Statistical Considerations in Demonstrating CMC Analytical Similarity for a Biosimilar Product

Demonstration of analytical similarity between a reference product and a biosimilar product is required as part of the biosimilarity approval process. A statistical two one-sided test (TOST) based on the difference of means proposed in the literature and recommended by the FDA for Tier 1 quality attributes is demonstrated to have a Type I error rate greater than the specified level, which cannot be corrected by increasing sample size. In this article, an alternative TOST based on the effect size is demonstrated to maintain the desired Type I error rate, and in some situations, provide greater power than the TOST based on the mean difference. Results are demonstrated both analytically and with computer simulations. An example with calculations is provided in the article. Supplementary materials for this article are avalilable online.

生物类似药审批流程中，需验证参比制剂与生物类似药之间的分析相似性（analytical similarity）。基于文献提出、且被FDA推荐用于一级质量属性分析的统计双单侧检验（two one-sided test, TOST），其一类错误率（Type I error rate）高于预设水准，且无法通过增大样本量予以校正。本文提出一种基于效应量（effect size）的替代型双单侧检验，该方法可维持预设的一类错误率，在部分场景下其检验效能高于基于均值差的双单侧检验。上述结论通过解析推导与计算机模拟两种方式得以验证，文中亦附有带详细计算过程的实例。本文的补充材料可在线获取。