Incorporating and Interpreting Regulatory Guidance on Estimands in Diabetes Clinical Trials: The PIONEER 1 Randomized Clinical Trial as an Example.

Regulatory guidelines describe the use of estimands when designing and conducting clinical trials. Estimands ensure alignment of the objectives with the design, conduct, and analysis of a trial. An estimand is defined by four inter-related attributes: the population of interest, the variable (endpoint) of interest, how to handle intercurrent events, and the population level summary. A trial may employ multiple estimands to evaluate treatment effects from different perspectives in order to address different scientific questions. Since estimands may be an unfamiliar concept for many clinicians treating diabetes, this paper reviews the estimand concept and uses the PIONEER 1 phase 3a clinical trial, which investigated the efficacy and safety of oral semaglutide versus placebo, as an example of how estimands can be implemented and interpreted. In PIONEER 1, two estimands were employed for each efficacy endpoint and labelled as: (1) the treatment policy estimand, which assesses the treatment effect regardless of the use of rescue medication or discontinuation of trial product, and provides a broad perspective of the treatment effect in the population of patients with type 2 diabetes in clinical practice; and (2) the trial product estimand, which assesses the treatment effect had all patients remained on trial product for the planned duration of the trial without rescue medication, and thereby provides information on the anticipated treatment effect of the medication. Both approaches are complementary in understanding the effect of the studied treatments. This article is protected by copyright. All rights reserved.