A Primer on Global Regulatory Guidance for Diversity in Clinical Trials
The global regulatory landscape is undergoing important changes: individual regulatory bodies around the world are introducing initiatives to enhance diversity in clinical trials. These initiatives will change the design and conduct of medical research in their home nations and worldwide. Differing regulatory mandates are not new for clinical development programs, but effectively navigating diversity guidance will require a comprehensive understanding not just of the global regulatory landscape but also why these initiatives are needed and what they hope to achieve.
More to come on our study at ISPOR USA 2024
Our newsletter series on global regulatory guidance for diversity in clinical trials is based on a recent targeted literature review we conducted, so you can be sure that our content is informed and current. In brief, we looked for guidance relevant to diversity and representation in clinical trials from regulators of the 10 largest pharmaceutical markets around the world, with a focus on guidance available in English.
Why Are These Changes Needed?
Randomized clinical trials are the gold standard for measuring the effectiveness of an intervention. However, numerous studies have found that clinical trials do not adequately represent large numbers of our society. For example, a review of representativeness of RCT samples found that RCT participants tend to be of lower risk than real-world patients, and that RCTs frequently excluded older patients and those with comorbidities [1]. This lack of representation makes it hard or impossible to know how well trial results apply to groups of individuals that were not included in clinical studies.
Compounding this problem, historically many clinical trials have not reported race and ethnicity data. Authors of a 2022 study reviewed race and ethnicity reporting for all US clinical trials registered on ClinicalTrials.gov from March 2000 to March 2020 and found that most registered trials (57%) did not report any race or ethnicity data [2]. Among those that did, the majority underrepresented racial and ethnic minorities. This lack of representation matters not only because interventions may work differently for different groups, as is the case with certain antihypertensive medications [3], but because lack of representation also hinders access to and uptake of effective medications in under-represented groups.
An experimental study found that physicians were more willing to prescribe medications to Black patients if the medication was tested in a representative sample. Similarly, Black patients were more likely to believe that a medication would be effective for them if the trial sample was representative [4].
Although it may sound straightforward, improving representation in clinical trials is not simple. There are many barriers to participation for under-represented groups – chief among them is distrust of medical and scientific professions. This distrust stems from a long history of exploitation and abuse of minority groups by the medical establishment [5-8], and persists in the discrimination and racism apparent in medical care today [9-11]. It is imperative that steps are taken to rebuild the trust that was broken. Improving diversity in health research and in clinical trials may be one way to begin to rebuild that trust [12, 13].
Diversity in Clinical Trials
The number of peer-reviewed studies focusing on Diversity, Equity, and Inclusion (DEI) in the context of clinical trials has been increasing, as shown in the Figure.
This surge points to increasing scientific dialogue on DEI and highlights the scientific community’s growing recognition of its importance in clinical research.
It is becoming increasingly critical to stay informed about evolving regulatory guidelines. These regulatory changes will facilitate the pharmaceutical industry’s efforts to change how clinical trials are conducted and shift towards inclusion. Understanding of the regulatory framework is essential for aligning with the growing body of scientific research.
Source: The number of published peer-reviewed articles related to “diversity, equity, and inclusion” and “clinical trials” on PubMed in the last three decades (1994 to 2024)
From Reporting to Accountability
Initiatives related to diversity in clinical trials are not new. In 1993, the federal government of the United States passed legislation directing the National Institutes of Health to create guidelines on the inclusion of women and minorities in clinical research (read more on the history here) [14]. Regulatory agencies followed suit shortly after. However, these early efforts by regulatory bodies focused primarily on improving reporting, rather than shaping participation and representativeness of clinical trials. This new era heralds a major change: guidance is evolving from mandating the collection and reporting of race, ethnicity, and gender data in clinical trials to enforcing accountability. This evolution includes a shift towards concrete measures that ensure clinical trials are conducted in a way that represents the true diversity present in our population. With these actions, regulatory agencies are committing to not only acknowledge but also actively address disparities in clinical research, promoting equitable access and outcomes for all demographic groups.
