Alternative confidence intervals for the assessment of bioequivalence in four-period cross-over designs.

Bioequivalence studies are conducted to demonstrate equivalence in the bioavailability of the active ingredient in different formulations. The U.S. Food and Drug Administration (FDA) requires pharmaceutical companies to show bioequivalence between different formulations or generic companies to show bioequivalence between generic drugs and brand drugs before approval. A recent FDA guidance on bioequivalence proposes criteria for assessment of population bioequivalence (PBE) and individual bioequivalence (IBE) in a four-period cross-over design. In this paper, computer simulation is used to compare modified large sample (MLS) upper bounds with those proposed by the FDA to test for both PBE and IBE. The comparison criteria are the ability to maintain the stated test size and the simulated power of tests based on these bounds.