Detection bias in open-label trials of anticancer drugs: a meta-epidemiological study.

Objectives: In anticancer clinical trials, particularly open-label trials, central reviewers are recommended to evaluate progression-free survival (PFS) and objective response rate (ORR) to avoid detection bias of local investigators. However, it is not clear whether the bias has been adequately identified, or to what extent it consistently distorts the results. Therefore, the objective of this study was to evaluate the detection bias in oncological open-label trials by confirming whether local investigators overestimate the PFS and ORR compared with the findings of central reviewers.
Design: Meta-epidemiological study.
Data Sources: MEDLINE via PubMed from 1 January 2010 to 30 June 2021.
Eligibility Criteria for Selecting Studies: Open-label, parallel-group superiority, randomised trials of anticancer drugs that adjudicated PFS or ORR by both central reviewers and local investigators.
Review Methods: We assessed the values for the same outcome (PFS and ORR) adjudicated by both central reviewers and local investigators. A random-effects model was used to estimate the ratio of HR (RHR) for PFS and the ratio of OR (ROR) for ORR between central reviewers and local investigators. An RHR lower than 1 and an ROR higher than 1 indicated an overestimation of the effect estimated by local investigators.
Results: We retrieved 1197 records of oncological open-label trials after full-text screening. We identified 171 records (PFS: 149 records, ORR: 136 records) in which both central reviewers and local investigators were used, and included 114 records (PFS: 92 records, ORR: 74 records) for meta-analyses. While the RHR for PFS was 0.95 (95% CI 0.91 to 0.98), the ROR of ORR was 1.00 (95% CI 0.91 to 1.09). The results remained unchanged in the prespecified sensitivity analysis.
Conclusions: This meta-epidemiological study found that overestimation of local investigators has a small impact on evaluating PFS and ORR in oncological open-label trials. However, a limitation of this study is that it did not include data from all trials; hence, the results may not fully evaluate detection bias. The necessity of central reviewers in oncological open-label trials needs to be assessed by further studies that overcome this limitation.
Trial Registration Number: CTR-UMIN000044623.
Competing Interests: Competing interests: SF received a research grant from Japan Society for the Promotion of Science KAKENHI (grant number JP 20K18964) and the Pfizer Health Research Foundation. YL received a Grant-in-Aid for JSPS Fellows (grant number 21J15050) for research. YK received a research grant from the Systematic Review Workshop Peer Support Group, the Japan Osteoporosis Foundation, and the Yasuda Memorial Medical Foundation for other research purposes. TY received a research grant from JSPS KAKENHI (grant number JP 21K17228) and the National Cancer Center Research Grant (grant number 2022-A-25) outside this work. NN was supported by a grant-in-aid for multicentre clinical research from Japanese Association for Acute Medicine. YN reported research funding from Taiho Pharmaceutical, Chugai Pharmaceutical, Guardant Health, Genomedia, Daiichi Sankyo and Seagen. KU reported personal fees from Sumitomo Pharma for other than the submitted work. RU reported personal fees from Eisai, Sawai Pharmaceutical and EPS Corporation for other than the submitted work, and a research grant from JSPS KAKENHI (grant number JP 20H04147 and 21KK0205). TAF reported grants and personal fees from Mitsubishi-Tanabe, personal fees from MSD, grants and personal fees from Shionogi, outside the submitted work; TAF has a patent pending (2020-548587) concerning a smartphone CBT app, and intellectual properties for Kokoro-app licensed to Mitsubishi-Tanabe.
(© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)