Revisiting patient diversity in clinical trials… again
Minority groups have historically been excluded from clinical research, an inequity that has led to well-documented public health problems in which therapies tested primarily in Caucasian patients do not work as well in other ethnic and racial groups. This problem is famously exemplified by Sanofi’s blood thinner Plavix, which was approved in 1997 but slapped with a boxed warning in 2010 after researchers realized up to half of Asian and Pacific Islander populations cannot process the drug.
In recent decades, the federal government has enacted mandates and incentives to improve minority participation in federally-funded research. In 1993, Congress passed the National Institute of Health (NIH) Revitalization Act, which required that minorities and women be included in all NIH-funded research studies.
Since 1993, “we’ve made some great strides in terms of sex differences” in NIH-funded research, said Sam Oh, Ph.D., MPH, research epidemiologist, University of San Francisco School of Medicine. “With respect to the other half of the mandate, we still have a long way to go.”
While enforcing the minority inclusion has been challenging for the NIH, over the last five years more than 30% of human participants in NIH-funded trials have been non-White, according to Eliseo Pérez-Stable, director, National Institute on Minority Health and Health Disparities, NIH.
Meanwhile, industry-funded research, which leans heavily on a limited number of major academic centers and prioritizes rapid recruitment, remains predominantly White. As of 2016, minorities only accounted for 16.7% of the participants of privately-funded trials, according to the nonprofit Center for Information and Study on Clinical Research Participation (CISCRP).
Unlike the NIH, which has the power to withhold grant funding, the FDA, which regulates research conducted by biomedical companies, has less punitive authority to encourage diversity. However, a growing recognition of this problem has led to several FDA-led efforts to improve the transparency of trial demographics and to bolster minority participation in clinical research.
There are also several new industry-led efforts, such as the “I’m In” campaign led by the trade group Pharmaceutical Research and Manufacturers of America (PhRMA), the “Aware for All” campaign led by CISCRP and the Roswell Park Cancer Institute’s diversity workshops, backed by Eli Lilly.
Broadly, the clinical research industry has pointed to complex challenges that have hindered the inclusion of minorities in clinical trials, such as the higher cost of reaching less affluent communities, language barriers for non-native English speakers and a well-recognized lack of trust in the research industry among marginalized populations.
However, new surveys of minority populations, coupled with the ubiquity of mobile technology, are contributing to a growing body of evidence that suggests these barriers are not as onerous as the industry previously assumed. Moreover, minority participation in research not only benefits minority populations by bringing more detailed and genetically-appropriate therapies to the market, but also benefits life science and biotech companies by creating new research possibilities.
“In the United States, we are less than one generation away from becoming a minority majority country,” meaning that minority groups will comprise a majority of the population, said Oh.
According to Oh, companies may be missing an opportunity to query new populations in the pursuit of new drug development opportunities. As an example, Oh points to a new, highly effective class of cholesterol drugs called PCSK9 inhibitors, which were discovered thanks to an African American aerobics instructor. She was found to have extraordinarily low cholesterol after checking into a clinic for a minor wrist injury, and further testing revealed she carried a mutation common among people with African ancestry, but rare among those with European ancestry.
“Low and behold, this mutation found in an African American woman led to a drug that works in people who are Black, White, blue or pink,” Oh said. “By widening the inputs, you really stack the deck in your favor in terms of what you get as an output.”
Barriers are complex, sometimes misunderstood
Experts agree that trust is a major barrier to minority enrollment in clinical research, and often point to the Tuskegee study, an unethical experiment conducted on black men, as an example of mistreatment that bred mistrust among minority groups Because of Tuskegee, explained Pérez-Stable, there is a belief within the research community that African Americans essentially won’t sign up for clinical trials. “That may be true for some individuals,” he said, “but the barrier is actually just in a general mistrust of institutions” that needs to be addressed by forging “a direct human connection.”
