A comparison between the assessments of progression-free survival by local investigators versus blinded independent cent
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CLINICAL TRIAL
A comparison between the assessments of progression-free survival by local investigators versus blinded independent central reviews in phase III oncology trials Cinzia Dello Russo 1,2 & Natalia Cappoli 1 & Pierluigi Navarra 1,2 Received: 26 November 2019 / Accepted: 8 May 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose In this study, we compared the assessments of progression-free survival (PFS) carried out by the local investigator or by a blinded independent central review in the framework of phase III registration randomized controlled trials (RCT) in oncology. Methods We carried out a search in the clinicatrials.gov database, looking at the RCTs reporting the results of both independently assessed and investigator-assessed PFS. The hazard ratios (HRs) of investigator-assessed PFS and independently assessed PFS were recorded, and a discrepancy index was obtained by calculating the ratio of their respective HRs. Moreover, we investigated possible factors of discrepancy by analyzing the trials in different groups (by year, by tumor type, by drug type, by study design). Results We analyzed 28 RCTs meeting the search criteria. The estimated mean discrepancy index was 0.98 (confidence interval 0.927–1.032 (n = 32)). Subgroup analysis showed that the confidence intervals in all cases included the value 1, except in the subgroup of studies started in the period 2003–2006. Conclusion In phase III oncology trials, we found no significant differences between the hazard ratios estimated by local investigators and those estimated by blinded independent central reviews. A relatively higher variability, in terms of large CI, was found in trials with biological agents. Keywords Randomized controlled trial . Progression-free survival . Local evaluation . Blinded independent central review . Oncology
Introduction Blinding of assigned treatments is a golden rule of clinical trials, which is set to minimize the risks of expectation bias [1, 2]. Blinding of the assigned intervention is seldom possible in oncology trials, since dosing, routes of administration, and side effects make it difficult to mask treatments; blinding and masking became even more challenging with the advent of clinical trials comparing standard chemotherapy regimens with target therapies involving monoclonal antibodies (mABs) and other biotechnological agents, or small molecules * Pierluigi Navarra [email protected] 1
Institute of Pharmacology, Catholic University Medical School, Largo F. Vito 1, 00168 Rome, Italy
2
Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
given orally. Because of such difficulties, most oncology trials normally adopt an open-label design. To counterbalance this methodological drawback, blinding can be applied in the setting of disease assessment. While overall survival (OS) is assessed objectively insofar as the timing of the event is known, blinding is important in the assessment of progression-free survival (PFS), in order to minimize subjectivity;
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