Investigation of the properties of the "switching decision rule" described in the Japanese guideline for human bioequivalence studies.

In a human bioequivalence (BE) study, the conclusion of BE is usually based on the ratio of geometric means of pharmacokinetic parameters between a test and a reference products. The "Guideline for Bioequivalence Studies of Generic Products" (2012) issued by the Japanese health authority and other similar guidelines across the world require a 90% confidence interval (CI) of the ratio to fall entirely within the range of 0.8 to 1.25 for the conclusion of BE. If prerequisite conditions are satisfied, the Japanese guideline provides for a secondary BE criterion that requires the point estimate of the ratio to fall within the range of 0.9 to 1.11. We investigated the statistical properties of the "switching decision rule" wherein the secondary criterion is applied only when the CI criterion fails. The behavior of the switching decision rule differed from either of its component criteria and displayed an apparent type I error rate inflation when the prerequisite conditions were not considered. The degree of inflation became greater as the true variability increased in comparison to the assumed variability used in the sample size calculation. To our knowledge, this is the first report in which the overall behavior of the combination of the two component criteria was investigated. The implications of the in vitro tests on human BE and the accuracy of the intra-subject variability have impacts on appropriate planning and interpretation of BE studies utilizing the switching decision rule.