Clinical trial enrollment has lacked diversity since the start, but a global racial reckoning has brought new attention to overcoming discrimination.
According to the most recent U.S. Food and Drug Administration (FDA) Drug Trials Snapshots Summary Report, of the 32,000 clinical trial volunteers whose participation led to the approval of 53 novel drugs in 2020, 75% were white. Only 11% were Hispanic and just 8% were Black.¹
Looking specifically at trials of oncology drugs, the percentage of Hispanic and Black participants decreased further to 6% and 5%, respectively. Among studies of drugs for certain conditions that disproportionately affect minorities, such as multiple myeloma, representation by Black participants varied greatly, from as much as 16% in selinexor trials to as low as 1% in isatuximab trials.
The consequences of this lack of diversity in clinical trials are twofold, explained Barbara
Bierer, MD, professor of medicine at Harvard Medical School and a hematologist at Brigham and Women’s Hospital. Dr. Bierer is also the faculty director of the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard, a research and policy center working to improve the integrity, safety, and rigor of global clinical trials.
“First, there is the biological question of whether individuals who are racially and ethnically diverse will respond differently to products in terms of safety and efficacy,” Dr. Bierer said. “The second – and likely the more important issue – is a question of equal access to clinical trials and health equity.”
Efforts to diversify trial populations have been underway for years, but they intensified in 2020 on account of the disparity in health outcomes related to the COVID-19 pandemic and an increased awareness of social and racial inequity.
The Centers for Disease Control and Prevention (CDC) has acknowledged that the COVID-19 pandemic has disproportionately affected certain racial and ethnic minority groups in the U.S. Looking at approximately 300,000 hospitalizations for COVID-19 from January through May 2020 for which race/ethnicity information was available, about one-third of cases occurred in Hispanic people, and 22% in non-Hispanic Black people.2 Meanwhile, in studies of the Pfizer-BioNTech, Moderna, and Johnson & Johnson vaccine candidates, 81.9%, 79.4%, and 74% of participants were white.3,4 The lack of diversity among vaccine trial populations was concerning enough that Moderna slowed enrollment to increase the representation of communities of color.5
This is not a new phenomenon. A study published in February 2021 showed that, historically, white individuals represented more than 75% of participants in completed U.S.-based vaccine trials that took place from 2011 to 2020.6
These data fly in the face of guidance from the National Institutes of Health (NIH) that mandates inclusion of minority groups and women in all NIH-funded clinical research “in a manner that is appropriate to address the scientific question under study.”7
ASH Clinical News spoke with Dr. Bierer and other researchers and clinical trialists about the lack of inclusivity in clinical trials, its implications, and efforts to strengthen the applicability of clinical trial results.
Race as a Social Construct
A key to breaking down these barriers is separating out the oft intertwined concepts of race and genetic ancestry. There are examples of differences in drug metabolism and genetic variants in people of different ethnicities, but they should not be the driving force behind diversifying clinical trials according to Monica Webb Hooper, PhD, deputy director of the National Institute on Minority Health and Health Disparities (NIMHD).
“Race is a social construct, not a genetic one,” Dr. Webb Hooper said. “The reason we have disparities is not because of biologic differences – this notion is an artifact of racism in science.”
She continued, “If we want to increase the validity of science and people’s confidence in it, it is important that our research participants reflect the diversity of the United States, especially communities disproportionately affected by the condition being studied.”
A lack of trust in the medical system is often cited as a reason why people of certain racial or ethnic minority groups hesitate to enroll in clinical trials. The legacy of the Tuskegee Syphilis Study still looms, and that distrust is understandable and justified, said Dr. Webb Hooper. However, a fixation on it reflects a one-sided view of the problem, downplaying racism and bias in medical encounters that Black patients experience today.
“We need to be focused instead on trustworthiness as researchers and how we can demonstrate trustworthiness to participants,” she said.
To diversify clinical trials, an important first step to take is making it easier for people of minority groups to join them. Both geographic access and a lack of access due to unconscious bias need to be addressed. The latter causes researchers to make assumptions about people’s willingness or ability to participate in a trial, or to adhere to all aspects of the trial protocol, according to their ethnic and racial make-up.
