生物类似药证据链完备性的合成P值法评估

最近几年,许多生物制药/生物技术公司对研发生物类似药物的兴趣越来越强。根据生物类似药物的研发需求,美国药监局(FDA)在2012年颁布了3个相关指导原则草案。FDA在这3个指导原则中表示,对于生物类似药物的注册申请的全部提交资料采用"证据链完备性(totality-of-the-evidence)"的方法来审查,并鼓励研发企业使用"逐步递进法stepwise"来找出与原研产品相比,仿制生物制品在每一工艺步骤中的残余不确定度,进而在后续的研发步骤中设法解决这些残余不确定度。尽管要获得"具有较小不确定度的充足证据链完备性"这样的概念可以理解,但是,如何根据提交的所有注册申请信息客观地评价"证据链完备性",以及如何基于已有信息确定下一步研发步骤的程度和范围仍然是需解决的具体操作问题。本研究探索了费舍尔合成P值的概念(Fisher,1932)在等效性检验设置中的应用,更具体地说,在一个生物类似药物的临床研究中,根据"逐步递进法"和"临床证据完备性"的概念,用它来设计和分析2个生物类似药物的临床相似性。

In the past few years, there have been increased interests in developing biosimilars by many biopharmaceutical and/or biotech companies.The FDA published three draft guidance documents in 2012 on the requirements for the development of biosimilars.Throughout these guidance documents, the FDA indicated that it would apply a "totality-of-the-evidence" approach in reviewing all of the information submitted for a biosimilar approval and encouraged sponsors to use a "stepwise" approach to identify the extent of remaining uncertainty at each step of the comparison, and use subsequent development steps to address that residual uncertainty.Although the concept of achieving strong evidence in totality with minimal uncertainty is clearly understandable, questions remain operationally on how to evaluate "totality-of-the-evidence" objectively based on all of the information submitted for approval, and how to determine the extent and scope of the next-step development based on the already available information.In this paper, we explore the application of the Fisher's combination of p-values concept in the equivalence testing setting, more specifically, using it to design and analyze two clinical similarity studies for a biosimilar clinical development program under the "stepwise" and the "totality-of-the-clinical-evidence" concepts.

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