The role of the upper sample size limit in two-stage bioequivalence designs

Two-stage designs (TSDs) are currently recommended by the regulatory authorities for bioequivalence (BE) assessment. The TSDs presented until now rely on an assumed geometric mean ratio (GMR) value of the BE metric in stage I in order to avoid inflation of type I error. In contrast, this work proposes a more realistic TSD design where sample re-estimation relies not only on the variability of stage I, but also on the observed GMR. In these cases, an upper sample size limit (UL) is introduced in order to prevent inflation of type I error. The aim of this study is to unveil the impact of UL on two TSD bioequivalence approaches which are based entirely on the interim results. Monte Carlo simulations were used to investigate several different scenarios of UL levels, within-subject variability, different starting number of subjects, and GMR. The use of UL leads to no inflation of type I error. As UL values increase, the % probability of declaring BE becomes higher. The starting sample size and the variability of the study affect type I error. Increased UL levels result in higher total sample sizes of the TSD which are more pronounced for highly variable drugs.