A small sample confidence interval approach to assess individual bioequivalence

The concept of interchangeable pharmaceutical products has been examined in great detail in the literature. Anderson and Hauck proposed a statistical random coefficient model to study 'switchability', and coined the phrase 'i ndividual bioequivalence' which they defined with a probability-based inequ ality. Since that paper there has been considerable work and discussion. Th e Food and Drug Administration has recommended the introduction of individu al bioequivalence (IBE) and population bioequivalence (PBE) methods in a dr aft guidance document. The proposal in the draft guidance includes criteria for IBE and PBE and recommends the use of non-parametric bootstrap 95 per cent upper confidence intervals for the conclusion of either IBE or PBE. Ho wever, this method requires intensive computations. We have developed an al ternative confidence interval procedure to assess IBE by the FDA recommende d criteria. This method utilizes Howe's approximation I to a Cornish-Fisher expansion. Our proposed method is applicable to balanced or unbalanced dat a in a broad class of extended cross-over designs, and can be easily progra mmed using readily available software. Copyright (C) 2000 John Wiley & Sons , Ltd.