backThe Food and Drug Administration (FDA) has issued a new guidance document entitled “Enhancing Participation in Clinical Trials – Eligibility Criteria, Enrollment Practices, and Trial Decision.”1See FDA, Guidance for Industry, Enhancing Participation in Clinical Trials – Eligibility Criteria, Enrollment Practices, and Trial Designs. Guidance for Industry (Dec. 2025), https://www.fda.gov/media/190162/download. The new guidance is applicable to clinical investigations of human drugs and biological products that are regulated as drugs. It addresses the demographic characteristics of biologic sex, race, age, and ethnicity that were the focus of prior FDA draft guidance documents that focused on “diversity.” This new guidance, however, does not explicitly cite diversity, and it has a much broader focus that includes other demographics, such as location of residency, as well as multiple non-demographic characteristics, such as organ dysfunction, comorbid diseases, extremes of weight, and presence of rare diseases or conditions.
FDA issued this guidance in response to the mandate of section 610(a)(3) of the FDA Reauthorization Act of 2017 (FDARA).2See FDA Reauthorization Act of 2017, Pub. L. No. 115-52, 131 Stat. 1005 (2017), at § 610(a)(3), https://www.congress.gov/bill/115th-congress/house-bill/2430/text. FDARA required FDA to convene a public meeting to discuss clinical trial eligibility issues to inform subsequent issuance of guidance. Accordingly, FDA held a public workshop in April 2018, followed by issuance of a report in July 2018 that summarized the discussion.3See FDA, Public Workshop, Evaluating Inclusion and Exclusion Criteria in Clinical Trials (July 2018), https://www.fda.gov/media/134754/download. This guidance is the first revision of the initial guidance issued in November 2020.4See FDA, Notice of Availability, Enhancing the Diversity of Clinical Trial Populations—Eligibility Criteria, Enrollment Practices, and Trial Designs; Guidance for Industry, 85 Fed. Reg. 71,654 (Nov. 10, 2020), https://www.govinfo.gov/content/pkg/FR-2020-11-10/pdf/2020-24881.pdf. Notably, the prior 2020 final guidance emphasized “enhancing the diversity of clinical trial populations”; in contrast, references to diversity are absent in this revised guidance.
Here, we discuss the three major frameworks of FDA’s recommendations for enhancing patient enrollment and retention, and the challenges that sponsors, as well as investigators and Institutional Review Boards (IRBs), may face in implementing these recommendations.
- BROADENING ELIGIBILITY CRITERIA. FDA emphasizes that sponsors should avoid focusing on an ideal lower risk study population and instead consider designing the premarket clinical testing program to identify the drug’s “risk-benefit profile across the patient population likely to use the drug in clinical practice.” This recommendation implies that sponsors should consider and study the “real-world” population of patients in the United States that are likely to be prescribed the drug by physicians.
- Avoid “automatic” exclusions of certain cohorts of traditionally higher risk patients. FDA provides the example of avoiding exclusion of patients who are elderly, thin, or obese, or those with multiple comorbidities and who use of other medications, unless there is strong clinical or scientific justification.
- Broaden eligibility criteria as the drug development program progresses. As early-stage clinical data on pharmacokinetics, metabolism, and drug-drug interactions are developed, FDA recommends that sponsors broaden eligibility criteria. In particular, FDA acknowledges that Phase 2 studies often have very restrictive exclusion criteria. However, FDA recommends that sponsors consider eliminating or substantially modifying the exclusion criteria for Phase 2 studies for subsequent Phase 3 trials to ensure inclusion of the broader population likely to be treated with the drug in real-world clinical practice.
- Include higher risk patient subsets by enrolling at clinical sites with expertise in treating such patients. This recommendation, which implies the identification of clinical research sites for selective enrollment of potentially “less safe” patients, is likely to raise major concerns for IRBs in its implementation, including processes for informed consent. Implicitly, this recommendation also raises the concern that postmarket treatment of such higher risk patients with the drug should only be done at specially qualified clinical sites.
