Patient Diversity In Clinical Trials: How To Meet The Need
By James J. Gillespie and Joseph P. Gaspero, Center for Healthcare Innovation
We need a new paradigm for increasing diversity in clinical trials. Identifying, recruiting, and retaining study participants are essential to trial success. In the case of prospective participants who are racially and ethnically diverse, the challenges are particularly profound.
The study participants in clinical trials are often homogenous. In 2020, the FDA analyzed global clinical trial participation and found significant differences between the enrolled participants and the global population. Of the nearly 300,000 global trial participants, 76% were white, 11% were Asian, and only 7% were Black.1 In contrast, the 7.8 billion global population is approximately allocated as 60% Asian, 16% African, 10% European, and 8% Latin American.2 Historically, in the U.S., drugs have been tested primarily on white Americans, particularly young and middle-aged men of European descent. Although 39% of the U.S. population is composed of people of color, they account for less than 16% of those in clinical trials. Black patients consistently account for only 5% of clinical trial participants in the United States.3 Even more striking, although Hispanic Americans are 16% of the overall population, they compose only 1% of those in trials.4
The persistent overrepresentation of white participants in clinical trials is particularly striking considering the heavy burden of chronic disease in minority racial and ethnic populations. The disproportionate negative impact of the COVID-19 pandemic upon Black and Latinx communities in the United States brought the topic of health disparities into sharp focus. We know that COVID-19 has disproportionally impacted racial and ethnic minority populations, particularly African American, Hispanic/Latino-American, and American Indian/Alaska Native patients, with a hospitalization rate three times higher than whites. COVID-19 particularly laid bare certain health disparities given that racial and ethnic minority groups experienced higher rates of hospital admissions, critical-care admissions, and mortality.
Why Promote Diversity?
And why is diversity in clinical trials so important? High-level reasons include: (i) improving the effectiveness, efficiency, and safety of the new drug, (ii) building broad confidence across all communities and increasing public perceptions as everyone sees representative participants, and (iii) reducing health disparities by providing access to unapproved investigational drugs and potentially lifesaving therapies when there are few or no alternatives. Everyone deserves access to cutting-edge diagnostics and therapeutics, so increasing clinical trial diversity is an ethical, medical, moral, scientific, and strategic imperative.
Clinicians and researchers must define the clinical trial sample in their studies as best as possible and consider whether their findings can be generalized across different communities with different lived experiences. Factors that impact the probability of developing a disease, treatment responses, and long-term outcomes include genetic ancestry/variation, environmental conditions, healthy/unhealthy behaviors, and life experiences. Different people may experience the same disease (and treatment) differently, so we know that a homogenous clinical trial population may not be generalizable to a broader patient population. This could cause the drug to be less beneficial or even harmful for some patient subgroups. Very simply, broad patient populations (e.g., different races, ethnic groups, sex/genders, or ages) help provide evidence that the drug or device will be effective and safe for the broader target patient pool if the FDA provides approval.
Based on genetic ancestry, different groups can metabolize drugs differently. There are known biological differences in how certain racial/ethnic groups respond to therapies attributable to variations in genetic coding. For example, certain drugs may be more or less toxic for one racial/ethnic subpopulation versus another. The distribution of age, sex, race, and high-burden medical comorbidities frequently fails to match disease epidemiology; this limits the study inferences that can be made regarding safety for underrepresented populations. Many drugs, such as Ninlaro (ixazomib), which is used to treat multiple myeloma, had trials that underrepresented minority populations, even when the incidence and prevalence of the disease were considerably higher in these populations than in European-Americans. Also, for example, 5-fluorouracil, a commonly used chemotherapeutic drug, was found to cause adverse effects, including hematological toxicities, at higher rates in African Americans than European-Americans, but this was not discovered until post-market, Phase 4 observational studies because the original pre-FDA approval clinical trials lacked sufficient diversity.
