FDA And OHRP Issue Draft Guidance On Including Biopsies In Clinical Trials

On January 6, 2025, the U.S. Food and Drug Administration ("FDA") and the Office for Human Research Protections ("OHRP") issued a joint draft guidance on including tissue biopsies in clinical trials that evaluate FDA-regulated investigational medical products¹ or are supported by the U.S. Department of Health and Human Services ("HHS").² The draft guidance defines a biopsy as a procedure that acquires tissue from a trial participant as part of the clinical trial protocol. The draft guidance does not address the acquisition of fluid samples, such as blood, urine, or saliva, nor does it apply to biopsies needed to inform routine clinical care.

Open for public comment until March 10, 2025, the draft guidance provides recommendations for clinical trial sponsors, investigators, institutions, and institutional review boards ("IRBs") to consider when determining whether to make biopsies a mandatory or optional component of a clinical trial protocol.

Overview

When including biopsies in clinical trials, the draft guidance advises sponsors to consider:

the purpose of the biopsies;
the reasons for their inclusion; and
their associated risks and degree of risk.

For riskier biopsies, alternative approaches should be considered, and a strong scientific justification for the biopsy should be provided.

Mandatory Biopsies

Under the draft guidance, sponsors should evaluate whether the risks of biopsies are reasonable in relation to the anticipated benefits to participants and the importance of the knowledge expected to result. The draft guidance states that requiring a biopsy may be reasonable when the information cannot be obtained from existing specimens or other less invasive means, and the biopsy is necessary to:

identify participants who may derive clinical benefit from the investigational medical product or other intervention;
identify participants who should not be enrolled due to the risk of certain side effects or toxicities;
identify participants whose current disease state would make it unlikely for them to derive benefit from the investigational medical product or other interventions;
evaluate the clinical trial's primary endpoints(s) or "key" secondary endpoint(s) (notably the guidance does not define what constitutes a "key" secondary endpoint);³
evaluate treatment response; or
obtain histological diagnosis of tissue to support performance testing of diagnostic investigational medical products by providing a "truth standard," defined as a procedure of known high validity.⁴

Optional Biopsies

Conversely, the draft guidance states that biopsies should be optional when:

the information will be used solely to evaluate non-key secondary and/or exploratory endpoints;⁵ or
the purpose of the biopsy is solely to obtain specimens for future unspecified research.

General Guidelines

When designing clinical trials with either mandatory or optional biopsies, the draft guidance urges sponsors to:

clearly state the rationale and scientific justification for including each biopsy in the clinical protocol;
clearly state in the statistical analysis plan how the results of the biopsy will be analyzed;
allow participants to withdraw consent for biopsies at any time. If biopsies are required, withdrawal of consent may affect trial continuation for the withdrawing participant, but withdrawal of consent for only optional biopsies should not affect a participant's ability to continue participation in the trial;
minimize risks to participants and exclude those for whom a biopsy would present an unacceptable level of risk;
ensure informed consent to obtain biopsies. The conditions under which informed consent is sought should minimize the possibility of coercion or undue influence;
clearly state in both the clinical protocol and informed consent documents whether each biopsy is required or optional. Investigators should clearly communicate to health care providers whether biopsies are required or optional; and
discuss their medical product development plans, including potential biopsies and their risks and benefits, with the appropriate review division early in development. For clinical trials conducted or supported by HHS, investigators should discuss any potential biopsies and their risks and benefits with their IRB.

Additional Considerations for Children

The draft guidance states that in a clinical trial involving children, a biopsy conducted solely for research purposes and not needed for clinical management or routine clinical care should be evaluated to determine whether it offers prospect of direct benefit to the child. If a biopsy offers the prospect of direct benefit, it may be included in the trial if the risks (e.g., potential for harm, invasiveness, frequency, and risks of any procedural sedation) are justified by the anticipated benefit to the child. The relation of the anticipated benefit to the risk should be at least as favorable to the child as that presented by available alternative approaches.

If the biopsy does not offer prospect of direct benefit, the risks should be limited to "minimal risk"⁶ or "a minor increase over minimal risk." If the risk that does not offer prospect of direct benefit exceeds "minimal risk" and is limited to "a minor increase over minimal risk," the biopsy must be likely to yield generalizable knowledge about the child's disorder or condition that is of vital importance for understanding or ameliorating the disorder or condition.

The draft guidance notes as an example that a single muscle biopsy is often considered a procedure that does not exceed a minor increase over minimal risk. By contrast, a large internal organ biopsy (e.g., liver or kidney) generally exceeds a minor increase over minimal risk and should not be conducted in children as part of a clinical trial unless part of their routine clinical care.

Lastly, the draft guidance notes that the IRB must obtain permission from each child's parent or guardian and solicit assent from the child when they are capable of providing it.

Conclusion

Filling a prior void, this draft guidance clarifies when requiring biopsies as a condition for trial participation is reasonable. It emphasizes that sponsors should evaluate the purpose for each biopsy to determine whether the biopsy may be made a mandatory component of the trial or whether it should be an optional component to which participants are asked to provide additional consent. The draft guidance also highlights the importance of specifying in clinical trial protocols and informed consent forms, as well as in communications to investigators, whether a biopsy is mandatory or optional. Extra care must be taken with respect to biopsies of participants who are children to determine whether the biopsy offers the prospect of direct benefit to the child, as this factor affects whether the biopsy may take place.

Footnotes

1. The draft guidance defines medical products as human drugs and biological products, devices, and combination products that are regulated by the Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, or Center for Devices and Radiological Health.

2. The draft guidance applies to HHS-supported or -conducted nonexempt human subjects research that is a "clinical trial," as defined in 45 C.F.R. § 46.102(b).

3. Primary endpoints are the endpoints that establish the effect(s) of the drug, product, or other intervention, and will be the basis for concluding the study meets its objective. Secondary endpoints can potentially provide evidence of additional effects of the drug, product, or intervention on the given disease or condition. They could be a clinical effect related to the primary endpoint that extends the understanding of that effect or provides evidence of a clinical benefit distinct from the effect shown by the primary endpoint. See FDA, Multiple Endpoints in Clinical Trials: Guidance for Industry (Oct. 2022).

4. See FDA, Guidance for Industry: Developing Medical Imaging Drug and Biological Products, Part 2: Clinical Indications (June 2004).

5. Exploratory endpoints can include endpoints for research purposes or for new hypotheses generation. FDA, Multiple Endpoints in Clinical Trials: Guidance for Industry.

6. "Minimal risk" means the "probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests." 21 C.F.R. §§ 50.3(k), 56.102(i); 45 C.F.R. § 46.102(j).

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