Adaptive two-stage bioequivalence trials with early stopping and sample size re-estimation

Excerpt

Bioequivalence between two products has to be demonstrated as an essential part of the generic approval process (new formulation vs. innovator product), bridging an innovator's product from the formulation used in clinical phase III to the marketed formulation, or in case of major variations of an approved product. The most common design of bioequivalence studies is a two-sequence two-period two-treatment crossover design, where inclusion of 90% confidence intervals of pharmacokinetic metrics in a pre-defined acceptance range has to be shown. Alternatively, bioequivalence can be established by using Two One-Sided Tests (TOST) each at an alpha level of 5%. However, this fixed sample approach offers no flexibility if in the planning phase parameters were misspecified. …