FDA Urges Broader, More Inclusive Clinical Trials
FDA has released updated guidance calling on drug and biologics developers to broaden eligibility criteria, modernize enrollment practices, and adopt more flexible trial designs to ensure clinical studies better reflect the patients who will ultimately use approved medicines.
The guidance, Enhancing Participation in Clinical Trials — Eligibility Criteria, Enrollment Practices, and Trial Designs, reiterates that while patient safety remains a priority, overly restrictive inclusion and exclusion criteria continue to limit participation by key populations, including older adults, women, racial and ethnic minorities, people with comorbid conditions, and patients with disabilities.
“Despite longstanding efforts to broaden eligibility criteria, challenges to participation remain, and certain groups continue to be underrepresented in many clinical trials,” the agency says.
The guidance cautions sponsors against relying on inherited or “template” eligibility criteria that may exclude patients without a strong scientific or clinical rationale. The agency urges companies to systematically review exclusion criteria at each stage of development and justify any remaining limitations, particularly in late-stage trials intended to support marketing applications.
As safety data accumulate during development, FDA says eligibility criteria should expand to include more medically complex patients, such as those with organ dysfunction or on concomitant medications, when dose adjustments or monitoring can mitigate risk.
The guidance also highlights populations that are frequently excluded without sufficient justification, including patients with body weight extremes, individuals with stable HIV or prior malignancies, non-English speakers, and people who require accommodations such as flexible visit schedules or transportation support.
“Unnecessary exclusion of such participants may lead to a failure to discover important safety information about use of the investigational drug in patients who will take the drug after approval,” the agency says.
In addition to age, sex, race, ethnicity, and geography, the agency emphasized the importance of enrolling patients with non-demographic characteristics that are common in real-world practice, such as comorbidities, disabilities, or rare disease subtypes. The agency specifically encourages adequate enrollment of women, children, adolescents, and underrepresented racial and ethnic groups, warning that insufficient participation can result in labeling that lacks meaningful safety or efficacy information for large segments of the population.
Beyond eligibility criteria, the guidance promotes trial designs that facilitate broader enrollment. These include adaptive trial designs that allow pre-specified changes to eligibility or population size based on interim safety data, as well as earlier characterization of drug metabolism and clearance in populations such as older adults or patients with kidney or liver impairment.
The agency also urges sponsors to rethink pediatric development strategies, cautioning that rigid, age-based sequencing of pediatric enrollment can unnecessarily delay access to medicines for children unless there is a clear scientific justification.
In a notable section, the FDA says sponsors should consider pharmacokinetic sampling in women who become pregnant during a trial when continued participation is appropriate, potentially generating valuable data on drug metabolism during pregnancy.
While acknowledging the role of enrichment strategies — such as enrolling patients more likely to respond to a therapy or reach study endpoints —FDA warnsd that enrichment should not result in the systematic exclusion of demographic groups. Even in enriched trials, sponsors should aim to keep eligibility criteria as broad as possible and consider including marker-negative patients when substantial real-world use is expected.