Paired and AB / BA Cross‐Over Design in Early Phase Clinical Trials: A Closer Look at Within‐Subject Variance Bias

ABSTRACT This manuscript advocates for the implementation of multiple‐sequence cross‐over designs in early‐phase clinical trials by investigating the bias in within‐subject variance present in paired and AB/BA cross‐over clinical trial designs. While the advantages of adding additional sequences to mitigate confounding effects are well established, the authors noted a lack of mathematical discussion regarding the estimation of random effects in early‐phase trials—an important consideration for planning subsequent studies. The manuscript illustrates the importance of multiple‐sequence designs by analysing data obtainable from a paired and AB/BA cross‐over design for a normally distributed variable. It reveals that the residual mean square error from these two designs serves as an unbiased estimator of within‐subject variability only under the rare conditions of no subject‐by‐treatment interaction and equal variances in both test and reference treatments. This implies that while paired or AB/BA cross‐over design might be suitable for early pharmacological studies, it should not be relied upon solely for sample size calculations in late‐stage studies due to its limited interpretative potential.