110. FDA Research Involving Investigational Drugs

Updated June 29, 2021

Investigators and IRBs must ensure that research (i.e., clinical investigation) involving investigational drugs or biologics is conducted in accordance with applicable federal regulations. These regulations describe, among other things, requirements for Investigational New Drug Applications (INDs), drug accountability and record retention, and responsibilities of investigators, IRBs, and sponsors when research is conducted with investigational drugs. The “off-label” use of an FDA-approved, marketed drug (i.e., a use other than the indication(s) approved by FDA) by a physician for treatment purposes does not require an IND or IRB approval. When such uses meet the regulatory definitions of research or clinical investigation, IRB approval is required. When human research involves the use of drugs or biological products, FDA regulations apply. Investigators must provide sufficient information about the drug or biologic for the IRB to evaluate its associated risks and benefits, including the FDA approval status of the product. FDA regulations under 21 CFR 312 provide definitions, and codify procedures and requirements for research involving an investigational new drug (synonymous with investigational drug) and INDs. See IRB policy on overview of FDA regulations, information sheets and guidance for a listing of relevant references.

The University requires Full Committee Review for all research conducted under an IND except for continuing reviews that meet the DHHS (Common Rule) criteria for expedited review under Categories 8(a), 8(b), or 8(c); and reviews of amendment requests that qualify for expedited review (see the expedited review section in the IRB policy concerning requirements for project amendments).

University and Affiliate investigators conducting research under an IND must provide the IRB with sufficient information to determine an IND has been obtained and is in effect. The IRB affirms validity of the IND by matching the IND number with information in the Sponsor protocol or through communication from the Sponsor or the FDA. Research requiring an IND cannot commence until the IRB has confirmed a valid IND is in place and approved the project. Alternatively, investigators may provide the IRB with sufficient information to determine the use is exempt from requirements for an IND (as itemized below).

In presenting the protocol to the IRB, the Primary Reviewer addresses the additional FDA regulatory requirements for research involving investigational drugs.

NOTE: This policy addresses only those FDA regulations that are relevant to Principal Investigators (PIs) and IRB review of research conducted under an IND application. It is not a comprehensive review of IND regulations. Individuals requiring additional information are encouraged to review §312 Subpart B; §312 Subpart C; FDA Guidance for Clinical Investigators, Sponsors, and IRBs: Investigational New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND; or contact Research Integrity.

IND Applicability and Requirements

An Investigational New Drug Application must be filed with FDA to test the safety and efficacy of a new (i.e., investigational) drug for marketing approval. Studies involving the “investigational/research use” of an approved drug also require an IND if the intent of the study is to generate data that will lead to a new clinical indication, formulation, or advertising claim, or the study includes a new dose, population, or other factor that significantly increases risk (or decreases acceptability of the risk). An IND allows an investigational drug to be exempt from applicable premarketing requirements and to be shipped lawfully for the purpose of conducting clinical investigations of that drug. Studies involving the “investigational/research use” of an approved drug also require an IND if the intent of the study is to generate data that will lead to a new clinical indication, formulation, or advertising claim, or the study includes a new dose, population, or other factor that significantly increases risk (or decreases acceptability of the risk).

An IND is required when a sponsor intends to conduct a clinical investigation with an investigational drug subject to the:

• Federal Food, Drug, and Cosmetic Act, Section 505) or
• Public Health Service Act, Subpart 1, Section 262.

An investigator obtaining an IND for the proposed use of a drug or biologic in research becomes a “sponsor-investigator,” and additional institutional resources are available to assist investigators in complying with applicable FDA regulations Per §312.20, a separate IND and prior written authorization from FDA is required for any clinical investigation involving an exception from informed consent.

Uses that Are Exempt from Requirements for an IND

Under §212.2, item (b)(1), the clinical investigation of a drug product that is lawfully marketed in the United States is exempt from the requirements for an IND if all the following conditions are true.

• The investigation is not intended to be reported to FDA in support of a new indication for use or to support any other significant change in the labeling for the drug.
• The investigation is not intended to support a significant change in the advertising of the drug product.
• The investigation does not involve a route of administration or dosage level, use in a participant population, or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.
• The investigation is conducted in compliance with the requirements for IRB review and informed consent (at §56.111 and §50.20, respectively).
• The investigation is conducted in compliance with the requirements concerning the promotion and sale of drugs as codified at (§312.7).
• The investigation does not intend to invoke an exception from informed consent requirements for emergency research as codified at §50.24.

Under §312.2, item (b)(2), a clinical investigation involving an in vitro diagnostic biological product (i.e., blood grouping serum, reagent red blood cells, or anti-human globulin) is exempt from the requirements for an IND if it:

• is intended for use in a diagnostic procedure that confirms the diagnosis made by another, medically established, diagnostic product or procedure; and
• is shipped in compliance with requirements at §312.160.

Under §312.2, item (b)(3), a drug intended solely for tests in vitro use or in laboratory research animals is exempt from requirements for an IND as long as it is shipped in compliance with requirements at §312.160.

Under §312.2, item (b)(4), FDA will not accept an IND for an investigation that is exempt under (b)(1) (see above).

