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 paper, 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 paper.

在生物类似药的获批审评流程中，需证明参比制剂与生物类似药之间的分析相似性。现有研究提出、且美国食品药品监督管理局（FDA）针对一级质量属性（Tier 1 quality attributes）推荐的基于均值差的双单侧检验（statistical two one-sided test, TOST），其I类错误率高于预设水准，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的替代双单侧检验方案，证明该方案可维持预设的I类错误率，且在部分场景下较基于均值差的双单侧检验具备更高的检验效能。上述结论通过解析推导与计算机模拟两种方式均得到验证，本文亦附带有完整计算示例。