Thus, inclusive research equals medically and scientifically sound research. Having a wide variety of participants promotes social justice, reduces health inequities, reduces biases, and yields more innovative science. To reduce the probability of side effects, comorbidity interactions, and early withdrawal from the trial, it is essential to have accurate eligibility criteria and ensure the enrollment of clinical trial participants fully represents the diversity of the final targeted patient population. Diverse clinical trials support more informed regulatory decisions and more accurate product labeling. Gaps in clinical trial populations (e.g., if there is a predominance of white male participants) can ultimately reduce the quality of healthcare decision-making and treatments, with an ultimate negative consequence on equitable health outcomes. Inclusive participation in clinical trials makes for better scientific discovery, and inclusive recruitment strategies help ensure high public confidence in the efficacy and safety of vaccinations for various racial and ethnic populations.
Participant Motivations
Why do people participate in clinical trials? Altruism is a common reason why people volunteer for clinical trials. It is an opportunity to contribute to the common good or help others who have or may develop similar health issues, allowing the person to help grow the base of scientific knowledge. Also, clinical trials can help in situations where no known cure exists.
Why do diverse people not participate? The primary issue is often a lack of awareness. Patients from certain racial/ethnic minorities do not even consider participation in clinical trials or are often not even asked to participate. The lack of trust is another critical barrier. The trust in pharmaceutical companies continues to lag that of other entities within the healthcare and clinical research ecosystems. We have to overcome this mistrust. This is more challenging because when patients from underrepresented groups are asked about participating in a clinical trial, they typically do not see themselves reflected physically in the face of the provider explaining the trial. Also, the perception that certain groups do not want to participate in clinical trials can become a self-fulfilling prophecy.
Trial-related costs and protocols consume significant participant time and energy. There may be a perception by certain potential participants that they are unable to afford trial-related costs. Tangible reasons include lack of convenient transportation, loss of time from work, childcare, health insurance barriers, linguistic barriers, and other caregiver obligations. One significant barrier to participating in a trial is simply getting to the clinical site, and the frequency of study visits can also be a barrier. Traditionally, frequent in-person visits are required for assessments, therapy administration, test monitoring results, and picking up medications. If a participant is dependent on public transportation, it could take 3 hours or more to get to and from an academic medical center for a 30- to 45-minute trial-related assessment. Participation can conflict with caregiver responsibilities for younger children or older parents. In contrast, relatively affluent patients have much greater financial and logistical slack to allow for participation in trials, being insulated from challenges such as family care obligations, inflexible work hours, and limited transportation options.
Significant Industry/Regulatory Progress
Fortunately, within the last few years, the life science ecosystem has been moving beyond just talking on this issue and into the doing phase. In the context of clinical trials, the government and the life sciences industry no longer tiptoe on the issues of racial and health disparities. Several regulatory guidelines, scientific papers, and industry articles provide trial sponsors with ample evidence to develop and operationalize a strategy to achieve diversity in the subject population. Today’s clinical trials are marked by greater ethical and regulatory oversight, leading to growing transparency. This has helped reduce distrust. The FDA and NIH are both deeply committed to inclusivity in clinical trial research. In recent years, the FDA has consistently encouraged trial sponsors to include proportional representation from applicable age, racial, and ethnic subgroups. The FDA published draft guidance on increasing the diversity of clinical trial populations in 2019 and issued a final version in 2020. Under the new federal administration, the FDA has continued this emphasis. The federal NIH Revitalization Act of 1993 created guidelines for women and racial/ethnic minority populations in clinical research with the goal of ensuring that research findings are generalizable to the entire U.S. population.
Pharmaceutical Research and Manufacturers of America (PhRMA) and its member companies issued the first-ever industrywide framework on clinical trial diversity in 2020, with these principles taking effect in 2021. PhRMA has also created the Equity Initiative. The American Medical Association, the National Academies of Sciences, Engineering, and Medicine, and the National Institutes of Health have also published important reports on diversity in clinical trials. The New England Journal of Medicine will now require that studies it publishes include information on how well the trial population compares to the broader patient population. Thus, the ecosystem is making progress.
Action Items For Improving Patient Diversity
As the life sciences industry moves to increase diversity in clinical trials, several best practices either have been or should be adopted. Here we describe the most promising of these.
1. Building Better Communication & Trust
First, the foundation to increasing diversity is building trust, communicating clearly, and operating with high transparency. We must rebuild faith in clinical trials within underrepresented communities by speaking to historical errors/injustices and recognizing the root cause of health disparities.
