Some of the most frequently reported trial criteria were the exclusion of participants with non-AD neurological disease, psychiatric illness, cardiovascular and cerebrovascular disease, obligated caregiver attendance, and cognitive impairment.
A systematic review of more than 100 Alzheimer disease (AD) trials showed that most patients were predominately White, with ethnoracially diverse participants underrepresented, a theme that has been previously documented before.
To be included in the review, the study needed to be a planned, ongoing, completed, or early terminated phase 2 or 3 drug trial for patients with AD dementia, prodromal AD, or amnestic mild cognitive impairment (MCI). Additionally, the experimental drug being evaluated must have been a disease-modifying treatment, defined as an agent that targets the pathogenic steps in amyloid-ß (Aß) or tau pathways.
After excluding trials that did not match criteria, lead author Sanna Franzen, MSc, PhD student, neuropsychologist, Alzheimer Center, Erasmus University Medical Center, and colleagues included a total of 101 AD trials for review. Race and ethnicity data of the enrolled participants was available for less than half of the clinical trials (n = 46 studies; 45.5%). At the conclusion of the analysis, investigators found that the median reported percentage of White participants in all studies was 94.7% (interquartile range [IQR], 81-96.7). These percentages were high regardless of whether the trial used specific eligibility criteria.
Of the 7 studies that reported Latinx background, the median percentage represented in these trials was 5.6% (IQR, 4.2-11.4). As for other races, the median percentage of Black/African American participants was 1.2% (IQR, 0.4-1.7), and the median percentage of Asian participants was 4.4% (IQR, 0.3-17.3%). Notably, there were 3 studies from Asian that had a 100% Asian population. The remaining “other” or multiracial participants made up 0.9% (IQR, 0.0-1.9) of the median trial population. Trial start year did not have a significant relationship on the percentage of white participants (p = –.26; P = .09).
"Both federal law (Public Health Service Act 492B) and NIH policy require studies involving human subjects to address the inclusion of ‘minorities,’ and Alzheimer Europe similarly calls upon researchers, ethics committees, and founders to address inequality in research," Franzen et al wrote. "To generalize safety and efficacy data of AD clinical trials to the general population, more diverse individuals need to be enrolled, and modifying or changing the eligibility criteria in AD clinical trials may play a key role in reaching this goal."
None of the trials included explicitly referred to socioeconomic status; however, 41.3% (19 of 46) reported on the participants education level. Across these studies, the mean number of years of education was 13.3 years, with a higher mean level significantly correlated with a higher percentage of White participants included in the trial (p = .61; P = .02).
In 78.2% of the included AD trials, non-AD neurological diseases and major psychiatric disorders were the top reason for exclusion, followed by cardiovascular disease (71.3%) and a history of cerebrovascular disease (68.3%). These medical conditions, along with diabetes, renal disease, alcohol/substance use disorder, liver disease, higher weight/body mass index, and human immunodeficiency virus diagnosis, were found to be more prevalent in either non-Latinx Black US residents, Latinx US residents, American Indian/Native Alaskan US residents, or Indigenous Australians compared to non-Latinx White US residents or non-Indigenous Australians.
"With regard to the impact of criteria related to medical conditions on the inclusion of ethnoracially diverse groups specifically, it is still uncertain if, how, and when race corrections should be used to evaluate various clinical laboratory results as indicators of specific medical conditions, such as indicators of kidney functioning and several other common laboratory values," the study authors wrote. “Although such race corrections could potentially make the process of inclusion in clinical trials more inclusive, they may also inadvertently perpetuate or amplify existing disparities."
As for criteria related to diagnostic tests and questionnaires, nearly all studies used cognitive tests, batteries, or screeners as part of inclusion criterion. The Mini-Mental State Exam (MMSE) score was the most frequently used assessment, found in 90.1% of trials. The Repeatable Battery for the Assessment of Neuropsychological Status (4%), the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (3%), and the Montreal Cognitive Assessment (1%) rounded out the rest of the observed screening tests.
Of the 19 studies using an education criterion, 8 studies also allowed a work history consistent with no intellectual disabilities. For language fluency, most studies required fluency in the test language (n = 11), in the “local” language (n = 11), or in English (n = 8), while 4 studies allowed fluency in 1 of a number of languages.