Crossover designs for clinical trials

I discuss three‐period crossover designs for an efficient comparison of two test treatments with special application to clinical trials which often have many practical limitations. In this paper I specify a subset of three‐period crossover designs so that the investigators are not left with the problematic two‐period two‐sequence design, should the trials be terminated after the second period. I show that there is a dramatic reduction in variability for estimating the direct and residual treatment effects in three‐period designs compared to two‐period designs. I also show that the universally optimal design with ABB and BAA sequences is unsuitable when a complex form of residual effects is suspected, such as the second‐order residual effects or treatment by period interactions. The design with ABB, BAA, AAB, and BBA sequences is relatively robust to these uncertain model assumptions. I also discuss missing data problems and conclude that, even with a large proportion of missing values, the three‐period design is far more efficient than the two‐period design.