The 2018 Revised FDA Guidance for Early Alzheimer’s Disease: Establishing the Meaningfulness of Treatment Effects

Abstract

The present report reviews the revised 2018 FDA guidance for early AD, with an emphasis on meaningfulness of clinical outcome assessments (COAs). A radical shift is evident in the importance given to establishing the meaningfulness of COAs in the 2018 draft versus the 2013 draft. The implications of this shift include the assertion that cognition is clinically meaningful, but that a persuasive effect on cognition, depending upon disease stage of the participants in the trial, is one that is of enough magnitude, established across multiple relevant domains, and can be supported by biomarkers reflecting underlying AD pathological changes. Meaningfulness is established through an understanding of the conceptual relevance of what is being measured and magnitude of any treatment effect. Precedent exists within other FDA guidance and independent good practices publications as to how meaningfulness may be assessed e.g. via evaluation of content validity and concepts such as minimally important difference. Additionally, FDA is developing a series of methodological Patient Focused Drug Development (PFDD) documents to provide further guidance on this topic, which are aimed at addressing gaps in methodology and recommended best practice. Importantly, application of PFDD approaches to AD is behind that in other areas and there is limited published content validity for COAs and a lack of supportive qualitative research. Initiatives to build robust conceptual models of AD and develop novel direct measures of meaningful health outcomes will have a significant impact on measurement of efficacy in clinical trials and on payer determinations of beneficiary value. Greater recognition of what is meaningful from the perspective of the patient and caregiver will inform regulatory reviews and determinations for payment and coverage of treatments.