Multiplicity in Bioequivalence Trials: Multiple Formulation and Multiple Stage Designs

• Activity Number: 673
• Type: Topic Contributed
• Date/Time: Thursday, August 8, 2013 : 10:30 AM to 12:20 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Lihui Zhao and Cheng Zheng*+ and Jixian (Jason) Wang
• Companies: Novartis Oncology and Novartis Oncology and Novartis Oncology
• Keywords: Bioequivalence ; Multiplicity

Abstract

Bioequivalence (BE) trials play an important role in drug development. We proposed pragmatic methods to address two multiplicity scenarios in BE studies: multiple formulations and multiple stages. For scenario I, we propose a Multiplication-Adjusted Two One-Sided Tests (MATOST). It combines multiple comparison adjustment approaches with TOST. Power and sample size calculations are illustrated via simulation. At the same overall type I error and power, our proposed design only requires a small increase in the total sample size. MATOST R package is available. Scenario II emerges when at design stage, there is high degree of uncertainty on variability of the formulation and the actual performance of the test vs reference formulation. Therefore an interim look is desirable to stop the study if there is no chance of claiming BE at the end (futility), or claim BE if evidence is sufficient (efficacy), or adjust the sample size. We applied slight adjustments to a published method by implementing a futility stopping and using a transparent multiplicity control method. Simulation is used to demonstrate the performance of this approach vs the original published method.