“We have made unprecedented progress in the development of new agents for treatment of many hematologic disorders and malignant disorders,” said Grzegorz S. Nowakowski, MD, hematologist and professor of medicine at Mayo Clinic in Rochester, Minnesota. “However, large groups of the population do not have access to these groundbreaking treatments. People may not live near sites with clinical trial programs, or they may not be able to devote the time or travel needed to participate in the trial.”
Of course, he added, some people “may never be offered the option of participating.” This disparity is likely driven by provider perception about who would be the best candidate to enroll. “These issues disproportionately affect people on the lower end of the socioeconomic scale – great portions of whom are … minorities and patients living in rural communities,” Dr. Nowakowski said.
Illustrating this point, Dr. Nowakowski referenced a framed photograph on his desk of a patient who had relapsed/refractory Hodgkin lymphoma. The photo showed him years after receiving treatment on a clinical trial, smiling with his two young children.
“Early access to investigational agents through clinical trials is changing people’s lives and outcomes. It is a fundamental right that everybody should have.”
—Grzegorz S. Nowakowski, MD
“This is a disease where before, the response to palliative chemotherapy after post-transplant relapse was measured in months, and now this patient is well over five years out, with no evidence of disease,” said Dr. Nowakowski, who is vice chair of the American Society of Hematology’s (ASH’s) Subcommittee on Clinical Trials. “This patient was one of the first in the world to be treated in a clinical trial with an anti–PD-1 therapy in relapsed/refractory Hodgkin lymphoma,” he continued. “Both of his children were born since, and the PD-1 inhibitor is now approved for previously treated Hodgkin lymphoma. Early access to investigational agents through clinical trials is changing people’s lives and outcomes. It is a fundamental right that everybody should have.”
The inclusion and exclusion criteria written into a trial’s protocol can be another barrier to increasing diversity among study populations, according to Alan Mast, MD, PhD, senior investigator at Versiti Blood Research Institute in Wisconsin. Inadvertently, a trial’s inclusion and exclusion criteria can unfairly disqualify patients with certain conditions.
“A simple example is excluding people with diabetes,” Dr. Mast said. Diabetes occurs more frequently among Black people, related to a complex interplay of environmental and genetic factors. The higher incidence increases the likelihood that they will be excluded from trials. Dr. Mast, who is the Chair of the ASH Subcommittee on Clinical Trials, said that the group aims to change the way clinical trials are developed to make them more inclusive from the start. Researchers should begin by examining whether all of the most commonly used inclusion and exclusion criteria – such as organ dysfunction, poor performance status, and other comorbidities – are medically necessary for each trial’s design.
Inclusion From Square One
The lack of diversity in clinical trials is well recognized in the research community, but the development of practical solutions has not received as much attention.
In her work to address changes in health behavior, Dr. Webb Hooper has discovered the importance of looking at study protocol through an equity lens from the early stages of trial design. That starts with making sure that trial staff is diverse and representative of the population that researchers expect to interact with. Trial literature – including informed consent documents – should be written simply and in a fashion that most people can understand.
“If you try to address that in the ninth inning, it will be much more difficult,” Dr. Webb Hooper said.
Dr. Bierer also noted the importance of planning during the pre-enrollment process. In 2020, the Multi-Regional Clinical Trials Center released guidance and a toolkit for achieving diversity, inclusion, and equity in clinical research, with diversity defined across a broad spectrum, incorporating race, ethnicity, sex, gender, age, genetics, and more.8
The guidance called for researchers to adjust trial protocols in order to address barriers to participation and enroll a participant cohort that is more representative of the real-world patient population. For example, reworking clinic hours or staying open on nights and weekends so that people do not have to miss work if they want to participate. In some cases, childcare could be made available, and reimbursement could be provided for travel expenses.
Dr. Bierer acknowledged that, in response to the COVID-19 pandemic and the need to limit patients’ exposure to infection, trialists have employed telehealth to overcome certain barriers. “We saw some change with the pandemic and more acceptance of the idea that maybe patients don’t have to drive hours to a cancer center just to wait for the doctor to ask them how they feel. Maybe that can be done through telehealth,” she said. “Much can be done to make it practically more possible for people to participate, which would benefit everyone.”
Working Toward Solutions
Another barrier to making trials more inclusive is bias among the research community. As Dr. Bierer explained, researchers may assume that a commitment to diversity and offering more flexibility will make conducting trials longer and more expensive. However, there is no evidence to support that assumption – if trials are planned appropriately.
