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THE COMMITTEE ON HUMAN RESEARCH

UCSF GUIDANCE ON RESEARCH TOPICS AND ISSUES

INVESTIGATIONAL NEW DRUGS AND BIOLOGICS (IND)
(June 2004, Revised May 2006, Revised February 2008, Revised August 2008)

•	Brief Overview
•	When is an IND Required?
•	When is an IND Not Required?
•	Types of IND Applications
•	Timing the IND Submission
•	CHR Application Requirements
•	Consent Form Requirements
•	Control of Investigational Drugs and Biologics
•	Adverse Event Reporting
•	Additional Reporting Obligations for Investigators-Sponsors
•	Additional Procedures for VA Investigators
•	Resources

Brief Overview

Food and Drug Administration (FDA) regulations 21 CFR 312 (drugs) and 601 (biologics) contain procedures and requirements governing the use of investigational new drugs and biologics. All clinical research projects involving drugs or biologics which are not FDA-approved for marketing must be reviewed by the FDA. This is done by filing an Investigational New Drug Application (IND).

When is an IND Required?

•	Any use of a drug or biologic not approved for marketing by the FDA, even if no study is being conducted.
•	Studies involving a drug or biologic that is not approved by the FDA.
•	Studies involving an approved (i.e., commercially available) drug or biologic that is being tested to support a new indication or significant change in labeling of the drug or biologic.
•	Studies involving an approved drug or biologic that is being tested to support a significant change in advertising for the drug or biologic.
•	Studies involving an approved drug or biologic that is being used or tested in a new route of administration, new dosage level, or new patient population that may increase the risk of the drug or biologic.

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When is an IND Not Required?

Please review the HRPP information sheet, Exemptions from IND Requirements for a complete list of all types of investigations which are exempt from FDA IND requirements, according to 21 CFR 312.2.

Additional discussion is provided below for clinical research of approved drugs or biologics.

•	Clinical Studies: Any clinical investigation of a marketed drug or biologic requires CHR review and approval. An IND is not required if all of the following conditions are met:
	•	It is not intended to be reported to the FDA in support of a new indication for use or to support any other significant change in the labeling; and
	•	It is not intended to support a significant change in the advertising for the product; and
	•	It does not involve a route of administration or dosage level, use in a subject population, or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the product; and
	•	It is conducted in compliance with the requirements for IRB review and informed consent [21 CFR parts 50 and 56 respectively]; and
	•	It is conducted in compliance with the requirements concerning the promotion and sale of drugs [21 CFR 312.7]. NOTE: Even when there is no immediate intent to change product labeling or advertising, investigators who are planning rigorous, carefully controlled clinical investigations of an off-label uses of approved drugs or biologics should obtain an IND for the study. The CHR has serious concerns about conducting such studies without an IND because the data, even if positive and important for public health, will not be considered by the FDA. Example: An investigator proposes a small pilot study of an approved drug for a novel use and states that an IND is not needed because the data will not be submitted to the FDA. The investigator explains that if the pilot data looks promising a larger trial will be submitted with an IND. The CHR is likely to approve the pilot study without an IND because a small pilot study is an appropriate first step in determining whether a change in labeling should be sought. Example: An investigator proposes a multicenter randomized trial of an approved drug for a novel use and states that an IND is not needed because the data will not be submitted to the FDA. The CHR is not likely to approve the study without an IND because the data could be important and should be considered by the FDA.
•	Off-Label Prescriptions: Neither an IND nor CHR review is required for off-label use of a marketed drug or biologic as long as such use is strictly for clinical purposes, and the results are not presented as research.

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Types of IND Applications

•	Commercial IND – submitted by a sponsor that intends to market the product upon FDA approval.
•	Investigator-Initiated IND – submitted by a physician who both initiates and conducts an investigation.
•	Emergency Use IND – issued by the FDA to allow the use of an experimental drug or biologic for the treatment of one patient when there are no other reasonable treatment options and there is not time for submission and review of a regular IND or for IRB review. Research may not be conducted under an emergency use IND. An emergency use IND exemption may be used one time only for a particular drug or biologic at a particular institution. Subsequent uses require prior CHR review and approval. For more information, please review the CHR Guidelines on the Emergency Use and Compassionate Use of Experimental Drugs and Devices.
•	Treatment Use of Investigational Drugs – submitted for experimental drugs showing promise in clinical testing for serious or life-threatening conditions while the final clinical work is conducted and the FDA review takes place. For more information, please see http://www.fda.gov/oc/ohrt/irbs/drugsbiologics.html-treatment. CHR review is required for any Treatment IND and Group C Treatment IND studies, even if the FDA has granted a waiver from local IRB requirements.

