Adaptive designs for IVPT data with mixed scaled average bioequivalence

Abstract

AbstractIn vitro permeation tests (IVPT) offer accurate and cost‐effective development pathways for locally acting drugs, such as topical dermatological products. For assessment of bioequivalence, the FDA draft guidance on generic acyclovir 5% cream introduces a new experimental design, namely the single‐dose, multiple‐replicate per treatment group design, as IVPT pivotal study design. We examine the statistical properties of its hypothesis testing method—namely the mixed scaled average bioequivalence (MSABE). Meanwhile, some adaptive design features in clinical trials can help researchers make a decision earlier with fewer subjects or boost power, saving resources, while controlling the impact on family‐wise error rate. Therefore, we incorporate MSABE in an adaptive design combining the group sequential design and sample size re‐estimation. Simulation studies are conducted to study the passing rates of the proposed methods—both within and outside the average bioequivalence limits. We further consider modifications to the adaptive designs applied for IVPT BE trials, such as Bonferroni's adjustment and conditional power function. Finally, a case study with real data demonstrates the advantages of such adaptive methods.