Thermo Fisher Scientific, Wilmington, NC, USA
Corresponding Author: Stephen J. Peroutka, MD, PhD, PPD, a part of Thermo Fisher Scientific, 929 North Front Street, Wilmington, NC 28401-3331, USA, +1 910 558 8843, Stephen.Peroutka@ppd.com
J Prev Alz Dis 2022;
Published online October 20, 2022, http://dx.doi.org/10.14283/jpad.2022.90
The Food and Drug Administration has that “sponsors should enroll participants who reflect the characteristics of clinically relevant populations”. Recent reports have noted that global Alzheimer’s Disease trials have enrolled predominantly White subjects. However, a thorough analysis of industry-sponsored, United States-only Alzheimer’s trials has yet to be performed. A search of the clinicaltrials.gov database and PubMed identified 101 industry-sponsored Alzheimer’s trials, performed solely in the United States, with gender data. The percentage of male (46%) vs. female (54%) subjects was higher than expected compared to real-world data. There were 50 Alzheimer’s trials with race data. There was a significant overrepresentation of White subjects (92%) compared to all other race groups. These data suggest that significant modifications of subject recruitment methods are needed to increase the enrollment of underrepresented populations into Alzheimer’s trials of potential new therapeutic agents in the United States.
Key words: Demographics, trials, Alzheimer’s, gender, race.
There has been a recent increased emphasis on the need for demographic diversity in clinical trials. For example, the Food and Drug Administration (FDA) stated in 2020 that “sponsors should enroll participants who reflect the characteristics of clinically relevant populations with regard to age, sex, race, and ethnicity” (1). Moreover, the FDA Guidance recommended that sponsors provide a plan for the inclusion of clinically relevant populations by the end of the Phase 2 meeting for all drugs and biological investigational therapeutics.
Since the 1980s, multiple analyses have shown that the gender and race demographics of clinical trial subject populations may differ significantly from the expected demographics in the general population (2). This disparity has been particularly apparent in Alzheimer’s Disease (AD) and related dementias trials.
For example, a demographic analysis of 6,500 subjects with AD obtained from the placebo arm of global clinical trials found that 89% of subjects were White (3). Similarly, a recent systematic review of global AD trials showed that subjects were predominantly White (median percentage = 95%) (4). However, these reviews evaluated global AD trial data from studies based in North America, Europe and/or Asia. As a result, the highly variable geographic distribution of global AD trial sites makes it difficult to compare the demographics of AD study populations to the expected demographics in the global trial site locations. Moreover, the ascertainment of demographic data varies widely between countries. In France, for example, the collection of demographic data is largely prohibited.
Therefore, the present analysis was designed to focus on US only, industry-sponsored Alzheimer trials. The rationale was to assess whether clinical trial subject populations in US AD trials reflect the demographic characteristics of the US AD population that would use a therapeutic product, if approved.
A search of the ClinicalTrials.Gov website (https://clinicaltrials.gov/) was made on March 31, 2022 for “Alzheimer’s Disease, Industry-sponsored” clinical trials that were at least partially performed in the US.
The analysis dataset included all US only trials that had gender and/or race demographic results available on either the ClinicalTrials.Gov website or in an associated publication identified via a PubMed search. For studies that involved both AD subjects and healthy volunteers, only AD subject data were included in the analysis. Race data were summarized according to the National Institutes of Health/Office of Management and Budget categories.
A total of 1,145 trials were identified initially. Approximately half of the trials were performed outside of the US, not yet completed and/or contained a mixture of AD and other subjects. The remaining trial data were then screened for US-only trials with AD subjects. Finally, all trials that had gender and or race demographic data either listed on clinicaltrials.gov, or in associated trial publications, were analyzed.
There were 101 AD clinical trials identified with gender and/or race demographic results. These trials were comprised of 16,681 AD subjects (see Appendix A for complete list of assessed trials). These studies were all performed solely in the US and were completed between 1997 and 2019. The subject enrollment per trial ranged from 2 to 1,649 individuals.
