Purpose

In 2010 the European Medicines Agency allowed a two-stage design in bioequivalence studies. However, in the public domain there are mainly articles describing the theoretical and statistical base for the application of the two-stage design. One of the reasons seems to be the lack of practical guidance for the Sponsors on when and how the two-stage design can be beneficial in bioequivalence studies.

Methods

Different variants with positive and negative outcomes have been evaluated, including a pivotal study, pilot + pivotal study and two-stage study. The scientific perspective on the two-stage bioequivalence study has been confronted with the industrial one.

Results

Key information needed to conduct a bioequivalence study – such as in vitro data and pharmacokinetics – have been listed and organized into a decision scheme. Advantages and disadvantages of the two-stage design have been summarized.

Conclusion

The use of the two-stage design in bioequivalence studies seems to be a beneficial alternative to the 2 × 2 crossover study. Basic information on the properties of the active substance and the characteristics of the drug form are needed to make an initial decision to carry out the two-stage study.

中文翻译：

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生物等效性两阶段设计十周年。为何至今仍未实施？

目的

2010 年，欧洲药品管理局允许生物等效性研究采用两阶段设计。然而，在公共领域，主要有描述两阶段设计应用的理论和统计基础的文章。原因之一似乎是申办者缺乏关于两阶段设计何时以及如何有益于生物等效性研究的实用指导。

方法

已经评估了具有积极和消极结果的不同变体，包括关键研究、试点+关键研究和两阶段研究。两阶段生物等效性研究的科学视角与工业视角面临着挑战。

结果

进行生物等效性研究所需的关键信息（例如体外数据和药代动力学）已被列出并组织成决策方案。总结了两阶段设计的优点和缺点。

结论

在生物等效性研究中使用两阶段设计似乎是 2 × 2 交叉研究的有益替代方案。需要有关活性物质性质和药物剂型特征的基本信息来做出进行两阶段研究的初步决定。