Bootstrap methods for the nonparametric assessment of population bioequivalence and similarity of distributions

A completely nonparametric approach to population bioequivalence in crossover trials has been suggested by Munk and Czado (1999). It is based on the Mallows (1972) metric as a nonparametric distance measure which allows the comparison between the entire distribution functions of test and reference formulations. It was shown that a separation between carry-over and period effects is not possible in the nonparametric setting. However when carry-over effects can be excluded, treatment effects can be assessed when period effects are or not. Munk and Czado (1999) proved bootstrap limit laws of the corresponding test statistics because estimation of the limiting variance of the test statistic is very cumbersome. The purpose of this paper is to investigate the small sample behavior of various bootstrap methods and to compare it with the asymptotic test obtained by estimation of the limiting variance. The percentile (PC) and bias correct- ed and accelerated (BCA) bootstrap were compared for multivariate normal and nonnormal populations. From the simulation results presented, the BCA bootstrap is found to be less conservative and provides higher power compared to the PC bootstrap, especially when skewed multivariate populations are present.