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4.4.2.
Similarity margin criterion endorsed by FDA.
The US FDA did not agree with the equivalence margins of ± 13.5% (for the difference in ACR20 response rates at Week 14) as outlined in Section 4.4.1 and instead favored using all 5 studies in the meta-analysis with 50% preservation of the 2-sided 95% lower bound of the historic effects sizes to derive a similarity margin.
FDA also recommended a 90% 2-sided CI for the difference in treatment groups in B5371002 to conclude similarity in ACR20 at Week 14.
In response to Pfizer’s proposed equivalence margins of ±13% (90% power with planned sample size of N=614 total), the Agency recommended (letter dated 08 April 2015) that the similarity margin for ACR20 response rates in the proposed CCS (comparative clinical study) in RA be set at ±12%, and that the type I error rate of a test of similarity be controlled at 1-sided 5%.
The Agency further noted that they would consider a proposal for a relaxed upper bound as part of an **asymmetric similarity margin**.