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Which Randomization Methods Are Used Most Frequently in Clinical Trials? Results of a Survey by the Randomization Working Group 哪些随机化方法在临床试验中最常用?随机化工作组的调查结果
IF 1.8 4区 医学 Q3 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2023-06-15 DOI: 10.1080/19466315.2023.2225451
O. Sverdlov, Kerstine Carter, R. Hilgers, C. Everett, V. Berger, Yuqun Abigail Luo, Jonathan J. Chipman, Y. Ryeznik, Jennifer Ross, Ruth Knight, Kazumi Yamada
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引用次数: 2
The Role of Statistical Thinking in Biopharmaceutical Research 统计思维在生物制药研究中的作用
IF 1.8 4区 医学 Q3 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2023-06-09 DOI: 10.1080/19466315.2023.2224259
F. Bretz, J. Greenhouse
Abstract The development of new drugs has evolved dramatically over the past decade. Advances in technology enable scientists to generate “big data” faster than ever before. The availability of complex, high-volume data in turn creates demand for innovative quantitative solutions and tools in a rapidly evolving landscape. As a result, the role of the statistical scientist in collaborative research has never been more important. Reflecting on these changes, Cox (2012) wrote, “…[A]lthough the tactics of statistical analysis have been utterly changed… the strategy of research design and analysis has been much less affected…” In this article, we argue that the practice of statistics is built on the foundation of good statistical thinking and consists of a complex combination of problem-solving skills, the essence of what Cox meant by the “strategy of research.” Although others have highlighted the role of statistical thinking in research design and analysis, in the age of data science, machine learning and artificial intelligence, it cannot be emphasized enough. We outline four general steps that contribute to good statistical thinking and illustrate them with five use cases (“vignettes”) as well as a detailed case study discussion from a maintenance therapy clinical trial for depression.
摘要在过去的十年里,新药的开发取得了巨大的进展。技术的进步使科学家能够比以往更快地生成“大数据”。复杂、高容量数据的可用性反过来又在快速发展的环境中创造了对创新定量解决方案和工具的需求。因此,统计科学家在合作研究中的作用从未像现在这样重要。Cox(2012)在反思这些变化时写道,“……尽管统计分析的策略已经完全改变……研究设计和分析的策略受到的影响要小得多……”在这篇文章中,我们认为统计学的实践建立在良好的统计思维的基础上,考克斯所说的“研究策略”的本质。尽管其他人强调了统计思维在研究设计和分析中的作用,但在数据科学、机器学习和人工智能时代,这一点再怎么强调也不为过。我们概述了有助于良好统计思维的四个一般步骤,并用五个用例(“小插曲”)以及抑郁症维持治疗临床试验的详细案例研究讨论来说明它们。
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引用次数: 0
A Bayesian Adaptive Umbrella Trial Design with Robust Information Borrowing for Screening Multiple Combination Therapies 筛选多种联合疗法的稳健信息借鉴贝叶斯自适应伞式试验设计
IF 1.8 4区 医学 Q3 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2023-05-18 DOI: 10.1080/19466315.2023.2215735
Qing Liu, Wenxi Yu, Leiwen Gao, Xun Jiang, Michael Wolf, M. Mo
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引用次数: 0
Vaccine development during a pandemic: General lessons for clinical trial design 大流行期间的疫苗开发:临床试验设计的一般经验教训
IF 1.8 4区 医学 Q3 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2023-05-09 DOI: 10.1080/19466315.2023.2211538
B. Hofner, E. Asikanius, W. Jacquet, T. Framke, K. Oude Rengerink, L. Aguirre Dávila, Maria Grünewald, Florian Klinglmüller, M. Posch, Finbarr P. Leacy, Thomas Lang, Armin Koch, J. Zinserling, Kit Roes
The COVID-19 pandemic triggered an unprecedented research effort to develop vaccines and therapeutics. Urgency dictated that development and regulatory assessment were accelerated, while maintaining all standards for quality, safety and efficacy. To speed up evaluation the European Medicines Agency (EMA) implemented "rolling reviews” allowing developers to submit data for assessment as they became available.We discuss the clinical trial designs and the applied statistical approaches in vaccine efficacy trials, focusing on aspects such as multiple testing, interim and updated analyses, and reporting of results for