Statistical Methods for Integrating Randomized Clinical Studies for Evaluation of Combination Treatment Therapy

Abstract

In regulatory applications, evaluation of a combination drug at a fixed dose is based on pairwise comparisons of the combination with its component drugs. These comparisons generate the least expected gain of the combination relative to its components as the key effect parameter for evaluation. Two test methods are developed for the evaluation to combine multiple clinical studies that are deemed combinable. One test method is based on a linear combination of the Min tests from individual studies. In the other test method, weighted estimators are first derived for the pairwise comparisons between the combination and the respective components by combining the studies. A Min test is then applied to these estimators. The latter test method tends to be more powerful than the former test method. A test-based confidence interval is constructed for the least expected gain of the combination relative to its components. A test for heterogeneity across studies is also developed.