Bioequivalence Study Design, Regulatory Requirements and Challenges for Generic Drug Approval: A Global Perspective

Abstract

Bioequivalence studies provide the scientific and regulatory basis for approval of generic drug products all over the world as they allow proof of therapeutic equivalence to the innovator reference product, thereby avoiding the need for complete clinical efficacy testing. The present review covers comprehensively the various principles for the design of BE studies, including the pharmacokinetic parameters, BCS classification, the crossover and parallel design, the fasting-state and fed-state, the statistical methodology, as well as subject selection criteria. Comparative assessment of the regulatory requirements of the major regulators USFDA, EMA, WHO, CDSCO, Health Canada and PMDA indicates that there are many similarities in the fundamental concepts, and differences in the expectations for highly variable drugs, narrow therapeutic index drugs, biowaiver eligibility and bioanalytical method validation. There is a critical discussion on special considerations for complex drug categories, modified-release formulations, endogenous compounds and ethnically diverse populations. The ICH M10 guideline has provided an appreciable harmonization to the bioanalytical method validation requirements and the ICH M13A project has great potential for more harmonization of BE study requirements worldwide. New technologies such as physiologically-based pharmacokinetic (PBPK) modeling, in vitro-in vivo correlation, adaptive study designs, and artificial intelligence-based prediction models are explored for their potential to improve generic drug development and alleviate clinical study burden. Today, the need for international cooperation and science-based regulatory development is highlighted by persistent challenges such as regulatory heterogeneity, resource limitations in developing countries and the complexity of highly variable and locally acting drug products.

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