Statistics in Medicine

Half blind superiority tests for clinical trials of anti‐infective drugs

Journal Article

This paper introduces a test of superiority of new anti‐infective drug B over comparator drug A based on a randomized clinical trial. This test can be used to demonstrate assay (trial) sensitivity for noninferiority trials and rigorously tailor drug choice for individual patients. Our approach uses specialized baseline covariates XA,XB, which should predict the benefits of drug A and drug B, respectively. Using a response surface model for the treatment effect, we test for superiority at the (XA,XB) point that is most likely to show superiority. We identify this point based on estimates from a novel half‐blind pseudo likelihood, where we augment a blinded likelihood (mixed over the treatment indicator) with likelihoods for the overall success rates for drug A and drug B (mixed over XA,XB). The augmentation results in much better estimates than those based on the mixed blinded likelihood alone but, interestingly, the estimates almost behave as if they were based on fully blinded data. We also develop an analogous univariate method using XA for settings where XB has little variation. Permutation methods are used for testing. If the “half‐blind” test rejects, pointwise confidence interval can be used to identify patients who would benefit from drug B. We compare the new tests to other methods with an example and via simulations.

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