Why should we worry about Lack of clinical trial diversity?
Selecting Subjects
An article by Mari Serebrov in BioWorld – “Lack of clinical trial diversity could have consequences”” – talked about the problems of not enrolling clinical trial participants from all walks of the population. BioWorld quoted Haynes and Boone, LLP Associate Jennifer Kreick in an article about potential risks for drug and device companies related to lack of clinical trial diversity in late-stage clinical trials. According to Kreick, “Drug and device companies dragging their feet on diversifying late-stage clinical trials could conceivably get a wake-up call in court or in FDA approval delays. A final guidance the FDA released in November suggests that the days of ignoring segments of the intended treatment population until safety signals flare in real-world use are coming to an end.
The guidance instructs sponsors to enroll trial participants who reflect the characteristics of clinically relevant populations with regard to age, sex, race and ethnicity. It also discusses ways of including people with comorbidities and other special populations in phase III trials.
Kreick pointed out that the guidance sets an industry standard. “It’s a really good starting point,” she said of the guidance, adding that more regulatory action is sure to follow. Kreick maintained that the guidance, and the push for greater trial diversity, might trigger a new kind of failure-to-warn lawsuit. Usually, such suits test new arguments, under state law, to go after companies for failing to disclose known safety information. Those suits are generally shot down because of preemption based on the FDA’s approval of the label. However, given the standards set in the guidance and the pressure for more data and trial inclusiveness, companies may be facing legal challenges for failing to include specific subpopulations in their trials when those groups are part of the intent-to-treat population.
Although Kreick is not aware of any such court challenges currently, she said that it could be a potential risk, especially when a sponsor intentionally excludes a significant subpopulation from a trial. The courts would then need to decide whether the failure-to-warn claims would be preempted by the FDA’s approval of a product, in spite of the trial exclusions.
Kreick’s practice, she advises drug and device companies to pay close attention to the guidance and to question every proposed exclusion when designing a trial. It is no longer acceptable to “cut and paste” the exclusionary criteria from one trial to the next, she said. Sponsors should analyze the criteria for each phase of a trial. Additionally, sponsors must do a balancing act to lower the chance of having a trial fail because of inclusion of participants with certain comorbidities, according to Kreick. She added that the FDA guidance offers suggestions on how to handle that situation, especially in drug trials.
Meanwhile, a team of scientific experts from across the U.S. and Puerto Rico are advocating for increased diversity in vaccine trials after publishing a new report that highlights a decade's worth of disparities. The new study, which was published in JAMA Network Open, found that among U.S.-based vaccine clinical trials, people who are Black/African American, American Indian/Alaska Native, Hispanic/Latino and age 65 and older were the most underrepresented groups. Adult women were overrepresented.
From July 2011 through June 2020 the research team examined 230 U.S.-based vaccine trials of all phases, with nearly 220,000 participants. The researchers discovered that many trials failed to fully report demographic information. For the studies that did, racial and ethnic minorities were frequently underrepresented as were older adults. Top findings from their analysis of the studies that reported demographic information include the following: white people accounted for 78 percent of all participants, women accounted for 56 percent, Black/African Americans accounted for 11 percent, American Indians/Alaska Natives accounted for 0.4 percent, Hispanics/Latinos accounted for 12 percent and people 65 and older accounted for 12 percent. Asian and Native Hawaiian/Pacific Islander participants were equitably represented in vaccine trials compared to the U.S. population.
Dr. Steve Pergam, an associate professor in the Vaccine and Infectious Disease Division at Fred Hutchinson Cancer Research Center and one of the corresponding authors of the study, said, "The COVID-19 pandemic and its devastating impact, particularly on BIPOC (Black, Indigenous and people of color) communities and older adults, is a painful reminder of the health disparities in our country. This collaborative work highlights a problem that's plagued the scientific community for too long -- inadequate representation in clinical trials. The diversity seen in COVID-19 vaccine trials demonstrate we can do this, but we need to assure future studies focus not just on rapid enrollment but also on inclusion."
There are still problems with capturing and underreporting participant demographics, according to the research team. This situation exists even though there have been efforts from the National Institutes of Health and Food and Drug Administration to implement policies and guidelines. The authors believe that improving racial and ethnic diversity in clinical trials is important because enrollment may impact vaccination rates among minorities.
According to Dr. Julie Silver, one of the senior authors on the study and an associate professor at Harvard Medical School in the Department of Physical Medicine and Rehabilitation, "Going forward, we need to ensure all vaccine studies report demographic information. Although we have some missing data, it is clear from the large number of studies which did report this information, that racial and ethnic minorities as well as older individuals are frequently not being equitably represented."
Dr. Michele Andrasik, a senior staff scientist at Fred Hutch and study co-author who also leads engagement efforts for the COVID-19 Prevention Network, added, "Vaccine hesitancy and a lack of understanding about safety is a major challenge we're facing with COVID-19. By improving enrollment diversity, we can better engage these underrepresented groups early in the trials stage and address the education and trust issues."
In order to address this situation, the National Academies of Sciences, Engineering, and Medicine recently set up a committee dedicated to improving the representation of women and underrepresented minorities in clinical trials and research. Dr. Carlos del Rio, distinguished professor of medicine at Emory University School of Medicine and co-author of the study, is a member of the committee. The authors also suggested that future trials emphasize the inclusion of older men and women. The aging of the population in the US and many other countries requires testing vaccines in older adults. As the current pandemic has shown, diseases like COVID-19 disproportionately impact older adults, especially people who live in long-term care facilities.