{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T20:09:23Z","timestamp":1789416563238,"version":"build-2803163510"},"reference-count":28,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T00:00:00Z","timestamp":1692144000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014475","name":"Pfizer Health Research Foundation","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100014475","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Kyoto University School of Public Health","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ EBM"],"accepted":{"date-parts":[[2023,6,4]]},"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Meta-epidemiological study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Data sources<\/jats:title><jats:p>MEDLINE via PubMed from 1 January 2010 to 30 June 2021.<\/jats:p><\/jats:sec><jats:sec><jats:title>Eligibility criteria for selecting studies<\/jats:title><jats:p>Open-label, parallel-group superiority, randomised trials of anticancer drugs that adjudicated PFS or ORR by both central reviewers and local investigators.<\/jats:p><\/jats:sec><jats:sec><jats:title>Review methods<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial registration number<\/jats:title><jats:p>CTR-UMIN000044623.<\/jats:p><\/jats:sec>","DOI":"10.1136\/bmjebm-2023-112332","type":"journal-article","created":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T17:36:37Z","timestamp":1692207397000},"page":"372-382","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Detection bias in open-label trials of anticancer drugs: a meta-epidemiological study"],"prefix":"10.1136","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8925-2348","authenticated-orcid":false,"given":"Satoshi","family":"Funada","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5271-5126","authenticated-orcid":false,"given":"Yan","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7982-5213","authenticated-orcid":false,"given":"Yuki","family":"Kataoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Yoshioka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Fujita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinya","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morihiro","family":"Katsura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Tada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norihiro","family":"Nishioka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiaki","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Ueno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuji","family":"Uozumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2159-3776","authenticated-orcid":false,"given":"Toshi A","family":"Furukawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,8,16]]},"reference":[{"key":"2024061407150972000_28.6.372.1","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.d5928","article-title":"The Cochrane collaboration's tool for assessing risk of bias in randomised trials","volume":"343","author":"Higgins","year":"2011","journal-title":"BMJ"},{"key":"2024061407150972000_28.6.372.2","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.e1119","article-title":"Observer bias in randomised clinical trials with binary outcomes: systematic review of trials with both blinded and non-blinded outcome assessors","volume":"344","author":"Hr\u00f3bjartsson","year":"2012","journal-title":"BMJ"},{"key":"2024061407150972000_28.6.372.3","doi-asserted-by":"publisher","DOI":"10.1503\/cmaj.120744"},{"key":"2024061407150972000_28.6.372.4","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyt270"},{"key":"2024061407150972000_28.6.372.5","article-title":"Comparison of central adjudication of outcomes and onsite outcome assessment on treatment effect estimates","volume":"3","author":"Ndounga Diakou","year":"2016","journal-title":"Cochrane Database Syst Rev"},{"key":"2024061407150972000_28.6.372.6","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.l6802","article-title":"Impact of blinding on estimated treatment effects in randomised clinical trials: meta-epidemiological study","volume":"368","author":"Moustgaard","year":"2020","journal-title":"BMJ"},{"key":"2024061407150972000_28.6.372.7","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1001\/jamainternmed.2013.627","article-title":"Characteristics of oncology clinical trials: insights from a systematic analysis of Clinicaltrials.Gov","volume":"173","author":"Hirsch","year":"2013","journal-title":"JAMA Intern Med"},{"key":"2024061407150972000_28.6.372.8","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1001\/jamainternmed.2020.1097","article-title":"FDA acceptance of surrogate end points for cancer drug approval: 1992-2019","volume":"180","author":"Chen","year":"2020","journal-title":"JAMA Intern Med"},{"key":"2024061407150972000_28.6.372.9","unstructured":"U.S. Food and Drug Administration . Clinical trial endpoints for the approval of cancer drugs and Biologics. 2018. Available: https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/clinical-trial-endpoints-approval-cancer-drugs-and-biologics"},{"key":"2024061407150972000_28.6.372.10","unstructured":"European Medicines Agency . Appendix 1 to the guideline on the evaluation of anticancer medicinal products in man. Methodological consideration for using progression-free survival (PFS) or disease-free survival (DFS) in Confirmatory trials. 