Also, in terms of human capital, sponsors should create clinical trial ambassador programs so prospective participants can read about, view, and even interact with similarly placed peers who received treatment. For example, newly diagnosed cancer patients can be matched with those who previously participated in cancer trials. These ambassadors can be guides through the clinical trial process.
There needs to be multilingual educational materials, public service announcements, and digital/social media outreach. It is essential to have communications that are free of unconscious biases. On the cognitive dimension, key considerations are culture competency, process transparency, and clear, straightforward oral and written communications. Varying levels of health literacy and overall literacy should be considered. One overarching goal of supporting community-based education is to elevate the general knowledge regarding clinical research in minority populations.
Increasing diverse participation in clinical trials is one vehicle for driving better health outcomes and improved care for traditionally marginalized racial and ethnic communities. One critical step is to make clinical trials more integrated into care options. Sponsors should make it clear that the goal is to advance community health, and without clinical trials, the development of new medicines to improve the human condition would not be possible. The primary emphasis should be on improving community and patient health – not gaining subjects for a study. Investing in underserved communities can yield a long-term positive impact on the health and wellness that transcends the clinical trial environment.
2. Building Partnerships In Local Communities
Sponsors and CROs should aim to proactively create (or identify) and then engage a network of clinical trial sites located in diverse, underserved communities. Partnerships with this network should be scalable and sustainable, with a long-term oriented strategy that bridges multiple indications. To be financially viable over time, sites (i.e., healthcare providers and principal investigators) require a continuous stream of studies. Building this consistent pipeline of clinical trials for community-based, underrepresented sites is key to maintaining economic sustainability because studies are too complex and expensive to run sporadically.
3. Improving Diversity In Our Clinical Trial Staff
To facilitate diversity in clinical trials, we need a diverse pool of investigators, providers, and trial coordinators, so we should recruit and develop the next generation of study leaders and facilitators.
4. Meeting Patients Where They Live
We must meet patients where they live – figuratively and literally. To facilitate patient centricity, there should be a truly bidirectional dialogue. Thus, more emphasis should be placed on neighborhood and grassroots approaches to gain community and prospective patient feedback on the study questions and the recruitment plan. Community engagement in research is defined as “a process of inclusive participation that supports mutual respect of values, strategies, and actions for authentic partnership.”5 The community and neighborhood perspectives should be proactively incorporated into trial design, target enrollment population, endpoint selection, recruitment, retention, and post-study reporting. It is essential to carry out studies with input from prospective participants on the front end and provide follow-up information on the study’s results on the back end.
Relatedly, we can leverage lay community navigators and community health workers to educate peers about clinical trial opportunities and even help with logistics during the post-enrollment period. We should further look to engage members of the communities as “citizen-scientists” to incorporate their insights that otherwise would likely be inaccessible.
5. Expanding Support Services & Ease Of Participation
A critical step is making it less logistically challenging to participate. Support services to provide include childcare service, transportation vouchers, expanded operation hours, and additional locations. Technology can also enable better logistics. New processes and technologies include adaptive trial designs, home-based trials, remote data collection, and virtual patient recruitment. Given disparities in broadband access, caregiver availability, and insurance reimbursement for home healthcare, moving to remotely monitored clinical trials could actually accentuate rather than reduce participation inequities. Thus, we must also provide the necessary hardware, software, and internet access to enable decentralized clinical trials. Another pathway to easing logistics is to reimburse for direct trial-related expenses such as childcare, lodging, and travel. There are currently regulatory prohibitions on doing this, so at the federal level, we need to create safe harbors so these can be offered without being considered coercion. As a financial component of this, we should do more to ensure that insurance covers clinical trials, whether governmental or private.
6. Being Intentional With Inclusion Criteria
Clinicians, investigators, and researchers should be thoughtful regarding trial exclusion/inclusion criteria. They should give careful consideration to the necessity of any given exclusion criteria as these may have unintended negative consequences for diverse participation, so we should eliminate as many medically/scientifically non-vital eligibility restrictions as possible. Also, retention is nearly as important as enrollment, but until recently, it received relatively little attention. Once someone passes the inclusion test, we must ensure they agree to participate and then remain in the trial for the duration. Ironically, part of pre-trial recruitment includes sharing research findings once the study is concluded. Why? Being transparent and providing some form of post-study results increases sponsor/PI credibility, which increases the probability of participation in future trials by the subject or those in the subject’s network. Meaningful communications should occur before, during, and after all trials.
