Central review
death, PPU, organ dysfunction
Two separate processes were specified for BICR of PFS in INTEGRATE (Pavlakis et al. The second review process used independent radiologists blinded to treatment allocation to evaluate PFS in de-identified CT scans from a sample of participants. The first participant at each of 18 sites was identified at randomisation, and sites notified of the need to provide images for the complete set of scans at each time-point (baseline to progression or death without progression). Independent radiologists reported the scans in a two-step process. First, the radiologist reported on each set of scans without knowledge of the target/non-target lesions. Second, the same radiologist verified the accuracy of the measurements and application of RECIST v1.1 to the site-selected lesions. Where discrepancy between site and central review occurred, a second radiologist provided an independent review without knowledge of the conclusions of the first. For both processes, the reasons for disagreement were recorded.A separate review process evaluated whether confirmation of RECIST progression occurred prior to PPU in these participants. Of the 152 participants, 86 (56%) were unblinded according to PPU processes, with 58% of those allocated to placebo subsequently receiving regorafenib. A second review team comprising the clinical leads not included in the study chairs’ review reviewed case records for all 86 participants after PPU. The results of each of the review components were not available to other review teams to prevent bias. The PPU date was compared to the date of radiologically confirmed progression to establish whether progression occurred prior to unblinding. The centrally confirmed date of progression was used where site and central investigators differed. Only the protocol criteria for RECIST v1.1 progression were reviewed centrally; there was no central review of other protocol criteria (e.g. performance status and organ dysfunction).