For decades, most major clinical trials have enrolled populations that do not reflect the patients who end up taking the approved therapies. According to FDA data, roughly 75 percent of clinical trial participants in the United States are white, even though white Americans represent approximately 58 percent of the population. Black or African American patients account for around 8 percent of trial participants despite making up 14 percent of the population. Hispanic and Latino representation shows a similar gap. This is a scientific problem as much as a fairness one. It affects drug safety data, efficacy labelling, and post-market outcomes.
This article covers why diversity in clinical trials matters, what regulators now require, the pharmacogenomic science behind population-specific drug responses, and how sponsors can build enrollment strategies that actually work.
The Diversity Gap in Clinical Research
The underrepresentation problem is not new, but it is getting harder to ignore. An analysis of FDA drug approvals between 2015 and 2022 found that across oncology, cardiology, and metabolic disease indications, Black patients were enrolled at rates 40 to 60 percent below their share of the disease burden for those conditions. For trials conducted outside the United States, the gap is often wider. Industry estimates suggest that fewer than five percent of participants in global registrational trials are of African descent, despite the continent carrying roughly 25 percent of the global disease burden.
The consequences show up after approval. Post-market safety signals disproportionately affect underrepresented populations. The FDA's own safety reviews have documented cases where adverse event rates differed across racial and ethnic groups, differences that were not detected during development because the trial populations were too homogeneous.
The heart failure drug BiDil, approved in 2005 specifically for self-identified African American patients, is the most visible example of population-specific efficacy. But the principle extends well beyond a single case. When trial populations do not match patient populations, sponsors are running an incomplete experiment. Regulators, payers, and prescribers are less willing to accept that than they used to be.
Why Diverse Populations Produce Better Drug Development Outcomes
The case for inclusive trials comes down to science, market access, and risk.
Better science. Drug metabolism varies across populations due to differences in cytochrome P450 enzyme expression, body composition, renal clearance rates, and disease comorbidity profiles. A trial that enrolls primarily from one genetic background may identify an optimal dose that is suboptimal, or unsafe, for other populations. Detecting these signals during Phase II or III avoids costly post-approval label changes and market withdrawals.
Broader market access. HTA bodies in the United Kingdom, Germany, France, and Australia now scrutinise trial demographics when evaluating reimbursement submissions. If the trial population does not resemble the local patient population, HTA reviewers may discount the efficacy data or require post-marketing commitments that delay formulary placement. For a blockbuster drug, even a six-month delay in reimbursement approval in a major market can mean hundreds of millions in lost revenue.
Lower post-approval risk. Post-market safety surveillance consistently shows that adverse drug reactions cluster in populations that were underrepresented during development. A diverse trial population reduces the likelihood of post-approval safety actions, REMS requirements, or label restrictions.
The economics are straightforward: investing in diverse enrollment upfront is cheaper than managing the consequences of homogeneous trials after approval. Industry estimates put post-approval safety-driven label changes at 50 to 200 million dollars per event, before counting reputational damage and loss of prescriber confidence.
FDA and EMA Diversity Requirements: What Sponsors Must Know
The regulatory environment around clinical trial diversity changed significantly in 2022. Sponsors that still treat diversity as voluntary are falling behind.
FDORA Section 3601. The Food and Drug Omnibus Reform Act of 2022, signed into law in December 2022, introduced Section 3601, which requires sponsors of new drug and biologic applications to submit a Diversity Action Plan (DAP) to the FDA. The DAP must include the sponsor's goals for enrollment of clinically relevant populations, a rationale for those goals, and a description of the methods that will be used to achieve them. The FDA can grant waivers, but the default expectation is that every IND submission for a Phase III or registrational trial includes a DAP.
FDA's draft guidance on diversity action plans. Released in 2024, this guidance clarified what the FDA expects in a DAP. It asks sponsors to define enrollment goals based on disease epidemiology and prevalence across demographic groups, rather than proportional to the general population. This epidemiology-based approach means that for conditions with higher prevalence in minority populations (type 2 diabetes, hypertension, lupus, certain cancers), enrollment targets for those groups may need to exceed their share of the general population.
FDA's Project Equity. Launched as an initiative within the Oncology Center of Excellence, Project Equity focuses on improving diversity in oncology trials. It has published analyses showing that trial populations for many cancer types diverge substantially from the populations in which those cancers are most prevalent. The initiative has become a model for how the agency uses data transparency to push sponsors toward more representative enrollment.
The DEPICT Act. The Diversifying Investigations Via Equitable Participation in Clinical Trials (DEPICT) Act and subsequent legislative efforts have reinforced the mandate by requiring applicants to report on demographic diversity in clinical trials by therapeutic area, creating a public accountability mechanism that reflects bipartisan consensus around trial diversity reporting.
EMA considerations. The European Medicines Agency's 2024 reflection paper on diversity in clinical trials signalled that marketing authorisation applications with highly homogeneous trial populations may face additional questions during assessment. The EMA has not yet mandated formal diversity action plans, but the direction is obvious.
