Choosing Inclusivity: Serving All Patients Through Scientifically Driven Eligibility Criteria
Samantha Roberts
Dylan Bechtle
Katherine Williams
Howard University
Rasika Kalamegham
Genentech, A Member of the Roche Group

he US Food and Drug Administration’s (FDA) 2020 Drug Trials Snapshots Summary Report found that clinical trials supporting the 53 new molecular entities approved by FDA’s Center for Drug Evaluation and Research (CDER) in 2020 included, on average, only 11% Hispanics and 8% African Americans. This lack of diversity in clinical trials can have a direct impact on health outcomes. Events of the past year and the Covid-19 pandemic have brought a renewed sense of urgency to ensure that underserved and understudied patient populations are not left behind in our age of personalized healthcare.

Re-Evaluating Eligibility Criteria

Strict eligibility criteria for clinical trials present a clear scientific and evidence-based opportunity to improve diversity in clinical studies. Clinical trial inclusion and exclusion criteria are necessary to define the study population of interest and ensure patient safety. However, many eligibility criteria used in contemporary clinical trials were designed for small molecule drugs and may not be appropriate for studies of therapeutic antibodies or the emerging treatment modalities of the future like cell and gene therapies. Furthermore, many criteria have been defined based on data from predominantly non-Hispanic whites. Nonetheless, several common exclusion criteria, such as laboratory test values, remain a static fixture of trial design. Here we discuss the need to reconsider eligibility criteria and shift from the default state of exclusion to a future state of inclusion in clinical trials.

Laboratory Test Requirements and Comorbidities
Common exclusion criteria in clinical trials include “abnormal” laboratory test results, which are often used as a proxy to evaluate organ function. Normal variations across ethnic and racial lines are an accepted truth for many standard laboratory tests in medical practice but not for purposes of accrual into clinical trials. Beyond laboratory values, certain comorbidities that are exclusion criteria could have an outsized impact on patient participation in trials, including HIV-positive status, kidney, liver, cardiac, and endocrine diseases like diabetes.

An evaluation of 401 prostate cancer trials found that 47% disproportionately restricted access for African American men by excluding patients based on serum creatinine (sCr) levels established for non-Hispanic whites, rather than race-adjusted measurements for renal function, and based on absolute neutrophil count (ANC) threshold, despite the fact that benign neutropenia is more common in African Americans than other populations. Considering that African American men are roughly twice as likely to be diagnosed with and die from prostate cancer, the impact of excluding this population from trials is profound.

Clinical trials that supported FDA approval of oncology drugs in 2019 allowed for little to no flexibility in requirements for laboratory test values that are known to vary across different racial groups, including sCr, ANC, hemoglobin, and aspartate transaminase. These trials included a broad range of therapeutic modalities, e.g., targeted and immunotherapies as well as small molecule drugs, all of which exhibit differences in metabolism and mechanism of action. The strict adherence to exclusion criteria despite these known differences and knowledge about variation in standard laboratory values provides an opportunity to improve inclusion in future clinical trials.

Biomarker-Driven Criteria
As drug development has evolved to address the underlying pathophysiology of disease, many clinical trials define inclusion or exclusion criteria based on the presence or absence of a specific mutation or biomarker threshold. Like laboratory values, our understanding of the molecular drivers of disease is based primarily on data derived from non-Hispanic white patients, and may not appropriately reflect markers of disease pathology in different racial and ethnic groups.

For example, a study of patients with Alzheimer’s Disease (AD) and their healthy aging counterparts found that relative to non-Hispanic whites, African Americans expressed significantly lower levels of tau protein, a biomarker frequently used as an inclusion criterion in AD trials, and that variants in APOE4 (the apolipoprotein E4 gene), which confers a high risk of AD in whites, were less likely to be associated with AD in African Americans. This suggests potential for underlying differences in expression of specific disease biomarkers between racial groups and the need to use caution when excluding patients on the basis of specific biomarker values. This discrepancy is underscored by the fact that studies associate over a 60% greater prevalence of AD in African Americans compared to non-Hispanic whites.


It is imperative that clinical research be designed to generate data that is representative of real world patient populations in order to improve clinical outcomes for all. Ameliorating the lack of clinical trial diversity is a monumental task, but one aspect that is evidence-based and can be addressed by both sponsors and regulators is rethinking exclusion criteria. This could improve participation in clinical trials and allow a better understanding of how medical products perform in different patient populations.

Given the population of interest and mechanism of action of the investigational product, sponsors should consider if exclusion based on standard laboratory test values and specific comorbidities is scientifically justified to determine whether and how these criteria should be employed. Sponsors should also consider potential variations in biomarker frequency across racial and ethnic patient subgroups when designing protocols.

FDA’s role in encouraging sponsors to diversify their clinical trial population cannot be overstated. We call on the Agency to expand on the recommendations provided in its 2020 Guidance on Enhancing Diversity of Clinical Trial Populations. One avenue to encourage clinical trial diversity is by describing how data collected in specific subpopulations through clinical trials or from real-world studies can be used to inform labeling. If drug labels can reflect information relevant to specific populations, it will empower individual patients and their providers to make better informed treatment choices.

Looking Forward

Many sponsors are modernizing their practices to embrace diversity and inclusion as a core component of clinical trial design. We recognize that broadening trial inclusion criteria is one step in a complex web and that other barriers should be addressed to increase diversity in clinical research. Addressing this complex problem will require sustained commitment and collaboration by multiple stakeholders across the clinical research community. We remain hopeful that clinical trials reflective of the population at large are an achievable goal in the near future.
Acknowledgements: We thank Quita Highsmith, Melissa Gonzales, and Nicole Richie for their insights on this topic, and Monica Veldman for editorial assistance.

References available upon request.