Bioequivalence revisited: non-parametric analysis of two-period cross-over studies.

Hauschke et al.'s non-parametric bioequivalence procedure for treatment effects and some aspects of computer implementation, among them Meineke and De Hey's algorithm and a recursive algorithm, are explored. For studies with up to sixty subjects, a table of indices of the ranked intersubject-intergroup mean ratios or differences is given, to establish non-parametric 90% confidence intervals. It is shown that non-parametric analysis is not limited to treatment effects: it can also be applied to period and sequence effects. This extended procedure can be seen as the non-parametric analogue of analysis of variance on two-period cross-over studies. A FORTRAN program (BIOEQNEW) incorporating Meineke and De Mey's algorithm is presented. This program provides non-parametric point estimates for treatment and period effects, 90% and 95% confidence intervals for test-versus-reference treatments, the 95% confidence interval for periods and a test on sequence effects, so that it can also be used for other than bioequivalence studies. BIOEQNEW can handle ratios ('multiplicative model') as well as differences ('additive model'). It optionally provides the complete non-parametric posterior probability distribution for treatment ratios or differences, so that Schuirmann's 'two one-sided tests procedure' can also be performed in a non-parametric way.