Stakeholders want FDA to address alternatives, sample retention in biopsy guidance

Commenting on a draft guidance on taking tissue biopsies in clinical trials, stakeholders said they want the US Food and Drug Administration (FDA) to address the use of alternative methods, such as liquid biopsies. They also want the guidance to clarify requirements for retaining samples for bridging studies when developing companion diagnostics.

In January, FDA published draft guidance on the risks and benefits of sampling tissue biopsies in clinical trials, which has received more than 30 comments. It addressed several issues, including ensuring trial participants are informed of the need to take tissue biopsy samples and when they can decline to give a sample and stay in the clinical trial. (RELATED: FDA draft guidance outlines appropriate use of tissue biopsies in clinical trials, Regulatory Focus 20 January 2025)

The Friends of Cancer Research (FoCR) commented on the guidance and asked FDA to clarify biopsy justifications for different trial phases. The group noted that in earlier phases of product development, limited data may exist to determine whether the drug will need a companion diagnostic. However, as the drug goes through clinical trials, more data may point to the need for biopsies in patient selection.

"Phase-based considerations can help assess the risk-benefit of a biopsy," said FoCR. "We recommend FDA to provide a structured framework for evaluating biopsy necessity across trial phases."

The research advocacy group asked FDA to encourage sponsors to use alternative biopsy approaches to reduce patient burden. More specifically, it said the agency should acknowledge the role of liquid biopsies and other emerging technologies that can reduce the need for invasive biopsies and encourage sponsors to consider using them for non-key secondary and exploratory endpoints.

"Patients should not be excluded from trial solely due to an inability to provide a biopsy if validated alternative data collection methods exist," said FoCR. "These less-invasive approaches can support collection of information to guide clinical development while maintaining patient safety and minimizing patient burden."

FoCR said that the guidance does not address a mandatory need to keep biopsies to validate diagnostic tests and noted that in cancer research, biopsies are often kept for bridging studies. Not clarifying the need to keep biopsies could impact trial efficiency, patient burden, and sample availability. The group asked FDA to clarify when biopsies should be retained to validate diagnostic tests, especially when other data sources may be available.

“For instance, FDA could encourage sponsors to minimize unnecessary sample retention and explore less burdensome alternatives, such as archived tissue samples or liquid biopsies, when scientifically appropriate,” said FoCR. “Additionally, the guidance could incorporate recommendations on best practices for managing retained biopsies, including ensuring transparency in informed consent documents so patients understand how and why their samples will be used.”

“Patients should be informed whether their biopsy samples will be used,” added the group. “This could include information detailing the intent and potential benefits of the research within the scope of the trial as well as for potential future research (e.g., stored as archival samples).”

Drugmaker Pfizer also commented on the guidance and asked for clarity on alternative approaches in using clinical trial biopsy samples in retrospective studies when developing diagnostic tests.

Pfizer noted that tissue biopsies, also known as paired biopsies, may be key to determining the drug's optimal dose in clinical trials by showing how it affects tumors. The drugmaker asked FDA to clarify how it will accept mandatory biopsies for key exploratory endpoints.

"Draft guidance directs that biopsies should go toward a clear rationale as covered within the development of the specific agent/trial," noted Pfizer.

"For larger questions, such information can be positioned for 'class effect' or differentiation relative to other agents of similar mechanism of action," the company added. "We request the agency provide additional detail on the collection of biopsy-derived data whose utility may extend beyond the immediate study."

The diagnostics testing company Labcorp also addressed the need to provide clarity on alternative biopsy methods, such as liquid biopsies. The company said it is concerned that by not including such alternative methods, FDA is missing an opportunity to address safer and less intrusive methods that could be better alternatives to tissue biopsies.

"We suggest that the guidance be revised to include a discussion of offering patients alternative, less-invasive biopsy options (such as liquid biopsy) to address non-key secondary and exploratory objectives of clinical studies," said Labcorp. "This addition will help achieve the agency’s intent of lessening burden on clinical trial participants to encourage enrollment while still enabling the trial to collect critical research data."

Echoing FoCR’s concern, Labcorp also noted that the guidance fails to address the retention of biopsy samples used in bridging studies when developing companion diagnostics, which it said was a common practice in oncology precision medicine studies. Based on current practices, the company said there is already a significant sample loss in bridging studies.

"Labcorp is concerned that the agency’s failure to discuss this use case may result in less rigorous clinical bridging study designs, more challenging statistical concerns, and increased reliance on procured clinical specimens that do not adequately reflect the clinical trial population to enable companion diagnostic filings," the company added. "Therefore, Labcorp recommends that the guidance be revised to include a discussion of mandatory biopsy collection to support companion diagnostic development, which may include an option to consider tissue or liquid biopsy collection to enable less invasive testing in clinical practice."

Labcorp noted that the guidance states that biopsies should be optional in clinical studies where they may be used to evaluate non-key secondary and exploratory endpoints. The company, however, noted that sponsors of oncology products often evaluate the impact of biomarkers on early signs of the drug's effectiveness as an exploratory endpoint in Phase 1 studies.

"While these endpoints are generally considered exploratory because the primary goal of the study is safety, this study population is frequently critical to informing accelerated drug approval pathways," said Labcorp. "Therefore, the samples are critical to companion diagnostic development."

The company asked the FDA to address biopsy collection in the guidance if the samples are used to develop companion diagnostics.

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Stakeholders want FDA to address alternatives, sample retention in biopsy guidance

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