Under §312.2, item (b)(5), a clinical investigation involving use of a placebo is exempt from the requirements for an IND if the investigation does not otherwise require submission of an IND.

Under §312.2, item (d), use in the practice of medicine for an unlabeled indication of a new drug product approved by FDA for marketing (per §314) or a licensed biological product is exempt from the requirements for an IND.

Emergency Uses Requiring an IND

Under §312.2, item (b)(6), an IND is required for a clinical investigation constituting planned emergency research that includes a waiver of signed consent. (For more information about submission and review of emergency uses, see IRB policy for treatment, emergency, and expanded uses of investigational drugs.

In Vivo Bioavailability or Bioequivalence Studies in Humans: IND Requirements and Exemption

Under §312.2, item (c), all in vivo bioavailability or bioequivalence studies in humans are subject to FDA requirements/regulations for an IND and as codified at §320.31. In vivo bioavailability or bioequivalence studies in humans subject to an IND requirement must comply with FDA regulations for the protection of human participants at §50, IRBs at §56, and INDs at §312.

In Vivo Bioavailability or Bioequivalence Studies in Humans: IND Required

Under §312.2, item (c) and §320.31, item (a) an IND is required for bioavailability/bioequivalence studies in humans if the test product contains a new chemical entity as defined in §314.108, item (a) or the study involves a radioactively labeled or cytotoxic drug product.

Under §312.2, item (c) and §320.31, item (b) an IND is required for in vivo bioavailability/bioequivalence studies in humans if a drug product containing an approved, non-new chemical entity is used use in one of the following study types:

•  a single-dose study in normal participants where either the maximum single or total daily dose exceeds that specified in the labeling of the drug product;
• a multiple-dose study in normal participants where either the single or total daily dose exceeds that specified in the labeling of the drug product; or
• a multiple-dose study on an extended release product for which no single-dose study has been completed.

In Vivo Bioavailability or Bioequivalence Studies in Humans: Exempt from IND Requirements

Under §312.2, item (c) and under §320.31, item (d) a bioavailability/bioequivalence study in humans is exempt from the requirements for an IND if the study is one described under §320.38, item (b) for bioavailability samples or §320.63 for bioequivalence samples.

• The person or research organization conducting the study must retain reserve samples of the test article and reference standard used in the study and release the reserve samples to FDA upon request.
• The studies are subject to FDA requirements for informed consent (at §50.20), IRB review (at §56.111), and reporting serious and fatal or life-threatening adverse events (as specified at §320.31, item (d)(3)).

FDA Requirements for Labeling and Promotion of Investigational New Drugs

University and Affiliate investigators are responsible for reviewing recruitment materials, consent documents materials, and other information for participants to verify the following FDA requirements are met for labeling and prohibition against promotion of investigational drugs.

• Per §312.6, the immediate package of an investigational drug intended for human use must bear a label with the statement: Caution: New Drug--Limited by Federal (or United States) law to investigational use.
• Per §312.7, item (a), sponsors, investigators, and persons acting on their behalf must not imply or state that an investigational drug is safe or effective for the purposes for which it is under investigation, or otherwise promote the drug.
• Per §312.7, item (b), a sponsor or investigator must not commercially distribute or test market an investigational drug.
• Per §312.7, item (c), a sponsor must not unduly prolong an investigation after finding that the results of the investigation appear to establish sufficient data to support a marketing application.

The prohibitions listed above do not limit the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media.

University and Affiliate investigators, and the IRB are expected to review recruitment materials, consent documents materials, and other information for participants to verify compliance with these requirements and prohibitions.

NOTE: The appropriate FDA Center Director (per §201.26 or §610.68, for biological products), may grant an exception or alternative to the provision requiring the cautionary label noted above, unless said labeling is explicitly required by statute. University and Affiliate investigators requesting an exception for the FDA cautionary labeling requirement must provide the IRB with written documentation from the FDA Center Director.

Charging for Investigational Drugs Under an IND

FDA requirements at §312.8 apply to charging for use of an investigational drug in a clinical trial (item (b)) or expanded access for treatment use (item (c)). When charging for an investigational drug, the sponsor may recover only the direct costs of making the investigational drug available.

PIs must provide the IRB with documentation confirming the sponsor obtained prior FDA authorization to charge for an investigational drug, including FDA-authorized cost amounts and number of patients to be charged.

Charges for investigational drugs must be noted in informed consent documents.

Investigational New Drug Applications

• See §312.20 for requirements for an IND.
• See §312.21 for descriptions of the phases of clinical investigations.
• See §312.22 for general information about IND submissions.
• See §312.23 for requirements for IND content and format.
• See §312.30 for information about a new protocol or changes to a protocol submitted under an IND.

Regulations under §312.31 describe requirements for sponsor information amendments for an IND.

University and Affiliate investigators must submit all sponsor amendments for IRB review as an Amendment submission type in IRBNet. The submission should include a modification request listing and justifying the amendments, and copies of the relevant sponsor correspondence and the amended materials.