“Initiating trials with a plan to recruit diverse populations and to set them up for success saves more time than realizing three-quarters of the way through the trial that you have failed to recruit the appropriate patients,” she said. “Now, you have to scramble to open new sites and potentially delay the trial.”
Regarding costs, Dr. Bierer noted that “changing how we do things may require a capital investment, but I would argue that committing to this upfront with good planning will allow for faster recruitment and a broader patient population.”
Finally, making real strides toward diversifying the medical workforce will accelerate innovation and build credibility within a broad variety of communities that need to be more engaged in clinical trials. With a clear eye toward the importance of a diverse and inclusive field, ASH established the Minority Recruitment Initiative, which includes various programs and awards designed to increase the participation of underrepresented minorities training in hematology-related fields and the number of minority hematologists with academic and research appointments.
Nurturing and supporting diversity and inclusion in research means bringing together people with varying life experiences. Exposure to different perspectives leads to innovation, to asking different questions, and to exploring different approaches. The homogeneity of the field is a long-standing problem and while there are programs like the ASH Minority Recruitment Initiative, more needs to be done. Black people are estimated to represent 14% of the U.S. population, yet they make up only 4% of the physician workforce.9 Further, while Hispanic people constitute 17% of the population, they represent 4% of the physician workforce.
“We need to have more principal investigators, more physicians, and more staff who are people of color,” Dr. Mast said, although he acknowledged that progress has been slow. “This is not an easy problem to fix. It will take a consistent effort over years.”
Reaching the Community
Community engagement is well recognized as a prerequisite for improving inclusivity in trials.
The Leukemia & Lymphoma Society’s IMPACT (Influential Medicine Providing Access to Clinical Trials) program supports trial inclusivity through research grants to increase enrollment of patients with hematologic malignancies who are from rural, minority, or economically disadvantaged communities. The first round of grants – awarded to Mayo Clinic, Vanderbilt University, and Weill Cornell Medicine – support establishment of “hub and spoke” infrastructure to expand access of trials into community-based hospitals and clinics that reach underserved populations.10
The ASH Research Collaborative (ASH RC) Sickle Cell Disease Clinical Trials Network (SCD CTN) was launched with a mission of improving outcomes for individuals with SCD, a disease that disproportionately affects Black people.11 The ASH RC is attempting to increase the number of trial sites throughout the country and promoting quality, patient safety, and efficiency in SCD clinical trials by centralizing functions, establishing a central data repository, and employing a patient-centered approach to trial design and enrollment.
Each of the consortia in the SCD CTN, which is also built in a “hub and spoke” model, is establishing a local SCD Community Advisory Board (CAB). A National Community Advisory Board comprising representatives of the local board will work closely with the CTN to bring the community voice to decision making and direction of the research network.
“The real heart of this network is the SCD community, and we are working very hard on building community engagement,” said Charles S. Abrams, MD, chair of the SCD CTN and vice chair for research and chief scientific officer of the Department of Medicine at Penn Medicine. “The CTN is committed to engaging the community that we serve, and it is essential that we work closely with, listening to and learning about the perspectives and concerns of patients, their families, and their caregivers.”
Shauna Whisenton is the manager of community engagement for the CTN and was once an individual living with SCD. She has engaged and educated the SCD community in support of the CTN’s mission and is working with participating sites to develop their CABs.
“To help inform the CTN community engagement efforts, we traveled the country to conduct a series of workshops in the cities with the highest population of people living with SCD, assessing what they wanted as it relates to clinical research,” Ms. Whisenton said.
Recruiting people to attend these workshops was a grassroots effort.
“We were creating flyers and digital campaigns and placing ads in the newsletters of some local organizations,” she recalled. “We found that that this wasn’t helping us meet our attendance quotas. We weren’t getting a very diverse population of the community.”
Following these setbacks, the group reassessed. “We began to garner support from ASH volunteers to conduct outreach with their patient population. We also contacted after-school programs, summer camps, barbershops, churches and other religious organizations, or other places where people in this community might talk about their health,” Ms. Whisenton said. “We also reached out to some specialty organizations like the National Black Nurses Association and the National Association of Hispanic Nurses.”
Their new efforts garnered overwhelming support.
“For example, one organization held a back-to-school event where they gave away backpacks and school supplies, then set up a laptop on site to register people for our workshop,” she explained. “We also made sure to offer things like mass transportation assistance, hotel rooms, or Lyft rides. We offered childcare and a nutritious lunch.”
