Meaningful benefits: a framework to assess disease-modifying therapies in preclinical and early Alzheimer's disease

Abstract

Background: The need for preventive therapies that interrupt the progression of Alzheimer's disease (AD) before the onset of symptoms or when symptoms are emerging is urgent and has spurred the ongoing development of disease-modifying therapies (DMTs) in preclinical and early AD (mild cognitive impairment [MCI] to mild dementia). Assessing the meaningfulness of what are likely small initial treatment effects in these earlier stages of the AD patho-clinical disease continuum is a major challenge and warrants further consideration. BODY: To accommodate a shift towards earlier intervention in AD, we propose meaningful benefits as a new umbrella concept that encapsulates the spectrum of potentially desirable outcomes that may be demonstrated in clinical trials and other studies across the AD continuum, with an emphasis on preclinical AD and early AD (i.e., MCI due to AD and mild AD dementia). The meaningful benefits framework applies to data collection, assessment, and communication across three dimensions: (1) multidimensional clinical outcome assessments (COAs) including not only core disease outcomes related to cognition and function but also patient- and caregiver-reported outcomes, health and economic outcomes, and neuropsychiatric symptoms; (2) complementary analyses that help contextualize and expand the understanding of COA-based assessments, such as number-needed-to-treat or time-to-event analyses; and (3) assessment of both cumulative benefit and predictive benefit, where early changes on cognitive, functional, or biomarker assessments predict longer-term clinical benefit.

Conclusion: The concept of meaningful benefits emphasizes the importance of multidimensional reporting of clinical trial data while, conceptually, it advances our understanding of treatment effects in preclinical AD and mild cognitive impairment due to AD. We propose that such an approach will help bridge the gap between the emergence of DMTs and their clinical use, particularly now that a DMT is available for patients diagnosed with MCI due to AD and mild AD dementia.

Keywords: Alzheimer’s disease; Biomarkers; Clinical meaningfulness; Clinical trials; Meaningful benefit; Mild cognitive impairment due to Alzheimer’s disease; Preclinical.

Fig. 1

Meaningful benefits: a comprehensive spectrum of approaches across Alzheimer’s disease. Each assessment is introduced when it first becomes relevant in the disease continuum (boxes) and each arrow shows the length of time for which the assessment strategy remains relevant. The numbered stages refer to stage definitions introduced by the Food and Drug Administration. *The reliability of patient-reported outcomes may be compromised early in the expression of AD dementia; however, a number of different concepts can best be assessed with PROs, particularly when the concept being measured is best known to the patient or best measured from the patient’s perspective, such as subjective cognitive decline. Abbreviations: AD, Alzheimer’s disease; COA, clinical outcome assessment; DMT, disease-modifying therapy; MCI, mild cognitive impairment; NNH, number needed to harm; NNT, number needed to treat; OR, odds ratio; RR, relative risk

Fig. 2

Theoretical rate of decline with DMTs. Model showing the theoretical rates of decline with disease-modifying treatment and without. There is an increasing drug–placebo difference over time with cumulative benefit of long-term therapy. Adapted from Cummings & Zhong [81]