FDA Issues Final Guidance On Clinical Trial Participation: What You Need To Do Now

By Brandon Miller and Hannah Yang, Clarkston Consulting

On December 15, 2025, the Food and Drug Administration (FDA) finalized its guidance on Enhancing Participation in Clinical Trials,¹ formally updating expectations for enrollment and trial design. While progress has been made since the draft guidance in 2020, many gaps remain among minority populations, older adults,² and patients with comorbidities. Regulatory commentary has long emphasized that traditional trial populations fail to reflect real-world patient complexity,³ creating challenges regarding generalizability and accuracy.

Trial representativeness is now an enterprise challenge spanning development strategy, analytics, regulatory planning, and commercial readiness, with implications that extend beyond clinical operations. In this piece, we break down key takeaways from the FDA’s guidance on clinical trials,⁴ which formalizes expectations that sponsors must now operationalize.

FDA Guidance Overview

To promote the enrollment of a representative trial population, the FDA calls on sponsors to broaden eligibility criteria. By removing exclusions that lack a clear scientific or safety rationale, the study can assess a wider range of characteristics that may affect the drug’s safety. Overly restrictive inclusion criteria⁵ are increasingly linked to limited generalizability, reduced label expansion opportunities, weakened payer and clinician confidence, and lower external validity of trial results. The FDA recognizes that certain exclusions are appropriate to protect vulnerable patient groups but recommends reevaluating criteria in later stages of drug development as safety experience increases.

Additionally, continuing to reduce participation burden through remote assessments and decentralized or hybrid elements⁶ is critical for improving enrollment and retention. Providing flexibility in visit windows or decreasing the frequency of study visits can also address recruitment challenges by improving accessibility. To reach populations historically underrepresented in clinical research, community-based recruitment and patient engagement are necessary. Reducing mistrust toward medical research requires intentional outreach through referral pathways such as community providers, advocacy groups, community leaders, or faith-based organizations.

Rare disease trials require tailored enrollment strategies due to limited populations and geographic dispersion, and communication with patient advocacy groups is key to understanding participant needs. Due to ethical access considerations, re-enrollment of participants from early-phase trials into later-phase randomized trials and open-label extension studies with broader inclusion criteria are recommended. Both of these strategies help maximize participation, which is essential to successfully interpret trials for patients with rare diseases or conditions.

Why It Matters For Pharma, Biotech, And Medical Device Leaders

It is crucial that pharma, biotech, and medical device organizations⁷ implement the FDA’s guidance in trial designs. Studies that underrepresent intended-use populations often result in narrower indications and more conservative labeling. Lack of adequate subgroup safety data increases the likelihood of post-marketing requirements⁸ and additional studies. Put simply, underrepresentation in clinical research creates both regulatory and commercial risk, not just reputational risk.

Moreover, incomplete safety and effectiveness evidence across diverse populations⁹ can delay physician confidence and adoption. This uncertainty extends beyond approval, shaping how clinicians interpret trial results and assess real-world risk. Without clear subgroup data, they may end up limiting prescriptions to patients who most closely resemble the trial population. For regulators and clinicians, representation is now viewed as an indicator of overall trial rigor and credibility.

What Leaders Can Do Now

Reassessing trials before pivotal phases enables sponsors to verify that enrolled populations reflect intended-use groups and anticipate labeling needs. Legacy designs, sites, and partners must also be evaluated to determine where new strategies are required to reach an inclusive audience.

Leaders should focus on the following steps throughout trial design:

1. Gauge operational readiness for decentralized and hybrid trial models¹⁰

These models can reduce logistical barriers that disproportionately limit participation among older adults and patients with mobility constraints. To assess readiness requires organizations to determine if remote visits or home-based services can be implemented without compromising data integrity.

2. Audit inclusion and exclusion criteria¹¹ across the program portfolio.

Eligibility criteria are often carried forward from earlier phases, but leaders should reassess them as safety data emerges. Reviewing the full portfolio enables sponsors to identify inconsistencies across programs and document rationale for exclusions.

3. Define representation metrics based on prevalence.

Prevalence-based targets provide a concrete reference point for enrollment planning and move beyond qualitative goals. Outlining these targets as early as possible is beneficial for site selection and forecasting during the enrollment process.

4. Embed enrollment Key Performance Indicators (KPIs) into a program governance structure.

Governance structures monitor representation alongside timelines and budget, making it easier to identify and intervene when risks appear. This approach reinforces enrollment performance as an organization-wide responsibility rather than an issue confined solely to trial sites.

5. Align trial targets with label strategy and health economics and outcomes research (HEOR) plans.

This continuity is necessary to ensure that enrollment decisions during trial design support future evidence needs. Otherwise, trials may succeed operationally but fall short in supporting labeling or value demonstration.

6. Modernize site, vendor, and community engagement ecosystems.

Modernization efforts help organizations expand beyond traditional site networks that no longer align with current trial objectives. This may involve adding community-based providers or adjusting vendor scopes to support local recruitment.

