Endpoints confirmatory trials

Treatment effects on surrogate endpoints therefore do not necessarily translate into treatment effects on clinical endpoints and the validity of the surrogate depends not only on the variable itself but also on the disease area and the mode of action of the treatment. Establishing new valid surrogates is very difficult. Fleming and DeMets conclude that surrogates are extremely valuable in phase II proof of concept studies but they question their general use in phase III confirmatory trials. 

Therapeutic exploratory (Phase lb/II) Explore use for the targeted indication Estimate dosage for subsequent studies Provide basis for confirmatory study design, endpoints, methodologies Earliest trials of relatively short duration in well-defined narrow patient populations, using surrogate or pharmacological endpoints or clinical measures Dose-response exploration studies... 

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 ... 

As the trial is ongoing there is also an opportunity to change some of the planned methods of analysis for example, information that a particular covariate could be important or that a different kind of effect could be seen in a certain subgroup may have become available based on external data from a similar trial that has now completed and reported. Such changes can be incorporated by modifying the SAP and if they represent major changes to the analysis, for example if they were associated with the analysis of the primary endpoint, then a protocol amendment would need to be issued. The reason for this, as mentioned earlier, is that only methods specified in the protocol can be viewed as confirmatory. 

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