Examining outlying subjects and outlying records in bioequivalence trials.

The problem of detecting outliers in bioequivalence trials is considered. We formulate the problem as a hypothesis-testing problem under a mean-shift model and propose a test procedure based on the likelihood function. The test statistic has two components: one is to detect whether a specific pharmacokinetic measurement of a subject for certain formulation/drug product is an outlying value; the other is to test whether a subject as a whole is an outlying subject (with unusual high or low bioavailability for all formulations/drug products). Under normality assumption, the proposed procedure is most powerful. The small sample distribution of the proposed test statistic is derived. A numerical example illustrates the use of the procedure. The proposed test is then compared in a simulation study against the Hotelling T2 test, recommended by Liu and Weng (1991) for the use of outlier detection in bioequivalence studies. The results from the simulation study show that the proposed test is more powerful than the Hotelling T2 test.