR. Such a request, which should be rare, must be justified in terms of serving the best interests of the patient.
		•	The request is for one-time, one-patient only.
		•	The request will be referred to the appropriate Chair who will evaluate the level of review required.
		•	If there is a study sponsor, an enrollment exception usually requires sponsor approval as well.
		•	Data collection should be reported using the standard study case report forms and become part of the scientific evaluation of the test article.
			IMPORTANT NOTE: CHR approval is required before a one-time, one-patient exception to the enrollment criteria of an approved protocol can be made. To help expedite the request and to make sure the paperwork is in order, researchers considering this option should call the CHR office at (415) 476-1814 and ask to speak with a committee analyst responsible for modifications.
•	Research in Emergency Medicine: Planned research designed to evaluate emergency care treatments is not “emergency use.” As with all other clinical research, prospective CHR review and approval are required before a clinical study in emergency medicine can begin. The unique exception from informed consent for these studies is provided by federal regulations enforced by the Food and Drug Administration [21 CFR 50.24] and the Office for Human Research Protections [45 CFR 46.101(i)] . The emergency medical research waiver of informed consent is described elsewhere.
•	Innovative Treatment (Off-Label Use): Emergency use provisions apply to investigational drugs, biologics, and devices. The innovative use of a marketed drug or device (sometimes called “off-label” use) for individual patient treatment rather than for research purposes does not require CHR review.
	IMPORTANT NOTE: Treating a series of patients in a novel or innovative manner and analyzing the results for publication is research requiring prior CHR review.
•	Humanitarian Device Exemption: A Humanitarian Device Exemption (HDE) is a special approval given by the FDA that allows marketing a device that is designed to treat or diagnose a condition that affects fewer than 4,000 individuals per year. An HDE is given even though the efficacy of the device has not been tested or proven, because it is not financially feasible to do the usual clinical testing when so few individuals are affected. The FDA requires CHR approval prior to use of a Humanitarian Use Device (HUD), even though the use is not considered research. The CHR requires a standard application, use of a consent form similar to research consent, and annual review. Call the CHR office for additional guidance. UCSF guidelines are under development.

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Ethical Considerations

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.

•	Unproven Efficacy: Physicians are often enthusiastic about the possible benefits of an investigational drug or device. However, the lack of FDA approval usually means the safety and efficacy have not been scientifically proven. The possible but unproven benefits of the experimental treatment must be weighed against its risks and against the possible benefits of available alternatives.
•	Lack of Scientific Benefit: 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.
•	Informed Consent: 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.

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Emergency Use Requirements

The following is an overall summary of requirements with links to more detailed information on each topic. A separate, one-page Compliance Checklist is provided.

•	Meeting the Emergency Use Criteria: The following five 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, and
	2)	The patient has a condition that is life-threatening or severely debilitating, and
	3)	No standard treatment is available, and
	4)	There is not sufficient time to obtain prior CHR review and approval, and
	5)	The CHR is notified of the emergency use within five working days; when possible the treating physician should consult with the CHR prior to use.
	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, given the frequency of the CHR meetings, that there is “not sufficient time” to obtain prior CHR approval.

