Bioequivalence (BE) trials play an important role in drug development for demonstrating the bioequivalence between test and reference formulations. The key statistical analysis for BE trials is the use of two one-sided tests (TOST) which is equivalent to show that the 90% confidence interval of the relative bioavailability is within a given range. Power and sample size calculations for the comparison between one test formulation and the reference formulation has been intensively investigated and tables and software are available for practical use. It is often more efficient to test more than one formulation in a single trial. However, approaches for controlling the overall type I error may be required. We propose a method called multiplicity adjusted TOST (MATOST) combining multiple comparison adjustment approaches, such as Holms method, with TOST. Since power and sample size calculations become more complex and are difficult to solve analytically, efficient simulation-based procedures for this purpose have been developed and implemented in an R. Some numerical results for a range of scenarios are presented in the paper. We show that given the same overall type I error and power, a BE crossover trial designed to test multiple formulations simultaneously only requires a small increase in the total sample size, compared with a simple 2x2 crossover design evaluating only one test formulation. Hence, we conclude that testing multiple formulations in a single study is generally an efficient approach.

Zheng, C., Wang, J. and Zhao, L. (2013).Authors’ reply to the letter to the editor by Olivier J.M. Guilbaud, Pharmaceutical Statisitics. 12(6):390-393.

Zheng, C., Wang, J. and Zhao, L. (2012). Testing bioequivalence for multiple formulations with power and sample size calculations, Pharmaceutical Statisitics. 11(4):334-341.

The sample code can be found here