Marzo A, Balant L P
I.P.A.S.S.A. - Institute for Pharmacokinetic and Analytical Studies, Stabio, Switzerland.
Arzneimittelforschung. 1995 Feb;45(2):109-15.
This paper reviews study procedures for bioequivalence trials, mainly addressed to the New Drug Application (NDA) of generic drugs, strictly referring to EU and USA guidelines on this matter. Specific attention is devoted to the most appropriate experimental designs, the size of the volunteer sample, the ethical issues involved, statistics to assess bioequivalence and the accepted standard format for final research reports. Some aspects which create serious problems in bioequivalence trials, most of which not fully covered by the EU and USA specific guidelines, are comprehensively discussed. These include a) drugs with elevated variability; b) endogeneous substances and the management of baseline value; c) modified release formulations; d) prodrugs; e) restrictions to be contained in forthcoming guidelines on chiral medicinal products; f) superbioavailability; g) drugs with elevated half-life and h) cases in which bioequivalence trials should not be needed. As generic drugs cost less than the innovator product, agencies have facilitated their NDA procedures by requiring a dossier on chemistry and pharmacy and a pivotal bioequivalence study to demonstrate that the generic formulation is fully interchangeable with the innovator product. Bioequivalence is thus the key requirement for an NDA of a generic drug, and trials should be planned, conducted and reported in the most appropriate way. With this in mind, this review is an up-to-date reappraisal that should stimulate the attention of scientists and regulatory authorities on some open questions on bioequivalence.
本文回顾了生物等效性试验的研究程序，主要针对仿制药的新药申请（NDA），严格参照欧盟和美国在这方面的指南。特别关注了最合适的实验设计、志愿者样本量、涉及的伦理问题、评估生物等效性的统计学方法以及最终研究报告的认可标准格式。对生物等效性试验中存在严重问题的一些方面进行了全面讨论，其中大多数未被欧盟和美国的具体指南充分涵盖。这些方面包括：a）变异性高的药物；b）内源性物质及基线值的处理；c）缓释制剂；d）前体药物；e）即将出台的手性药品指南中应包含的限制；f）超生物利用度；g）半衰期长的药物；h）无需进行生物等效性试验的情况。由于仿制药的成本低于创新产品，监管机构通过要求提供化学和药学资料以及一项关键的生物等效性研究，以证明仿制药制剂可与创新产品完全互换，从而简化了新药申请程序。因此，生物等效性是仿制药新药申请的关键要求，试验应以最合适的方式进行规划、实施和报告。考虑到这一点，本综述是一次最新的重新评估，应能引起科学家和监管机构对生物等效性一些未决问题的关注。