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Timing the IND Submission

•	Pre-IND Advice: Investigators considering submitting an IND application to the FDA should consult the FDA’s Office of Drug Evaluation IV (ODE IV) Pre-IND Consultation Program before submitting an IND application.
•	The IND Submission: The IND submission to the FDA and the CHR application should be initiated at the same time. The FDA has 30 days to review the IND application. Likewise, the CHR typically reviews an application within a 30-day window, but it may take longer to secure approval. Subjects may not be recruited or enrolled before FDA and CHR approval.

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CHR Application Requirements

•	IND Number - When an investigation requires an IND number, the CHR will not issue final approval until the IND number is reported to and verified by the CHR. Verification can be accomplished by providing a copy of the sponsor's protocol with the IND number listed, or by submitting correspondence from the sponsor or FDA indicating the IND number for the study. However, the CHR will review the research before the IND application is submitted to the FDA. The FDA does not require local IRB approval before issuing IND numbers.
•	Investigator’s Brochure - For any study involving an investigational drug or biologic, one copy of the Investigator’s Brochure must be submitted with the CHR application.
•	Protocol – If there is a sponsor’s, multicenter, or “full” protocol, one copy of that protocol must accompany the CHR application.
•	FDA Form 1572 – This form is required for FDA purposes and does not need to be submitted to the CHR.

Consent Form Requirements

•	Purpose and Background Section:
	•	Must include a clear statement that the drug or biologic is investigational and has not been approved or, if studying an approved drug or biologic, that it is approved but not for the use being studied.
	•	Should include a brief lay description of what the drug or biologic is and how it is thought to act.
	•	Must not state or imply that the issuance of an IND is an approval or endorsement by the FDA.
•	Confidentiality Section:
	•	Must state that the FDA may review subjects’ medical records and research records which identify the subjects.
•	Alternatives Section:
	•	If studying an approved drug or biologic, must explain that subjects can receive drug or biologic without participating in the study. An exception to this may be granted if the off-label prescription of the drug or biologic is unrealistic or unsafe outside of a carefully controlled clinical study.
•	Costs Section:
	•	Must state how the costs of the study drug or biologic will be covered.

Control of Investigational Drugs and Biologics

Local Dispensing Policies and Regulations

Hospitals or other clinical settings have their own policies regarding the use of investigational drugs and biologics in order to assure patient safety and comply with JCAHO standards, California law, and California Department of Health Services regulations. Investigators conducting research in clinical settings other than those listed below should consult those local policies and the personnel charged with compliance with those policies. Consultation should take place before preparing the budget for the clinical study.

UCSF Medical Center Policies can be found at: InvestigationalNewDrugs.pdf

Investigational Drug Pharmacists:
•	Parnassus / Mt Zion campus:	Scott Fields, PharmD 415.353.1798
•	UCSF/Mt Zion Cancer Center:	Monica Lee, PharmD 415.353.7052
•	San Francisco VAMC:	Henry Leung, PharmD 415.221.4810 x 2925
•	San Francisco General Hospital:	David Dupre, PharmD 415.206.4926

Investigator Responsibilities for Control of Investigational Drugs/Biologics

Investigators conducting studies in which an investigational drugs/biologics will be used must ensure adequate control of the drug or biologic. Adequate control and handling of investigational drug/biologic include all of the following:

•	The investigator should ensure that the investigational drug/biologic is used only in accordance with the CHR-approved protocol.
•	An investigator must administer the investigational drug/biologic only to participants under the investigator’s direct personal supervision or under the supervision of a sub-investigator directly responsible to the investigator.
•	The investigator must not supply the investigational drug/biologic to any person not authorized to receive it.
•	An investigator is required to maintain adequate records of the disposition of the investigational drug/biologic, including dates of dispensing, quantity currently maintained for dispensing, and amount of the investigational product dispensed to participants.
•	If the investigation is terminated, suspended, discontinued, or completed, the investigator must return any unused supplies of the investigational drug/biologic to the study sponsor, or otherwise provide for disposition of the unused supplies as directed by the sponsor.
•	If the investigational drug is subject to the Controlled Substances Act, the investigator must take adequate precautions, to prevent theft or diversion of the substance into illegal channels of distribution. These precautions include: storage of the investigational drug in a securely locked, substantially constructed cabinet, or other securely locked, substantially constructed enclosure to which access is limited.

Sample Investigational Agent Accountability Record

Adverse Event Reporting

Under federal regulations for the protection of human subjects in research both the Committee on Human Research (CHR) and the FDA require that adverse events associated with research participation be reported in an expedited manner.

