Background: In the past few decades various methods have been proposed to handle missing data of clinical studies, so as to assess the robustness of primary results. Some of the methods are based on the assumption of missing at random (MAR) which assumes subjects who discontinue the treatment will maintain the treatment effect after discontinuation. The agency, however, has expressed concern over methods based on this overly optimistic assumption, because it hardly holds for subjects discontinuing the investigational product (IP). Although in recent years a good number of sensitivity analyses based on missing not at random (MNAR) assumptions have been proposed, some use very conservative assumption on which it might be hard for sponsors and regulators to reach common ground.
Methods: Here we propose a multiple imputation method targeting at “treatment policy” estimand based on the MNAR assumption. This method can be used as the primary analysis, in addition to serving as a sensitivity analysis. It imputes missing data using information from retrieved dropouts defined as subjects who remain in the study despite occurrence of intercurrent events. Then imputed data long with completers and retrieved dropouts are analyzed altogether and finally multiple results are summarized into a single estimate. According to definition in ICH E9 (R1), this proposed approach fully aligns with the treatment policy estimand but its assumption is much more realistic and reasonable.
Results: Our approach has well controlled type I error rate with no loss of power. As expected, the effect size estimates take into account any dilution effect contributed by retrieved dropouts, conforming to the MNAR assumption.
Conclusions: Although multiple imputation approaches are always used as sensitivity analyses, this multiple imputation approach can be used as primary analysis for trials with sufficient retrieved dropouts or trials designed to collect retrieved dropouts.