Estimation Bias in Complete-Case Analysis in Crossover Studies with Missing Data

Crossover designs are used often in clinical trials. It is not uncommon that subjects discontinue before completing all treatment periods in a crossover study. Despite availability of statistical methodologies utilizing all available data and software for obtaining valid inferences under the assumption of missing at random (MAR), naïve approaches, such as the complete case (CC) analysis, which is only valid with a strong assumption of missing completely at random are still widely used in practice. In this article, we obtain the analytical form of the estimation bias of treatment effects with CC for linear mixed models. We use simulation studies to examine the inflation of Type I error and efficiency loss in the inferences with CC under MAR. Invalidity and inefficiency of two other commonly used approaches for defining analyzed data in the presence of missing data, including data from at least two periods in three period crossover and available cases for a specific comparison of interest, are also demonstrated through simulation studies.