The need to show minimum clinically important differences in Alzheimer's disease trials

Abstract

Deciding on the smallest change in an outcome that constitutes a clinically meaningful treatment effect (ie, the minimum clinically important difference [MCID]) is fundamental to interpreting clinical trial outcomes, making clinical decisions, and designing studies with sufficient statistical power to detect any such effect. There is no consensus on MCIDs for outcomes in Alzheimer's disease trials, but the US Food and Drug Administration's consideration of aducanumab clinical trials data has exposed the uncertainty of the clinical meaning of statistically significant but small improvements. Although MCIDs for outcomes, including Clinical Dementia Rating-Sum of Boxes and Mini-Mental State Examination in Alzheimer's disease have been reported, the Food and Drug Administration's guidelines, drafted in 1989 to facilitate regulatory approval of substantially effective antidementia drugs, do not specify quantified minimum differences. Although it is important that regulatory requirements encourage drug development and approval, without MCIDs, sponsors are motivated to power trials to detect statistical significance for only small and potentially inconsequential effects on clinical outcomes. MCIDs benefit patients, family members, caregivers, and health-care systems and should be incorporated into clinical trials and drug development guidance for Alzheimer's disease.