Comparison of Models for Average Bioequivalence in Replicated Crossover Designs

• Activity Number: 266
• Type: Contributed
• Date/Time: Tuesday, August 9, 2005 : 10:30 AM to 12:20 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Susan Willavize*+ and Elizabeth A. Morgenthien
• Companies: Pfizer, Inc. and The Quincunx Group
• Keywords: average bioequivalence ; replicated crossover design ; subject-by-formulation interaction

Abstract

Average bioequivalence (ABE) has been the regulatory standard for bioequivalence (BE) since the 1990s. BE studies are commonly two-period crossovers, but also may use replicated designs. The replicated crossover will provide greater power for the ABE assessment. FDA has recommended ABE analysis of replicated crossovers use a model that includes terms for separate within- and between-subject components for each formulation and allows for a subject-by-formulation interaction component. Our simulation study compares the performance of four alternative mixed-effects models: the FDA model, a three-variance component model proposed by Ekbohm and Melander (EM), a random intercepts and slopes model (RIS) proposed by Patterson and Jones, and a simple model that contains only two variance components. The simple model fails (when not "true") to provide adequate coverage and it accepts the hypothesis of equivalence too often. FDA and EM models are frequently indistinguishable and often provide the best performance. The RIS model concludes equivalence too often when both the within- and between-subject variance components differ between formulations. The FDA analysis model is recommended.