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

Purpose: Progression 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 methods: The 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. Results: Results 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. Conclusion: The 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. (C) 2011 Elsevier Ltd. All rights reserved.