The IRB will review and approve or acknowledge sponsor amendments as follows:

• Substantive sponsor amendments require Full Committee review and approval.
• Sponsor amendments are eligible for Expedited Review if the changes do not increase participant risk and are limited to research activities that are represented by one or more of the DHHS Categories of research eligible for review by expedited procedures.
• Sponsor amendments are eligible for Administrative Review if the changes are administrative in nature (e.g., textual changes) and do not alter the risk to benefit ratio of the study.

Additional Responsibilities of Sponsor-Investigators

Investigators obtaining an IND to initiate and conduct research must also fulfill the federal requirements of sponsors. These requirements include (but are not limited to) additional FDA reporting (e.g., annual progress reports), data monitoring, and recordkeeping obligations.

IND Safety and Annual Reports

IND Safety Reporting

FDA regulations at §312.32 describe requirements for IND safety reporting by sponsors which include requirements for sponsors to:

• review and assess all information received or identified that is relevant to the safety of any drug for which the sponsor holds an IND (e.g., serious adverse events, findings from other studies including animal and in vitro studies, occurrence rates for serious adverse events, and study endpoints); and
• notify FDA and all participating investigators (i.e., investigators to whom the sponsor is providing an investigational drug under its or an investigator IND) of potential serious risks to participants.

University and Affiliate investigators must submit sponsor safety reports for assessment and IRB review. (See IRB policies for information about reporting problems in research, assessment of problems/complaints, and IRB review of adverse events and unanticipated problems.)

Withdrawal of an IND

FDA regulations at §312.38 address requirements for sponsors to withdraw an IND. When an IND is withdrawn for safety reasons, the sponsor must promptly notify the FDA, participating investigators, and reviewing IRBs of the reason for the withdrawal.

General Requirements for Use of an Investigational Drug in Clinical Investigation

FDA regulations at §312.40 specify an investigational drug may be used in a clinical investigation only when:

• the sponsor of the investigation submits an IND for the drug to FDA; the IND is in effect (per §§(b)); and the sponsor complies with all applicable requirements for an IND at §312; and
• the sponsor and each participating investigator comply with FDA requirements for the protection of human participants (at §50) and IRBs (at §56).

The regulations codify when a sponsor may ship an investigational drug named in an IND to investigators (§§(c)) and specify that investigators may not administer an investigational drug to humans until the IND goes into effect (§§(d)).

A qualified physician will serve as the Principal Investigator or Co-Investigator for the clinical trial and is responsible for all clinical trial-related medical decisions. During and following a participant’s participation in a clinical trial, the investigator-physician ensures that adequate medical care is provided to a participant for any adverse events, including clinically significant laboratory values, related to the clinical trial. The investigator-physician provides evidence of his or her qualifications through up-to-date curriculum vitae or other relevant documentation requested by the sponsor, the IRB or the regulatory authority. She/he/they will be familiar with the appropriate use of the investigational product, as described in the protocol, in the current investigator brochure, in the product information, and in other information sources provided by the sponsor.

FDA Regulations for Control of Investigational Drugs

Per §312.59, investigators whose participation in the clinical investigation is terminated must return the unused supplies of the drug to the sponsor or dispose of the unused supplies by an alternative method approved by the sponsor.

Per §312.61, investigators may only administer investigational drugs to participants under the investigator's personal supervision or the supervision of a sub-investigator responsible to the investigator. The investigator must not supply the investigational drug to any person not authorized to receive it).

Per §312.62, investigators must maintain adequate records of the disposition of the drug; prepare and maintain adequate and accurate case histories for each individual administered the investigational drug or employed as a control in the investigation; and retain the required records for at least 2 years after the date a marketing application is approved for the drug for the use being investigated or until 2 years after the investigation is discontinued and FDA is notified.

Per §312.69, for investigational drugs subject to the Controlled Substances Act, the investigator must store the investigational drug in a securely locked, substantially constructed cabinet or enclosure to which access is limited.

University/Affiliate investigators conducting research involving investigational drugs must complete the supplemental form for drugs and biological products. The form requires investigators to describe how they will maintain control of the drug/biological product during and after the investigation. The IRB may request additional documentation from the performance site to assess the investigator's control of investigational drugs.

Expanded Access

Expanded access, sometimes called "compassionate use," is the use outside of a clinical trial of an investigational medical product (i.e., one that has not been approved by FDA). Expanded access refers to the use of an investigational drug when the primary purpose is to diagnose, monitor, or treat a patient’s disease or condition rather than to obtain the kind of information about the drug that is generally derived from clinical trials. Except for emergency expanded access use when there is not sufficient time to secure prospective IRB review, an investigator treating a patient with an investigational drug under expanded access is responsible for obtaining IRB review and approval before treatment with the investigational drug may begin.

Under FDA’s current regulations for investigational drugs and biologics, there are three categories of expanded access:

• Expanded access for individual patients, including for emergency use;
• Expanded access for intermediate-size patient populations (generally smaller than those typical of a treatment IND or treatment protocol – a treatment protocol is submitted as a protocol to an existing IND by the sponsor of the existing IND);
• Expanded access for widespread treatment use through a treatment IND or treatment protocol (designed for use in larger patient populations).