Finding and recruiting clinical trial participants who fit the ever-narrower patient profiles sought nowadays to test novel therapies is a serious challenge for the pharma industry. For some clinical trial sites, even enrolling healthy volunteers willing to undergo safety and efficacy testing for a new treatment is a struggle. The COVID-19 pandemic and the race for a vaccine have created much-needed public awareness around the societal value of trial participation, although in the context of a global emergency, signing up volunteers seems to be easier compared to recruiting participants who match the rigid requirements for testing other interventions. Yet, regardless of the therapies being tested, the volunteers’ health profiles, or the urgency of the moment, one major problem for clinical study teams endures: ensuring a racially diverse cohort that is representative of the demography of the U.S. population.
In 2019, Racial diversity among clinical trial volunteers overall was abysmally low, with only 9% who identified as African-American and 18% who identified as Hispanic. For their part, American Indian and Alaskan Native participants accounted for a mere 1% and were not even reflected in the FDA´s annual Drug Trials Snapshots report [1]. According to U.S. Census data from the same year, these groups make up 13.4%, 18.5%, and 1.3% of our population [2], respectively, which means clinical research is disproportionately missing out on evaluating the effects of new drugs and treatments on African-Americans. This can have unpredictable and undesirable consequences in the future since pharmacogenetic research has shown that different Racial groups may respond differently to identical medications due to underlying metabolic, genetic, or environmental factors and variation in drug sensitivities [3, 4].
So, what explains the underrepresentation of African-Americans in clinical trials? One historical event often cited as a root cause of this phenomenon is the Tuskegee Syphilis Study in Alabama, which ran for four decades beginning in 1932. In that study, 600 impoverished African-American sharecroppers were enrolled by employees of the U.S. Public Health Service, who deceived them by promising free medical care, but conducted instead – unbeknownst to the study participants – syphilis tests with the aim of observing the natural course of the disease when left untreated. Although penicillin had been approved for syphilis treatment by the Centers for Disease Control and Prevention in the mid-1940s, the men who had tested positive were never treated nor informed of their condition. A technical paper published by the National Bureau of Economic Research in 2016 evaluated the effects that the eventual disclosure of the study had on Black men and found it was a major contributor to their mistrust towards the health care system and their low involvement in medical research [5].
But the Tuskegee Experiment ended 48 years ago and although it played a significant role in the development of research participant rights, it is too narrow an explanation for the persistently low levels of Black Americans’ participation in clinical trials. Considering how clinical trial diversity-related concerns have floated to the top of the research agenda in the context of COVID-19 provides further insight.
Although diversity of all kinds was a popular topic in research industry discussions before the pandemic, coronavirus vaccine trials are shining a bright light on the issue as participant enrollment data start streaming in. Recent figures released by Moderna, which is conducting one of the most high-profile COVID-19 vaccine clinical studies in the U.S. due to its being the first one to begin Phase III enrollment, reveal 28% minority participation as of September 18 (company updates on enrollment numbers are provided every Friday afternoon). This is about 5% shy of being representative of the U.S. Black, Hispanic, American Indian, and Alaskan Native population, as reflected in the 2019 U.S. Census data, and far short of Dr. Anthony Fauci’s recommendation that minorities represent about 66% of study participants [6]. Dr. Fauci has pointed out that although this number is not a requirement, it ought to be seen as a goal by pharma companies and clinical research sites because minorities are disproportionately affected by COVID-19; hence they need greater representation. Accompanying his call for ensuring equitable representation, the COVID-19 Prevention Network, a clinical trials network that leverages the collective reach of four existing NIH-funded networks, has released TV ads encouraging minority volunteers to join coronavirus vaccine trials [7].
Despite such targeted “push” and “pull” efforts to diversify clinical trial cohorts, the unfortunate truth is that clinical trial sites and networks are likely to struggle with satisfying the high demand for minority participation for current and future vaccine studies. This is due to the fact that many of them rely on potential study volunteers on proprietary databases of affiliated medical practices or on their own curated databases. When required to recruit a higher-than-usual volume of minority patients, they may find that those databases do not contain such high percentages and turn to advertising via social media to make up the deficit. And therein lies a paradox: Facebook, a popular platform for clinical trial advertising, has taken significant steps to avoid racial and ethnic discrimination in ads for housing, employment, and insurance. An unintended consequence of this well-intentioned policy is that the ads that research sites run for clinical trial recruitment cannot be targeted to minority populations.
