Important Changes in FDA’s Approach to Tissue Biopsies in Clinical Trials

The U.S. Food and Drug Administration (FDA) and the Office for Human Research Protections (OHRP) have released a draft guidance document, Considerations for Including Tissue Biopsies in Clinical Trials, issued in January 2025. It provides recommendations for sponsors, investigators, institutions, and Institutional Review Boards (IRBs) on the safe and ethical incorporation of tissue biopsies in clinical trials.

This guidance has major implications for medical device manufacturers. Companies developing biopsy tools, diagnostic devices, and companion diagnostics must align with new regulatory expectations. Compliance with these evolving guidelines is critical for maintaining market access and advancing research.

Essential Takeaways and Ethical Guidelines from the Draft Guidance

The Tissue Biopsies in Clinical Trials draft guidance outlines considerations for conducting tissue biopsies in adult and pediatric clinical trials that evaluate investigational medical products. It addresses ethical concerns, regulatory requirements, and best practices for minimizing risks while ensuring that required biopsies contribute meaningfully to clinical research objectives.

Key focus areas include:

• Differentiating between required and optional biopsies
• Risk-benefit considerations for biopsy procedures
• Ethical and regulatory standards for informed consent
• Additional safeguards for pediatric participants
• Implications for medical device manufacturers and steps for compliance
• Use of alternative, less invasive methods for data collection

The FDA guidance also emphasizes the importance of ensuring compliance with Institutional Review Boards (IRBs) to oversee biopsy inclusion in trials and mitigate ethical concerns. Risk minimization strategies should be integrated into clinical trial designs to prevent undue participant burden.

Adapting to Regulatory Changes: Strategies for Medical Device Manufacturers

Medical device manufacturers, especially those involved in biopsy tools, diagnostic devices, and companion diagnostics, will need to carefully evaluate how this guidance affects their product development and regulatory strategies. As the guidance reinforces the importance of risk minimization, ethical considerations, and informed consent, manufacturers must ensure that their devices align with these regulatory expectations.

To align with these evolving requirements, medical device companies should take the following strategic actions:

• Review their technologies to ensure they offer the least invasive methods possible while still providing accurate and clinically relevant data.
• Collaborate with clinical trial sponsors to integrate their devices into trial designs that comply with the FDA’s requirements for required and optional biopsies.
• Engage with regulatory authorities early in the product development cycle to seek feedback on their device’s role in clinical trials.
• Develop and refine their risk-benefit assessments to align with the guidance.
• Prepare comprehensive documentation on safety, effectiveness, and ethical compliance to secure regulatory approval.
• Anticipate shifts in trial designs that could influence device adoption.

Balancing Ethics and Innovation in Biopsy Procedures

The Tissue Biopsies in Clinical Trials guidance provides key distinctions between required and optional biopsies within clinical trials:

Required Biopsies

Clinical trial protocols require these to confirm eligibility, assess key endpoints, or evaluate treatment responses. The necessity of these biopsies must be justified by demonstrating that no alternative, less invasive approach can provide equivalent information.

Study sponsors should:

• Use existing pathology specimens whenever possible to minimize additional invasive procedures.
• Clearly outline the rationale and risks associated with required biopsies in the study protocol.
• Ensure that patient selection is equitable, preventing undue exclusion of eligible participants.
• Provide adequate follow-up care to monitor and address potential complications.
• Maintain transparency by informing participants about biopsy requirements before trial enrollment.
• Explore alternative methods, such as imaging techniques and liquid biopsies, to reduce participant burden.

Optional Biopsies

These biopsies are used for exploratory endpoints, non-key secondary endpoints, or future unspecified research and should remain voluntary. Participants should be able to decline these procedures without facing negative consequences.

Best practices for optional biopsies include clearly explaining their purpose and benefits.

• Minimizing discomfort and risk through the use of less invasive techniques when possible.
• Offering incentives or additional support, such as covering travel costs or providing post-procedure care.
• Ensuring transparent consent processes that allow participants to withdraw consent at any time.
• Implementing measures to destroy unused samples if a participant chooses to opt out later.

Real-World Applications and Safety Measures in Clinical Trials

1. Use of Biopsies to Identify Eligible Participants

In some clinical trials, a biopsy is necessary to confirm that participants have a specific biomarker associated with the disease. For example, in a trial evaluating a new targeted therapy for HER2-positive breast cancer, a biopsy may be required to confirm HER2 (human epidermal growth factor receptor 2) expression before enrollment. Without this step, patients who do not have the biomarker might be included, skewing trial results and potentially exposing them to ineffective treatments.

This required biopsy ensures that only those most likely to benefit from the investigational drug are included, improving both safety and study integrity. Investigators must clearly justify why this biopsy is necessary and explore whether archived tissue samples could be used instead to minimize invasiveness.

2. Assessing Treatment Response Through Biopsies

Some studies require biopsies to evaluate how well a drug is working at a molecular level. For instance, a trial studying a novel immunotherapy for lung cancer may require pre- and post-treatment biopsies to assess changes in tumor microenvironment markers. These biopsies help researchers understand whether the therapy is effectively engaging the immune system as intended.

However, because repeated biopsies can pose additional risks, researchers must justify their necessity and assess whether imaging or blood-based biomarkers could provide comparable insights. Trials requiring multiple biopsies should include extra monitoring and safety measures.

3. Optional Biopsies for Future Research Use

Researchers often collect optional biopsies for exploratory research not directly tied to primary or secondary endpoints. For example, a study investigating a new melanoma treatment might offer participants the option to provide additional tissue samples for future biomarker discovery. While these biopsies are not required for trial participation, they can significantly contribute to future advancements in precision medicine.

Researchers should explain how samples will be stored and used and provide an opt-out option if needed. Proper ethical oversight and transparent communication are essential to maintaining participant trust in such cases.

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