the first four vaccines recommended for approval by the EMA. The fast accrual of COVID-19 cases in the clinical vaccine efficacy trials led to multiple data updates within a short time frame, which had consequences for the evaluation and interpretation of results. Key trial results are discussed in the light of these aspects. Notably, the aspects discussed did not affect the benefit/risk relationship in a meaningful way, which was clearly positive for all four vaccines.Assessment of the development and evaluation of the four vaccine trials during the pandemic has led to a proposal for standardised terminology for trials with multiple analyses and a recommendation to appropriately pre-plan the timing of primary and updated analyses. For the reporting of updated estimates of vaccine efficacy, we discuss how to best describe the uncertainty around estimates of vaccine efficacy (e.g., via confidence intervals). Finally, we briefly highlight the benefit of a comprehensive discussion on estimands for vaccine efficacy trials. [ FROM AUTHOR] Copyright of Statistics in Biopharmaceutical Research is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)
新冠肺炎大流行引发了开发疫苗和疗法的前所未有的研究努力。紧迫性要求加快开发和监管评估,同时保持质量、安全性和有效性的所有标准。为了加快评估,欧洲药品管理局(EMA)实施了“滚动审查”允许开发人员在数据可用时提交数据进行评估。我们讨论了临床试验设计和疫苗疗效试验中应用的统计方法,重点讨论了多项测试、中期和更新分析以及EMA建议批准的前四种疫苗的结果报告等方面。新冠肺炎病例的快速累积s在临床疫苗疗效试验中导致在短时间内多次更新数据,这对结果的评估和解释产生了影响。根据这些方面讨论了关键的试验结果。值得注意的是,所讨论的方面并没有以有意义的方式影响收益/风险关系,这对所有四种疫苗都是积极的。对疫情期间四项疫苗试验的开发和评估进行了评估,提出了一项针对多项分析试验的标准化术语建议,并建议适当预先规划初步和更新分析的时间。为了报告疫苗效力的最新估计,我们讨论了如何最好地描述疫苗效力估计的不确定性(例如,通过置信区间)。最后,我们简要强调了全面讨论疫苗疗效试验要求的好处。[作者]生物制药研究统计的版权归Taylor&Francis Ltd所有,未经版权持有人明确书面许可,不得将其内容复制或通过电子邮件发送到多个网站或发布到listserv。但是,用户可以打印、下载或通过电子邮件发送文章供个人使用。这可能会被删节。对复印件的准确性不作任何保证。用户应参考材料的原始发布版本以获取完整信息。(版权适用于所有人。)
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引用次数: 0
Minimizing Selection Bias Under the Blackwell and Hodges Model with an Equal Allocation Procedure in a Symmetric Allocation Space 对称分配空间中等分配Blackwell和Hodges模型下选择偏差的最小化
IF 1.8 4区 医学 Q3 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2023-05-09 DOI: 10.1080/19466315.2023.2208061
O. Kuznetsova
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引用次数: 0
A note on stratification errors in the analysis of clinical trials 关于临床试验分析中分层误差的说明
IF 1.8 4区 医学 Q3 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2023-04-27 DOI: 10.1080/19466315.2023.2241415
Neal Thomas
Stratification in both the design and analysis of randomized clinical trials is common. Despite features in automated randomization systems to re-confirm the stratifying variables, incorrect values of these variables may be entered. These errors are often detected during subsequent data collection and verification. Questions remain about whether to use the mis-reported initial stratification or the corrected values in subsequent analyses. It is shown that the likelihood function resulting from the design of randomized clinical trials supports the use of the corrected values. New definitions are proposed that characterize misclassification errors as `ignorable' and `non-ignorable'. Ignorable errors may depend on the correct strata and any other modeled baseline covariates, but they are otherwise unrelated to potential treatment outcomes. Data management review suggests most misclassification errors are arbitrarily produced by distracted investigators, so they are ignorable or at most weakly dependent on measured and unmeasured baseline covariates. Ignorable misclassification errors may produce a small increase in standard errors, but other properties of the planned analyses are unchanged (e.g., unbiasedness, confidence interval coverage). It is shown that unbiased linear estimation in the absence of misclassification errors remains unbiased when there are non-ignorable misclassification errors, and the corresponding confidence intervals based on the corrected strata values are conservative.