We anticipate that any such challenges to reach a diverse population will be further increased as time goes on, FDA approvals are awarded, and second- and third-wave Phase III trials seek to repeat the enrollment cadence enjoyed by current frontrunners in the COVID-19 vaccine race, such as Pfizer and Moderna. In fact, there is already a real concern among clinical trial sites that not only minority patients but healthy study volunteers of all races and ethnicities may be hard to find if altruistic motivation wanes as news of an approved vaccine is just weeks or months away.
The horizon for clinical trial recruitment rates gets even cloudier when we consider that participants in a vaccine study, which in the case of COVID-19 lasts around two years, cannot participate in most other vaccine studies, be they for COVID-19, the seasonal flu, or RSV. The toll of these vaccine-preventable diseases is immense, as they account for hundreds of thousands of hospitalizations and deaths. As a result, future and postponed vaccine studies will necessarily feel the impact of there being so many healthy patients tied up in COVID-19 vaccine trials and unavailable for research activities that advance the discovery of vaccines for other diseases.
In this high-stakes scenario, for study teams selecting from a limited number of sites capable of high-volume vaccine studies, the old problem of competing trials emerges in a new way. They will find that only larger networks with advanced recruitment capabilities that can spread vaccine work across multiple centers are likely to perform well on forthcoming trials, as many individual sites will have exhausted their known healthy volunteers once the first rush of vaccine enrollment is over. If the fact that many sites are already participating in multiple vaccine studies is any indication, there is a likely supply problem in terms of both qualified sites and trial participants to meet the enrollment demands of COVID-19 studies.
This mismatch of supply and demand must be resolved sooner rather than later so that clinical study teams can manage expectations and investigators can prepare their sites for future demands. The existing system of site feasibility must be revised such that study teams can effectively support the development of more vaccine sites that favor minority access. What is not feasible is simply asking sites to do more in terms of recruitment with the same resources and capabilities, even as they have already suffered the loss of nearly all new patient enrollment as a result of the confinement measures taken to limit the spread of the pandemic. Augmenting those resources and capabilities requires federal support.
A recent precedent for such support in the aftermath of COVID-19 exists in plain sight. Operation Warp Speed, born out of necessity last March, is an initiative of the U.S. Department of Defense that leverages federal money into early vaccine development in order to accelerate R&D timelines, scale up production capacities, and enable the rapid collection and analysis of data in large Phase III trials [8]. If the research industry or government truly wants to incentivize diversity in COVID-19 vaccine studies, as well as in all clinical trials going forward, study sites need a similar commitment as that offered to pharma companies and suppliers to support their network expansion, database amplification, and minority outreach and recruitment efforts. Here's to hoping they heed the call.
References:
1. 2019 Drug Trials Snapshots Summary Report. U.S. Food and Drug Administration. https://www.fda.gov/media/135337/download
2. United States Census Bureau QuickFacts. https://www.census.gov/quickfacts/fact/table/US/PST045219
3. Ramamoorthy A, Pacanowski MA, Bull J, Zhang L. Racial/Racial differences in drug disposition and response: review of recently approved drugs. Clin. Pharmacol. Ther. 2015;97(3):263-273. https://pubmed.ncbi.nlm.nih.gov/25669658/
4. Burroughs VJ, Maxey RW, Levy RA. Racial and Racial differences in response to medicines: towards individualized pharmaceutical treatment. J Natl Med Assoc. 2002;94(10 Suppl):1-26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2594139/
5. Alsan M and Wanamaker M. Tuskegee and the Health of Black Men. The Quarterly Journal of Economics. 2018;133(1):407-455. https://www.nber.org/papers/w22323
6. https://www.cnn.com/2020/08/29/health/moderna-coronavirus-vaccine-minorities-goal/index.html
7. https://edition.cnn.com/2020/09/08/health/coronavirus-vaccine-trial-ads-minorities/
8. Operation Warp Speed Timeline. U.S. Department of Defense. https://www.defense.gov/Explore/Spotlight/Coronavirus/Operation-Warp-Speed/Operation-Warp-Speed-Timeline/