Boddy A W, Snikeris F C, Kringle R O, Wei G C, Oppermann J A, Midha K K
Biostatistics Dept., Sanofi Research Division, Malvern, Pennsylvania 19355, USA.
Pharm Res. 1995 Dec;12(12):1865-8. doi: 10.1023/a:1016219317744.
Highly variable drugs pose a problem in bioequivalence assessment because they often fail to meet current regulatory acceptance criteria for average bioequivalence (80-125%). This paper examines alternative approaches to establishing bioequivalence.
Suggested solutions have included alternate study designs, e.g., replicate and multiple dose studies, reducing the level of the confidence interval, and widening the acceptance limits. We focus on the latter approach.
A rationale is presented for defining wider acceptance limits for highly variable drugs. Two previously described methods are evaluated, and a new method having more desirable properties is proposed.
We challenge the "one size fits all" current definition of bioequivalence acceptance limits for highly variable drugs, proposing alternative limits or "goal posts" which vary in accordance with the intrasubject variability of the reference product.
高变异性药物在生物等效性评估中存在问题，因为它们常常无法满足当前关于平均生物等效性（80%-125%）的监管接受标准。本文探讨了建立生物等效性的替代方法。
建议的解决方案包括替代研究设计，例如重复和多剂量研究、降低置信区间水平以及放宽接受限度。我们重点关注后一种方法。
提出了为高变异性药物定义更宽接受限度的基本原理。对两种先前描述的方法进行了评估，并提出了一种具有更理想特性的新方法。
我们对当前高变异性药物生物等效性接受限度“一刀切”的定义提出质疑，建议根据参比制剂的个体内变异性制定不同的接受限度或“目标范围”。
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