Use of the repeated cross-over designs in assessing bioequivalence.

Abstract

We consider applications of the repeated 2 x 2 cross-over design to evaluating bioequivalence between the two formulations. The repeated 2 x 2 cross-over design allows us not only to assess bioequivalence on average bioavailability and to examine the subject-by-formulation interaction but also to obtain independent unbiased estimates of intrasubject variability. One consequence of unequal intrasubject variabilities is that the sum of squares of intersubject residuals and the sum of squares of subject-by-formulation residuals are not independent. We also discuss the relative merits of this design as compared to the standard 2 x 2 cross-over design without repeated measurements in terms of precision and sample size with respect to the ratio of the number of subjects to the repeated measurements per subject. We investigate other uses of the 2 x 2 cross-over in examining the bioequivalence between the two different dosing regimens. Possible applications of other repeated cross-over designs to bioequivalence for more than two formulations are explored. A numerical example illustrates the proposed procedure.