Study protocols confirmatory trials

Safety analyses are not typically prespecified in the study protocol and/or the study analysis plan. Studies are typically powered on efficacy outcomes (the primary objective in therapeutic confirmatory trials see Chapter 9), and the sample size that results from this sample-size estimation may be considerably smaller than would be needed for a thorough investigation of safety data. 

The following are some of the fundamental components in a study protocol for a therapeutic confirmatory trial for an investigational antihypertensive drug ... 

A study protocol is often supplemented with another very important document called the statistical analysis plan (sometimes referred to by similar names such as a data analysis plan or reporting analysis plan). The statistical analysis plan often supplements a study protocol by providing a very detailed account of the analyses that will be conducted at the completion of data acquisition. The statistical analysis plan should be written in conjunction with (and at the same time as) the protocol, but in reality this does not always happen. At the very least it should be finalized before the statistical analysis and breaking of the blind. In many instances (for example, confirmatory trials) it may be helpful to submit the final statistical analysis plan to the appropriate regulatory authorities for their input. 

It is good practice to pre-specify in the protocol, or certainly in the statistical analysis plan, the statistical method to be used for analysis for each of the endpoints within the confirmatory part of the trial. This avoids the potential for bias at the analysis stage, which could arise if a method were chosen, for example, which maximised the treatment difference. As a consequence changing the method of analysis following unblinding of the study in an unplanned way, even if there seem sound statistical reasons for doing so, is problematic. Such a switch could only be supported if there was a clear algorithm contained within the statistical analysis plan which specified the rules for the switch. An example of this would be as follows ... 

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