For example, a 2010 paper that analyzed the decision-making process of 70,000 research participants found that although African and Asian Americans are less aware of clinical trials, they are just as willing to participate when approached about doing so.
In addition, African Americans were more likely to volunteer in HIV vaccine trials than the general population, despite the fact that they distrusted the researchers’ motivations, according to a 2005 survey from the National Institute of Allergy and Infectious Diseases.
In fact, lack of minority recruitment may come down to the fact that the principal investigators and funders in charge of research are predominantly White and male. Researchers may not know how to connect with minority communities and “give up easily,” said Pérez-Stable.
“In the industry, we continue to go back to the same resources and use the same strategies” around patient recruitment, said Jennifer Byrne, founder, Greater Gift Initiative. “It’s almost a cut-and-paste process.”
“A lot of large, industry-sponsored research is more about the volume and speed of enrollment rather than patient makeup,” said Steven Steinhubl, director of Digital Medicine, Scripps Translational Science Institute. That means trial participants are usually comprised of people who live around medical centers. Meanwhile, many hospital systems have left areas where minority communities live, either building new hospitals in the suburbs or gentrifying the urban settings in which they are based, Steinhubl said.
“The best way to deal with the trust issue is to reach out through community engagement programs,” which could include churches, YMCAs and other community groups, Steinhubl said. “Faith-based leaders, community organizations, health leaders, they will act for you [to] support science,” said Pérez-Stable. “It just takes effort.”
As well, companies could look outside traditional academic centers, said Steinhubl, instead seeking to partner with federally qualified health systems, which are government-supported hospitals that treat people without insurance or the ability to pay for health expenses.
“There is an extra challenge on follow-up in those communities, but it is an important population that has been ignored as part of research,” said Steinhubl. “If you really want to understand how the disparities in healthcare affect the entire U.S. population, federally qualified health centers are the perfect place to go to.”
In addition, industry can rely on physicians, principle investigators and research staff from minority communities to help bridge the divide between research and those communities. “I don’t hear as much about that in the literature or at conferences, but we can’t talk about patient engagement without providers, the trusted source for all patients,” said Byrne.
Steinhubl, who leads Scripps’ digital technology efforts under the Precision Medicine Initiative, said mobile apps can now be used to create a “digital community.” “We’re not limited geographically, and we believe that’s one of the stronger ways to bring much greater diversity to clinical research,” he said.
Ultimately, there are many tried-and-tested strategies to improve minority recruitment. Although it may be slightly more difficult that the current recruitment process, “the barriers are surmountable,” Pérez-Stable said.
The FDA as a bully pulpit
The FDA, tasked with regulating the pharmaceutical and medical device industries, does not have as much leverage as the NIH to urge research coordinators to include diverse participants in trials.
“The NIH is doing well on diversity inclusion because Congress gave them a big stick,” said Robert Califf, Donald F. Fortin, M.D. Professor of Cardiology, in the School of Medicine, Duke University and former FDA Commissioner. “The FDA is really left with a bully pulpit. It has no legal authority,” Califf said. However, when Congress passed Section 907 of the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012, it gave the FDA more leeway to establish programs to address diversity in clinical trials.
Since 2012, the FDA’s Office of Minority Health put together multi-media campaigns and information kits to help minority groups connect with clinical trials taking place in their areas. The FDA also launched a pilot program called the Drug Trials Snapshots, which asks industry sponsors to collect data about age, gender and race for all new drug applications.
According to the most recent Snapshots report, 31,468 patients participated in trials used to support the approval of 221 new drugs or biologics in 2016. Of those patients, 7% were African American, compared to 13% in the overall U.S. population, and 76% were White, compared to only 62% in the population. Meanwhile, 11% of trial participants were Asian, compared 5.6% in the U.S. population.
While Hispanic and Latinos comprise 16% of the population, they were largely under represented in industry-funded trials. Monitoring the participation of Hispanic and Latino people has proven challenging because this group is comprised of many different ethnic identities, said Califf. In addition, some are reluctant to report their information and demographics because many Latino-Americans are recent immigrants, or members of immigrant families.
