Early Covid-19 Research Isn’t As Inclusive As It Should Be
Experts agree that people of color must be adequately represented in coronavirus vaccine and drug trials. It’s unclear whether that’s happening.
The Tuskegee Syphilis Study is one of the most infamous — and, ultimately, atrocious — biomedical research experiments in American history.
According to the Centers for Disease Control and Prevention, the study began in 1932 as a Depression-era effort to secure funding and justify treatment programs for Black Americans with syphilis. The U.S. Public Health Service recruited 600 Black men in Alabama, 399 of whom had the infection. The men were told they were being treated for “bad blood,” the colloquial term used at that time to describe a number of medical issues, though they never received proper care or drugs.
The study’s true aim — one never disclosed to its participants — was to document the effects of untreated syphilis. Though it was originally intended to last six months, the study went on for 40 years. By 1972, when an Associated Press exposé and a government inquiry led to the study’s termination, doctors had known for more than three decades that penicillin was an effective treatment for syphilis. The men in the study never got it, and more than 100 of them died of the infection or related complications. Many passed the infection on to their partners and children.
The ugly legacy of the Tuskegee Syphilis Study is just one reason why, almost 50 years after its termination, Black Americans and members of other marginalized or disadvantaged groups may still be leery of medical science and are often not appropriately represented in biomedical research.
Black Americans make up 12% of the population but just 5% of clinical trial participants.
“Historically, participation has been low for racial and ethnic minorities, and I think the legacy of [the] Tuskegee [Syphilis Study] is a part of that,” says Ruqaiijah Yearby, JD, MPH, a professor of law and executive director of the Saint Louis University Institute for Healing Justice and Equity. “But I think there’s also distrust from clinical trials that have exploited people of color even much more recently.” Some of Yearby’s work documents medical research efforts in the 1980s, 1990s, and 2000s that exposed minority or disadvantaged groups, including children, to elevated lead levels in drinking water, to experimental drugs that were proven to be dangerous, and to other risky situations or interventions.
“We have a long legacy of the government not doing things that measure up to the ethical standards of the era,” says Nelson Michael, MD, PhD, director of the Walter Reed Army Institute of Research’s Center for Infectious Disease Research. Among African Americans and some other marginalized groups, he says that “trust is low.”
People of color are underrepresented in early Covid-19 research
According to a Pew Research Center Covid-19 poll, published June 4, Black Americans are more hesitant to trust medical professionals and experimental treatments, and are also less likely to sign up for vaccine trials, than are members of some other racial or ethnic groups. At the same time, there’s evidence that researcher bias and structural barriers also work to keep people of color out of clinical research. A 2011 analysis from the Society for Women’s Health Research and the U.S. Food and Drug Administration (FDA) found that Black Americans make up 12% of the population but just 5% of clinical trial participants. The incongruity is even greater among Hispanics, who make up 16% of the population but just 1% of trial participants.
Considering that Black Americans are approximately five times more likely than whites to die of Covid-19, and Hispanics are roughly four times more likely to die than whites, poor representation among these groups in SARS-CoV-2 research efforts could have serious and negative implications for the development of successful drugs. And yet, some of the most significant early work on the coronavirus vaccines and treatments suggests that people of color may be underrepresented.
As the coronavirus-related drug trials move into the larger, later phases of testing and development, experts broadly agree that participant diversity will be critical.
On July 14, the New England Journal of Medicine published the phase 1 results of Moderna’s promising mRNA vaccine, which the drug company is developing with the help of the National Institute of Allergy and Infectious Diseases (NIAID) and researchers at more than a dozen major American universities and hospitals. The results of that trial were encouraging: Every one of the trial’s 45 participants showed a promising immune response to the vaccine, and no major safety concerns turned up. But among the 45 people enrolled in the trial — a group that, according to the trial’s stated protocol, should have reflected “the community at large” — just two participants identified as Black and six identified as Hispanic or Latino. While 40 identified as white.
