Objective Unbiased assessment of tumour response is crucial in randomised controlled trials (RCTs). Blinded independent central review is usually used as a supplemental or monitor to local assessment but is costly. The aim of this study is to investigate whether systematic bias existed in RCTs by comparing the treatment effects of efficacy endpoints between central and local assessments.
Design Literature review, pooling analysis and correlation analysis.
Data sources PubMed, from 1 January 2010 to 30 June 2017.
Eligibility criteria for selecting studies Eligible articles are phase III RCTs comparing anticancer agents for advanced solid tumours. Additionally, the articles should report objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) or time to progression (TTP); the treatment effect of these endpoints, OR or HR, should be based on central and local assessments.
Results Of 76 included trials involving 45 688 patients, 17 (22%) trials reported their endpoints with statistically inconsistent inferences (p value lower/higher than the probability of type I error) between central and local assessments; among them, 9 (53%) trials had statistically significant inference based on central assessment. Pooling analysis presented no systematic bias when comparing treatment effects of both assessments (ORR: OR=1.02 (95% CI 0.97 to 1.07), p=0.42, I2=0%; DCR: OR=0.97 (95% CI 0.92 to 1.03), p=0.32, I2=0%); PFS: HR=1.01 (95% CI 0.99 to 1.02), p=0.32, I2=0%; TTP: HR=1.04 (95% CI 0.95 to 1.14), p=0.37, I2=0%), regardless of funding source, mask, region, tumour type, study design, number of enrolled patients, response assessment criteria, primary endpoint and trials with statistically consistent/inconsistent inferences. Correlation analysis also presented no sign of systematic bias between central and local assessments (ORR, DCR, PFS: r>0.90, p<0.01; TTP: r=0.90, p=0.29).
Conclusions No systematic bias could be found between local and central assessments in phase III RCTs on solid tumours. However, statistically inconsistent inferences could be made in many trials between both assessments.
- blind independent central review
- local assessment
- oncological randomized control trials
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JZ, YZ and ST contributed equally.
Contributors JRZ, WHL and JXH conceived and designed the study. JRZ conducted article researching and selection, and quality assessment. JRZ, YYZ and SYT took the lead for data extraction, which was checked by YQC, HRL, DFC, YH, XYW, KXD, SHJ, JQZ, JXX and XZC. JRZ, YYZ, SYT, LJ, QHH, LTH, JXH, ZHX and JYW analysed and interpreted the data. JRZ drafted the manuscript, which was critically revised for important intellectual content by all authors. WHL and JXH supervised the study. All authors, including JRZ, YYZ, SYT, LJ, QHH, LTH, JXH, ZHX, JYW, YQC, HRL, DFC, YH, XYW, KXD, SHJ, JQZ, JXX, XZC, WHL and JXH, have read and approved the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Requests for additional details regarding the study protocol may be made by contacting the author JRZ (firstname.lastname@example.org).
Presented at Some data of this research have been presented at ESMO 2016 Annual Meeting.
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