A new report commissioned by Congress makes significant recommendations for improving clinical trial diversity, including offering financial incentives that have typically been off the table for ethical reasons. The 403-page report addresses a range of stakeholders but specifically urges the US Food and Drug Administration (FDA) to hold sponsors accountable for enrolling more diverse participants in trials.
 
On 17 May, the National Academies of Sciences, Engineering and Medicine published a report titled, Improving Representation in Clinical Trials and Research, which lists how the clinical trial environment in the US fails to adequately represent minority populations and women, and makes specific recommendations on how to improve representation.
 
The report states that “large swaths” of the US population have received less benefit from medical advancements that have been made in recent years. They note that in many cases, those populations are also the ones who most need such advancements.
 
“While progress has been made on some fronts, particularly with representation of white women in clinical trials and clinical research, progress has largely stalled on participation of racial and ethnic minority population groups,” the report says. “Additionally, older adults, pregnant and lactating individuals, LGBTQIA+ populations, and persons with disabilities remain underrepresented and even excluded from clinical trials and clinical research.”
 
The report goes on to list a number of flaws in the current system that act as barriers to improving trial diversity, including the fact that while reporting to ClinicalTrials.gov is required for ongoing studies, there are significant inconsistencies in how data is reported to ClinicalTrials.gov and the National Institutes of Health’s lack of longitudinal enrollment data by disease type.
 
Over the years, researchers have used the excuse that well-documented historical and contemporary abuses against underrepresented groups have led to self-exclusion from trials. One frequently cited example is distrust of clinical research among Black Americans stemming from unethical experiments such as the Tuskegee Syphilis Study. While acknowledging that the “distrust and mistrust” felt by underrepresented groups “are certainly factors that influence the participation” of those communities, the authors write that other research shows that other barriers “related to being offered the opportunity to participate” were commonly cited.
 
“The evidence on this issue is clear: Asian, Black, Latinx Americans, and American Indian/Alaska Native individuals are no less likely, and in some cases are more likely, to participate in research if they are asked,” the report says. “Distrust and mistrust are commonly assumed to be the reason underlying a lack of participation in clinical trials. While there is no doubt that the legacy of abuses in medical research is an important factor driving the lack of engagement of underrepresented and excluded populations with both health care and research, several studies have found that distrust and mistrust are not necessarily associated with a lack of willingness to participate in medical research.”
 
Authors of the report note that while all stakeholders have a responsibility to achieve more inclusivity in clinical trials, the federal government has a more prominent role. They note the government is the primary funder of clinical research in the country, regulates scientific research, and is responsible for regulating and allowing new medical products on the market. This oversized role means the federal government needs more coherent policies to align medical investments and accountability.
 
“The committee is aware that the complexity of the United States health-care system poses significant challenges to transforming the clinical research system, and these systematic challenges will also influence the implementation of the committee’s recommendations,” the report states. “While providing a complete policy assessment for each recommendation was outside of the committee’s scope and charge, the committee does not deny that there will be costs—both fiscal and political—associated with the implementation of the recommendations.”
 
“These costs must be carefully weighed against the potential for long-term benefit,” the authors write. “Changing our nation’s approach to clinical research may require significant upfront costs to more equitably recruit and retain a diverse group of participants and to hold investigators accountable when they do not meet these goals. In addition, it will require incentivizing sponsors of clinical research to change the status quo. However, based on the committee’s expert opinion and the available evidence, the committee believes that implementation of its recommendations is necessary to truly drive significant and sustained change to the clinical research system.”
 
The report makes 17 specific recommendations, many of which target the work of the federal agencies, including FDA and how it sets standards for clinical trial data used to review and approve medical products.
 
For instance, the report says that the agency should require study sponsors to submit detailed recruitment plans by they time they submit investigational new drug (IND) and investigational device exemption (IDE) applications. The plans should explain how sponsors will ensure that trial populations appropriately reflect the demographics of the disease or condition under study, and provide justifications if enrollment targets do not match the demographics of the intended patient population.
 
A controversial area addressed by the report is whether to compensate trial participants for their time and effort. Typically, Institutional Review Boards (IRB) frown on the idea because it may create an impression of coercion or undue influence. But the report authors note that limiting such incentives ultimately may be unfair to potential underrepresented participants.
 
“Federal regulatory agencies, including … FDA, should develop explicit guidance to direct local IRBs on equitable compensation to research participants and their caregivers,” the report recommends. “In recognition that research participation may pose greater hardship or burdens for historically underrepresented groups, the new guidance should encourage and allow for differential compensation to research participants and their caregivers according to the time and financial burdens of their participation.”
 
“Differential compensation may include additional reimbursement for expenses including but not limited to lost wages for those with lower socioeconomic status (SES), transportation costs, per diem, dependent care, and housing/lodging where applicable,” it adds.
 
The report also notes that improving representation of underrepresented and excluded populations in clinical trials and clinical research requires a substantial investment of time, money, and effort. Such investments are needed to restore trust with underrepresented and excluded communities considering past injustices.
 
“Building trust with local communities cannot be episodic or transactional and pursued only to meet the goals of specific studies; it requires sustained presence, commitment, and investment,” the report states. “Investments are also needed in the systems and technologies that reduce burdens to participation by underrepresented and excluded populations, such as by adequately compensating participants financially for their time when participating in research and by investing resources in making participation more physically accessible, and by providing research materials that are culturally informed and multilingual.”
 
Additionally, the report recommends Congress to direct the FDA to enforce existing accountability measures for sponsors to do their part to improve clinical trial diversity and establish a taskforce to study new incentives for products that achieve representative enrollment in clinical trials.
 
Some of the ideas for creating incentives for sponsors include potential tax credits for research and development, fast-track reviews and fee exemptions for drug applications, extended marketing exclusivity for sponsors who meet predefined representativeness criteria, and refusing to file an application that does not appropriately represent the target population under study.
 
Report