Adjusting pairwise nonparametric equivalence hypothesis tests and confidence intervals for period effects in 3 x 3 crossover trials.

In pharmacokinetic and pharmacodynamic 3 x 3 crossover trials, average bioequivalence and noninferiority between treatments need to be only assessed pairwise in most cases. Due to the restricted number of subjects in such trials, normal distribution assumptions cannot be checked and frequently outliers are encountered, so that a nonparametric approach is more adequate. Therefore, to assess average bioequivalence or noninferiority, a new method is proposed to derive period adjusted nonparametric confidence intervals for pairwise treatment differences.