The information gained from these events – soon to be published – was invaluable and sometimes surprising, Ms. Whisenton said. Many of the findings reflected that members of the SCD community were willing to participate in research, but wanted to feel involved and invested in the research.
Dr. Mast added that his experiences have taught him that, when trial groups are reaching out to specific communities for their help and participation in a clinical trial, they have to offer a co-equitable partnership, not a one-way partnership.
“When planning the study, we should be asking what benefit we are bringing to the community we are asking to participate,” Dr. Mast said.
One such co-equitable partnership involved the recruitment of more Black blood donors to aid in transfusions needed for people with SCD. After brainstorming with members of the community they aim to serve on how to secure this valuable resource, a local blood center is moving toward opening a satellite donor site closer to where the majority of the Black community lives and works.
“We are asking for help and, by putting this center in the community, we are giving something back in the form of a community resource and possibly jobs,” Dr. Mast said.
Inclusion Includes Everyone
“It is not easy to change the system and the way things have been done for decades,” said Dr. Webb Hooper. “We have to continue to have a real conversation about this topic, understanding why it is important and developing a health system and research projects with specific plans to address the problem.”
Dr. Bierer agreed, adding that it is no single group’s problem to solve.
“Everybody has a role in changing the paradigm and the way we engage with one another including participants, investigators, study sponsors, and journal editors,” Dr. Bierer said.
“If we believe that participation in trials is the best care we can recommend and we cannot deliver that to everyone,” said Dr. Nowakowski, “then we are failing a significant portion of our patients.” —By Leah Lawrence
- U.S. Food and Drug Administration. 2020 Drug Trials Snapshots Summary Report. February 2021. Accessed May 24, 2021. https://www.fda.gov/media/145718/download.
- Stokes EK, Zambrano LD, Anderson KN, et al. Coronavirus disease 2019 case surveillance – United States, January 22-May 30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(24):759-765.
- Kaiser Family Foundation. Racial Diversity within COVID-19 Vaccine Clinical Trials: Key Questions and Answers. January 26, 2021. Accessed June 11, 2021. https://www.kff.org/racial-equity-and-health-policy/issue-brief/racial-diversity-within-covid-19-vaccine-clinical-trials-key-questions-and-answers/.
- Johnson & Johnson. Our Commitment to the Communities Most Impacted by COVID-19. January 27, 2021. Accessed June 21, 2021. https://www.jnj.com/our-commitment-to-the-communities-most-impacted-by-covid-19.
- CNBC. Moderna slows coronavirus vaccine trial enrollment to ensure minority representation, CEO says. September 4, 2020. Accessed June 21, 2021. https://www.cnbc.com/2020/09/04/moderna-slows-coronavirus-vaccine-trial-t-to-ensure-minority-representation-ceo-says.html.
- Flores LE, Frontera WR, Andrasik MP, et al. Assessment of the inclusion of racial/ethnic minority, female, and older individuals in vaccine clinical trials. JAMA Network Open. 2021;4:e2037640.
- National Institutes of Health. Grants & Funding. Inclusion of Women and Minorities as Participants in Research Involving Human Subjects. Updated March 23, 2021. Accessed May 24, 2021. https://grants.nih.gov/policy/inclusion/women-and-minorities.htm.
- Multi-Regional Clinical Trials Center. Diversity, Inclusion, and Equity in Clinical Research. Published August 2020. Accessed May 24, 2021. https://mrctcenter.org/diversity-in-clinical-research/.
- Multi-Regional Clinical Trials Center. Achieving Diversity, Inclusion, and Equity in Clinical Research Guidance Document Version 1.1. Published August 2020. Accessed May 26, 2021. https://mrctcenter.org/diversity-in-clinical-research/guidance/guidance-document/.
- The Leukemia & Lymphoma Society. The Leukemia & Lymphoma Society Launches IMPACT Research Grants to Help Underserved Patients Access Clinical Trials. May 6, 2021. Accessed May 26, 2021. https://www.prnewswire.com/news-releases/the-leukemia–lymphoma-society-launches-impact-research-grants-to-help-underserved-patients-access-clinical-trials-301285367.html.
- ASH Research Collaborative. Clinical Trials Network. Accessed June 11, 2021. https://www.ashresearchcollaborative.org/s/clinical-trials-network.