Estimand framework: Delineating what to be estimated with clinical questions of interest in clinical trials

Abstract

ICH (International Council for Harmonization) E9 R1 (2019) proposes a framework to define estimands in clinical trials. Although the concept of estimand was proposed previously when US Food and Drug Administration (FDA) issued the panel report on handling missing data in clinical trials, many details including attributes and different strategies have not been developed until the recent ICH E9 (R1) addendum. A clearly defined estimand should include considerations of five attributes including patient population, treatment regimen of interest, endpoint/variables, handling of intercurrent events (IEs), and summary measures for assessing treatment effect. To evaluate the underlying treatment effects of a new investigational drug or biologic product, it is desirable to consider estimands that are aligned with the objectives of the study and that are meaningful to the stakeholders such as physicians or patients, health authority administration, and payers, etc.. In this paper, the concepts, attributes and strategies of the estimand framework will be reviewed and illustrated with clinical trial examples. Some common estimands and their associated scientific questions are discussed within a causal inference framework for longitudinal clinical trials.