Complicating the FDA’s efforts to bring diversity to biomedical research is the fact that it must consider data from trials that are global in nature, whereas the NIH deals exclusively with U.S.-based studies. For example, in 2015 the Approved Corlanor (ivabradine), a cardiac drug that was developed by a French company and tested primarily on White patients in Europe. While the FDA would have preferred to have a more diverse cohort, it also wanted to bring this life-saving drug to the market.
“The FDA doesn’t have a big stick but it’s using transparency to try to deal with [this issue],” Califf said. Moving forward, “the most effective strategy is for the FDA or review groups to emphasize [diversity] and to keep the pressure on companies ... throughout the lifecycle of products.” The Snapshots program is a good start, Califf said. “Sunshine does fix a lot of problems.”
Industry-led efforts to improve
Ultimately, however, the movement to include more minorities in privately-funded research will begin with company executives. “They have to have a commitment to more diversity, and they have to modify their economic model to fit that,” said Pérez-Stable. “In the long run, it will pay off.”
Although privately-funded research may trail behind NIH-funded research in terms of diversity of patient cohorts, in recent years several high-profile initiatives have brought this issue to the forefront of corporate ethical commitments.
For private companies, “we have to be able to change the calculus to what’s important and why we need to get a more diverse population,” said Steinhubl. A study like the Precision Medicine Initiative All, an ambitious plan to recruit one million Americans, with an emphasis on enrolling people with diverse ethnic and genetic profiles, could help begin to build scientific justification for why the industry should start recruiting from a broader patient population, Steinhubl said.
For example, Oh said, the new class of PCSK9 inhibitors never would have been discovered if researchers continued to exclusively study genetic profiles of people with European descent, yet the drugs ultimately developed are effective in people of many races and ethnicities.
“The potential for broad-based participation brings some compelling data and track record in terms of the commercialization experience,” said Byrne.
The concept of diversifying clinical trials is gaining momentum within the pharmaceutical and life science industries. In 2003, the nonprofit group CISCRP launched a free education program called “Aware for All,” an event that aims to educate communities about clinical research and celebrate “Medical Heros” who have already participated. In 2013, the industry trade group PhRMA announced a partnership with the National Minority Quality Forum and Microsoft to create a database of minority trial participants.
Also in 2013, Eli Lilly announced it would sponsor an annual three-day workshop, hosted by the Roswell Park Cancer Institute designed specifically to train minority physicians to become investigators and research coordinators. And in 2014, PhRMA launched the “I’m In” campaign, and is now partnered with more than 50 patient advocacy societies. The “I’m In” campaign also makes use of the Clinical Trial Engagement Network, which allows drug sponsors to register for a database of diverse clinical trial investigators who want to become more actively involved in clinical research.
It’s important for sponsors to understand that not every trial should necessarily aim to recruit a patient population that perfectly reflects U.S. demographics, said Pérez-Stable. “We cannot have studies that are powered for all groups” all the time, he said.
The goal is to try to include a diverse cohort framed around the group of people most likely to suffer from that illness. For example, because “diabetes is two to three times more common in all minority groups” sponsors should endeavor to include a significant number of minorities in the study cohort, Pérez-Stable said.
“Diversity in samples facilitates scientific discovery,” said Pérez-Stable. “If we shut ourselves out of that, we lose.”
Sony Salzman is a freelance journalist reporting on healthcare and medicine. She earned her Master’s degree from Boston University’s Science Journalism program, and has won multiple awards for narrative writing and radio journalism. She can be reached at firstname.lastname@example.org, or on Twitter @sonysalz.
This article was reprinted from Volume 24, Issue 07, of The CenterWatch Monthly, an industry leading publication providing hard-hitting, authoritative business and financial coverage of the clinical research space. Subscribe >>