The Ethical and Scientific Imperative for Greater Diversity in Clinical Trials
By: Biotech Square
Tags: Biotechnology, Diversity, Pharmaceutical, Clinical Trials, Medicine

by Max Yaghchi — December 09, 2020

The need for greater diversity in clinical trials has been an area of focus since the NIH Revitalization Act of 1993, which required clinical trials funded by the U.S. National Institute of Health (NIH) to include female and minority patients [1]. A lack of diversity in clinical trial poses an ethical and scientific challenge for regulators, sponsors, investigators, healthcare providers, patients, and other key stakeholders [2]. The ethical challenge is that underrepresentation of minorities in clinical trials prevents equal access to medical innovations, and further contributes to health disparities. The scientific challenge is that results from clinical trials may not accurately reflect the clinical response from patients that would receive the treatment or be generalizable to these patients. Participant demographic characteristics such as sex, race, ethnicity, age, location of residency and non-demographic characteristics including organ dysfunction, concomitant conditions, disabilities, and rare conditions have been identified as factors that have excluded patients from clinical trials [3]. In this article, we will explore the clinical significance of representation of patients from these groups, and strategies recommended by regulatory bodies to enhance diversity in clinical trials.

One of the earliest concerns about diversity in clinical trials was centered on the representation of female participants in clinical trials. It was once believed that data from clinical trials conducted on male patients could be extrapolated to females if the innovation did not impact reproductive health [4]. This practice has been addressed in a guidance by Health Canada, which pointed out pharmacokinetic differences between females and males due to body weight, plasma volume, plasma protein levels, gastric emptying time, metabolizing enzyme function, drug transport and clearance. Differences between the sexes in pharmacodynamics have also been documented in drugs acting on the central nervous, immune, and cardiovascular systems [4]. The clinical significance of these differences includes a 1.5–1.7 fold increased risk of adverse drug reactions in females, and drugs have been removed from market due to adverse reactions related to sex [5]. Anatomical differences between females and males has been another concern in clinical trials for medical devices, especially in cardiovascular device trials for pacemakers, where sex distribution has been 67% male [5]. Furthermore, the FDA has reported that only 38% of participants were female in 2018 drug trials [6].

Lack of representation in clinical trials has also impacted patients with organ dysfunction and concomitant conditions including renal dysfunction, hepatic disease, malignancies and pregnancy. Exclusion of patients based on these conditions may prevent adverse effects in clinical trials, however the FDA has stated that these exclusions have become standard practice without documented scientific rationalization for individual innovations [3]. The clinical significance of excluding participants based on underlying conditions or treatments is that the efficacy and safety of novel treatments cannot be established in these groups. Subsequently, healthcare providers have had limited treatment options for these patients, which are more vulnerable to adverse health events. Moreover, patients with rare conditions are at risk of being excluded from clinical trials that could provide treatments for their concomitant conditions, in addition to having few treatment options for their rare condition. Another barrier faced by patients with rare conditions is that they are often excluded from phase 3 clinical trials for participating in earlier phases of clinical trials [3]. Concerns about prior exposure to a treatment in early clinical trials is justified in cases where there is an adequate number of patients with the condition available for later phases. That said, conditions with low prevalence may not have adequate recruitment if patients with these conditions are excluded in later phases of clinical trials [3]. In turn, trials conducted on participants without the rare condition may not be generalizable to those with the condition.

Poor racial and ethnic diversity in clinical trials has been another barrier to ensuring that medical innovations have efficacy and safety data for their target patient population. The underrepresentation of racial minorities in clinical trials is particularly worrisome for cancer treatments, since genetic variations can directly impact clinical response [6,7]. A review of clinical trials that led to oncology drugs being approved by the FDA from 2008 to 2018 found that race was not reported in more than one-third of trials, and that representation of African Americans and Hispanics was low relative to the incidence of cancer in these populations [7]. When data from the U.S. and Canada was combined (Figure 1), patients of African descent represented 7.7% and Hispanics represented 5.6% of cancer trial participants from 2010 to 2016 [2]. The underrepresentation of African Americans in cancer trials is worsened by their higher cancer-specific mortality, compared to Caucasian patients, which was independent of sociodemographic factors, disease stage, and access to treatment [6].

Figure 1: Representation of racial minorities in U.S. and Canadian cancer drug trials [2].

Researchers have identified five critical barriers to minority participation in clinical trials: mistrust, lack of comfort with the clinical trial process, lack of information about clinical trials, time and resource constraints associated with the clinical trial process, and lack of clinical trial awareness [1]. Collaboration and outreach between investigator sites and participant communities has been recommended to enhance diversity [1]. The FDA and Health Canada have also developed guidance documents with mitigating strategies for underrepresentation of patient groups in clinical trials [3,4,8]. One recommendation from the FDA was to consider removing exclusion criteria used in phase 2 of clinical trials when designing phase 3 trials, since early safety and pharmacokinetic data may support the use of the innovation in previously excluded patients [3]. A recommendation from Health Canada was for investigators to develop pre-specified plans to assess sex related differences in phase 3 trials even if early phases did not indicate a difference between male and female participants [4]. Moreover, Health Canada stated that investigators with data from foreign participants should conduct bridging studies with local participants, if the innovation has safety and efficacy outcomes affected by genetic polymorphisms [8].

References

1. Clark, Luther T., et al. “Increasing Diversity in Clinical Trials: Overcoming Critical Barriers.” Current Problems in Cardiology, vol. 44, no. 5, 2019, pp. 148–172., doi:10.1016/j.cpcardiol.2018.11.002.

2. Dickmann, Leslie J., and Jennifer L. Schutzman. “Racial and Ethnic Composition of Cancer Clinical Drug Trials: How Diverse Are We?” The Oncologist, vol. 23, no. 2, 2017, pp. 243–246., doi:10.1634/theoncologist.2017–0237.

3. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, and Center for Biologics Evaluation and Research. “Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices and Trial Designs Guidance for Industry.” November 2020.

4. Government of Canada. “Guidance Document: Considerations for Inclusion of Women in Clinical Trials and Analysis of Sex Differences” March 2013.

5. Coakley, Meghan., et al. “Dialogues on Diversifying Clinical Trials: Successful Strategies for Engaging Women and Minorities in Clinical Trials.” Journal of Women’s Health, vol. 21, no. 7, 2012, pp. 713–716., https://doi.org/10.1089/jwh.2012.3733

6. Nezha, Bassel., et al. “Enrollment of Racial Minorities in Clinical Trials: Old Problem Assumes New Urgency in the Age of Immunotherapy.” American Society of Clinical Oncology Educational Book. 2019: 39, 3–10.

7. Loree, Jonathan M., et al. “Disparity of Race Reporting and Representation in Clinical Trials Leading to Cancer Drug Approvals from 2008 to 2018.” JAMA Oncology, 2019., doi:10.1001/jamaoncol.2019.1870

8. Government of Canada. “Guidance Document: Ethnic Factors in the Acceptability of Foreign Clinical Data ICH Topic E5(R1).” December 2015.