USFDA Guidance: Participation in Clinical Trials and Study of Sex Differences in the Clinical Evaluation

Clinical trials are the foundation for understanding whether a medical product is safe and effective. However, for many years, clinical trial populations have not fully reflected the patients who ultimately use these products in real-world settings.

To address this gap, the U.S. Food and Drug Administration (FDA) has issued two complementary guidance documents:

• Enhancing Participation in Clinical Trials — Eligibility Criteria, Enrollment Practices, and Trial Designs (December 2025), and

• Study of Sex Differences in the Clinical Evaluation of Medical Products (November 2025).

Enhancing Participation in Clinical Trials — Eligibility Criteria, Enrollment Practices, and Trial Designs

The guidance on enhancing participation in clinical trials focuses on making trials more representative of the populations likely to use a product if it is approved. It applies to drugs and biological products intended to support marketing applications and is issued in response to statutory requirements under the FDA Reauthorization Act.

Broadening Eligibility Criteria

FDA explains that while some exclusions are necessary to protect participants—such as excluding individuals at unreasonable risk—many commonly used exclusion criteria persist without strong scientific justification. Examples include unnecessary exclusion of older adults, people with stable comorbidities, individuals at the extremes of body weight, or patients with controlled infections.

As safety data accumulate during development, FDA encourages sponsors to re-evaluate and broaden eligibility criteria, especially in later-phase trials, to include medically complex patients who more closely resemble real-world users.

Trial Design and Methodological Approaches

The guidance recommends designing trials in ways that support broader participation. This includes early characterisation of pharmacokinetics in populations such as older adults or patients with organ impairment, which can reduce the need for later exclusions. FDA also highlights the value of adaptive trial designs, which allow pre-planned changes to eligibility or population size based on interim data.

Reducing Burden and Improving Retention

Beyond eligibility criteria, the guidance addresses practical barriers to participation. FDA encourages sponsors to reduce unnecessary site visits, allow flexible scheduling, use digital health technologies for remote data collection, and consider mobile healthcare professionals. Providing reimbursement for reasonable expenses, offering multilingual materials, and engaging directly with communities can further improve enrollment and retention.

Expanded access pathways are also discussed for patients who cannot participate in trials but have serious or life-threatening conditions. While expanded access is not a substitute for trials, data generated may sometimes inform development.

Studying Sex Differences in Clinical Evaluation

The guidance on studying sex differences addresses the long-standing underrepresentation of females in clinical research and the need to better understand differences in safety, effectiveness, pharmacokinetics (PK), and pharmacodynamics (PD) between females and males.

Why Sex Differences Matter

FDA explains that biological differences between females and males can affect disease manifestation, drug metabolism, dosing requirements, and adverse event profiles. Failure to study these differences can lead to incomplete benefit–risk assessments and inadequate product labeling.

Historically, fewer females were included in trials, particularly in early phases. Although representation has improved, gaps remain in certain therapeutic areas. The guidance aims to close these gaps by integrating sex-based considerations throughout product development.

Clinical Trial Design and Conduct

FDA recommends enrolling sufficient numbers of females and males to reflect disease prevalence and enable meaningful analyses. Sponsors should avoid unjustified exclusions based on sex and should reassess eligibility criteria if female participation drops disproportionately at screening or enrollment stages.

For pregnant and lactating women, FDA encourages a thoughtful, risk-based approach. While exclusion may be appropriate in some cases, the guidance highlights opportunities for collecting pharmacokinetic data when participants become pregnant during a trial, provided it is safe to do so.

Statistical Considerations and Data Analysis

The guidance provides detailed recommendations on analysing sex differences. Sponsors should plan analyses to both:

• assess differences in treatment effects between females and males, and

• estimate treatment effects within each sex.

FDA cautions that lack of statistical significance does not necessarily mean there is no clinically meaningful difference. Results should be interpreted in context, considering confidence intervals, biological plausibility, and other contributing factors such as age or body weight.

Reporting of sex-specific data is essential, and findings may inform dosing recommendations, monitoring requirements, or labeling statements.

For sponsors, aligning development programs with these guidances is not only a regulatory expectation—it is a critical step toward improving patient care. For authoritative and up-to-date information, readers should consult the official FDA guidance documents linked above.