Blinded independent central review of progression in cancer clinical trials: Results from a meta-analysis

Abstract

PurposeProgression free survival (PFS) is increasingly used as a primary end-point in oncology clinical trials. This paper provides observations and recommendations on the use of a blinded independent central review (BICR) for progression. Patients and methodsThe findings and recommendations are based on extensive simulations and a meta-analysis based on 27 previously conducted randomised phase III trials with BICR performed by the Pharmaceutical Research and Manufacturers Association (PhRMA) sponsored PFS Independent Review Working Group. ResultsResults of the meta-analysis demonstrate a strong correlation between LE and BICR estimates of treatment effect (R=0.947). Further, differences between treatment groups in discordance rates predict the differences between LE and BICR estimates of treatment effect supporting the use of a sample-based BICR on a subgroup of patients. ConclusionThe meta-analysis demonstrates that local evaluation (LE) provides a reliable estimate of the treatment effect with little evidence for systematic evaluation bias. Therefore, when a trial is blinded or a large effect on PFS is observed a BICR may not be warranted. When a BICR is warranted, a sample-based BICR may provide a reduction in operational complexity without compromising the credibility of trial results. While for large trials that are not adequately blinded a sample-based BICR may be recommended. A full BICR should be considered in the case of smaller trials or in situations in which there is a particular need to increase the confidence in the LE results.