Diversity in Clinical Trials Should Start with the Fundamentals
Clinical trial processes should begin with diversity in mind
Diversity in clinical trials involves more than just including more minority participants, panelists said at a recent webinar, Increasing Diversity in Clinical Trials. It is a commitment from leadership that addresses the diversity topic within every aspect of the clinical trial process.
PRA Health Sciences, a contract research organization (CRO) in Raleigh, NC, sponsored the April 28 virtual event. PRA chief scientific officer and executive vice president Kent Thoelke spoke about how the COVID-19 pandemic has given everyone a stark reminder about the inequity in healthcare delivery among different patient populations. “This only highlighted the need for making sure that clinical trials actually matched the patient populations that we were trying to treat.”
This topic is about good science as well, he said. “Beyond the moral imperative of ensuring equity among access to clinical trials, the concept of good science is critical.”
Relative to drug development, mechanisms of action can and do vary in different populations, such as by gender, race, or background. Drugs have failed when they have been tested in the wrong population or have been approved for the minority population when the target population is different. “From a scientific perspective, there is a paramount need to ensure that the populations we’re treating in clinical trials match the populations that will be using the drug, and that we understand if there’s a difference in safety or efficacy by mechanism of action that may be related to different racial or ethnic backgrounds. That’s all critical.”
The entire paradigm the drug development industry created needs to be reimagined. “[When] we create representative populations in our clinical trials, we create better science,” Thoelke said. “We create safer drugs. We create better understanding and profiles around the efficacy of the drugs for testing, so this conversation is an incredibly important one.”
The Importance of Trial Diversity
Diversity involves several critical issues, and is the thread one pulls to realize there are fundamental problems with science, said Jonathan Jackson, PhD, assistant professor of neurology at Harvard Medical School and director of the CARE Research Center at Massachusetts General Hospital.
“[T]here is this fundamental truth that the medicines that we develop should work for everyone, but they don’t,” he said. “In order to be sure about that, and to make sure that we are more confident about the vaccines, the biologics, and the devices that we develop, we need to get this right during the clinical trials — not when a drug is out in the wild and people are paying for that risk.”
People who are not white, not wealthy, not male, and who do not live on the East or West coast of the United States in an urban or a suburban center are underrepresented in trials. “That means we don’t know if the drugs we are developing work for us until we’re paying for them and taking them ourselves,” Jackson noted. “We can do better. We’re scientists, so let’s science this.”
In the future, clinicians will use genomic information to make treatment decisions. Algorithms will use those data, said Quita Beeler Highsmith, MBA, vice president and chief diversity officer at Genentech in San Francisco.
“Right now, 91% of the genomic material available to sciences are of European ancestry. Over 33 pharma companies are using artificial intelligence for drug discovery and in partnerships and collaborations,” she said.
As a Black woman who could be diagnosed with triple-negative breast cancer, Highsmith’s treatment algorithm could be based on that of a white woman. How does she know if the drug will be safe and effective for her treatment? “It is critically important that we begin to expand who gets to participate so that we can ensure that our future generations have the same opportunities for safety and efficacy as others have had in the past.”
The third panelist reiterated the diversity conversation is not just about race. “There are people in rural environments who are unrepresented,” said Clyde W. Yancy, MD, MSc, vice dean of diversity and inclusion for medicine, professor of medical social sciences, and chief of the division of cardiology at the Northwestern University Feinberg School of Medicine. Populations of non-English-speaking people, people with poor health literacy, older people, children, and adolescents are underrepresented. “The cause that we are advocating is really not planning a race or ethnicity play. It’s saying time out. We need to completely pivot and rethink a broad landscape of how we approach trials. This isn’t a political problem. Let’s use science to answer this question.”
Genomics can better identify patients at risk, and information technologies can better communicate risks and benefits. “There are ways that we can use contemporary technologies and science to more quickly, more appropriately, and in a much more representative way answer questions,” Yancy said. “The question we pose is ‘Why is this conversation necessary?’ It’s not necessary. It’s critical. We’re at a time where everything — everything in health and society — is undergoing a fundamental pivot — a pivot, we hope, toward equity. As Dr. Jackson pointed out, equity for all cohorts. This is the time to pause and rethink exactly how we do things. We should not fear the disruptive moment; that’s what we need in clinical trials. We need to come up with a way to get more information relevant to more patients more quickly, more efficiently, and with more intelligence. We can’t be just more of the same. We have to do it differently and be smart about it.”
Barriers to Trial Diversity
Jackson named 10 reasons why it is difficult to achieve diversity in clinical trials:
- lack of awareness of research opportunities;
- deep mistrust of the healthcare system and research studies;
- confusion and concern over what research is;
- limited transportation options/times;
- study inclusion/exclusion criteria;
- lack of plain language use in documents;
- fear of placebo and/or fear of intervention;
- health insurance coverage;
- limited diversity of study staff;
- insufficient return of value.
“We hear about famous studies that have some kind of diversity,” Jackson said. “People will really tout it, but we don’t have a clear understanding about why that is.”