The NIAID oversaw recruitment for the trial. A spokesperson for NIAID told Elemental in an emailed reply that “the population enrolled reflects those that responded to recruitment at the participating sites.” That spokesperson also emphasized that forthcoming trials would be more inclusive: “Analyzing clinical trial results by sex, age, and race is most meaningful for a clinical trial enrolling a large number of participants, like the phase 2/3 trials. The phase 3 trial of this vaccine is planned to start in late July and is expected to enroll about 30,000 volunteers. The NIAID-funded Covid-19 Prevention Network (COVPN) is working with stakeholders to enact a community engagement plan to reach priority populations, including Native Americans, Black Americans (including African Americans), the Latinx community, people who are at higher risk of exposure to SARS-CoV-2 infection due to occupation, people with preexisting health conditions, people living in assisted living facilities, and communities experiencing health disparities.”
Some other high-profile and promising Covid-19 research efforts have done a better job of including a diverse range of participants. A preliminary study on the effects of the antiviral drug remdesivir, published May 22 in the NEJM, included more than 1,000 people hospitalized with Covid-19. That study found that the drug shortened recovery times. Again, NIAID was in charge of overseeing recruitment. Roughly 21% of the study’s participants were Black and 23% were Hispanic, compared to 53% who were white — percentages that more closely reflect U.S. demographics.
As the coronavirus-related drug trials move into the larger, later phases of testing and development, experts broadly agree that participant diversity will be critical. While efforts are underway to ensure that these trials reflect the groups who are most at risk, it’s unclear whether those efforts will pay off.
Why inclusiveness matters in biomedical research
Some sick or at-risk people who participate in clinical trials gain special access to treatments that may save their lives. For example, people involved in SARS-CoV-2 vaccine trials may end up with immunity to the virus, and Covid-19 treatment trials may save the lives of some participants.
These potential benefits are one of the most obvious justifications for trial inclusiveness; if some groups are excluded or underrepresented in these trials, their members are denied equal access to potentially life-saving drugs.
“If you’re not doing research on a diverse population, then you don’t know how it’s going to be safe and effective across a diverse population.”
But inclusiveness is also essential to ensure that new vaccines or treatments work for everyone — not just for a small slice of the population. “If you’re not doing research on a diverse population, then you don’t know how it’s going to be safe and effective across a diverse population,” says Yearby.
A 2015 U.S. Food and Drug Administration (FDA) review found that approximately one-fifth of recently approved drugs demonstrated exposure or response differences based on a recipient’s race or ethnicity. There are many explanations for these differences, including the unequal occurrence of metabolic diseases, such as obesity and Type 2 diabetes, among certain groups. These health conditions can influence drug-treatment outcomes. So, potentially, can a person’s age, sex, or ancestry. “If the people getting sick and dying of Covid-19 are predominantly Hispanic and Black people in their fifties to seventies that have comorbid diseases like hypertension, diabetes, and obesity, our trials need to reflect that,” says Walter Reed’s Michael. “We don’t want studies where the community at risk and the community being tested are different.”
“There are a lot of ways that studies can be found to be effective in groups that participate but that don’t necessarily translate to other groups,” says Michael Paasche-Orlow, MD, an associate professor of medicine and a health literacy specialist at Boston University and Boston Medical Center. For this reason, he says that it’s essential that minority and low-income people take part in clinical research. “If you want the results of a study to be used successfully in society, then the participants in that study should reflect society,” he says. “We fail at this if we’re only studying people who are wealthy or otherwise well.”
Making the coronavirus research inclusive
Including a diverse mix of people — those of all races, ethnicities, ages, and sexes — may seem like a straightforward task for those charged with clinical trial recruitment. But experts say complications abound.
For one thing, biases on the side of clinicians and researchers may depress participation among certain groups of people. “A lot of times, investigators aren’t asking minorities to participate because they think those individuals will say no,” says Jill Fisher, PhD, a professor of social medicine at the University of North Carolina, Chapel Hill’s Center for Bioethics.
“So these trials may be set up in ways that work better for more affluent individuals with more flexible work schedules.”
Fisher also says that some trials require participants to report to a lab or clinical facility that is not accessible via public transportation. The trial may also require multiple visits that take place during normal, weekday work hours. “So these trials may be set up in ways that work better for more affluent individuals with more flexible work schedules,” she says.
Trust is also an issue, Paasche-Orlow says. “There is a trust gap based on race and ethnicity, and it is because investigators have proven themselves to be untrustworthy,” he says.