- Ensure that patient enrollment reflects the intended-use population based on age, sex, race, and ethnicity. Consistent with other current clinical trial guidance regarding sex, FDA emphasizes enrollment of women in sufficient numbers to permit detection of clinically meaningful sex-related difference in drug response compared with men. FDA also emphasizes inclusion of underrepresented racial and ethnic subgroups for deliberate analysis of potential differences in pharmacokinetics, efficacy, or safety. Unlike FDA’s now‑obsolete guidance documents on “diversity,” FDA does not mandate development of “diversity action plans.” However, the recommendation suggests that FDA intends to identify population-based differences in safety and/or efficacy based on age, sex, race, and ethnicity, and that the study protocol should clarify how this will be accomplished.
- STUDY DESIGN AND METHODOLOGY. FDA proposes several models of clinical trial design to enhance enrollment of broader populations. The Agency suggests inclusion of more complex patient groups, such as patients who are elderly or have liver or kidney damage, in very early studies of drug metabolism and clearance. This proposal is not likely to be rapidly implemented unless a large proportion of the target postmarket population is such higher risk patients. Other strategies proposed in the guidance are already being implemented by some drug manufacturers in premarket drug development.
- Consider adaptive clinical trial design. FDA proposes use of adaptive clinical trial design that begins with a “safer” narrow patient population and expands to a broader population based on purposeful interim analyses of safety. For this model, FDA advises analyses of safety and efficacy, including analysis to support adjustment of enrollment of specific patient subgroups, based on pre-specified criteria.
- Include a broad pediatric program early in clinical development. The guidance advises avoidance of staggering enrollment of children by age. It specifically warns that staggering enrollment of older children first and younger children later “should be justified with a clear scientific rationale.”
- Use caution in implementing enrichment strategies. Enrichment strategies are increasingly used in premarket clinical development because of the potential ability to rapidly show the effect of a drug, if any. Examples of enrichment strategies include enrollment of patients with a specific genetic trait or biomarker or patients who are at a specific stage of the disease that may cause them to be more likely to respond favorably to a treatment. FDA acknowledges that even if the primary endpoint is based on an enriched population, sponsors should consider enrollment of a broader population for a secondary prespecified analysis of efficacy. The guidance fails to address the potential implications of reliance on an enriched study population for the analysis of product safety.
- Make the trial less burdensome to improve enrollment. FDA emphasizes many of the strategies that were previously suggested in public meetings conducted by the Agency regarding enhancing diversity in clinical trials. Suggestions for making participation less burdensome include enhancing accessibility to clinical trial sites, reducing the frequency of study visits, using electronic informed consent, replacing site visits with electronic or telephone communications, and the use of mobile medical professionals, such as phlebotomists, for home visits. In addition, FDA emphasizes the importance of informing and reassuring patients about financial reimbursement of expenses. FDA cites the separate incentive of “payment for participation” with the reminder that IRB review and approval is required.
- Adopt practices to enhance recruitment and retention. FDA discusses strategies for enhancing community engagement including conduct of recruitment events at sites convenient for specific underrepresented racial and ethnic groups that traditionally are hesitant to participate in clinical trials, including sites such as churches, community centers, and barber shops. Separate from cultural considerations, FDA stresses the importance of implementing legal contractual agreements between sites and creating patient informed consent documents to facilitate timely exchange of medical records and reduce the common problem of clinical trial participant drop-out in this situation. Unfortunately, this guidance fails to provide a sample template.
- Don’t forget expanded access. The guidance reminds industry sponsors that FDA’s expanded access regulations provide an opportunity for providing potential access to investigational drugs for patients who do not meet eligibility criteria or otherwise cannot participate in a clinical trial. Interestingly, FDA asserts that use of expanded access may benefit sponsors by informing “future clinical development (e.g., by identifying patients for subsequent studies.” To our knowledge, FDA has not gathered or published data on the frequency of this suggested benefit to sponsors who agree to provide an investigational drug under the expanded access regulations.