	•	Investigator’s Responsibilities: All investigators have an obligation to report certain adverse events (AE) directly to the IRB. Please review the CHR Guidelines on Adverse Event Reporting for a detailed description of the CHR reporting requirements. When an IND is issued, there are additional and separate federal requirements for reporting adverse events to the FDA. When the study sponsor holds the IND, investigators need to report all adverse events to the sponsor and the sponsor will submit appropriate reports to the FDA.
	•	Investigator-Sponsor Responsibilities: An Investigator who files an IND is also said to “hold the IND” for the specific study protocol. Investigators who hold an IND (investigator-initiated/investigator-sponsor IND) have responsibilities for reporting AEs to the FDA as well as the CHR. In addition to reporting to the CHR, an investigator-sponsor must directly report the following AE information to the FDA:
		•	Within 7 calendar days after the study sponsor’s initial receipt of the information. The sponsor should notify the FDA by telephone or by facsimile transmission of any unexpected fatal or life-threatening experience associated with the use of the drug.
		•	Within 15 calendar days after the sponsor’s initial receipt of the information. The sponsor should notify the FDA and all participating investigators in a written IND safety report of: (A) Any adverse experience associated with the use of the drug that is both serious and unexpected; or (B) Any finding from tests in laboratory animals that suggests a significant risk for human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
		•	Additionally, an investigator-sponsor is responsible for reporting safety information to the FDA:
				“The sponsor shall promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from any source, foreign or domestic, including information derived from any clinical or epidemiological investigations, animal investigations, commercial marketing experience, reports in the scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory authorities that have not already been previously reported to the agency by the sponsor” (21 CFR 321.32(b)).

Additional Reporting Obligations for Investigators-Sponsors

When an Investigator files an IND, the Investigator is considered the Sponsor and as such carries all of the FDA regulatory responsibilities and reporting obligations of both the Investigator and Sponsor as outlined below described in the FDA regulations 21 CFR 312 (drugs) and 21 CFR 601 (biologics). Please refer to the regulations for complete information.

•	FDA reporting obligations of investigators under an IND include:
	•	Drug disposition
	•	Case histories
	•	Progress reports
	•	Safety reports
	•	Final report
	•	Financial disclosure report
	•	Specific record keeping and record retention
•	FDA reporting obligations of sponsors under an IND include:
	•	Protocol amendments
	•	Information amendments
	•	IND Safety Reports
	•	Annual Reports
	•	Withdrawal of an IND
	•	Specific record keeping and retention

Additional Procedures for VA Investigators

When the study is conducted at the SFVAMC, the following additional reporting obligations must be met:

Resources

•	FDA reporting obligations of investigators under an IND include:
	•	Drug disposition
	•	Case histories
	•	Progress reports
	•	Safety reports
	•	Final report
	•	Financial disclosure report
	•	Specific record keeping and record retention
•	FDA reporting obligations of sponsors under an IND include:
	•	Protocol amendments
	•	Information amendments
	•	IND Safety Reports
	•	Annual Reports
	•	Withdrawal of an IND
	•	Specific record keeping and retention

•	RKS • Regulatory Knowledge and Support Service The Regulatory Knowledge and Support Service, part of the UCSF Clinical and Translational Science Institute, is available to help researchers understand and meet the many regulatory and compliance requirements in the pre-award and post-award process. The RKS Program includes the Diagnostics and Therapeutics Regulatory Consulting Service (DTRCS), which is available to provide advice and guidance to investigators planning submissions to the U.S. Food and Drug Administration.
•	FDA Center for Drug Evaluation and Research
	•	Information For Sponsor-Investigators Submitting INDs
	•	Pre-IND Consultation Program
	•	Forms
•	FDA Guidance for Institutional Review Boards and Clinical Investigators: Drugs and Biologics
•	Applicable FDA Regulations:
•	21 CFR 11: Electronic Records; Electronic Signatures
•	21 CFR 54: Financial Disclosure by Clinical Investigators
•	21 CFR 210: Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General
•	21 CFR 211: Current Good Manufacturing Practice for Finished Pharmaceuticals
•	21 CFR 312: Investigational New Drug Application
•	21 CFR 314: Applications for FDA Approval to Market a New Drug
•	21 CFR 320: Bioavailability and Bioequivalence Requirements
•	21 CFR 330: Over-The-Counter Human Drugs Which Are Generally Recognized As Safe And Effective And Not Misbranded
•	21 CFR 601: Biologics Licensing