Under-representation of people of color in clinical trials is a long-standing problem in medical research with far-reaching consequences on research outcomes and equity towards access to treatments. Clinical trials on the newly approved Alzheimer’s disease (AD) drug, Leqembi and Eli Lilly’s Donanemab, currently awaiting FDA’s decision, have both been criticized (1) for having less diverse representation of people of color. Since last year FDA (US Food and Drug Administration) has recommended in its guidelines to include diverse population in clinical trials to reflect the diversity of people who will use the drug. Black and Hispanic people constitute about 13% and 19% of the US population. However, only 20% of the clinical trial participants for Leqembi (2) were people of color, whereas for Donanemab it was a meagre 10% (3). It is concerning as both ethnic groups have twice the risk of developing AD compared to whites. Failing to include these groups in clinical trials limits our understanding of disease mechanisms and potential treatment responses in these high-risk populations.
Leqembi and Donanemab are monoclonal antibody drugs that respectively targets abeta, and both abeta and tau in the brain. Eligibility for Leqembi’s clinical trial was early stage AD with accumulated abeta, whereas with Donanemab PET (positron emission tomography) and abeta positivity. However, it appears that population specific risk variants might contribute to the overall lower abeta and tau accumulation in the brains of Black and Hispanic patients, making it difficult for them to qualify in these studies. Fewer years of formal education and stress also contribute to dementia risk, with people of color at a less advantageous position. Additional factors that limit their recruitment in clinical trials include proximity to clinical trial centers and PET scan facility, higher rates of disqualifying factors like presence of cardiovascular and autoimmune diseases, recruitment campaigns specifically targeting white patients, and medical mistrust.
Although Leqembi and Donanemab slow cognitive decline among early cases of AD and dementia with mild cognitive impairment, they do not stop disease progression. In addition, these drugs can lead to amyloid related imaging abnormalities (ARIA) that might cause cerebral edema, micro-hemorrhage, seizures and even death. As side effects and efficacy of these drugs were not ethnically tested, clinicians might be hesitant to prescribe them to non-white patients.
By designing separate studies to include those disqualified from the main trials, actively engaging with diverse communities to build trust and encourage their participation can address lack of ethnically diverse people in clinical trials. Eli Lilly is taking steps to recruit more diverse participants in multiple studies, including its Donanemab clinical trial. Although this is a positive sign, broader systemic changes are needed to ensure clinical research reflects the diversity of the populations it aims to serve.
Reference:
2. N Engl J Med 2023; 388:9-21.
– Rueben Das
