Considerations of multiple imputation approaches for handling missing data in clinical trials.

Missing data exist in all clinical trials and missing data issue is a very serious issue in terms of the interpretability of the trial results. There is no universally applicable solution for all missing data problems. Methods used for handling missing data issue depend on the circumstances particularly the assumptions on missing data mechanisms. In recent years, if the missing at random mechanism cannot be assumed, conservative approaches such as the control-based and returning to baseline multiple imputation approaches are applied for dealing with the missing data issues. In this paper, we focus on the variability in data analysis of these approaches. As demonstrated by examples, the choice of the variability can impact the conclusion of the analysis. Besides the methods for continuous endpoints, we also discuss methods for binary and time to event endpoints as well as consideration for non-inferiority assessment.