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) with the Food and Drug Administration (FDA).

FDA regulations 21 CFR 312 (drugs) and 601 (biologics) contain procedures and requirements governing the use of investigational new drugs and biologics. The IND Submissions section of the UCSF CTSI HUB provides additional info on this topic. Also review the Investigational New Drug (IND) Application section of the FDA website, as well as the definitions for “drug” and “biologics.”

FDA Regulatory Support at UCSF provides free consultations to the UCSF community on compliance with FDA regulations, including IND applications.

Note: All clinical investigations of drugs or biologics, whether or not approved for marketing by the FDA, require IRB review and approval.

When Is an IND Required?

An IND is required for:

Note: Any use of an IND requires IRB approval, except in the rare care of an Emergency Use IND as described below.

When Is an IND Not Required?

Please review the IND Decision Worksheet on the UCSF HUB for a complete list of all types of investigations involving drugs and biologics that are exempt from FDA IND requirements according to FDA regulations 21 CFR 312.2.

The following are examples of the use of drugs or biologics that are exempt from FDA IND requirements:

Important 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 IRB 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.

Note: Any clinical investigation of a marketed drug or biologic requires IRB review and approval.

3. A clinical investigation involving use of a placebo is exempt from IND requirements if the investigation does not otherwise require submission of an IND.

4. A drug intended solely for tests in vitro or in laboratory research animals is exempt from IND requirements if shipped in accordance with 21CFR 312.160.

Neither an IND nor UCSF IRB review is required for an off-label use of a marketed drug (approved under part 21 CFR 314) or a licensed biologic as long as such use is strictly for clinical purposes, and the results are not collected for or presented as research.

Example of when an IND may not be needed: 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 IRB 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 of when an IND is needed: An investigator proposes a multi-center 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 IRB is not likely to approve the study without an IND because the data could be important and should be considered by the FDA.

Types of IND Applications

The FDA makes the following distinction between a “sponsor” and a “sponsor-investigator” and a “commercial IND” and an “investigator-initiated” IND.

"Sponsor" means a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor, not a sponsor-investigator, and the employees are investigators.

A commercial IND is submitted by a sponsor that intends to market the product upon FDA approval.

“Investigator-Sponsor” means an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. The term does not include any person other than an individual. The requirements applicable to a sponsor-investigator under this part include both these applicable to an investigator and a sponsor.

An investigator-initiated IND is submitted by an investigator (physician or PhD or PharmD) who both initiates and conducts an investigation.

An emergency use IND is 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 IRB review and approval.

For more information, please review the UCSF IRB guidelines on the Emergency Use and Compassionate Use of Experimental Drugs and Devices.

Expanded Access to Unapproved Drugs for Treatment

FDA allows certain individuals not enrolled in clinical trials to obtain expanded access to investigational drugs, agents, or biologics through the methods described below, under the following circumstances:

Important Notes:

In some cases, an IRB Chairperson can concur with individual patient expanded access treatment via an expedited review procedure. A physician submitting an individual patient expanded access IND using Form FDA 3926 may select the appropriate box on that form to request a waiver of full IRB review. FDA concludes that such a waiver is appropriate for individual patient expanded access INDs when the physician obtains concurrence by the IRB Chairperson or another designated IRB member before treatment use begins. A physician submitting an individual patient expanded access IND using Form FDA 1571 may include a separate waiver request with the application. Review the FDA guidance document for more information.

Please note: If the IRB Chairperson has concerns about the treatment, he/she reserves the right to refer the expanded access application to the IRB Committee for review at a convened meeting.

Various Expanded Access Programs

This type of expanded access to an investigational drug is generally limited to a single course of therapy in a single patient for a specified duration unless FDA authorizes multiple courses or chronic therapy. The FDA must determine that the patient cannot obtain the drug under another IND or protocol.

Emergency Use for a single patient is mentioned above in “Types of INDs” and in detail at UCSF IRB Guidelines on the Emergency Use and Compassionate Use of Experimental Drugs and Devices.

