A practical approach for evaluating population and individual bioequivalence

Pharmacokinetic measurements provided by subjects to each of two formulatio ns of a drug have a joint distribution that can be characterized by paramet ers reflecting scale and correlation as well as location. The bioavailabili ty of the formulations can be expressed in terms of the means of the margin al distributions, their means and variances, or the marginal means and vari ances and the joint correlation. These expressions correspond, respectively , to 'average', 'population', and 'individual' bioequivalence when the join t distribution of the measurements is bivariate normal. Current proposals f or assessing the degree of bioequivalence of two formulations are based on statistics that are composites of variance components and squares of expect ed mean differences from a mixed linear model. There are technical and prac tical issues associated with these proposals, particularly that they requir e more complicated designs than the familiar 2x2 cross-over. This paper des cribes an alternative approach that can be applied with standard 2x2 cross- over designs, and that provides evaluations of population and individual bi oequivalence that should be adequate for all practical clinical purposes. T he approach is based on easily computed correlation and regression coeffici ents whose statistical properties under normality are well known and for wh ich non-parametric and robust alternatives exist when normality cannot be a ssumed. The approach yields conclusions consistent with those obtained by t he current proposals when applied to data sets supplied by the FDA. In the cases where the conclusions do not match, the new approach appears to be mo re consistent with the data. Copyright (C) 2000 John Wiley & Sons, Ltd.