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.