Although this is a scientific problem, researchers are not necessarily taking a scientific approach. “We’re sort of hoping that the plural of anecdote is data, and it’s just not true here as it’s not true anywhere else,” he added. These issues need to be rethought from a more systemic framework. “Systemic problems need systemic solutions.”
Historically, the burden of solving the diversity problem has been placed on potential research participants. “Nowadays, there’s a bit of a shift, and we’re putting that burden on individual research teams,” Jackson explained. “That’s not going to work, either. We need to build an infrastructure that’s full of carrots and sticks in order to get this right, but it’s not going to happen if we leave teams underresourced, unequipped, with no data practices, ontology, or frameworks, and without any real incentive to get this right.”
The 10 barriers are downstream phenomena, Yancy said. “We need to go back upstream and say at the outset, at the intent, ‘When you establish the hypothesis or set the drug discovery plan, are you writing a protocol with an inclusive angle?’”
The root cause of the barriers is culture, he said. What is the culture of the sponsor? Does the sponsor want to get this done in the most expedient way? Is the sponsor looking for a population where the answer will most likely be positive and will give greatest return on investment?
“We have to immerse in this notion of inclusiveness,” Yancy said. “If we talk about inclusivity with a predominant question, with a primary question, and deal with this upstream, these barriers that we will articulate in the moment would be much less difficult to overcome.”
Highsmith said Genentech has asked all of its molecule teams to create inclusive research plans from the beginning. “To this point, you have to be thinking about this from the very start.” Genentech’s EMPACTA study of COVID-19 pneumonia dispels the myth that patients of color do not want to participate in clinical research, she added.
Of the more than 380 patients in the study, 85% were from minority racial and ethnic groups. Most patients were Hispanic, with significant representation of Native American and Black populations. The trial was conducted in the United States, South Africa, Kenya, Brazil, Mexico, and Peru.1
“The patients are out there, and they’re willing to participate if you ask them. But we also have to think about the reward system a little bit differently,” Highsmith said. “Most of the time, we’re rewarding the company people and site on first patient in. When we did EMPACTA, we went to other sites.”
Genentech has conducted studies in cities such as Oakland and Detroit. “Some of those sites we had never used before, and maybe it did take one, two, or three days longer to get the IRB up and running, but at the end of the day, we had a bigger pool of patients to choose from,” Highsmith said. “Site election is really critical in thinking about where are people living. ZIP codes can routinely determine your health.”
Highsmith added, “One of the things that we’ve learned in our EMPACTA study is you’ve got to be in the community, the hospital that people are driving by in their neighborhood. That’s the hospital they trust. They don’t trust having to go across town to the big academic institutions.”
Genentech is starting a new research site alliance initiative in which the company will work with communities of color to “broaden who has access,” Highsmith said. “Then, we have to work on our processes, and we have to look at our inclusion/exclusion criteria. So many times, the inclusion/exclusion criteria are based on a white male from 20 years ago. We need to be thinking about it differently, thinking about body mass index, thinking about creatinine clearance. Thinking about things that might be normal for people of color that would exclude them from the clinical trial for no real scientific or valid reason.”
Incentives for Diversity
The panel also discussed the idea of giving incentives or even enforcing penalties as a way of increasing diversity. The qualifying language on last year’s FDA statement about diversity is nonbinding, Yancy said. “The language is just that. There are no consequences. It’s guidance as it intends to be.”
A carrot-stick approach could be used, but advocacy and awareness could be a different approach, as well as incentives. “For example, if there is an entity, a corporate entity in particular, that really makes a good faith effort and recruits a diverse population, why not extend the patent protection?” Yancy asks. “We should make this less of a binary question about whether we support underrepresented groups, and instead make it a more intellectual question: How do we approach this differently? Then I think we have an opportunity to be uniquely different than we have ever been before.”
According to Jackson, the question is: How do we do good science? “Good science is inclusive. Good science is representative from the very beginning,” he said. When you get it “right,” you get more participants from a bigger pool, and trials enroll faster.
“Some incentives are great, but we don’t incentivize having the right statistical test,” Jackson said. “We don’t necessarily incentivize having a thoughtful Data Safety and Monitoring Plan. We just expect those things to be done, and when they’re not done, there are consequences. There are punishments, but most importantly, you kind of lose the respect of your peers. You lose that market edge, and I think the quicker we clarify that there is a market opportunity here, the less that we need those incentives.”
“[Diversity] is a business imperative for our organization,” Highsmith added. “I do think that our industry — whether it’s pharma, whether it’s the FDA — is saying to us that we want to see commitment to enhance participation in clinical research. There are those of us who are stepping up to get it done.”
That success needs to start at the top. “I think the only way real change happens is that it starts with leadership and that it ends with culture,” Yancy said. “If we can get those two things accomplished, then everything else just becomes an exercise of execution. Change the composition of clinical leadership, change the culture of performing clinical trials, and we will reap a return that we’ve not seen before.”
REFERENCE
- Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with Covid-19 pneumonia. N Engl J Med 2021;384:20-30.
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