盲态独立中央审查与局部评估之间客观缓解率和疾病控制率的评估偏倚：过去七年III期随机对照试验的研究水平汇总分析
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.
作者信息
Zhang Jianrong, Zhang Yiyin, Tang Shiyan, Liang Hengrui, Chen Difei, Jiang Long, He Qihua, Huang Yu, Wang Xinyu, Deng Kexin, Jiang Shuhan, Zhou Jiaqing, Xu Jiaxuan, Chen Xuanzuo, Liang Wenhua, He Jianxing
机构信息
Department of Thoracic Surgery and Oncology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease, Guangzhou 510120, China.
出版信息
Ann Transl Med. 2017 Dec;5(24):481. doi: 10.21037/atm.2017.11.24.
BACKGROUND
In previous studies, complete-case implementation of blind independent central review has been considered unnecessary based on no sign of systematic bias between central and local assessments. In order to further evaluate its value, this study investigated evaluation status between both assessments in phase III trials of anti-cancer drugs for non-hematologic solid tumors.
METHODS
Eligible trials were searched in PubMed with the date of Jan 1, 2010 to Jun 30, 2017. We compared objective response rate (ORR) and disease control rate (DCR) between central and local assessments by study-level pooled analysis and correlation analysis. In pooled analysis, direct comparison was measured by the odds ratio (OR) of central-assessed response status to local-assessed response status; to investigate evaluation bias between central and local assessments, the above calculated OR between experimental (exp-) and control (con-) arms were compared, measured by the ratio of OR.
RESULTS
A total of 28 included trials involving 17,466 patients were included (28 with ORR, 16 with DCR). Pooled analysis showed central assessment reported lower ORR and DCR than local assessment, especially in trials with open-label design, central-assessed primary endpoint, and positive primary endpoint outcome, respectively. However, this finding could be found in both experimental [exp-ORR: OR=0.81 (95% CI: 0.76-0.87), P<0.01, I=11%; exp-DCR: OR=0.90 (0.81-1.01), P=0.07, I=42%] and control arms [con-ORR: OR=0.79 (0.72-0.85), P<0.01, I=17%; con-DCR: OR=0.94 (0.86-1.02), P=0.14, I=12%]. No sign of evaluation bias between two assessments was indicated through further analysis [ORR: ratio of OR=1.02 (0.97-1.07), P=0.42, I=0%; DCR: ratio of OR=0.98 (0.93-1.03), P=0.37, I=0%], regardless of mask (open/blind), sample size, tumor type, primary endpoint (central-assessed/local-assessed), and primary endpoint outcome (positive/negative). Correlation analysis demonstrated a high-degree concordance between central and local assessments (exp-ORR, con-ORR, exp-DCR, con-DCR: r>0.90, P<0.01).
CONCLUSIONS
Blind independent central review remained irreplaceable to monitor local assessment, but its complete-case implementation may be unnecessary.
背景
在以往研究中，基于中心评估与本地评估之间无系统偏差迹象，认为完全实施盲法独立中心评估并无必要。为进一步评估其价值，本研究调查了非血液系统实体瘤抗癌药物Ⅲ期试验中两种评估之间的评估状况。
方法
在PubMed中检索2010年1月1日至2017年6月30日期间符合条件的试验。通过研究水平的汇总分析和相关性分析，比较中心评估与本地评估之间的客观缓解率（ORR）和疾病控制率（DCR）。在汇总分析中，直接比较通过中心评估的缓解状态与本地评估的缓解状态的比值比（OR）来衡量；为调查中心评估与本地评估之间的评估偏差，比较上述实验组（exp-）和对照组（con-）之间计算出的OR，通过OR的比值来衡量。
结果
共纳入28项试验，涉及17466例患者（28项有ORR数据，16项有DCR数据）。汇总分析显示，中心评估报告的ORR和DCR低于本地评估，特别是在开放标签设计、中心评估的主要终点和主要终点结果为阳性的试验中。然而，这一发现同时出现在实验组[exp-ORR：OR=0.81（95%CI：0.76-0.87），P<0.01，I=11%；exp-DCR：OR=0.90（0.81-1.01），P=0.07，I=42%]和对照组[con-ORR：OR=0.79（0.72-0.85），P<0.01，I=17%；con-DCR：OR=0.94（0.86-1.02），P=0.14，I=12%]。通过进一步分析，未显示两种评估之间存在评估偏差迹象[ORR：OR比值=1.02（0.97-1.07），P=0.42，I=0%；DCR：OR比值=0.98（0.93-1.03），P=0.37，I=0%]，无论是否设盲（开放/盲法）、样本量、肿瘤类型、主要终点（中心评估/本地评估）以及主要终点结果（阳性/阴性）。相关性分析表明中心评估与本地评估之间具有高度一致性（exp-ORR、con-ORR、exp-DCR、con-DCR：r>0.90，P<0.01）。
结论
盲法独立中心评估对于监测本地评估而言仍不可替代，但其完全实施可能并无必要。
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