Data is essential. Even before a trial begins, there should be sharp intentionality regarding data on diverse participation (e.g., specific numerical targets). We need enhanced collection and analysis capabilities regarding ethnic and racial data. The starting point is establishing uniform standards for categorizing and collecting demographic information. We should develop technology platforms to capture baseline data on race and ethnicity, as well as include measures/metrics to track participation and retention. Eventually, either by FDA regulation or industry self-action, more strict requirements may be established for the representation of diverse populations as an expectation of new drug approval. If that occurs, having accurate, comprehensive data will become even more important.
7. Understanding Social Determinants Of Health
Social determinants of health (SDOH) have become a high-profile topic in the healthcare provider domain, but oddly, it is not nearly as frequently mentioned in the clinical trial domain. Clinical trials rarely report participants’ socioeconomic status, so social determinants are too often underplayed. Yet, we know access to items such as convenient transportation, exercise/recreation facilities, and nutritious foods are significant contributors to overall health and wellness. This is a two-fold problem. We are failing to capture potential barriers to trial participation, and we are less likely to have a group of fully representative trial participants. To address this, sponsors and CROs should place more emphasis on the social determinants of participation (SDOP) in clinical trials.
Conclusion
There should be even greater strategic collaboration among companies because increasing clinical trial diversity is a much bigger job than one individual company. The clinical trial ecosystem includes academia/investigators/researchers, biopharmaceutical companies, clinical research organizations, community leaders, government, healthcare providers, patients, patient advocates, and technology experts. Key community resources include barbers, beauty shops, civic leaders, community organizers, educators, faith-based organizations, recreation facilities, restaurants, and successful business owners. Key health providers and extenders include physicians, nurses, pharmacists, care navigators, community health workers, and social workers. Federal, state, and local governments should also play a role. These multistakeholder partnerships involving the clinical trial industry, community resources, health providers, and government should work to build a sustainable community-based, patient-centric infrastructure.
The lack of diversity in clinical trials remains a challenge. Many communities and marginalized neighborhoods of color in the U.S. face other persistent economic and social challenges (e.g., endemic poverty, health inequality, mass incarceration, and structural racism), and it often seems that solutions to these problems are decades away or they may never be fully solved. Fortunately, in contrast, the battle to secure more diverse clinical trials is actually winnable. It is one of the rare opportunities where, well within our lifetimes, we can achieve a decisive victory against a seemingly endemic social inequity. The best practices delineated above provide the essence of a game plan for addressing the persistent problem of diversity in clinical trials. If the industry collaborates with communities, patients, governments, and other parts of the ecosystem, we can achieve equity and parity in clinical trials within the next decade.
References
- https://www.fda.gov/media/143592/download (2020)
- https://worldpopulationreview.com/continents
- https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2780381#zld210093r1
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8875029/
- Holzer JK, Ellis L, Merritt MW. Why we need community engagement in medical research. Journal of investigative medicine: the official publication of the American Federation for Clinical Research. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108547/. Published August 2014. Accessed December 20, 2019.
About The Authors:
James Gillespie, Ph.D., is a faculty member at Saint Mary’s College and President of the Center for Healthcare Innovation. His expertise covers clinical trials, data analytics, and healthcare strategy. His experience includes McKinsey & Company, Stanford University School of Medicine’s Clinical Excellence Research Center, and Yale University School of Medicine’s Center for Digital Health & Innovation. Gillespie’s education includes Carnegie Mellon University, Harvard University, Massachusetts Institute of Technology, Northwestern University, and Princeton University.
Joseph Gaspero is the CEO of the Center for Healthcare Innovation (CHI), which he founded in 2009 as an independent, objective, and interdisciplinary research and education institute for reducing health disparities for marginalized communities of color. Gaspero leads research and educational initiatives at CHI, including research focused on increasing diversity in clinical trials, understanding how social determinants of health drive disparities for BIPOC communities, decreasing medical mistrust, and understanding how chronic conditions disproportionately impact Black and Brown communities.