Recent Statistical Developments in Bioequivalence Trials — A Review of the FDA Guidance*

Abstract

This paper provides an overview of recent statistical developments in bioavailability and bioequivalence studies, including background, the fundamental bioequivalence concept, decision rules, and statistical methods for assessment of bioequivalence. Statistical issues addressed in the 1986 bioequivalence hearing and in the “Guidance on Statistical Procedures for Bioequivalence Studies” issued by the Division of Bioequivalence of the Office of Generic Drugs of the United States Food and Drug Administration (FDA) are discussed. These issues consist of the comparison of pharmacokinetic versus statistical models in determination of a proper scale for analyses and the impact of a significant sequence effect and outlying data on the evaluation of bioequivalence. Other issues such as the concept of population and individual bioequivalence and their relationship, the application of a repeated crossover design to bioequivalence assessment, alternative bioequivalence measures, and statistical procedures of assessing bioequivalence with more than two formulations are also addressed.