For sponsors, this means diversity planning has to start at the protocol design stage. Trying to enroll underrepresented populations after sites have been selected and eligibility criteria locked is expensive and usually unsuccessful.
Genetic Diversity and Drug Metabolism: The Science
The scientific case for diversity goes deeper than demographic fairness. It is rooted in pharmacogenomics, the study of how genetic variation affects drug response.
Cytochrome P450 variability. The CYP2D6 enzyme metabolises approximately 25 percent of all prescribed drugs. The frequency of poor-metaboliser phenotypes varies dramatically by ancestry: roughly 5 to 10 percent in European populations, 2 to 7 percent in African populations, and below 1 percent in East Asian populations. Meanwhile, ultra-rapid metaboliser phenotypes (which can render standard doses ineffective) are found in up to 29 percent of individuals of Ethiopian and Saudi Arabian ancestry, compared to 1 to 2 percent in Northern Europeans. A trial that misses these phenotypes misses clinically relevant dosing information.
CYP2C19 and cardiovascular drugs. Clopidogrel, one of the most widely prescribed antiplatelet agents, is a prodrug activated by CYP2C19. Loss-of-function alleles that reduce clopidogrel activation are carried by approximately 33 to 40 percent of individuals of African ancestry and over 50 percent of individuals of East Asian ancestry. Trials that enrolled predominantly European populations underestimated the prevalence of poor response, contributing to years of clinical uncertainty about the drug's real-world effectiveness in non-European populations.
HLA diversity and immunogenicity. Human leukocyte antigen (HLA) alleles, which influence immune response to biologic therapies, show the highest diversity in African populations. This means that immunogenicity signals, including the development of anti-drug antibodies that reduce biologic efficacy, may manifest differently across populations. Enrolling genetically diverse populations in biologic trials provides a more complete immunogenicity profile before approval.
Disease-gene interactions. Conditions like sickle cell disease, G6PD deficiency, and certain HLA-associated drug hypersensitivities are concentrated in specific populations. Excluding these populations from trials means sponsors may miss critical safety signals or, conversely, may fail to demonstrate efficacy in the populations that stand to benefit most from new therapies.
This pharmacogenomic evidence is what links clinical trial diversity to precision medicine. You cannot match the right drug to the right patient if your trial data only covers a fraction of human genetic variation.
Practical Strategies for Recruiting Diverse Trial Participants
Understanding why diversity matters is the easier part. Achieving it requires changes to protocol design, site selection, and community engagement. Effective patient recruitment strategies for diverse populations share several common elements.
Redesign eligibility criteria to reduce unnecessary exclusions. Overly restrictive eligibility criteria are the single largest barrier to diverse enrollment. Requirements around organ function thresholds, prior therapy washout periods, and comorbidity exclusions often disproportionately screen out minority patients who have higher rates of comorbid conditions. The FDA's Broadening Eligibility Criteria guidance, initially developed for oncology, provides a framework for identifying criteria that can be relaxed without compromising safety or data integrity.
Select sites in communities with high prevalence of the target condition. Site selection drives enrollment demographics more than any other single factor. If all sites are located at academic medical centres in majority-white suburbs, no amount of recruitment advertising will produce a diverse cohort. Community health centres, safety-net hospitals, and Federally Qualified Health Centers (FQHCs) in the United States, and analogous public-sector facilities in other countries, serve patient populations that are structurally more diverse.
Invest in community engagement before the trial starts. Trust deficits between minority communities and the clinical research establishment are real and historically grounded. The legacy of exploitative research practices, from the Tuskegee syphilis study to more recent controversies around informed consent in genetic research, has created warranted scepticism. Sponsors that invest in pre-trial community engagement, including partnerships with trusted community organisations, patient advocacy groups, and local healthcare providers, consistently report higher enrollment and retention rates among minority participants.
Reduce the participation burden. Transportation, childcare, time off work, and out-of-pocket costs disproportionately affect lower-income participants, who are more likely to be racial and ethnic minorities. Practical measures like decentralised trial elements, home nursing visits, travel reimbursement, flexible scheduling, and mobile health monitoring reduce these barriers and improve retention. According to industry survey data, sponsors who implement at least three of these measures report a 25 to 40 percent improvement in minority enrollment rates.
Use real-world data for feasibility analysis. Before selecting sites or finalising eligibility criteria, sponsors can use electronic health record (EHR) data to map the geographic distribution and clinical characteristics of the target population. This data-driven approach identifies where eligible patients are actually receiving care, rather than relying on assumptions about which sites will recruit well.
Set enrollment targets and monitor them actively. Diversity goals without monitoring mechanisms are aspirational statements. Leading sponsors now build demographic tracking into their clinical trial management systems and conduct monthly enrollment reviews against targets, with site-level corrective actions when enrollment skews away from the plan.
