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
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 co...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2018-09-01
|
| Series: | BMJ Open |
| Online Access: | https://bmjopen.bmj.com/content/8/9/e017240.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823857157775294464 |
|---|---|
| author | Jianrong Zhang Yu Huang Hengrui Liang Wenhua Liang Jianxing He Yiyin Zhang Jiaxi He Jieyu Wu Long Jiang Shiyan Tang Qihua He Lindsey Tristine Hamblin Zhiheng Xu Yaoqi Chen Difei Chen Xinyu Wang Kexin Deng Shuhan Jiang Jiaqing Zhou Jiaxuan Xu Xuanzuo Chen |
| author_facet | Jianrong Zhang Yu Huang Hengrui Liang Wenhua Liang Jianxing He Yiyin Zhang Jiaxi He Jieyu Wu Long Jiang Shiyan Tang Qihua He Lindsey Tristine Hamblin Zhiheng Xu Yaoqi Chen Difei Chen Xinyu Wang Kexin Deng Shuhan Jiang Jiaqing Zhou Jiaxuan Xu Xuanzuo Chen |
| author_sort | Jianrong Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-bc9059ce424e44ec8bcef551fe1cbd62 |
| institution | Kabale University |
| issn | 2044-6055 |
| language | English |
| publishDate | 2018-09-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | BMJ Open |
| spelling | doaj-art-bc9059ce424e44ec8bcef551fe1cbd622025-02-11T23:20:15ZengBMJ Publishing GroupBMJ Open2044-60552018-09-018910.1136/bmjopen-2017-017240Systematic 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 tumourJianrong Zhang0Yu Huang1Hengrui Liang2Wenhua Liang3Jianxing He4Yiyin Zhang5Jiaxi He6Jieyu Wu7Long Jiang8Shiyan Tang9Qihua He10Lindsey Tristine Hamblin11Zhiheng Xu12Yaoqi Chen13Difei Chen14Xinyu Wang15Kexin Deng16Shuhan Jiang17Jiaqing Zhou18Jiaxuan Xu19Xuanzuo Chen202 Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease, Guangzhou, ChinaGuangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China1 Department of Thoracic Surgery and Oncology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaDepartment of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, China7 Department of General Surgery, Zhejiang University, Hangzhou, China3 National Clinical Research Centre of Respiratory Disease, Guangzhou, China10 Department of Pathology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China1Neogap Therapeutics AB, Stockholm, Sweden5 Nanshan School, Guangzhou Medical University, Guangzhou, China1 Department of Thoracic Surgery and Oncology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China9 Institute of International Education, Guangdong University of Foreign Studies, Guangzhou, China2 Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease, Guangzhou, China1 Department of Thoracic Surgery and Oncology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China5 Nanshan School, Guangzhou Medical University, Guangzhou, ChinaSchool of Public Health, Southern Medical University, Guangzhou, Guangdong, China5 Nanshan School, Guangzhou Medical University, Guangzhou, China5 Nanshan School, Guangzhou Medical University, Guangzhou, China5 Nanshan School, Guangzhou Medical University, Guangzhou, China5 Nanshan School, Guangzhou Medical University, Guangzhou, China5 Nanshan School, Guangzhou Medical University, Guangzhou, ChinaObjective 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.https://bmjopen.bmj.com/content/8/9/e017240.full |
| spellingShingle | Jianrong Zhang Yu Huang Hengrui Liang Wenhua Liang Jianxing He Yiyin Zhang Jiaxi He Jieyu Wu Long Jiang Shiyan Tang Qihua He Lindsey Tristine Hamblin Zhiheng Xu Yaoqi Chen Difei Chen Xinyu Wang Kexin Deng Shuhan Jiang Jiaqing Zhou Jiaxuan Xu Xuanzuo Chen 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 BMJ Open |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | https://bmjopen.bmj.com/content/8/9/e017240.full |
| work_keys_str_mv | AT jianrongzhang systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT yuhuang systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT hengruiliang systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT wenhualiang systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT jianxinghe systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT yiyinzhang systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT jiaxihe systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT jieyuwu systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT longjiang systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT shiyantang systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT qihuahe systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT lindseytristinehamblin systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT zhihengxu systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT yaoqichen systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT difeichen systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT xinyuwang systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT kexindeng systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT shuhanjiang systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT jiaqingzhou systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT jiaxuanxu systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour AT xuanzuochen systematicbiasbetweenblindedindependentcentralreviewandlocalassessmentliteraturereviewandanalysesof76phaseiiirandomisedcontrolledtrialsin45688patientswithadvancedsolidtumour |