Review of the FDA Draft Guidance: Considerations for Including Tissue Biopsies in Clinical Trials

Introduction

In January 2025, the Food and Drug Administration (FDA) and The Office for Human Research Protections (OHRP) issued a draft guidance on recommendations to industry, investigators, institutions, and Institutional Review Boards (IRBs) when tissue biopsies are included in clinical trials to evaluate investigational medical products. The draft guidance defines a biopsy as a procedure that involves the collection of tissue from a study participant as part of a clinical trial protocol. The draft guidance reflects a potential change in approach on how the assessment of risk and benefit for a child might be evaluated in a trial that includes a research biopsy.

Biopsies for Research Purposes

Biopsies are often needed to ensure that a participant has a particular condition or biomarker that is targeted by the drug or biologic product before enrollment in a trial, to obtain other data related to eligibility, or to evaluate a primary or secondary endpoint. Of note, any time a biopsy is considered for inclusion in a clinical trial, the risks of obtaining the biopsy must be weighed against the anticipated benefits and the importance of any knowledge gained from collection of the biopsy. When a biopsy is included in a clinical trial, the rationale and scientific justification should be clearly outlined in the protocol. If a biopsy for a particular participant includes an unacceptable level of risk, that participant should not be included in the trial. If biopsies are included in protocols as non-key secondary or exploratory endpoints, are not needed for determining eligibility, or are solely collected for future use, the FDA and OHRP state that these biopsies should be optional (protocol specified but not necessary to participate) since these biopsies may unnecessarily increase risks and burdens to participants and may discourage participation in the trial. 

Informed consent should be obtained before any research related biopsies are collected. It should outline if the biopsy is required or optional, describe the risks and benefits associated with the collection of the biopsy, and be conducted in an environment where there is no possibility of coercion or undue influence. Participants should have the right to withdraw their consent to provide a biopsy at any point during the trial, noting that if a biopsy is required, not collecting the biopsy may impact the participant’s ability to continue in the trial. Withdrawal of consent for optional biopsies would not have an impact on continued trial enrollment.

Certain types of biopsies may involve more risk. For example, a brain biopsy involves significantly more risk than a skin biopsy. In situations where the biopsy involves considerable risk, a strong scientific rationale for the biopsy should be provided and alternative approaches, such as collecting information from existing pathology, rather than obtaining a new biopsy, should be considered whenever possible.

A biopsy could be required in adults in the following situations:

• To identify participants with a particular finding that may make them more likely to respond to a particular treatment, like human epidermal growth factor 2 (HER2) positive disease for HER2-targeted therapies.
• To identify participants who may be more likely to have side effects or toxicities from use of the investigational treatment, (e.g., increased toxicities for patients with Kirsten rat sarcoma viral oncogene homolog [KRAS] and/or neuroblastoma Ras viral oncogene homolog [NRAS] mutated colon cancer treated with certain epidermal growth factor receptor antagonists).
• To identify participants who would not be likely to benefit from the treatment (e.g., a patient with significant renal scar tissue may have no signs of inflammation and therefore may not respond to immunosuppression).
• To evaluate primary and key secondary trial endpoints.
• To evaluate treatment response.
• Obtain tissue to produce a gold standard (truth standard) by a known high-validity diagnostic method to test an investigational diagnostic product. For example, to verify that an imaging agent is effective in recognizing a tumor compared to histology.^1,2

Biopsies for Pediatric Participants

A biopsy done in children as part of a clinical trial must comply with special considerations under 21 CFR 50, subpart D and 45 CFR 46, subpart D.³ A biopsy (and any biopsy associated procedures, such as procedural sedation) that is performed 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 enrolled child.

One nuance outlined in this draft guidance is that if a biopsy is performed to establish whether a child is likely to benefit from treatment with the investigational agent, performing the biopsy as part of the clinical trial could also be considered a benefit. For example, if a drug or biologic targets a particular biomarker or condition, the biopsy may be needed to establish whether the child has the biomarker or condition and is more likely to respond to the therapy and thus benefit from the treatment. Otherwise, in situations where there is no benefit and a biopsy is performed for research purposes, such as to evaluate a primary or key secondary endpoint, the risk must be limited to “minimal risk” or a “minor increase over minimal risk.” Biopsies that exceed minimal risk but are considered to meet criteria as a minor increase over minimal risk must also contribute to generalizable knowledge about the child’s disorder or condition. Large organ biopsies are generally considered to exceed the minor increase over minimal risk threshold and should not be done in a clinical trial unless needed for clinical purposes or offer a prospect of direct benefit as described above.

In pediatric trials, particularly those in oncology where treatments may be focused on a specific molecular marker,⁴ establishing whether the child is likely to benefit from the treatment is important. Unnecessarily exposing a child to a treatment without establishing a tumor type or tumor biomarker targeted by the investigational agent would expose the child to unnecessary risk without any anticipated benefit. In the past, these biopsies may have been considered by IRBs to not offer a benefit, thus limiting enrollment to children who either had previously had a biopsy done for clinical purposes or who had stored tissue for analysis. This approach may have inadvertently excluded children who would have benefited if the biopsy could have been done as part of the trial.

Conclusion

The draft guidance provided by the FDA and OHRP underscores the critical considerations necessary when including tissue biopsies in clinical trials. It highlights the importance of weighing the risks and benefits, obtaining informed consent, and ensuring that the scientific rationale is robust and justified. Biopsies should be optional if not essential for determining eligibility or other primary trial endpoints. For children, a biopsy and any biopsy associated procedures performed solely for research purposes and not needed for clinical management or routine clinical care should be evaluated to determine whether performing the biopsy offers a prospect of direct benefit to the enrolled child. A biopsy performed as part of a research study could be considered to offer a benefit to the child if the biopsy is performed to establish whether a child is likely to benefit from treatment with the investigational agent, such as to identify a specific molecular target or condition.

If you have additional questions regarding biopsies in adult or pediatric studies or other IRB-related inquiries, please don’t hesitate to contact us by completing the form below. WCG’s IRB experts are here to assist you with any ethical or regulatory questions. Reach out today.

---

References:

1. Guidance for Industry Developing Medical Imaging Drug and Biological Products Part 2: Clinical Indications, accessed January 7, 2025, https://www.fda.gov/media/71226/download.
2. Guidance for Industry Developing Medical Imaging Drug and Biological Products, Part 3: Design, Analysis, and Interpretation of Clinical Studies, accessed January 7, 2025, https://www.fda.gov/media/71237/download.
3. Ethical Considerations for Clinical Investigations of Medical Products Involving Children Guidance for Industry, Sponsors, and IRBs, accessed January 7, 2025, https://www.fda.gov/media/161740/download.
4. How to Navigate Researching Targeted Therapies in Pediatric Oncology Clinical Trials, Fierce Biotech, accessed January 7, 2025, How to Navigate Researching Targeted Therapies in Pediatric Oncology Clinical Trials | Fierce Biotech.