Improving Inclusion in Clinical Trials: FDA's Draft Guidance on the Use of Laboratory Values

The draft guidance by the FDA represents a significant step toward making clinical trials more inclusive and representative of real-world populations. This guidance aims to correct overly stringent criteria defined by laboratory values, which exclude various patient populations from different clinical trials, thus limiting the generalizability and applicability of clinical trial results.

Laboratory value-based eligibility criteria are crucial to patient protection in clinical trials. Usually, these criteria ensure that a minimum threshold of organ function levels is available in the participants to prevent risks due to investigational drugs. However, strict criteria can exclude a significant portion of the patient population, especially those with mild lab-value abnormalities that do not pose clinical risks. The FDA draft guidance encourages using more balanced criteria to increase trial inclusivity without compromising patient safety.

Highlights of the FDA Draft Guidance

Scientific Justification for Laboratory Tests as Exclusion Criteria: The guidance emphasizes that laboratory value-based criteria should be individualized to the drug under investigation, reflecting its mechanism of action, pharmacokinetics, pharmacodynamics, and expected toxicities. For example, if a drug does not undergo hepatic metabolism and is not thought to possess hepatic toxicity, the eligibility criteria for liver function tests should be broad enough to avoid unnecessary exclusions.

Accounting for Potential Expected Variations in Laboratory Values:

• Natural Variations: Laboratory values naturally vary among individuals based on age, sex, race, and ethnicity. Eligibility criteria should consider such variations to avoid excluding diverse populations.
• Clinical Insignificance: Some lab value abnormalities may not hold any clinical significance, especially in cancer patients. Eligibility criteria should exclude only those abnormalities with significant clinical risks related to the investigational drug.

Routine Reassessment of Laboratory-Based Exclusion Criteria: The guidance encourages regular reassessment of eligibility criteria as investigational drugs move from early to later phase trials. Criteria needed in early trials as precautionary measures may be relaxed in later phases based on accumulating safety and efficacy data.

Implications for Stakeholders

Sponsors and CROs: Embrace more flexible and scientifically justified laboratory value-based eligibility criteria to enhance the diversity in trial populations and the generalizability of the trial results. Early interaction with the FDA can help navigate regulatory requirements and potential issues.

Investigators and Study Sites: Broaden eligibility criteria to allow more representative enrollment of the real-world patient population. Training in the revised criteria and open communication with participants will ensure successful trial execution.

Participants: More inclusive eligibility criteria will help involve more patients in clinical trials, giving them access to potentially beneficial treatments and making the results more generalizable.

Best Practices for Inclusive Trial Design

• Tailored Eligibility Criteria: Use laboratory value-based eligibility criteria specific to the investigational drug. Avoid carrying over requirements from previous phases without reevaluation.
• Flexibility in Criteria: Allow for natural variability in laboratory values and consider repeat testing where appropriate to prevent unnecessary exclusions of patients with transient or minor abnormalities.
• Regular Reassessment: Reevaluate and modify inclusion criteria as additional trial data and post-market experience are gathered to ensure ongoing relevance and scientific justification.
• Engagement with Regulatory Bodies: Engage frequently with the FDA and other regulatory bodies to align expectations and receive feedback on trial design, facilitating the adoption of more inclusive eligibility criteria.

Conclusion

The FDA's draft guidance for laboratory value-based eligibility criteria in cancer clinical trials is a crucial step toward enhancing trial inclusivity and relevance. By utilizing more flexible, scientifically justified criteria, stakeholders can improve the diversity and representativeness of trial populations, leading to better applicable and generalizable trial results. Adhering to these recommendations will be essential for advancing oncology research and improving treatment options for all patients.

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