Pharmaceutical and medical device companies have an ethical duty to develop products that are safe and efficacious for all patients who may use them. This includes racially and ethnically distinct subgroups, in whom differences in pharmacokinetics, efficacy, and safety may be observed.1 A review of 167 new molecular entities approved by the Food and Drug Administration (FDA) between 2008 and 2013 revealed that approximately 1 in 5 entities displayed differences in exposure and/or response across racial and ethnic groups.2 These data highlight the need for diversity in clinical trials, where these differences may be elucidated.
Despite the increasing diversity of the US population as a whole, people of color have been, and continue to be, underrepresented in clinical trials in the United States. For example, people of Hispanic/Latinx ethnicity make up 16% of the US population, but only 1% of clinical trial participants.3 However, the ideal approach is a bit more complex than simply attempting to match the demographics of the US population.
According to the FDA, clinical trials should enroll a population which reflects the population most likely to use the drug if it is approved2, which may or may not match the demographics of the US as a whole.
A striking example of this: African American/Black people make up 13% of the overall US population but disproportionately constitute 35% of all patients receiving dialysis for kidney failure.4 When considering these data, it is clear that proper representation of the African American/Black population is essential in clinical trials in kidney disease, if the scientific community is to truly understand the safe and effective use of new therapies.
The issue of diversity in clinical trials is not limited to underrepresentation in later-stage clinical trials. People of color are, in fact, overrepresented in Phase 1 clinical trials, which are normally used to establish safety and appropriate dosing. Phase 1 trials typically involve the greatest risk to patients with the lowest likelihood of clinical benefit. Frequently, there is a lack of compensation to those injured because of participation.5 Thus, attention must be paid to the composition of clinical trial populations across the spectrum of clinical development.
The factors determining the current lack of diversity in clinical trials are vast, systemic, and historical.
One key factor is that documented unethical medical research practices against marginalized populations has fostered distrust. A landmark example of injustice by the medical research community was the U.S. Public Health Service Syphilis Study at Tuskegee, which denied Black male participants informed consent and withheld standard of care for over 40 years.6 Another well-known example is the Holmesburg Prison experiment, in which prisoners were subjected to inhumane experimentation and suffered long-term side effects or death. The government permitted these experiments to continue for 10 years after there was documented evidence of wrongdoing and an ongoing investigation by the FDA.7 Past and ongoing patterns of discrimination have led to concerns among vulnerable populations about potential exploitation, poorly- communicated or undisclosed risks of experimental treatment, and the true motivations of researchers.8
Importantly, the onus of overcoming this distrust lies not with patients but with the medical and scientific communities, including those conducting clinical trials.
While some people of color are justifiably distrusting of or unwilling to participate in the clinical trial process, additional factors contribute to their lack of representation. A review of cancer trials found that African American/Black and Hispanic/Latinx patients were less likely to be enrolled in trials, in relation to the number of US cancer cases in each subgroup, than their white counterparts. The study highlighted that, based on past research, these populations may be less likely to be offered trial participation.8 Potential explanations for this disparity include difficulty accessing underserved populations and cultural or language barriers between investigators and prospective participants.8 Socioeconomic factors may present a barrier to recruitment, as structural racism, low income, and lack of access to healthcare can contribute to lower clinical trial participation rates.8 Investigator bias also plays a role. In one study, van Ryn et al used survey data from 618 patient encounters with 193 physicians to assess physician perceptions of patient intelligence, feelings of affiliation toward the patient, and beliefs about patients’ likelihood for high-risk behavior and adherence to medical advice. They found that physicians tended to perceive African American/Black patients more negatively than white patients.9 Together, these studies demonstrate the many ways in which structural factors and implicit bias, prevalent in our healthcare system, impact the composition of clinical trial populations.
The solution to this complex problem requires a multifactorial approach. Despite ordinances outlined in the Revitalization Act of 1993, which encouraged the inclusion of women and marginalized populations in NIH-funded clinical trials, systemic factors influencing clinical trial recruitment persist.10 More recently, the FDA Guidance for Industry, issued in 2020, provided recommendations to enhance the diversity of clinical trial populations by broadening eligibility criteria, enrolling participants reflective of disease state populations, and adopting more-inclusive enrollment practices to make trial participation less burdensome for patients.1 The Patient-Centered Outcomes Research Institute (PCORI) encourages investigators to partner with patient advisors or coinvestigators throughout the research process. Patient advisors can bring value in developing and prioritizing research questions, choosing outcomes that are important to patients, anticipating recruitment barriers, interpreting study data, and deciding how best to disseminate study results.11 Adoption of recommendations put forth by government bodies, such as the FDA and PCORI, is a starting point for changing industry practices.
The healthcare industry must also address the disproportionately small number of principal investigators of color, who are more likely to successfully recruit racially diverse trial participants.
For example, the NIH funding rate for R01 applications is approximately 1.7-fold higher in white versus African American/Black scientists. In addition, Hoppe et al found applications from African American/Black scientists were discussed 24% less frequently as those from white scientists, with poorer overall impact scores (numerical representation of the application’s scientific and technical merit) on average.12 Organizations dedicated to training female and racially diverse investigators, such as Project Increase Minority Participation and Awareness of Clinical Trials (IMPACT) and the National Hispanic Research Network, are promising examples of current efforts to address this issue.3 Eli Lilly and Company has collaborated with external partners, such as patients, nurses, physicians, and study coordinators, to recruit physicians of color as clinical trial investigators.13 While pharmaceutical companies may tend to select established investigators with a proven track-record, providing an opportunity to investigators of color is imperative to improve the racial and ethnic diversity of clinical trials.