2012. Available: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/appendix-1-guideline-evaluation-anticancer-medicinal-products-man-methodological-consideration-using_en.pdf"},{"key":"2024061407150972000_28.6.372.11","doi-asserted-by":"crossref","DOI":"10.21037\/atm.2017.11.24","article-title":"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","volume":"5","author":"Zhang","year":"2017","journal-title":"Ann Transl Med"},{"key":"2024061407150972000_28.6.372.12","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2017-017240","article-title":"Systematic bias between blinded independent central review and local assessment: literature review and analyses of 76 phase III randomised controlled trials in 45 688 patients with advanced solid tumour","volume":"8","author":"Zhang","year":"2018","journal-title":"BMJ Open"},{"key":"2024061407150972000_28.6.372.13","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1007\/s00228-020-02895-z","article-title":"A comparison between the assessments of progression-free survival by local investigators versus blinded independent central reviews in phase III oncology trials","volume":"76","author":"Dello Russo","year":"2020","journal-title":"Eur J Clin Pharmacol"},{"key":"2024061407150972000_28.6.372.14","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1002\/jcph.1790","article-title":"Local investigators significantly overestimate overall response rates compared to blinded independent central reviews in phase 2 oncology trials","volume":"61","author":"Dello Russo","year":"2021","journal-title":"J Clin Pharmacol"},{"key":"2024061407150972000_28.6.372.15","doi-asserted-by":"crossref","unstructured":"Lian Q , Fredrickson J , Boudier K , et al . Meta-analysis of 49 Roche oncology trials comparing blinded independent central review (BICR) and local evaluation to assess the value of BICR. Oncologist 2023:oyad012. doi:10.1093\/oncolo\/oyad012","DOI":"10.1093\/oncolo\/oyad012"},{"key":"2024061407150972000_28.6.372.16","unstructured":"Funada S , Luo Y , Kataoka Y , et al . Detection bias in open-label trials of cancer drug: a meta-epidemiological study. 2021. doi:10.17605\/OSF.IO\/CSX7H"},{"key":"2024061407150972000_28.6.372.17","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.jclinepi.2022.06.020","article-title":"Inadequate reporting of adjudicators in open-label trials of anticancer drugs between 2017 and 2021: a methodological review","volume":"150","author":"Funada","year":"2022","journal-title":"J Clin Epidemiol"},{"key":"2024061407150972000_28.6.372.18","doi-asserted-by":"crossref","DOI":"10.1186\/s13643-021-01626-4","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews","volume":"10","author":"Page","year":"2021","journal-title":"Syst Rev"},{"key":"2024061407150972000_28.6.372.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2019.10.011"},{"key":"2024061407150972000_28.6.372.20","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/92.3.205"},{"key":"2024061407150972000_28.6.372.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026"},{"key":"2024061407150972000_28.6.372.22","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19810101)47:1<207::AID-CNCR2820470134>3.0.CO;2-6"},{"key":"2024061407150972000_28.6.372.23","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.d2090","article-title":"How to obtain the confidence interval from a P value","volume":"343","author":"Altman","year":"2011","journal-title":"BMJ"},{"key":"2024061407150972000_28.6.372.24","doi-asserted-by":"publisher","DOI":"10.1002\/sim.1184"},{"key":"2024061407150972000_28.6.372.25","unstructured":"Viechtbauer W . 'Package Metafor' 2022. Available: https:\/\/www.metafor-project.org\/doku.php\/metafor"},{"key":"2024061407150972000_28.6.372.26","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdp478"},{"key":"2024061407150972000_28.6.372.27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/2168479013499572","article-title":"Local evaluation and blinded central review comparison: a victim of meta-analysis shortcomings","volume":"47","author":"Raunig","year":"2013","journal-title":"Ther Innov Regul Sci"},{"key":"2024061407150972000_28.6.372.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2011.02.013"}],"container-title":["BMJ Evidence-Based Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjebm-2023-112332","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T14:17:53Z","timestamp":1718374673000},"score":1,"resource":{"primary":{"URL":"https:\/\/ebm.bmj.com\/lookup\/doi\/10.1136\/bmjebm-2023-112332"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,16]]},"references-count":28,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,11,22]]},"published-print":{"date-parts":[[2023,12]]}},"alternative-id":["10.1136\/bmjebm-2023-112332"],"URL":"https:\/\/doi.org\/10.1136\/bmjebm-2023-112332","relation":{},"ISSN":["2515-446X","2515-4478"],"issn-type":[{"value":"2515-446X","type":"print"},{"value":"2515-4478","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,16]]}}}