Equivalence tests for ratio of means in bioequivalence studies under crossover design

Abstract

There are several problems concerning the statistical definition of average bioequivalence provided by the U.S. Food and Drug Administration. We proposed a ratio of means based on the original bioavailability measure as the definition for average bioequivalence. Under the log-normal distribution assumption, we proposed a hypothesis testing-based method and a confidence interval-based method to answer the question of whether the ratio of means falls into a predetermined interval. For the hypothesis testing-based method, we decomposed the null two-sided hypothesis of the ratio of means into two one-sided hypotheses. With the intersection–union theorem for asymptotic tests, we constructed two asymptotic size-[Formula: see text] tests for the original null hypothesis. The method of variance estimation recovery was adopted to develop the confidence interval-based method. Simulation studies showed that the proposed methods can maintain the empirical type I error rate closely at the nominal level and is as powerful as the two one-sided [Formula: see text]-test for testing the ratio of means under different settings. The application of the proposed methods was illustrated through six datasets in real-world examples.