Africa's Role in Closing the Diversity Gap
Any serious strategy for achieving genetic diversity in clinical trials must include Africa. Sub-Saharan African populations harbour more genetic variation than all other global populations combined, a consequence of humanity's evolutionary origins on the continent. Yet Africa remains the most underrepresented region in global clinical research. Fewer than three percent of clinical trials registered on ClinicalTrials.gov include African sites, and most pharmacogenomic reference data comes from European and East Asian cohorts.
That gap is both a scientific liability and a strategic opportunity.
The scientific case. Drug metabolism studies conducted without African-ancestry populations are incomplete by definition. The high frequency of unique CYP450 alleles, HLA variants, and disease-gene interactions in African populations means safety and efficacy signals relevant to these patients are systematically missed. As regulators evaluate diversity action plans against disease epidemiology rather than general population demographics, the absence of African-ancestry data will be harder to justify.
The operational case. Africa has practical advantages for diverse enrollment that sponsors are starting to recognise. Countries like Nigeria, with approximately 230 million people and more than 250 ethnic groups, provide access to genetically diverse patient populations at scale. High disease prevalence for conditions like type 2 diabetes, hypertension, HIV, hepatitis B, sickle cell disease, and several cancers means eligible patient populations are large and concentrated. Treatment-naive patient pools reduce confounding from prior therapy exposure. Site activation costs in established African research hubs run well below equivalent sites in North America or Western Europe.
The data infrastructure case. The availability of structured real-world health data from African facilities has improved substantially. EMR adoption across East and West Africa now covers thousands of facilities, and health data platforms like Kapsule aggregate de-identified records from multiple facility networks into research-ready datasets. This lets sponsors conduct feasibility analyses, identify optimal site locations, and validate patient profiles before committing to site activation, reducing the risk and timeline of entering a new research geography.
For sponsors building their first diversity action plan, Africa should not be an afterthought. The regulatory, scientific, and operational case for including African sites in global development programmes is strong and getting stronger.
Building Inclusive Trial Protocols: A Checklist for Sponsors
Diversity does not happen by accident. It has to be built into the trial from protocol design through database lock. The following checklist covers the operational steps that should be part of every clinical development process.
Protocol design phase:
- Conduct a disease epidemiology review to establish the demographic profile of the patient population for the target indication, including prevalence rates by race, ethnicity, age, and sex.
- Map enrollment goals to epidemiology data, not general population demographics. If a condition disproportionately affects a particular group, enrollment targets for that group should reflect the disease burden.
- Review eligibility criteria against the FDA's broadening eligibility guidance. For each exclusion criterion, document the safety rationale and assess whether it disproportionately screens out minority patients.
- Include pharmacogenomic sampling in the protocol to enable post-hoc analysis of drug metabolism across genetic subgroups.
Site selection phase:
- Use EHR-based feasibility data to identify sites serving high concentrations of the target patient population, including sites outside traditional academic medical centre networks.
- Include sites in geographically and demographically diverse regions, including African countries where the target condition is prevalent and research infrastructure supports GCP-compliant trials.
- Require each site to submit a recruitment plan that addresses local barriers to minority enrollment.
Enrollment and monitoring phase:
- Build demographic tracking into the clinical trial management system with automated alerts when enrollment deviates from targets by more than 10 percent.
- Conduct monthly enrollment reviews at the therapeutic area level, not just the trial level, to identify systematic patterns across the portfolio.
- Deploy decentralised trial elements (telemedicine visits, home nursing, mobile monitoring) at sites where participation burden is a documented barrier.
- Engage community advisory boards in the countries and regions where the trial operates, with a mandate to advise on recruitment messaging, consent processes, and participant experience.
Regulatory submission phase:
- Prepare the diversity action plan for inclusion with the IND or clinical trial application, documenting goals, methods, and anticipated challenges.
- If enrollment targets were not fully met, document the efforts made and the corrective actions taken. Regulators have indicated that good-faith effort with transparent reporting is acceptable; unexplained homogeneity is not.
- Include subgroup analyses by race, ethnicity, and genetic ancestry in the clinical study report, even when not statistically powered for individual subgroups. Directional signals inform labelling discussions and post-market commitments.
Where this is heading
Clinical trial diversity has gone from an aspirational goal to an operational requirement. FDORA Section 3601, FDA diversity action plans, and EMA reflection papers now sit alongside the pharmacogenomic evidence and the commercial reality of global market access. Sponsors who treat diversity as a box-checking exercise will find themselves at a disadvantage in regulatory discussions, HTA submissions, and competitive positioning.
Inclusive enrollment is how better drugs get developed. The sponsors who figure that out first will have an edge that compounds over time.
Kapsule provides access to structured, de-identified health records covering over 75 million patients across 9 African countries. Contact our team to discuss how diverse African patient data can support your diversity action plan and trial enrollment strategy.
This article is intended for informational purposes only and does not constitute legal, medical, or regulatory advice. Readers should obtain independent professional counsel for their specific circumstances.