7. Leverage data and analytics to support site and key opinion leader (KOL) selection.

Using analytics promotes more objective decision-making when choosing between sites and investigators for a study. Data can highlight patterns related to patient access and geographic coverage that might not have been considered.

Prior to launching the trial, development, regulatory, analytics, and medical affairs teams must align shared enrollment goals and definitions of representativeness. Inclusive trial design should be treated as a discipline with governance, management, and support across therapeutic areas and business units, not a stand-alone DEI initiative.

Looking Ahead

The FDA’s final guidance reinforces a clear shift toward clinical relevance as a defining characteristic of regulatory-grade evidence. It is increasingly important to incorporate population science, HEOR, data and analytics, and reporting teams early in trial design. Studies that reflect real-world populations are more likely to generate evidence that withstands regulatory scrutiny and supports broader labeling.

By adapting efficiently, organizations can reduce regulatory risk and late-stage evidence gaps. Inclusive trial strategies also accelerate enrollment and shorten development timelines when participation barriers are addressed upstream. Evidence generated from representative trials is more likely to support faster clinical adoption and commercialization across diverse patient populations.

In accordance with the FDA’s guidance, inclusive design should be treated as a competitive advantage and strategic priority, strengthening regulatory confidence while improving market readiness.

References:

1. U.S. Food and Drug Administration. (2025, December 15). Enhancing Participation in Clinical Trials — Eligibility Criteria, Enrollment Practices, and Trial Designs. U.S. Food and Drug Administration. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enhancing-participation-clinical-trials-eligibility-criteria-enrollment-practices-and-trial-designs
2. Charron, N.; Yang, H. (2025, September 30). Age Diversity In Clinical Trials: Considerations For Improving Older Adult Representation. Clinical Leader. https://www.clinicalleader.com/doc/age-diversity-in-clinical-trials-considerations-for-improving-older-adult-representation-0001
3. Propes, C.; Mehl, K.; Morain, S. R. (2024, November 20). Untapped Potential? Representativeness in Pragmatic Clinical Trials. JAMA. https://jamanetwork.com/journals/jama/article-abstract/2826609
4. Stone, L. (2026, January 9.) 2026 Clinical Trials Trends. Clarkston Consulting. https://clarkstonconsulting.com/insights/2026-clinical-trials-trends/
5. Anand, S. S.; Arbour, L.; Ogilvie, G. S.; Tita, A. T. N. (2025, March 11). Inclusive research: a path to equity and better outcomes. The BMJ. https://www.bmj.com/content/388/bmj-2024-082486
6. Firestein, J. (2019, April 4). Breaking Down the Keys to Decentralized Clinical Trials. Clarkston Consulting. https://clarkstonconsulting.com/insights/decentralized-clinical-trials/
7. Saiontz, L.; Firestein, J. (2026, January 15). 2026 Medical Device Industry Trends. Clarkston Consulting. https://clarkstonconsulting.com/insights/2026-medical-device-industry-trends/
8. Parks Murray, E.; Stone, L. (2023, May 26). Leveraging Digital Marketing Tactics to Increase Diversity in Clinical Trial Recruitment. Clarkston Consulting. https://clarkstonconsulting.com/insights/digital-marketing-tactics-clinical-trial-recruitment/
9. Parks Murray, E.; Stone, L. (2024, January 19). Top 3 Reasons Why You Need to Incorporate DEI into Clinical Trials Today. Clarkston Consulting. https://clarkstonconsulting.com/insights/why-you-need-to-incorporate-dei-into-clinical-trials/
10. Davies, C. (2026, January 5). How To Meet FDA Expectations For Hybrid And Decentralized Trial Oversight. Clinical Leader. https://www.clinicalleader.com/doc/how-to-meet-fda-expectations-for-hybrid-and-decentralized-trial-oversight-0001
11. Parks Murray, E. (2024, December 20). Clinical Trial Diversity and Inclusive Research: Guidance from the FDA and ICER. Clarkston Consulting. https://clarkstonconsulting.com/insights/clinical-trial-diversity/

About The Authors:

Brandon Miller is a data-driven, people-focused health equity strategist and organizational transformation leader at Clarkston Consulting. He has expertise in and a passion for organizational efficiency, DEI, and talent development and is a firm believer that a culture of belonging is a critical component in unleashing organizations’ innovation and effectiveness. Miller received his Bachelor of Science degree in biomedical engineering with a minor in technology & management from the Georgia Institute of Technology. He is the co-author of The Intersection: Shifting into Greatness and the cofounder of Too Fly Foundation, an organization that provides passports and travel grants to students in underserved communities.

Hannah Yang is a sophomore at Duke University studying economics and sociology. Through her work at Clarkston, Yang has developed an interest in clinical trial trends and innovative models to improve accessibility. At Duke, Yang is involved in the Duke Consulting Club, Duke Association for Business Oriented Women, and the Backpack Project Durham.