A comparison of four different methods for outlier detection in bioequivalence studies

Bioequivalence studies, required by law whenever a new formulation of an existing drug product is introduced to the market, are designed to test whether the bioavailability, defined as the rate and extent to which a substance reaches systemic circulation, is equivalent for each of two or more formulations. Detection and treatment of outlying data in bioequivalence studies are practically important, because inclusion or deletion of potential outlying data may lead to a different conclusion concerning bioequivalence. A review of the literature reveals that four different methods have been proposed for detecting outliers in bioavailability/bioequivalence studies. We present the results of an extensive computer simulation testing the small sample performance of these four testing methods, the results of which indicate that one of these, the estimates distance test, is substantially more powerful than the alternatives.