The U.S. Food and Drug Administration (FDA) and the Office for Human Research Protections (OHRP) have released a joint draft guidance addressing the inclusion of tissue biopsies in clinical trials. This guidance, open for public comment until March 10, 2025, 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.
The draft guidance aims to assist stakeholders in understanding the ethical and practical considerations of incorporating biopsies into clinical research protocols, ultimately enhancing participant safety and furthering clinical research.
Key Considerations for Biopsy Inclusion
The guidance emphasizes that sponsors should carefully evaluate the purpose, reasons for inclusion, and associated risks when considering biopsies in clinical trials. For riskier biopsies, alternative approaches should be considered, and a strong scientific justification for the biopsy should be provided.
Richard Pazdur, M.D., director of the FDA's Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the Center for Drug Evaluation and Research, stated, "Tissue biopsies in clinical trials are often needed to determine eligibility or to understand the effect of the medical product being studied in the trial. This new draft guidance builds on the agency's ongoing efforts to enhance clinical trials by providing recommendations to improve participant safety and further clinical research."
Mandatory vs. Optional Biopsies
The draft guidance distinguishes between mandatory biopsies, which are required as a condition of trial participation, and optional biopsies, which are not. It suggests 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.
- Identify participants who should not be enrolled due to the risk of certain side effects or toxicities.
- Evaluate the clinical trial's primary endpoints or key secondary endpoints.
- Evaluate treatment response.
- Obtain histological diagnosis of tissue to support performance testing of diagnostic investigational medical products.
Conversely, the guidance states that biopsies should be optional when:
- The information will be used solely to evaluate non-key secondary and/or exploratory endpoints.
- The purpose of the biopsy is solely to obtain specimens for future unspecified research.
General Guidelines for Clinical Trials
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.
- Minimize risks to participants and exclude those for whom a biopsy would present an unacceptable level of risk.
- Ensure informed consent to obtain biopsies.
- Clearly state in both the clinical protocol and informed consent documents whether each biopsy is required or optional.
- Discuss their medical product development plans, including potential biopsies and their risks and benefits, with the appropriate review division early in development.
Additional Considerations for Children
The draft guidance includes specific considerations for clinical trials involving children. It states that 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 a prospect of direct benefit to the child. If it does, the risks should be justified by the anticipated benefit.
If the biopsy does not offer a prospect of direct benefit, the risks should be limited to "minimal risk" or "a minor increase over minimal risk." 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
This draft guidance clarifies when requiring biopsies as a condition for trial participation is reasonable, emphasizing the importance of evaluating the purpose of each biopsy and specifying whether it is mandatory or optional. It also highlights the need for extra care with respect to biopsies of participants who are children, ensuring that the biopsy offers the prospect of direct benefit to the child.