In addition, diversifying clinical trial recruitment sites to include areas with a higher concentration of underserved and indigenous populations will promote more inclusive trial practices. Sponsors can utilize disease maps and real-world data to identify potential trial site locations that will target populations most affected by the disease.1,3 In addition, direct community outreach, through patient advocacy groups and education initiatives, will promote a clear understanding of the importance of clinical research, patient protections, and potential medical benefit.1,2 Community-based participatory research is based on collaboration between research and community stakeholders to conduct studies that will address specific problems to improve community health.14 Such partnerships can identify diverse trial participants by targeting non-traditional settings and community events.3
Lastly, it’s important to remember that any external work must begin with internal work. Investigators that wish to combat distrust in clinical research and increase engagement between investigators and participants might consider cultural competency training.15 This type of training may help decrease investigator bias and increase patient retention by reducing cultural generalizations and stereotypes in patient interactions. Likewise, pharmaceutical and medical device companies might begin by examining their own practices and historical approach to research, and provide internal training around these important issues.
Despite the consistent underrepresentation of people of color in clinical trials in the United States, the future is promising.
The disproportionate impact of the COVID-19 pandemic on underserved populations and recent acts of racial injustice have exposed long-standing inequities as a public health crisis, and prompted a much-needed call to action in the healthcare community.
In response, many pharmaceutical companies, such as AstraZeneca and AbbVie,16,17 and regulatory agencies have announced inclusion and diversity as priorities. With the coordinated efforts of our entire healthcare system, the hope is that the complex problem of clinical trial diversity might be mitigated, creating more inclusive and relevant scientific practices.
- Food and Drug Administration. Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry. https://www.fda.gov/media/127712/download. Published November 2020. Accessed May 4, 2021.
- Clark LT, Watkins L, Piña IL, et al. Increasing Diversity in Clinical Trials: Overcoming Critical Barriers [published correction appears in Curr Probl Cardiol. 2021 Mar;46(3):100647]. Curr Probl Cardiol. 2019;44(5):148-172. doi:10.1016/j.cpcardiol.2018.11.002.
- Coakley M, Fadiran EO, Parrish LJ, Griffith RA, Weiss E, Carter C. Dialogues on diversifying clinical trials: successful strategies for engaging women and minorities in clinical trials. J Womens Health (Larchmt). 2012;21(7):713-716. doi:10.1089/jwh.2012.3733.
- African Americans and Kidney Disease. National Kidney Foundation. https://www.kidney.org/news/newsroom/factsheets/African-Americans-and-CKD. Updated January 2016. Accessed May 4, 2021.
- Caplan A, Friesen P. Health disparities and clinical trial recruitment: Is there a duty to tweet?. PLoS Biol. 2017;15(3):e2002040. Published 2017 Mar 1. doi:10.1371/journal.pbio.2002040.
- The Tuskegee Timeline. Centers for Disease Control and Prevention. https://www.cdc.gov/tuskegee/timeline.htm. Updated March 2, 2020. Accessed May 4, 2021.
- MacLure J. Unnatural Resources: The Colonial Logic of the Holmesburg Prison Experiments [published online ahead of print, 2020 Aug 13]. J Med Humanit. 2020;10.1007/s10912-020-09651-5. doi:10.1007/s10912-020-09651-5.
- Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: race-, sex-, and age-based disparities. JAMA. 2004;291(22):2720-2726. doi:10.1001/jama.291.22.2720.
- van Ryn M, Burke J. The effect of patient race and socio-economic status on physicians’ perceptions of patients. Soc Sci Med. 2000;50(6):813-828. doi:10.1016/s0277-9536(99)00338-x.
- Geller SE, Koch A, Pellettieri B, Carnes M. Inclusion, analysis, and reporting of sex and race/ethnicity in clinical trials: have we made progress?. J Womens Health (Larchmt). 2011;20(3):315-320. doi:10.1089/jwh.2010.2469.
- Forsythe LP, Carman KL, Szydlowski V, et al. Patient Engagement In Research: Early Findings From The Patient-Centered Outcomes Research Institute. Health Aff (Millwood). 2019;38(3):359-367. doi:10.1377/hlthaff.2018.05067
- Hoppe TA, Litovitz A, Willis KA, et al. Topic choice contributes to the lower rate of NIH awards to African-American/black scientists. Sci Adv. 2019;5(10):eaaw7238. Published 2019 Oct 9. doi:10.1126/sciadv.aaw7238.
- Clinical Trials. Lilly. https://www.lilly.com/clinical-research/clinical-trials. Accessed May 4, 2021.
- Smith SA, Whitehead MS, Sheats JQ, Ansa BE, Coughlin SS, Blumenthal DS. Community-based participatory research principles for the African American community. J Ga Public Health Assoc. 2015;5(1):52-56.
- Otado J, Kwagyan J, Edwards D, Ukaegbu A, Rockcliffe F, Osafo N. Culturally Competent Strategies for Recruitment and Retention of African American Populations into Clinical Trials. Clin Transl Sci. 2015;8(5):460-466. doi:10.1111/cts.12285.
- AbbVie’s commitment to racial justice. AbbVie Inc. https://www.abbvie.com/our-company/our-principles/our-commitment-to-racial-justice.html. Accessed May 4, 2021.
- Villafana T. Achieving diversity in vaccine clinical trials. AstraZeneca. https://www.astrazeneca.com/what-science-can-do/topics/disease-understanding/achieving-diversity-in-vaccine-clinical-trials.html. Published March 5, 2021. Accessed May 4, 2021.