FDA guidance on clinical trial participation highlights eligibility reform and expanded access

New FDA guidance on enhancing participation in clinical trials sets out practical recommendations to improve representativeness in study populations, while also highlighting expanded access and real-world evidence (RWE) as complementary components of medicines development. 

Clinical trials underpin regulatory decision-making, yet enrolled populations often do not fully reflect patients seen in routine practice. In December 2025, the US Food and Drug Administration (FDA), through its Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) issued updated guidance for industry titled ‘Enhancing Participation in Clinical Trials — Eligibility Criteria, Enrollment Practices, and Trial Designs’. The non-binding guidance sets out approaches sponsors can take to improve enrolment of representative populations in trials intended to support new drug applications or biologics license applications. 

The guidance addresses both demographic characteristics, such as sex, race, ethnicity, age, and geography; and non-demographic factors, including comorbidities, organ dysfunction, disability, extremes of body weight, and rare diseases. The FDA states that enrolling participants with a wide range of baseline characteristics may: 

“Create a study population that more accurately reflects the patients likely to take the drug if it is approved,”  

enabling better assessment of how those characteristics influence safety and effectiveness. 

A key focus of the guidance is the systematic review of eligibility criteria. While exclusions are sometimes necessary to protect participants, the FDA observes that criteria are frequently carried forward from earlier development stages or used as standard templates without sufficient justification. Sponsors are encouraged to: 

“Examine each exclusion criterion to determine if it is needed to help assure the safety of trial participants or to achieve the study objectives,” 

and to remove or modify criteria that unnecessarily limit participation. The guidance cautions that unnecessary exclusion of groups such as older adults, individuals with stable comorbidities, people with disabilities, or those at the extremes of body weight “may lead to a failure to discover important safety information” relevant to real-world use. 

Demographic representativeness is also emphasized. The FDA states that inadequate participation from populations reflecting the intended use of a product can result in “insufficient information pertaining to medical product safety and effectiveness for product labeling.” Observed differences in pharmacokinetics, efficacy, and safety across racial and ethnic groups highlight the importance of subgroup analyses to identify population-specific effects. 

To support broader enrollment, the FDA guidance encourages sponsors to consider flexible trial designs. Adaptive designs may allow studies to start with narrower populations when safety is uncertain and expand eligibility as interim data accrue. Early characterization of drug metabolism and clearance across populations is also highlighted as a way to support appropriate dosing and avoid later exclusions. Even when enrichment strategies are used to improve efficiency, FDA stresses that eligibility criteria should remain “as broad and representative as possible.” 

The guidance also explicitly addresses expanded access, acknowledging that some patients will remain unable to participate in trials despite broader eligibility. Expanded access pathways may provide treatment options for patients with serious or life-threatening conditions who lack satisfactory alternatives and, in limited circumstances, may generate data that inform development. 

Commenting on the guidance, Stephanie Ferket, Director of Expanded Access Strategy & Customer Success at myTomorrows, described it as: 

“Another signal from the FDA that clinical trials and expanded access are not silos.” 

She noted that the guidance highlights how expanded access programs can complement trials by “facilitating access to underrepresented patients who can’t enroll, while yielding early real-world insights to fuel development.” Ferket added that: 

“Proactively integrating expanded access programs into your development plans is patient centric and accelerates innovation,”  

while cautioning that “a reactive approach to expanded access does not serve any stakeholder.”