BERLIN — As the COVID-19 death toll rose, the disparities were impossible to ignore: The novel coronavirus was taking a disproportionate toll on underserved communities. Imbalances between ethnic groups gained the most attention, but the disparities extended to older adults and communities grappling with job and food insecurity, as well as poverty.
That was not the only thing that became clear. The same groups already dying disproportionately from COVID-19, in part because of their earlier exclusion from health research, were being underrepresented in clinical trials of COVID-19 vaccines and treatments.
“The poor representation of large parts of the community is an old problem,” said Shaun Treweek, a professor of health sciences research and leader of Trial Forge, an initiative to improve trial design. “Now that COVID has highlighted this, funders and many, many others are starting to recognize it. It should change the way we work.” And it is.
In September, global charity Wellcome adopted a clinical trials policy that requires researchers to engage with underserved communities in their efforts to recruit trial participants. The policy presses researchers to recruit a group of participants that, “at a minimum, represent the population needing the healthcare intervention,” according to the new guidelines.
This follows the August publication of guidance on how to include underserved communities in research by the National Institute for Health Research, the United Kingdom’s largest funder of health and care research.
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Though both institutions are based in the U.K., Treweek said there are wider implications — particularly given the global reach of Wellcome’s funding, including an international grant portfolio of £1.2 billion in 2018-19. These changes could presage not just an expansion of who is included in research but an overhaul of systems that have historically prioritized the health outcomes of some communities above others.
“I think we will look back, years in the future, and say this is the moment where we took seriously, finally, the way we have failed to serve large parts of our community,” Treweek said.
Lack of diversity
While COVID-19 put a spotlight on the lack of diversity in clinical trials, the problem has not been a secret, said Miles Witham, a professor of trials for older people at the NIHR Newcastle Biomedical Research Centre. Witham has had geriatrician colleagues who were skeptical of guidance because it drew on research that did not consider the patients they actually care for.
“If you don’t get the right people into trials, then clinicians tend to feel the evidence doesn’t apply to the people in front of them” he said. More broadly, there was an understanding that “trying to base health care delivery on that research is problematic, because you don’t know if you’re actually doing the right thing.”
Witham was part of the INCLUDE project that NIHR mooted in 2017 to draft a road map for how researchers might begin to grapple with — and redress — the lack of diversity. The guidelines published in August were the result of years of research and consultations, and they offer examples of underserved groups and interventions to improve inclusion while expanding the scope of who is responsible for addressing the problem.
“You can’t fix this issue just by focusing on the people designing trials or the people who are recruiting patients,” Witham said, which is why INCLUDE has also held discussions with regulators and, particularly, funders. “We told funders, ‘Where you lead, researchers will follow.’”
Wellcome staffers had been engaging in discussions about how to improve diversity for several years, said Kalaiyashni Puvanendran, diversity and inclusion project manager at the charity. But as the COVID-19 pandemic accelerated in March, “it became clearer how important this is when we saw the disproportionate impact that COVID was having on different groups of people,” she said. “This pushed us to work faster and be a bit bolder in what we’re trying to do and specifically in relation to clinical trial participants.”
By September, Wellcome was ready to update its clinical trial requirements to require applicants to explain how they plan to recruit and retain underserved groups and to describe and justify their inclusion and exclusion criteria for study participants.
The policy acknowledges that determining who is underserved will be contextual, dependent on the population and conditions being studied, the questions research teams are asking, and the interventions being tested.
“We want health care interventions to be safe and effective for everyone,” Puvanendran said. “For that to happen, research should include the people it’s meant to help, but we didn’t want to be too prescriptive in how we approached this.”
Wellcome points applicants to the NIHR guidance, which encourages researchers to consider a landscape of demographic, social, and economic factors — age, ethnicity, religion — as well as health status, including mental health conditions and pregnancy.
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Within that guidance, there is a particular emphasis on pushing beyond relying on ethnicity or geographical ancestry as the primary lens for achieving diversity and considering how some communities have been historically disadvantaged — and the role that those inequities, rather than ethnicity or race, might play in determining health outcomes.
Kerry Garfitt, grants policies and liaison officer at Wellcome, cautioned that the introduction of a new policy will not prove an immediate panacea to the diversity problem in clinical trials.
“We’re aware that making this change is the first step,” she said. “We’re leading researchers to think in a certain way. I don’t think it’s safe to assume change will automatically result.”
To make that transition easier, the INCLUDE team drew on its general road map to offer specific guidance for researchers working on COVID-19. In addition to highlighting potential underserved populations, the road map recommends points of intervention, including at the initial point of research priority setting and throughout the trial design and funding.
Treweek also helped lead an effort to draft worksheets with questions that researchers — working on COVID-19 or other health care issues — can ask themselves to help ensure their trial is designed for everyone who could benefit. They begin with querying who the trial results should apply to and then push researchers to consider how those communities might respond to the treatment and the research intervention. The first set of worksheets focused on ethnicity and applied the questions to five actual trials.
“The idea behind it is to help researchers improve the representation of minority ethnic individuals within the trial and how to help them do that,” Treweek said. Future worksheets will apply a similar approach to other factors, he said, even as they look for overlaps so they are able to synthesize some of the exercises.
The policies and guidelines also push researchers to look beyond just considerations of who should be included and to engage with communities to identify barriers that might prevent their actual participation.
“We will look back, years in the future, and say this is the moment where we took seriously, finally, the way we have failed to serve large parts of our community.”— Shaun Treweek, lead, Trial Forge
That will encourage researchers to address some “low-hanging fruit,” Treweek said, like building interventions around people’s schedules and offering free taxi rides to participants who might not be able to join if doing so requires long journeys on public transportation.
Other barriers will not be as easy to address, including skepticism of clinical trials that has built up in some communities because of their earlier exclusion or mistreatment. That includes the notorious Tuskegee syphilis experiment, in which U.S. researchers withheld treatment — and even diagnoses — from Black men with syphilis, leading to dozens of preventable deaths.
Investing in the global south
Convincing historically neglected communities to participate will take time, commitment, and persistent engagement. Witham said researchers in higher-income countries might do well to look to their counterparts in low- and middle-income settings who have built diverse platforms for conducting clinical trials.
“Many have been better at thinking through these issues and embedding inclusivity into their clinical studies,” he said. “They have managed to build long-term relationships with underserved groups. This stuff takes years, and starting and building those relationships at an early stage and coevolving research is very much the way to make this happen.”
At the same time, the conversations about diversity taking place among funders in higher-income countries might accelerate similar discussions in the global south, said Jenniffer Mabuka, manager for the Human Heredity and Health in Africa program at the African Academy of Sciences.
AAS has been actively trying to increase the number of clinical trials that take place on the African continent while also diversifying where they take place and which communities are included. At the moment, according to Mabuka, trials are disproportionately centered in South Africa and Egypt.
“To allow an increase in visibility of these other countries and sites and centers, we hope that sponsors or funders might start to diversify where they go,” she said. And as they push to diversify clinical trials, she challenged them to take a global lens and think about how they can better integrate underserved communities around the world — including by investing in community engagement programs in the global south that attract and retain a variety of clinical trial participants.
“Any decision that expands the diversity of clinical trials,” Mabuka said, “should have happened a long time ago.”