生物等效性与治疗等效性的现代思考

A contemporary view of bioequivalence and therapeutic equivalence

Bioequivalence studies play an important role in the drug development as well as during the post-approval period for both new drugs and generic drugs. In principle, the goals of these studies are two-fold: (1) serve as bridging studies to provide supportive evidence for safety and efficacy of a drug product; and (2) ensure product quality and performance throughout the life time of a drug product in the presence of changes in formulation or manufacturing. Additionally, in the context of generic drugs, the current U.S. regulation dictates that evidence of bioequivalence and pharmaceutical equivalence provides the assurance of therapeutic equivalence, hence interchangeability. The conventional wisdom for bioequivalence studies indicates that the testing is best performed using the most accurate, sensitive, and reproducible approach available for the drug under examination. Accordingly, to date, comparative pharmacokinetic studies have been used in most cases for bioequivalence determination. In vitro tests are seldom utilized while pharmacodynamic studies and clinical trials are employed for locally acting drug products or when drug levels cannot be measured in the blood. This trend, however, is changing with the recent advances in pharmaceutical science and technology. For example, the introduction of the Biopharmaceutics Classification System (BCS) has provided a valuable tool for predicting drug absorption and bioavailability. The rapidly growing knowledge of pharmacogenetics/genomics combined with formulation science may facilitate a better understanding of the potential interplay between pharmaceutical characteristics and biological system in humans. In the future, an enhanced prediction and assessment of bioequivalence may be achieved through the rational design of formulations and use of in vitro, in situ or in silico test methods. Implicit in the inclusion of pharmaceutical equivalence as part of the definition of therapeutic equivalence has been the regulatory objective of achieving ’sameness’ to the greatest extent possible between a generic and innovator product, thereby avoiding unnecessary in vivo human testing. Perceivably, the better the drug substance and product are characterized, the more accurate and precise the determination of pharmaceutical equivalence will be. An increased assurance of pharmaceutical equivalence based on state-of-the-art science and technology may lessen the uncertainty of ’sameness’ in the clinical responses and reduce the burden for requiring in vivo evidence of bioequivalence. Over the last three decades, scientists have worked diligently to develop guidance and recommendations on how to demonstrate bioequivalence and pharmaceutical equivalence (hence therapeutic equivalence). Approaches to establishing any type of equivalence depend on the scientific knowledge and tools available at the time of evaluation. Continuing efforts and research are encouraged to improve the current approaches, and ensure product quality and performance over time for both new and generic drug products.

Bioequivalence studies play an important role in the drug development as well as during the post-approval period for both new drugs and generic drugs. In principle, the goals of these studies are two-fold： （ 1 ） serve as bridging studies to provide supportive evidence for safety and efficacy of a drug product; and （2） ensure product quality and performance throughout the life time of a drug product in the presence of changes in formulation or manufacturing. Additionally, in the context of generic drugs, the current U.S. regulation dictates that evidence of bioequivalence and pharmaceutical equivalence provides the assurance of therapeutic equivalence, hence interehangeability. The conventional wisdom for bioequivalence studies indicates that the testing is best performed using the most accurate, sensitive, and reproducible approach available for the drug under examination. Accordingly, to date, comparative pharmacokinetic studies have been used in most cases for bioequivalence determination. In vitro tests are seldom utilized while pharmacodynamic studies and clinical trials are employed for locally acting drug products or when drug levels cannot be measured in the blood. This trend, however, is changing with the recent advances in pharmaceutical science and technology. For example, the introduction of the Biopharmaceutics Classification System （BCS） has provided a valuable tool for predicting drug absorption and bioavailability. The rapidly growing knowledge of pharmacogenetics/genomics combined with formulation science may facilitate a better understanding of the potential interplay between pharmaceutical characteristics and biological system in humans. In the future,