FDA, OHRP Issue Joint Guidance on Collection of Tissue Biopsies in Clinical Trials

The guidance specifically addresses the inclusion of tissue biopsies in clinical trial protocols for both adults and children. The draft guidance applies to FDA-regulated clinical investigations and HHS-supported or -conducted nonexempt human subjects research that is a “clinical trial” as defined in the Federal Policy for the Protection of Human Subjects. The draft guidance does not apply to the acquisition of fluid samples such as blood, urine, or saliva or tissue biopsies needed for routine clinical care.

FDA and OHRP acknowledge that biopsies inherently include varying degrees of risk and that in some cases requiring biopsies may unnecessarily increase risk, create undue burden for trial participants, limit access to trials, and even discourage participation. The draft joint guidance aims to clarify:

• When a biopsy is necessary for a study such that it is appropriate for consent to the biopsy to be a condition for study participation
• When a biopsy should be considered optional.

The guidance suggests several factors for sponsors, investigators, institutions, and IRBs to consider when evaluating the necessity of biopsies during clinical trials. These factors include the purpose of the biopsies, the reasons for their inclusion in the study, and the risks posed by the biopsies. The guidance also suggests that for biopsies that pose higher risks, alternative methods of intervention should be evaluated and a strong scientific justification should be provided.

MANDATORY BIOPSIES

The guidance states that mandatory biopsies may be justified when the information cannot be obtained from existing pathology specimens or other less invasive means, and the information is necessary to, for example:

• Identify participants who may benefit from the investigational product
• Exclude participants at risk of side effects or toxicities
• Determine participants unlikely to benefit from the investigational product
• Evaluate primary or key endpoints of the trial
• Assess treatment response
• Support performance diagnostic testing with a high validity “truth standard.”

OPTIONAL BIOPSIES

Biopsies should be optional when the information obtained from them is used solely for non-key secondary or exploratory endpoints. Additionally, if the purpose of the biopsy is to collect specimens for future unspecified research, the biopsy should not be mandatory. This approach helps to minimize unnecessary risks and burdens on trial participants, ensuring that only essential biopsies are required.

GENERAL GUIDELINES

The draft guidance also outlines considerations and recommendations for designing clinical trials that include one or more biopsies. Sponsors should clearly state the rationale and scientific justification for the inclusion of each biopsy in the study protocol. The draft guidance emphasizes that risks should be minimized for both required and optional biopsies, and that participants for whom a biopsy presents an unacceptable level of risk should be excluded from the study. Sponsors are also encouraged to specify how a biopsy will be analyzed when the biopsy information is used in endpoint analyses.

A participant’s informed consent, which is required for all biopsies, should be obtained under conditions that minimize coercion or undue influence, and that specify foreseeable risks or discomforts. Investigators also must communicate the necessity of the procedure to healthcare providers performing the biopsy and ensure that these providers minimize risks to the extent possible for the trial participants. Participants can withdraw consent for a biopsy at any time during a clinical trial, although doing so when a biopsy is required may affect the participant’s continuation in the trial. According to the draft guidance, however, declining one or more optional biopsies should not negatively impact a participant’s trial enrollment, participation in other aspects of the trial, care the participant receives during the trial, or other study considerations.

SPECIAL CONSIDERATIONS FOR CHILDREN

The guidance emphasizes additional safeguards for clinical trials involving children. The draft guidance suggests that biopsies conducted solely for research purposes should present minimal risk or a minor increase over minimal risk to the child, or the biopsy should offer the prospect of a direct benefit to the child. For example, a biopsy that identifies whether a child would likely have a favorable response to an investigational medical product offers the prospect of a direct benefit. If a biopsy offers the child a direct benefit, the biopsy’s risks must be reasonably justified in relation to the anticipated benefit. If a biopsy is not for a child’s direct benefit and is not considered minimal risk, the biopsy must be likely to yield vital knowledge about the child’s condition. In addition to the required parental consent, the draft guidance encourages obtaining a child’s assent to the biopsy where appropriate given the child’s age, maturity, and psychological state.

KEY TAKEAWAYS

This draft guidance is particularly useful for clinical trial sponsors, investigators, institutions, and IRBs involved in planning and conducting clinical trials. The guidance provides a useful framework for determining when biopsies are necessary in clinical trials and helps to balance the need for biopsy data with the safety and comfort of trial participants. It underscores the need for clear communication in trial protocols and informed consent documents, helping participants understand when biopsies are optional and what risks they involve.

For more information about the draft guidance and its potential impact on clinical research, contact one of the authors of this article or any other member of McDermott’s Health & Life Sciences Practice Group.