What the Aducanumab Approval Reveals About Alzheimer Disease Research

Abstract

The US Food and Drug Administration (FDA) recently provided accelerated approval for aducanumab to treat Alzheimer disease (AD). The decision was controversial within and outside the FDA because of inadequate evidence of medication efficacy. The Peripheral and Central Nervous System Drugs Advisory Committee voted against recommendation of aducanumab and several committee members resigned after approval. FDA approval was based on trials that were not inclusive of the people who bear a disproportionate burden of disease. 1 Only 0.6% (ie, 19 individuals) of participants identified as Black, 3% as Hispanic, 0.03% (1 person) as American Indian or Alaska Native, and 0.03% as Native Hawaiian or Pacific Islander. Of the 9% identified as Asian, 94% were recruited in Asia. 2 Older Black adults are estimated to have AD incidence up to double the rates in older White people. Despite this, Biogen reported that only 6 Black people were randomized to the treatment dose approved by the FDA.Why should there be concern about inadequate representation of people from historically excluded racial and ethnic backgrounds in AD clinical trials? Because the safety and efficacy of treatments among a narrow subgroup of people cannot be assumed to generalize to other groups. We focus on underrepresentation of Black people in aducanumab trials, but identical arguments hold for numerous other groups for whom safety and efficacy may vary.Racial categories are sustained by social norms and policies that shape nearly every dimension of life. These phenomena-interlocking to create systemic racism-drive racial health inequalities 3 and may influence preclinical biomarkers, medication adverse effects, and medication efficacy. As a result of exposure to interpersonal and structural racism throughout life, older Black people are more likely than White people to have hypertension and diabetes, to experience ischemic and hemorrhagic stroke, and to have white matter hyperintensities.The omission of Black patients from the aducanumab trials is particularly troubling given these racial health inequities. Vascular disease may exacerbate the common adverse events attributed to aducanumab, including microhemorrhages and vasogenic edema, ie, amyloid-related imaging abnormalities (ARIA). People with recent strokes or transient ischemic attacks were excluded from the trials, presumably for safety considerations, but these are not contraindications to prescription on the FDA-approved medication label. Adverse events were also far more common for APOE e4 allele carriers. Most research indicates thatcompared with White individuals-APOE e4 is more common, although less strongly associated with AD risk, VIEWPOINT

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