Improved Wald Test for Equivalence Assessment of Analytical Biosimilarity

The equivalence test in analytical similarity assessment uses a margin of 1.5 times of the standard deviation of a reference product. In the current practice, the standard deviation, estimated from study data, is considered as a fixed constantin the margin. The impact of such a practice leads to the inflation of type I error rate and the reduction of power as previous studies showed. In order to accommodate the fact that the margin is a parameter and improve the efficiency when the numbers of lots for both products are small. Chen, et al. proposed to use Wald test with Constrained Maximum Likelihood Estimate (CMLE) of the standard error, resulting in the type I error rate is below the nominal value. In this paper, we further improve the Wald test with CMLE standard error by replacing the maximum likelihood estimate of reference standard deviation in the margin with the sample estimate.