Gender demographics were available from 101 AD trials involving 16,681 subjects. There were 9,084 (54%) females and 7,796 (46%) males in these trials (Table 1A).
Race demographics were available from 50 trials involving 12,014 AD subjects (Table 1B). There were 11,078 (92%) White, 393 (3.3%) Black or African American, 61 (0.5%) Asian and 482 (4.0%) Other (e.g., Other, Mixed, Unknowns). The percentage of White subjects per study in the 50 trials with race data ranged from 0%-100%, with a median of 94% and a mean of 92%.
The gender and race trial demographics showed no major changes across the more than ~25 years of trial completions (Appendix A).
The major finding of the present study is that an analysis of 101 industry-sponsored AD trials, performed solely in the US, shows that the gender and race demographics of AD study populations over the past 25 years have not been consistent the gender and race demographics of AD patients in the US. First, there is a decreased frequency of female vs. male participation in the trials as compared to real-world data from large electronic health record databases (5, 6). Second, 92% of AD trial subjects have been White over the past 25 years in the US. This fact is also a significant deviation from the known race demographics of AD based on multiple sources (Table 1).
Traditionally, epidemiological studies have been used to describe disease demographics. Large scale epidemiological studies in AD involving the entire US population have not been performed. For example, the Einstein Aging Study (7) used systematic recruiting methods to enroll 1,944 individuals from Bronx County, NY, between 1993 and 2004. Detailed cognitive assessments were made at baseline and at 12-month intervals thereafter. There were 67% females and 33% males. White subjects represented 67% and Black or African American subjects 29% of the trial population, in comparison to each race group comprising 44% of the population in the Bronx County, NY in the 2020 Census. However, this study identified only 102 individuals with AD in a small geographic area, so extrapolation of these data to the much larger population of US AD patients in not reasonable.
In comparison to epidemiological research, electronic healthcare databases allow for “real-world” evidence that can be generated within minutes. For example, the OneFlorida Data Trust contains information on 17.2 M individuals, obtained from 10 healthcare systems within the state (8). The database contained information on 100,033 individuals with AD, as of 2022 (6). There were 69% females and 31% males, with a higher percentage females than in the 101 US AD trials. White and Hispanic subjects comprised 74% of the OneFlorida AD patients. This percentage is consistent with 2020 Florida Census data of 77% White residents, but far less than the 92% in the US AD industry-sponsored trial populations.
The TriNetX Analytics Network contains health records on more than 145 M individuals from more than 70 healthcare organizations across the entire US (9). The data in this, and other health record databases, do not contain the level of detail nor the diagnostic rigor of traditional epidemiological studies, yet they do provide real-world evidence that may be more indicative of patient populations that are likely to use new therapies. As noted above, the TriNetX database gender and race distributions are also inconsistent with the data from US-only, industry sponsored, clinical trials.
These data overwhelmingly indicate that significant modifications of AD subject recruitment methods are needed to increase the enrollment of underrepresented populations. The consistently high percentage of White subjects per trial, in the 50 studies analyzed with race data, suggests that these disparities are a likely result of a recruitment process that has not focused on subject diversity. The result is that an immediate need exists to increase the enrollment of all non-White populations of AD patients in US clinical trials.
Based on a review of clinical trial participation barriers in underrepresented populations (e.g., Black or African-America, Hispanic and American Indian), two consistent themes have emerged that limit research participation: mistrust and lack of information (10, 11). These obstacles can be overcome, but they require a significant and long-term investment in community outreach programs. In the short-term, information about ongoing trials needs to be communicated effectively to underrepresented communities via local health centers, senior community centers, neighborhood association meetings, pharmacies, churches, etc. Although limited research has suggested that this approach can be successful, more research is needed to determine the optimal ways to inform underrepresented populations about clinical trial research opportunities. A more challenging need is to determine the optimal ways to build trust between the medical research community and historically underrepresented populations in Alzheimer’s Disease clinical trials.
Ethical standards: There were no participants in this study. All data were derived from publicly available information.
Conflict of interest: Dr. Peroutka has nothing to disclose.
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