Abstract
BackgroundSometimes, 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.MethodsWe 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.ResultsThe 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.ConclusionWhen 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.
Highlights
Sometimes, protocol amendments that change the inclusion and exclusion criteria are required in clinical trials
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
When one or more protocol amendments change the inclusion and exclusion criteria, one should realize that the populations may differ
Summary
Protocol amendments that change the inclusion and exclusion criteria are required in clinical trials. Protocol amendments are often necessary in clinical trials. Sometimes a change in the inclusion and/or exclusion criteria is required. There are various reasons for a change of the inclusion and exclusion criteria, some of them are mentioned in the ICH E9 guideline [1] and by Cleophas et al [2]. Newly emerging medical knowledge can be one reason especially for long-term trials, on the other hand, regular violations of entry criteria and too low recruitment rates could make changes necessary. Changes of the inclusion/exclusion criteria have to be described in a protocol amendment. According to Cleophas et al [2], the "amendment should cover any statistical consequences ... According to Cleophas et al [2], the "amendment should cover any statistical consequences ... and alterations to the planned statistical analysis"
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