FDA draft guidance outlines appropriate use of tissue biopsies in clinical trials

When are tissue biopsies really needed in clinical trials of medical products? Draft guidance from the US Food and Drug Administration (FDA) offers recommendations for weighing the risks and benefits of these potentially invasive procedures and ensuring informed consent from child and adult trial participants.

The guidance – titled Considerations for Including Tissue Biopsies in Clinical Trials Guidance for Industry, Investigators, Institutions, and IRBs – was developed by FDA in collaboration with the Department of Health and Human Services (HHS) Office for Health Research and Protections (OHRP) and applies to trials of medical products.

The draft guidance distinguishes between mandatory and optional biopsies. In the announcement, FDA and OHRP noted that a biopsy, defined as a “procedure that involves acquisition of tissue from a trial participant as part of a clinical trial protocol,” is sometimes essential for determining eligibility or evaluating treatment effects.

As explained in the draft guidance, a biopsy is sometimes the only way to show that a patient has a condition being studied in a particular clinical trial, for example, a drug targeting a specific tumor mutation, when pathology specimens are not available or sufficient. Biopsies may also be crucial for evaluating the primary and key secondary endpoints of a clinical study. These are examples where requiring biopsies for all trial participants “may be reasonable.”

“Sponsors should consider, among other things, whether the risks of the biopsies and any other risks of the trial are reasonable in relation to the anticipated benefit(s), if any, to the participants, and the importance of the knowledge that may be expected to the result,” according to the draft guidance.

If the biopsies are not needed to determine eligibility or measure the effects on key endpoints, “requiring biopsies may unnecessarily increase risk to or create undue burden for the trial participant, limit access to clinical trials, and/or discourage participation.”
“In general, when biopsies are to be conducted for evaluation of non-key secondary endpoints and/or exploratory endpoints for unspecified future research uses, they should be optional,” per the guidance.

Patients should be free to decline optional biopsies and still participate in a trial.

The new guidance is part of the FDA’s overall efforts to improve participant safety while advancing clinical research, the agency said in a statement (RELATED: Stakeholders welcome FDA’s informed consent ‘key information’ guidance, Regulatory Focus 6 May 2024).
As University of Michigan specialists Sarah Dermody MD, and Andrew Shuman MD, noted in a 2021 article in The Oncologist, “biospecimens are invaluable lynchpins in translational oncology,” and biopsies are now commonly part of clinical research trials, creating challenges for providers and patients.

“When a patient or research subject fails to understand the distinction between the goals of clinical research and standard of care treatment, a therapeutic misconception occurs as the patient may erroneously attribute therapeutic intent to interventions designed for research purposes,” Dermody and Shuman wrote. “Despite clinicians’ best efforts to convey the purpose and possible risks of research biopsies, patients may still presume personal benefit as a possible outcome—especially when their doctor is part of the enrollment process.”

In a section on considerations for adults, the draft guidance reviews factors that increase the risk associated with biopsy, such as how easy it is to access the anatomical site for tissue, and advises sponsors to consider alternatives in cases where biopsies are particularly risky.

“In all instances (required or optional biopsies), it is important to minimize risks to participants,” the guidance notes. “Eligibility criteria for trials with required biopsies should exclude participants for whom a biopsy would present an unacceptable level of risk.”
To help minimize safety problems, for example, sponsors should identify the following:

participants who should not be enrolled due to the risk of certain side effects or toxicities associated with an investigational medical product; and
participants whose current disease state would render it unlikely for them to derive benefit from the investigational medical product or other study interventions.

Sponsors also should be proactive in raising issues about the benefit versus risk of biopsies to the relevant regulatory departments early in research development and the rationale and scientific justification for the inclusion of every biopsy in a trial should be clearly included in the trial protocol.

“When biopsy information is used in endpoint analyses (i.e., primary endpoint, secondary endpoint, exploratory endpoint, etc.), the statistical analysis plan should clearly state how the results of the biopsy will be analyzed,” according to the guidance.
Informed consent of adult trial participants for biopsies should include descriptions of physical risks from the biopsy, discomforts of the procedure, and informational risks, that is, disclosure of private information from the biopsy results.

A section of the guidance document on children in clinical trials advises that a biopsy and associated procedures should be “evaluated to determine whether it offers prospect of direct benefit to the enrolled child,” for example, showing whether an investigational product could be effective.

“If the biopsy does not offer prospect of direct benefit, the risks of the biopsy should be limited to ‘minimal risk’ or a ‘minor increase over minimal risk,’” per the guidance. “If the risk of a biopsy 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 the understanding or amelioration of the child’s disorder of condition.”

Furthermore, FDA and OHRP wrote that large internal organ biopsies should not be done on children “unless the procedure is performed as part of the routine clinical care for that child in the treatment of their condition.”

The informed consent process for parents and guardians should include information about potential risks and discomforts and involve the child participant where appropriate.

“In determining whether children are capable of providing assent, the [institutional review board] should take into account the ages, maturity, and psychological state of the children,” according to the guidance. “If the IRB determines that the children are capable of providing assent, developmentally- and age-appropriate information about the biopsy should be included in the assent process.”

The draft guidance is open for public comments through March 10, following a January 7 announcement in the Federal Register.

Draft Guidance

FDA draft guidance outlines appropriate use of tissue biopsies in clinical trials

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