A PRACTICAL APPROACH FOR THE ASSESSMENT OF BIOEQUIVALENCE UNDER SELECTED HIGHER-ORDER CROSS-OVER DESIGNS

The two-period cross-over design with two sequences of drug administra tion is a standard experimental design when bioequivalence of one test formulation is to be assessed in comparison with a reference formulat ion. Previously, an approach based on Fieller's confidence interval ha s been presented for the assessment of average bioequivalence under th is particular design. However, the two-sequence two-period cross-over design is not very useful in the presence of unequal carry-over effect s. Besides, this basic design does not provide independent estimators for the intra-subject variabilities. To overcome these limitations, it might be of interest to consider a higher-order cross-over design in which the number of periods and/or the number of sequences is greater than the number of formulations to be compared. Because of this, the p resent communication will concentrate on the generalization of Fieller 's confidence interval concept for a particular group of higher-order cross-over designs. In addition to this, since the evaluation of simpl e average bioequivalence does not guarantee that the two products can be used interchangeably, the assessment of population and individual b ioequivalence is addressed through the application of a comprehensible three-step decision rule. An example study with a two-sequence four-p eriod design is also analysed to illustrate the use of the proposed me thods. (C) 1997 by John Wiley & Sons, Ltd.