The complexity of the American health care and clinical-research systems may also create disparities. “We need to attend to the fact that not everyone is a college graduate, and not everyone comes into these situations fully empowered with all the social privileges and capital of wealthy people,” he says. “You hand out 20- or 30-page consent forms, and that’s going to freak a lot of people out and drive the whole system toward the most empowered groups.”
He and others involved in Covid-19 research say that they’re making efforts to overcome these sorts of obstacles. “It’s important to have a diverse workforce — including staff and clinicians — that can be there as advocates and companions to support the decision-making process,” he says. In his research network, he says that those involved in trial recruitment undergo training to ensure that they’re adept at explaining the benefits and risks of trial participation, and that they’re able to ensure that those who sign up are able to give truly informed consent.
St. Louis University’s Yearby says that these sorts of efforts may help, but they’re not enough. “I think that, oftentimes, the same institutions doing these studies are the ones that poor people or racial or ethnic minorities are having trouble accessing for care,” she says. If major hospitals or health care systems aren’t there for these groups when they need care — for example, if a health care system routinely turns away individuals who rely on Medicaid — then those systems can’t expect these same people to show up when they put out the call for research volunteers. “It has to be about building a relationship when it’s not all about trial participation,” she says.
Major pharmaceutical companies are aware of the need to recruit diverse study cohorts, and some say that they’re taking steps to ensure that their Covid-19 studies are inclusive. “Our goal is to be conducting studies in locations with diverse communities, [which] will be instrumental in recruiting and retaining minority and female participants,” says Jerica Pitts, a spokesperson for the drugmaker Pfizer, which is developing some of the leading Covid-19 vaccine and treatment candidates. To accomplish this, Pitts says that Pfizer is using county-level data from Johns Hopkins University and the U.S. Census Bureau to “identify areas of opportunity for study placement in communities of color and areas that have seen higher rates of Covid-19 infection.”
There’s evidence that this strategy could be effective. A 2013 study in Clinical Care Medicine looked at trials involving lung injury patients. It found no evidence of underrepresentation based on race, ethnicity, or gender, and credited the trial network’s focus on “centers serving diverse populations” as one likely explanation.
Creating true engagement
Over and over again, experts say that “community engagement” will be critical when it comes to ensuring all groups are represented in the coronavirus trials. Community engagement is a broad concept. But, in a nutshell, it means that people who are members of disparate communities — whether privileged or disadvantaged — are included as partners in the planning, development, and implementation stages of scientific research, including recruitment efforts.
“People who are underrepresented or marginalized need to be brought into the fold throughout the process,” says Charmaine Royal, PhD, an associate professor of African and African American studies, biology, and community health at Duke University. “Researchers at academic institutions and other places very often are not in the communities where many of these groups of people live, and so it takes a little more effort and getting out of our environments to engage and build relationships.”
She also says that people in underrepresented communities are often more willing to participate than some researchers might assume. “But they are just not asked,” she says.
Walter Reed’s Michael says that the necessity of effective community engagement strategies emerged from the AIDS epidemic and that it has led to good participatory practice guidelines that research and public health organizations around the world have adopted. “Community engagement is always important,” he says. But it may be even more important today given the political, economic, and social justice forces that are agitating American society. “A lot of divisive forces are all hitting us together,” he says of the current moment. And so it’s essential that members of a diverse range of communities who have in-group knowledge and “competencies” be involved in trial design and recruitment, he adds.
During the early days of the outbreak, he says that SARS-CoV-2 research efforts were racing forward so quickly that appropriate community engagement efforts “couldn’t keep up.” Fortunately, that’s no longer the case. “We’ve had more time to get the community engagement framework set up, and I think it’s getting the attention it needs,” he says. He points to the creation of the Covid-19 Prevention Network — a consortium of government and nonprofit institutions involved in clinical trial work — as a big step in the right direction.
“But at the end of the day,” he says, “the metrics that will show us how well we’re doing will be the data we can collect on demography for enrollment in each of the trials we’re conducting — and is it matching up with those affected.” If it doesn’t match up, he says that on-the-fly adjustments will happen “so that we end up with equitable uptake and participation.”
As of today, it remains to be seen whether those efforts are going to pay off.