Article Abstract

Evaluation bias in objective response rate and disease control rate between blinded independent central review and local assessment: a study-level pooled analysis of phase III randomized control trials in the past seven years

Authors: Jianrong Zhang, Yiyin Zhang, Shiyan Tang, Hengrui Liang, Difei Chen, Long Jiang, Qihua He, Yu Huang, Xinyu Wang, Kexin Deng, Shuhan Jiang, Jiaqing Zhou, Jiaxuan Xu, Xuanzuo Chen, Wenhua Liang, Jianxing He


Background: In previous studies, complete-case implementation of blind independent central review has been considered unnecessary based on no sign of systematic bias between central and local assessments. In order to further evaluate its value, this study investigated evaluation status between both assessments in phase III trials of anti-cancer drugs for non-hematologic solid tumors.
Methods: Eligible trials were searched in PubMed with the date of Jan 1, 2010 to Jun 30, 2017. We compared objective response rate (ORR) and disease control rate (DCR) between central and local assessments by study-level pooled analysis and correlation analysis. In pooled analysis, direct comparison was measured by the odds ratio (OR) of central-assessed response status to local-assessed response status; to investigate evaluation bias between central and local assessments, the above calculated OR between experimental (exp-) and control (con-) arms were compared, measured by the ratio of OR.
Results: A total of 28 included trials involving 17,466 patients were included (28 with ORR, 16 with DCR). Pooled analysis showed central assessment reported lower ORR and DCR than local assessment, especially in trials with open-label design, central-assessed primary endpoint, and positive primary endpoint outcome, respectively. However, this finding could be found in both experimental [exp-ORR: OR=0.81 (95% CI: 0.76–0.87), P<0.01, I2=11%; exp-DCR: OR=0.90 (0.81–1.01), P=0.07, I2=42%] and control arms [con-ORR: OR=0.79 (0.72–0.85), P<0.01, I2=17%; con-DCR: OR=0.94 (0.86–1.02), P=0.14, I2=12%]. No sign of evaluation bias between two assessments was indicated through further analysis [ORR: ratio of OR=1.02 (0.97–1.07), P=0.42, I2=0%; DCR: ratio of OR=0.98 (0.93–1.03), P=0.37, I2=0%], regardless of mask (open/blind), sample size, tumor type, primary endpoint (central-assessed/local-assessed), and primary endpoint outcome (positive/negative). Correlation analysis demonstrated a high-degree concordance between central and local assessments (exp-ORR, con-ORR, exp-DCR, con-DCR: r>0.90, P<0.01).
Conclusions: Blind independent central review remained irreplaceable to monitor local assessment, but its complete-case implementation may be unnecessary.