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

•	Contacting the Committee on Human Research (CHR)
	•	Detailed instructions are provided in the Compliance Checklist. A brief summary follows:
	•	A physician planning to use an unapproved drug, biologic, or device under emergency use provisions must contact the CHR office at (415) 476-1814 prior to the procedure, if at all possible. The CHR office is well staffed and calls regarding emergency use are handled as expeditiously as possible.
	•	The CHR office will ask a few questions and direct the treating physician to the appropriate Chair or vice chair so that the chair can review the case with the physician to determine if the case meets FDA criteria for emergency use.
	•	If it is known in advance that it will not be possible to obtain consent from the patient or the patient’s legally authorized representative, the physician should also discuss with the Chair whether the use meets FDA criteria for waiving consent.
	•	If the Chair agrees that the proposed treatment meets the FDA criteria for emergency use and, if applicable, waiver of consent, the CHR will send the physician a letter documenting that the FDA criteria have been met. Sponsors often require a copy of this letter from the CHR before they will ship or release the test article. Early interaction with the CHR will help expedite the preparation of the letter, if needed.
	•	If it is not possible to contact the CHR office prior to the emergency use, a Post-Use Written Report (see below) must be submitted to the CHR within 5 working days of use.
•	Obtaining Informed Consent
	•	Patient protection measures are specified under the emergency use regulations.
	•	Written informed consent signed by the patient or the patient’s surrogate (legally authorized representative) is required. If written informed consent is not possible, there are special provisions for an informed consent waiver. Please follow the links or scroll down to the “Obtaining Informed Consent” section for more details
•	Notifying the FDA
	•	The FDA must be notified of the emergency use by the holder of the IND/IDE. If the physician is not the IND/IDE holder, he/she must notify the sponsor about the emergency use so that the sponsor can notify the FDA.
	•	See the separate section Notifying the FDA for FDA contact information and for investigator/sponsor responsibilities.
•	Submitting a Post-Use Written Report
	•	For tracking purposes, the FDA requires the treating physician to document the emergency use in writing and submit the report to the Institutional Review Board, the Committee on Human Research at UCSF. The report must include the treatment justification, a copy of the informed consent, and a description of the results obtained from using the test article.
	•	The report should be submitted to the CHR within five working days of the emergency use. See Post-Use Written Report for detailed instructions. An optional form may be used.
Obtaining Informed Consent
•	Written informed consent is required for the emergency use of an unapproved drug, biologic, or medical device.
	•	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).
		•	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 most of the elements of informed consent found in the UCSF template “Consent to Be a Research Subject”. It must be stated clearly that:
			•	the subject is NOT part of a research study, and
			•	there is no guarantee of benefit, and
			•	the treatment is experimental and not approved by the FDA.
	•	A signed copy of the informed consent must be included in the post-use written report. IMPORTANT NOTE: Because the FDA exempts emergency use from requirements for CHR review, prior CHR approval of the consent form is not needed.
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•	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.
Notifying the FDA
•	The FDA must be notified by the holder of the IND (investigational drugs and biologics) or IDE (medical devices). The FDA usually provides a new number for the specific emergency use.
	•	Industry-sponsored IND/IDE: The physician must notify the manufacturer or sponsor about the emergency use and the sponsor notifies the FDA for IND/IDE approval.
	•	Physician-sponsored IND/IDE, or if no IND/IDE exists: The physician must notify the FDA about the emergency use; the contact information is provided below: Test article (Branch) Office/Division Drugs (CDER) Division of Drug Information (HFD-240) 301-827-4570 Biologics (CBER) Office of Communication, Training and Manufacturers Assistance (HFM-40) 301-827-2000 Devices (CDRH) Program Operation Staff 301-594-1190 After normal working hours FDA Office of Emergency Operations (HFA-615) 301-443-1240
Submitting a Post-Use Written Report
	•	Within five working days after the emergency use occurrence, the treating physician is required to submit a written report to the CHR. To facilitate the preparation of the report, an optional form is available. Regardless of format, the report must contain the following information:
		1.	Physician’s name, department address, phone numbers
		2.	Name of test article (unapproved drug, biologic, or device)
		3.	Name of sponsor (IND/IDE holder for test article)
		4.	Date of CHR notification
		5.	Date the test article was used
		6.	Name of patient
		7.	Rationale for test article use
		8.	Results of test article use: If not available within the initial reporting period (5 working days), results must be reported to CHR within 10 working days of the occurrence.
		9.	The IND or IDE number.
		10.	Copy of signed Informed Consent form or justification to waive informed consent.
		IMPORTANT NOTE: Any adverse event (AE) that results from the emergency use of an investigational drug or device is subject to AE reporting requirements.

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Consequences of Noncompliance with Federal Regulations

As mentioned in the “Brief Overview” of these guidelines, the University and the FDA wish to support a physician's obligation to treat a seriously ill patient with all available modalities. If, however, 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.

CHR Oversight:

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

Forms

Resources