Aligning Treatment Policy Estimands and Estimators—A Simulation Study in Alzheimer’s Disease

Abstract

Draft ICH E9(R1) Addendum on “Estimands and Sensitivity Analysis in Clinical Trials” provides different strategies for addressing intercurrent events in defining an estimand and describing the treatment effect that is targeted. The set of considered intercurrent events will depend on the specific therapeutic setting and trial objectives. This article considers a case study of a long-term prevention trial investigating the treatment effect of a new drug in asymptomatic subjects who are at risk for developing Alzheimer’s dementia to illustrate the definition of different estimands, which correspond to different scientific questions of interest. The potential intercurrent events are identified. This article shows how the selection of various strategies for intercurrent events translates into different estimators. A simulation investigation is included, which explores the properties of several estimators aligned with estimands that apply a treatment policy strategy for the intercurrent event of treatment discontinuation. Different scenarios are considered for the on-treatment versus the off-treatment mean efficacy trajectory, under a potential range of retrieval rates of off-treatment data. This simulation exercise illustrates how the selection of the estimators for an estimand could have a strong impact on the estimates of the treatment effect and, consequently, on the decision making in a clinical trial.