Introduction
Over 6.5 million Americans are estimated to live with Alzheimer disease, which disproportionately affects women and members of the Black and Hispanic communities.1 Despite the significant burden of Alzheimer disease, only recently have drugs intended to slow Alzheimer disease progression entered the market. Nonetheless, these approvals were met with controversy, reasons among which included the exclusion of older adults and low enrollment of Black participants in some pivotal trials supporting approval.2 Whether these patterns were exceptional or common among Alzheimer disease trials is unknown. To investigate potential disparities in trial participation, we characterized the demographic characteristics of participants of all completed clinical trials of drugs to treat Alzheimer disease.
Methods
We performed a cross-sectional analysis of completed Phase 2–4 clinical trials of drugs to treat Alzheimer disease with start date after January 1, 2008 and primary completion date prior to March 10, 2023, when the search was conducted. Using ClinicalTrials.gov, we identified and characterized trials by phase, disease severity, indication, and size. We identified whether the trials reported results through ClinicalTrials.gov or through a publication, using a two-step process of searching PubMed for matching trials by NCT number and by trial name.
We abstracted participant demographic characteristics, including mean age, sex, race, and ethnicity, from the data source with the most complete information. We calculated the participation-to-prevalence ratio (PPR), the ratio between the proportion of a demographic subgroup among trial participants to that among the patient population.3 We used previously-published demographic characteristics from a 100% Medicare fee-for-service (FFS) population of people with Alzheimer disease to determine the denominator.4 A PPR between 0.8 and 1.2 was considered adequate representation.3 95% confidence intervals were calculated using t-tests.
Analyses were conducted using R version 4.1.2. The study was determined to be exempt by the Duke Health Institutional Review Board.
Results
We identified 277 completed Phase 2–4 trials of 159 drugs to treat Alzheimer disease, enrolling over 80,000 patients (Table 1). 207 (74.7%) trials released results, whether through ClinicalTrials.gov or publication. Of these, 184 (88.9%) reported mean age, 202 (97.6%) reported sex, 134 (48.4%) reported race, and 67 (32.4%) reported ethnicity.
Table 1.
Characteristics of Completed Clinical Trials of Drugs to Treat Alzheimer Disease, 2008–2023
| Trials (%) | |
|---|---|
| Total | 277 (100) |
| Year of Completion | |
| 2008–2010 | 30 (10.8) |
| 2011–2015 | 108 (39.0) |
| 2016–2020 | 114 (41.2) |
| 2021–2023 | 25 (9.0) |
| Phase | |
| Phase 2 | 179 (64.6) |
| Phase 3 | 65 (23.5) |
| Phase 4 | 33 (11.9) |
| Indication | |
| Disease Modification | 146 (52.7) |
| Cognitive Enhancement | 93 (33.6) |
| Neuropsychiatric Symptoms | 38 (13.7) |
| Illness Severity 1 | |
| Preclinical | 14 (5.1) |
| Prodromal | 59 (21.3) |
| Mild-Moderate Dementia | 236 (85.2) |
| Severe Dementia | 54 (19.5) |
| Size (Median [IQR]) | 130 (43–368) |
| Availability of Trial Results | |
| Any | 207 (74.7) |
| Results Reporting on ClinicalTrials.gov | 149 (53.8) |
| Days to Results Reporting (Median [IQR]) | 560 (434–1078) |
| Publication | 142 (51.3) |
| Days to Publication (Median [IQR]) | 731 (513–1103) |
| Availability of Any Demographic Data | |
| Age (as mean) | 184 (88.9) |
| Sex | 202 (97.6) |
| Race | 134 (48.4) |
| Ethnicity | 67 (32.4) |
Percentages sum to greater than 100% as trials could include participants of multiple severity levels.
The mean of mean age was 72.7 (SD 4.1). In the 202 (97.6%) studies reporting sex, men were overrepresented (mean 44.3%, PPR 1.33 [95% CI 1.27–1.38]) (Figure 1). In the 113 (54.6%) trials with complete reporting of race, Black participants were underrepresented (mean 4.8%, PPR 0.49 [95% CI 0.30–0.68]) and Asian participants were overrepresented (mean 10.0%, PPR 3.45 [95% CI 1.93–4.97]). Only 66 (31.9%) trials included complete reporting of ethnicity, with a mean 10.7% Hispanic participants (PPR 1.39, 95% CI 0.92–1.85). When restricting to 88 trials that enrolled only in the United States, trends were similar except for the reversal of Asian representation to underrepresentation.
Figure 1. Participation-to-Prevalence Ratios of Alzheimer Disease Clinical Trial Participants to Medicare Fee-For-Service Population by Sex, Race, and Ethnicity.
A. Participation-to-Prevalence Ratios of Trial Participants for All Trials
B. Participation-to-Prevalence Ratios of Trial Participants in Trials Conducted Solely Within the United States
PPR is calculated by dividing the proportion of trial participants of a demographic subgroup (e.g. White, Black, or Asian) by the proportion of a demographic subgroup among the patient population. PPR from 0.8 to 1.2 indicates adequate representation; PPR less than 0.8 indicates underrepresentation; PPR greater than 1.2 indicates overrepresentation. Dotted blue lines indicate these boundaries. Error bars indicate 95% CIs. 113 (54.6%) of all trials and 40/88 (45.5%) US trials reported race data for white, black, and Asian participants. 66 (31.9%) of all trials and 27/88 (30.7%) US trials reported ethnicity data for Hispanic and non-Hispanic participants.
