Introduction
Pavlakis, toxicity, PPU, gastro-oesophageal cancer, rash
Clinical trials require accurate endpoint assessment to yield valid and reliable estimates of treatment effects. This is particularly important in phase 2 trials with smaller numbers of participants, where variability in measurement and assessment has greater potential to affect trial outcomes. Accurate evaluation of treatment activity in phase 2 trials helps ensure decisions about moving to phase 3 evaluation are well informed (Dancey et al. Overall survival (OS) is a gold standard for evaluating efficacy in phase 3 trials (Driscoll and Rixe The reliability of PFS as an endpoint is affected by the criteria used to assess it as well as aspects of trial design (Dancey et al. Non-differential error is measurement error that is equally likely regardless of which treatment group participants have been allocated to. An example of this is differences between blinded central reviewers in applying RECIST that affects the observed date of progression. Non-differential error has little impact if the treatment effect is large (Korn et al. Controversy exists about the required extent of blinded independent central review (BICR) of PFS. Given the time and expense required, the utility of reviewing 100% of cases has been questioned (Bergmann et al. AGITG INTEGRATE was a randomised, double-blind, phase 2 trial evaluating the addition of regorafenib, a tyrosine kinase inhibitor of multiple angiogenic pathways, or placebo, to best supportive care in advanced gastro-oesophageal cancer (Pavlakis et al. Due to concerns that treatment allocation could be discernible in at least a proportion of participants as a result of the known toxicity profile of regorafenib (e.g. rash), and because unblinding of treatment allocation after documented progression (post-progression unblinding, PPU) was permitted in participants who were fit to receive open-label regorafenib subsequently, BICR of progression was planned a priori and conducted before analysing the trial outcome data. Our main objective was to compare BICR of PFS based on CT scan reports and clinical data versus standard site assessment of PFS and to determine the impact of discordance on the trial results and conclusions. In addition, we examined the effect of BICR of CT scan images (versus site assessment of the same) in a sample of participants; the potential for any bias in assessment where unblinding of treatment allocation had occurred; and the level of disagreement required to impact on trial conclusions in a simulation study.