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癌症临床试验中,生存和次优控制臂的差异删失关联。

Association of differential censoring with survival and suboptimal control arms among oncology clinical trials.

机构信息

Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

出版信息

J Natl Cancer Inst. 2024 Jun 7;116(6):990-994. doi: 10.1093/jnci/djae028.


DOI:10.1093/jnci/djae028
PMID:38331394
Abstract

Differential censoring, which refers to censoring imbalance between treatment arms, may bias the interpretation of survival outcomes in clinical trials. In 146 phase III oncology trials with statistically significant time-to-event surrogate primary endpoints, we evaluated the association between differential censoring in the surrogate primary endpoints, control arm adequacy, and the subsequent statistical significance of overall survival results. Twenty-four (16%) trials exhibited differential censoring that favored the control arm, whereas 15 (10%) exhibited differential censoring that favored the experimental arm. Positive overall survival was more common in control arm differential censoring trials (63%) than in trials without differential censoring (37%) or with experimental arm differential censoring (47%; odds ratio = 2.64, 95% confidence interval = 1.10 to 7.20; P = .04). Control arm differential censoring trials more frequently used suboptimal control arms at 46% compared with 20% without differential censoring and 13% with experimental arm differential censoring (odds ratio = 3.60, 95% confidence interval = 1.29 to 10.0; P = .007). The presence of control arm differential censoring in trials with surrogate primary endpoints, especially in those with overall survival conversion, may indicate an inadequate control arm and should be examined and explained.

摘要

差异删失是指处理组之间的删失不平衡,可能会影响临床试验中生存结局的解释。在 146 项具有统计学意义的时间事件替代主要终点的 III 期肿瘤学试验中,我们评估了替代主要终点的差异删失、对照臂充分性以及随后总生存结果的统计学意义之间的关联。24 项(16%)试验显示出有利于对照臂的差异删失,而 15 项(10%)试验显示出有利于实验组的差异删失。在有对照臂差异删失的试验中(63%),阳性总生存比没有差异删失的试验(37%)或有实验组差异删失的试验(47%)更为常见(比值比=2.64,95%置信区间=1.10 至 7.20;P=0.04)。与没有差异删失的试验(20%)和有实验组差异删失的试验(13%)相比,对照臂差异删失的试验更频繁地使用非最优对照臂(46%)(比值比=3.60,95%置信区间=1.29 至 10.0;P=0.007)。在具有替代主要终点的试验中存在对照臂差异删失,尤其是在那些总生存转换的试验中,可能表明对照臂不充分,应进行检查和解释。

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[1]
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[3]
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本文引用的文献

[1]
Informative censoring of surrogate end-point data in phase 3 oncology trials.

Eur J Cancer. 2021-8

[2]
Survival-Inferred Fragility Index of Phase 3 Clinical Trials Evaluating Immune Checkpoint Inhibitors.

JAMA Netw Open. 2020-10-1

[3]
Progression-free survival is a suboptimal predictor for overall survival among metastatic solid tumour clinical trials.

Eur J Cancer. 2020-9

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Limitations in Clinical Trials Leading to Anticancer Drug Approvals by the US Food and Drug Administration.

JAMA Intern Med. 2020-8-1

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Informative censoring - a neglected cause of bias in oncology trials.

Nat Rev Clin Oncol. 2020-6

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Factors Associated With Age Disparities Among Cancer Clinical Trial Participants.

JAMA Oncol. 2019-12-1

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Analysis of Control Arm Quality in Randomized Clinical Trials Leading to Anticancer Drug Approval by the US Food and Drug Administration.

JAMA Oncol. 2019-6-1

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Strength of Validation for Surrogate End Points Used in the US Food and Drug Administration's Approval of Oncology Drugs.

Mayo Clin Proc. 2016-5-10

[9]
Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma.

N Engl J Med. 2015-11-5

[10]
The Strength of Association Between Surrogate End Points and Survival in Oncology: A Systematic Review of Trial-Level Meta-analyses.

JAMA Intern Med. 2015-8

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