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.

作为生物类似药审批流程的必要环节，需证实参比制剂（reference product）与生物类似药（biosimilar product）之间的分析相似性。现有研究显示，基于文献提出、美国食品药品监督管理局（FDA）推荐用于一级（Tier 1）质量属性的均值差法双单侧检验（two one-sided test, TOST），其I类错误率（Type I error rate）超出预设阈值，且无法通过增加样本量进行校正。本文提出一种基于效应量（effect size）的替代型双单侧检验，经证实可维持预设的I类错误率，且在部分场景下较基于均值差的双单侧检验拥有更高的检验效能。本文通过解析推导与计算机模拟两种方式验证了上述结果，文中还附带了带完整计算过程的实例。本文的补充材料可在线获取。