Discussion
Clinical trials of drugs to treat Alzheimer disease enrolled participants that were not representative of the Medicare fee-for-service population, with younger mean age, underrepresentation of Black participants, and overrepresentation of Asian participants, mirroring findings in other disease areas.5–7 Previous studies have identified potential explanatory factors including variation by demographic characteristics in recruitment sources, specific trial exclusion criteria, and overall likelihood of inclusion.8–10 These factors must continue to be addressed to ensure representative trial participation, and to close knowledge gaps that threaten to exacerbate disparities for older adults and Black adults experiencing a greater burden of disease.
Study limitations include dependence on public results reporting to identify trial participant characteristics; limitations intrinsic to using Medicare claims algorithms to identify adults with Alzheimer dementia; and inability to distinguish between different stages of dementia severity.
The National Institute on Aging and Food and Drug Administration have long made it a priority to enhance diversity in clinical trials, including for Alzheimer disease. Nonetheless, gaps in representativeness of participants in trials of Alzheimer disease therapeutics persist. Clinicians and patients should be aware of the ongoing need to tailor recruitment efforts for participants in trials for Alzheimer disease.
Acknowledgments
Funding:
This project was supported by the National Institute on Aging though the Duke Creating ADRD Researchers for the Next Generation - Stimulating Access to Research in Residency (CARiNG-StARR) program (R38AG065762).
Sponsor’s Role:
The research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health. The sponsor was not involved in the design, collection, analysis, or interpretation of the data, or in the writing or submission of the manuscript for publication. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health.
Conflict of Interest:
Dr. Zhang is also a member of the Junior Investigator Intensive Program of the US Deprescribing Research Network, which is funded by the National Institute on Aging (R24AG064025). Dr. Anderson reports additional research funding from the National Institute on Aging, American Heart Association, and US Deprescribing Research Network outside of the submitted work.
Footnotes
An earlier version of this work was previously presented as an oral presentation at the American Geriatrics Society Annual Scientific Meeting.
References
- 1.HHS ASPE. Racial and Ethnic Disparities in Alzheimer’s Disease: A Literature Review. Published online 2014:34. [Google Scholar]
- 2.Manly JJ, Glymour MM. What the Aducanumab Approval Reveals About Alzheimer Disease Research. JAMA Neurol. 2021;78(11):1305–1306. doi: 10.1001/jamaneurol.2021.3404 [DOI] [PubMed] [Google Scholar]
- 3.Poon R, Khanijow K, Umarjee S, et al. Participation of Women and Sex Analyses in Late-Phase Clinical Trials of New Molecular Entity Drugs and Biologics Approved by the FDA in 2007–2009. J Womens Health. 2013;22(7):604–616. doi: 10.1089/jwh.2012.3753 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Anderson TS, Ayanian JZ, Souza J, Landon BE. Representativeness of Participants Eligible to Be Enrolled in Clinical Trials of Aducanumab for Alzheimer Disease Compared With Medicare Beneficiaries With Alzheimer Disease and Mild Cognitive Impairment. JAMA. Published online September 9, 2021. doi: 10.1001/jama.2021.15286 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Tahhan AS, Vaduganathan M, Greene SJ, et al. Enrollment of Older Patients, Women, and Racial/Ethnic Minority Groups in Contemporary Acute Coronary Syndrome Clinical Trials: A Systematic Review. JAMA Cardiol. 2020;5(6):714–722. doi: 10.1001/jamacardio.2020.0359 [DOI] [PubMed] [Google Scholar]
- 6.Khan SU, Khan MZ, Subramanian CR, et al. Participation of Women and Older Participants in Randomized Clinical Trials of Lipid-Lowering Therapies: A Systematic Review. JAMA Netw Open. 2020;3(5):e205202–e205202. doi: 10.1001/jamanetworkopen.2020.5202 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Smyth B, Haber A, Trongtrakul K, et al. Representativeness of Randomized Clinical Trial Cohorts in End-stage Kidney Disease: A Meta-analysis. JAMA Intern Med. 2019;179(10):1316–1324. doi: 10.1001/jamainternmed.2019.1501 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Raman R, Quiroz YT, Langford O, et al. Disparities by Race and Ethnicity Among Adults Recruited for a Preclinical Alzheimer Disease Trial. JAMA Netw Open. 2021;4(7):e2114364. doi: 10.1001/jamanetworkopen.2021.14364 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Heller C, Balls-Berry JE, Nery JD, et al. Strategies addressing barriers to clinical trial enrollment of underrepresented populations: A systematic review. Contemp Clin Trials. 2014;39(2):169–182. doi: 10.1016/j.cct.2014.08.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Zulman DM, Sussman JB, Chen X, Cigolle CT, Blaum CS, Hayward RA. Examining the Evidence: A Systematic Review of the Inclusion and Analysis of Older Adults in Randomized Controlled Trials. J Gen Intern Med. 2011;26(7):783–790. doi: 10.1007/s11606-010-1629-x [DOI] [PMC free article] [PubMed] [Google Scholar]