This type of expanded access to an investigational drug is for use by more than one patient, but generally fewer patients than are treated under a typical treatment IND or protocol submitted under a new IND. The FDA must determine that there is at least preliminary clinical evidence of effectiveness of the drug, or of a plausible pharmacologic effect of the drug to make the expanded access use a reasonable therapeutic option in the anticipated patient populations.

This type of expanded use of an investigational drug outside of a controlled clinical trial is intended for widespread treatment use. The FDA must determine that: (a) The drug is being investigated in a controlled clinical trial under an IND designed to support a marketing application for the expanded access use or that all clinical trials of the drug have been completed. (b) The sponsor is actively pursuing marketing approval of the drug. (c) There is sufficient clinical evidence of safety and effectiveness to support the expanded access use.

The following are some specific types of treatment protocols:

A study designed to obtain additional safety data, typically done when the controlled trial has ended and treatment continues. The purpose of such a study is to allow subjects to continue to receive the benefits of the investigational drug, agent, or biologic until marketing approval is obtained.

A method approved by the FDA that expands the availability of investigational drugs, agents, or biologics as quickly as possible to persons with AIDS and other HIV-related diseases. These drugs, agents or biologics are utilized in separate protocols that “parallel” the controlled clinical trials and are essential to establish the safety and effectiveness of these new drugs, agents, or biologics.

The "Group C" treatment IND was established by agreement between the FDA and the National Cancer Institute (NCI). The Group C program is a means for the distribution of investigational agents to oncologists for the treatment of cancer under protocols outside of a controlled clinical investigation.

Timing of IND Applications

Pre-IND Advice: Investigators considering submitting an IND application to the FDA may request a meeting with the FDA Pre-IND Consultation Program before submitting an IND application. If you think a pre-IND meeting is warranted, please contact the HUB for assistance. The IND Submissions section of the HUB also provides information, templates and resources to guide you through the IND process.

The IND Submission: The IND submission to the FDA and the IRB application should be initiated at the same time. The FDA has 30 days to review the IND application. Likewise, the IRB typically reviews an application within a 30-day window, but it may take longer to secure approval. Because subjects may not be recruited or enrolled before both FDA and IRB approval have been granted, consider both timelines when planning the study.

In June 2021, FDA released a new tool: Expanded Access eRequest, which is a web-based tool that enables physicians to complete, sign, and submit non-emergency Expanded Access (EA) requests to FDA.

IRB Application and Consent Form Requirements

Include the following information in your IRB submission. Note: Do not submit FDA Form 1572 to the IRB; it is used for FDA and sponsor purposes only.

The IND number can be verified either by the IND number being identified in the associated sponsor protocol or by a letter from the FDA attached to the protocol confirming than an IND number has been obtained. The IRB will not issue final approval until the IND number is reported to and verified by the IRB. However, the FDA will review an IND application without IRB approval.

For any study involving an investigational drug or biologic, the Investigator’s Brochure must be attached to the initial review.

If there is a sponsor’s or multicenter protocol, attach it to the initial submission.

Purpose and Background Section:

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, as well as the administration of the product will be covered.

Control of Investigational Drugs and Biologics

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.

The UCSF Investigational Drugs Services page has info on the policies and procedures at UCSF (MyAccess login required).

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:

Reporting Requirements

All investigators must report certain adverse events directly to the IRB within certain specified time frames. When an IND is issued, there are additional federal requirements for reporting AEs to the FDA. When the study sponsor holds the IND, investigators need to report all AEs to the sponsor and the sponsor will submit appropriate reports to the FDA. Investigators who hold an IND (investigator-initiated/investigator-sponsor IND) have responsibilities for reporting AEs to the FDA, as described below.

Please see UCSF IRB Adverse Event or Safety Information for information about what, when and how to report. You can also review the IND Submissions for Sponsor-Investigators information on the UCSF CTSI HUB.

Note: When the study is conducted at the SFVAHCS, additional reporting obligations must be met by the researcher, as described on the Research at the SFVAHCS page.

In addition to reporting to the IRB, an investigator-sponsor must directly report the following AE information to the FDA within the following time frames, which are slightly different than those required for IRB reporting:

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 601 (biologics). Please refer to the regulations for complete information.

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