Estimation of treatment effects in short-term depression studies. An evaluation based on the ICH E9(R1) estimands framework.

Abstract

Estimands aim to incorporate intercurrent events in design, data collection and estimation of treatment effects in clinical trials. Our aim was to understand what estimands may correspond to efficacy analyses commonly employed in clinical trials conducted before publication of ICH E9(R1). We re‐analysed six clinical trials evaluating a new anti‐depression treatment. We selected the following analysis methods—ANCOVA on complete cases, following last observation carried forward (LOCF) imputation and following multiple imputation; mixed‐models for repeated measurements without imputation (MMRM), MMRM following LOCF imputation and following jump‐to‐reference imputation; and pattern‐mixture mixed models. We included a principal stratum analysis based on the predicted subset of the study population who would not discontinue due to adverse events or lack of efficacy. We translated each analysis into the implicitly targeted estimand, and formulated corresponding clinical questions. We could map six estimands to analysis methods. The same analysis method could be mapped to more than one estimand. The major difference between estimands was the strategy for intercurrent events, with other attributes mostly the same across mapped estimands. The quantitative differences in MADRS10 population‐level summaries between the estimands were 4–8 points. Not all six estimands had a clinically meaningful interpretation. Only a few analyses would target the same estimand, hence only few could be used as sensitivity analyses. The fact that an analysis could estimate different estimands emphasises the importance of prospectively defining the estimands targeting the primary objective of a trial. The fact that an estimand can be targeted by different analyses emphasises the importance of prespecifying precisely the estimator for the targeted estimand.