Translating AD Clinical Trial Results to Meaningful Benefits: Expectations, Definitions, Challenges and Opportunities.

Abstract

AbstractBackgroundClinical trials in Alzheimer’s disease (AD) are designed and powered to detect treatment impact on validated research outcome measures necessary for regulatory approval. However, what constitutes a clinically meaningful benefit, how to define, measure and translate it from the results of clinical trial results to multiple stakeholders, including clinicians and patients requires better clarification.MethodsReview and synthesis of recent publications (Assuncao, Sperling, et al. Alz Res Therapy 2022; Petersen, Aisen Andrews, Atri, et al. Alzheimers Dementia. 2023 in press) and AD therapeutics developments to provide overview and frameworks for translating AD clinical trial results to meaningful benefits with respect to expectations, definitions, challenges and opportunities that may resonate with multiple stakeholders, including patients, patient care partners and clinicians.ResultsRational for realistic expectations of putative AD disease‐modifying treatments (DMTs) are reviewed including expectations of not improving symptoms but of slowing disease progression and modestly moderating between‐group (treatment versus placebo) clinical decline. Definitions postulated to represent clinically meaningful benefits are reviewed. Confusion, misunderstanding or misinterpretations in regards to representation of thresholds for meaningful within‐patient progression are discussed, including recent misinterpretation of necessary thresholds for determining meaningful group‐level differences having created misguided expectations for clinical meaningfulness in DMT clinical trial results. Discuss confounding minimal detectable change (MCD) and utilizing between‐group differences (to assess outcome efficacy) with and to define minimal clinically important differences (MCID) (an individual, within‐patient change in outcome assessment). Within‐patient change thresholds are not intended to assess meaningfulness of differences between group‐level changes over time, but may represent meaningful within‐patient trajectories via complementary (e.g. responder/progressor) analyses. Multiple frameworks show the challenges and opportunities to multidimensionally better represent and translate results to face‐valid and patient‐centered representations to resonate with AD stakeholders. These include expanded outcomes (e.g. neuropsychiatric symptoms, socioeconomic burden); patient‐ and caregiver‐reported outcomes; complementary analyses (standardized effect‐sizes, RR/OR, NNT, Time‐to‐Event, Time‐Equivalent‐Gained); and concepts such as predictive benefit (via a disease biomarker/core domain) and cumulative benefits (accrual and potentially increasing over time).ConclusionExpanded data, analyses and frameworks for defining and translating clinically meaningful patient‐centered benefit to multiple stakeholders, particularly patients, care‐partners and clinicians, are proposed.