For those conducting clinical trials, it may be easy to lose sight of the bigger picture. But remember, each trial can move us one step closer to equitable health research. Trials that intentionally recruit underrepresented participants will generate findings that are more applicable to the population overall. When added together, the effect of these individual trials on the overall evidence base will be substantial and will allow for a more nuanced understanding of medical interventions across different demographic and social groups. An increasing evidence base for underrepresented groups will inform not only regulatory decisions but also those made by health care providers, payers, and other policy makers and enable them to make more informed decisions that better serve everyone.
Understanding the Global Landscape: Limited Guidance
Over the coming weeks, we will share what we found in our review and highlight the differences in guidance provided by four agencies
As regulatory processes vary across countries and regions, so too does guidance on diversity in clinical trials. In our targeted review, we identified four regulatory agencies with guidance documents (or plans for guidance documents) related to improving the representativeness of clinical trials: the Food and Drug Administration, The European Medicines Agency, Health Canada, and the Medicines and Healthcare products Regulatory Agency (MHRA). Next newsletter, we will focus on the FDA’s efforts to improve DEI in clinical trials.
Summary
From the current regulatory landscape along and the surge in scholarly activities related to DEI in clinical trials, there are several important takeaways. The increasing scholarly articles on DEI for clinical trials shows these issues are now gaining traction within the scientific community. On a global level, the current guidance on DEI for clinical trials is somewhat limited, but regulatory agencies are pushing for action and there are important steps for trialists to take.
Now is the time to go beyond reporting. Now is the time to develop tangible plans and measures to ensure trials represent the true diversity of our population.
References:
Kennedy-Martin T, Curtis S, Faries D, Robinson S, Johnston J. A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results. Trials. 2015;16(1):495.
Turner BE, Steinberg JR, Weeks BT, Rodriguez F, Cullen MR. Race/ethnicity reporting and representation in US clinical trials: a cohort study. Lancet Reg Health Am. 2022;11:100252.
Reichman ME, Wernecke M, Graham DJ, Liao J, Yap J, Chillarige Y, et al. Antihypertensive drug associated angioedema: effect modification by race/ethnicity. Pharmacoepidemiology and Drug Safety. 2017;26(10):1190-6.
Alsan M, Durvasula M, Gupta H, Schwartzstein J, Williams HL. Representation and Extrapolation: Evidence from Clinical Trials. National Bureau of Economic Research; 2022.
Global News | Canada subjected Indigenous people to ‘cruel’ medical experiments, lawsuit claims | Globalnews.ca.
Nuriddin A, Mooney G, White AIR. Reckoning with histories of medical racism and violence in the USA. Lancet. 2020;396(10256):949-51.
Scharff DP, Mathews KJ, Jackson P, Hoffsuemmer J, Martin E, Edwards D. More than Tuskegee: Understanding Mistrust about Research Participation. J Health Care Poor Underserved. 2010;21(3):879-97.
MacDonald NE, Stanwick R, Lynk A. Canada’s shameful history of nutrition research on residential school children: The need for strong medical ethics in Aboriginal health research. Paediatr Child Health. 2014;19(2):64.
Mary Ellen T-L, Health BCMo. In Plain Sight: Addressing Indigenous-specific Racism and Discrimination in B.C. Health Care. 2020.
PBS NewsHour | With a history of abuse in American medicine, Black patients struggle for equal access.
Nobles M, Womack C, Wathuti E. Science must overcome its racist legacy. Nature.
Oster RT, Lightning P. Commentary: Developing Relationships through Trust in Indigenous Health Research. Healthc Policy. 2022;17(4):56-62.
Schwartz AL, Alsan M, Morris AA, Halpern SD. Why Diverse Clinical Trial Participation Matters. NEJM. 2023;388(14):1252-4.
National Academies of Sciences, Engineering, and Medicine. 2022. Improving Representation in Clinical Trials and Research: Building Research Equity for Women and Underrepresented Groups. Washington, DC: The National Academies Press