The statistical analysis of a clinical trial when a protocol amendment changed the inclusion criteria

Sometimes, protocol amendments that change the inclusion and exclusion criteria are required in clinical trials. Then, the patient populations before and after the amendment may differ.

We propose to perform separate statistical tests for the different phases, i.e. for the patients recruited before and after the amendment, and to combine the tests using Fisher's combination test. After a significant combination test a multiple testing procedure can be applied to identify the phase(s) to which a proof of efficacy refers. We assume that the amendment(s) are not based on any type of unblinded data. The proposed method is investigated within a simulation study.

The proposed combination approach is superior to the 'naïve' strategy to ignore the differences between the phases and pooling the data to perform just one statistical test. This superiority disappears when there are hardly any differences between the two phases.

When one or more protocol amendments change the inclusion and exclusion criteria, one should realize that the populations may differ. In this case, separate tests for the different phases together with a combination test are a powerful method that can be applied in a variety of settings. The (first) amendment should specify the combination test to be applied in order to combine the different phases.