- RARE DISEASES AND CONDITIONS. FDA appreciates that clinical trials of investigational drugs for rare diseases or conditions present special challenges, since the small number of affected patients heightens the need for enhanced subject enrollment and retention. The guidance emphasizes consideration of strategies that are commonly used in premarket clinical development of drugs for rare diseases, including engagement of patient advocacy groups, as well as the later use of open-label extension studies with broad inclusion criteria to ensure that all study participants, including those assigned to placebo, have access to the investigational drug. However, FDA also proposes the novel and potentially controversial concept of re-enrollment of participants from early Phase 1 studies into later phase randomized trials “if there is no unreasonable anticipated safety issue and as long as the therapy received in phase 1 is not expected to change the course of the disease.” In making this recommendation, FDA notably does not reference the recently proposed “New Plausible Mechanism Pathway,” touted by Vinay Prasad, Director, Center for Biologics Evaluation and Research, and Martin A. Makary, FDA Commissioner, as a new pathway for “bespoke” treatments for rare diseases based on biologic plausibility of the treatment.5See Prasad, V. & Makary, M.A., FDA's New Plausible Mechanism Pathway, 393 N. Engl. J. Med. 2365, 2025, https://www.nejm.org/doi/full/10.1056/NEJMsb2512695.
Unanswered Issues
This revision of a prior final guidance document provides a detailed discussion of multiple potential strategies to enhance subject enrollment and retention in clinical trials of investigational drugs. The guidance fails, however, to consider whether many of the recommendations may enhance the complexity of conduct and oversight of clinical studies for sponsors, and it does not address challenges IRBs may face in reviewing novel clinical trial designs, such as the proposal for the re-enrollment of participants from Phase 1 studies into later Phase 3 studies in rare diseases.
Notably, this revised guidance fails to address two “elephants” in the room. The guidance emphasizes enhancement of enrollment of women, as well as racial and ethnic subgroups who are frequently under-represented in clinical trial development. However, it fails to clarify how FDA will determine if signals of either less efficacy or worse safety between subgroups are clinically meaningful and not merely the “play of chance.” Separately, FDA continues to grapple with the question of inclusion of pregnant women in clinical trials of investigational drugs. For novel investigational drugs, FDA and sponsors generally continue to exclude pregnant women from clinical investigations of new drugs and default to voluntary and scanty participation in “pregnancy registries” for women who do become pregnant while participating in a clinical investigation.
Summary
This new guidance envisions multiple strategies for enhancing enrollment and participation in clinical trials of investigational drugs and biological products regulated as drugs. Although novel, many of the proposed strategies could be readily implemented. However, as with the prior and now obsolete guidance documents that focused on clinical trial diversity, this guidance fails to address how potential differences in safety or clinical outcomes in subgroups, such as women or patients in racial or ethnic subgroups, should be assessed to determine if the difference is clinically meaningful and not the play of chance. At present, such findings present major challenges for internal assessment by FDA and external public review by its Advisory Committees. In addition, FDA’s current default position is to recommend or require postmarket studies to evaluate such concerns. This strategy, however, fails to address the issue that the investigational drug, if approved, will be used in broad populations, including in patients in subgroups with potential heightened safety concerns or for whom the drug potentially has lesser efficacy. The guidance also fails to address multiple additional issues pertinent to study enrollment and treatment with an investigational drug, including considerations regarding informed consent, reliance on complex clinical trial designs, use of special sites for higher risk patients, and potential new burdens for IRBs, sites, and clinical investigators, as well as sponsors. We encourage drug manufacturers to closely track further developments regarding this new guidance and its recommendations.
If you have questions regarding this new guidance or would like assistance in preparing comments to FDA, we are glad to help. Please contact Beverly Lorell, Chris Markus, Lauren Roth, Kyle Sampson, or Elaine Tseng for more information.