Bioequivalence Assessment for Locally Acting Drugs: A Framework for Feasible and Efficient Evaluation

Establishing bioequivalence is especially challenging for locally acting drugs, where products exert their effects at the application site rather than systemically. These settings often yield multivariate measurements, small sample sizes, and substantial experimental noise, making standard methods such as the Two One-Sided Tests (TOST) inadequate for controlling type I error and maintaining power. We develop a general framework for multivariate bioequivalence assessment that simultaneously corrects the TOST significance level and the equivalence margins to preserve nominal test size. In large samples, our approach reduces to the optimal univariate adjustment; in multivariate settings, it maintains valid marginal and joint error rates while improving power across realistic scenarios. Extensive simulations and a case study involving two antifungal topical formulations demonstrate the feasibility, stability, and practical advantages of the proposed methodology.

arXiv