随机临床试验的设计和分析中的分层是常见的。尽管自动随机化系统具有重新确认分层变量的功能,但可能会输入这些变量的错误值。这些错误通常在随后的数据收集和验证过程中被检测到。在随后的分析中,是使用错误报告的初始分层还是使用校正值仍然存在问题。结果表明,随机临床试验设计产生的似然函数支持校正值的使用。提出了新的定义,将错误分类错误描述为“可忽略”和“不可忽略”。可忽略的误差可能取决于正确的地层和任何其他建模的基线协变量,但它们与潜在的治疗结果无关。数据管理审查表明,大多数错误分类错误是由分心的研究人员任意产生的,因此它们是可忽略的,或者至多是弱依赖于测量和未测量的基线协变量。可忽略的错误分类误差可能会导致标准误差的小幅增加,但计划分析的其他特性不变(例如,无偏性、置信区间覆盖率)。结果表明,当存在不可忽略的误分类误差时,在没有误分类误差的情况下的无偏线性估计保持无偏,并且基于校正的地层值的相应置信区间是保守的。
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引用次数: 0
Rejoinder to Comments on “Non-Proportional Hazards – An Evaluation of the MaxCombo Test in Cancer Clinical Trials” 对“非比例风险——对MaxCombo试验在癌症临床试验中的评价”评论的答复
IF 1.8 4区 医学 Q3 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2023-04-03 DOI: 10.1080/19466315.2023.2203007
Y. Shen, Sirisha L. Mushti, Flora Mulkey, T. Gwise, Xin Wang, Jiaxi Zhou, Xin Gao, Shenghui Tang, M. Theoret, R. Pazdur, R. Sridhara
This rejoinder continues a discussion initiated by the Oncology Center of Excellence’s call (2016–2017) for statistical approaches to address the problem of assessing treatment effects in the presence of non-proportional hazards (NPH) (Duke-Margolis Workshop 2018; Lin et al. 2020a, Lin et al. 2020b; Roychoudhury et al. 2021). The publication of the method was met with much discussion, several commentary articles (Freidlin and Korn 2019; Bartlett et al. 2020; Lin et al. 2020a; Magirr and Burman 2021; Roychoudhury et al. 2021) and a rejoinder by the MaxCombo test coauthors (Lin et al. 2020b). After consideration of the proposed method and review of its accompanying responses and rejoinder, we expressed our views on the MaxCombo tests and provided general thoughts on design issues when NPH is expected in our article (Shen et al. 2021). In response to the publication of our article, the Cross-PhRMA working group (Lin et al. 2023) and Posch, Ristl, and König (2022) published additional commentary providing further clarification and views. We appreciate the great interest in NPH issues in the regulatory statistical community and would like to take this opportunity to provide additional clarifications and comments. Although the primary objective of our 2021 article was to focus on the MaxCombo test, as noted by Lin et al. (2023), a number of the issues are more general and are equally applicable when using many other methods and testing statistics, for example, the difficulty in interpretation or failure to incorporate underlying reasons of NPH. In fact, recognizing the shortcomings of the more commonly used tests such as log-rank test, etc., FDA initiated the dialogue and invited PhRMA to come together to develop methodology to address this issue. The MaxCombo test is presented as representing a flexible testing procedure impervious to a variety of shapes of curves under NPH. Cross-PhRMA working group suggested a 3-step method for evaluation of treatment effect when NPH is expected (Lin et al. 2020a, Lin et al. 2020b, Roychoudhury et al. 2021). Lin et al. (2023) clarified that in this scenario, a successful treatment effect would not be claimed based solely on results from the MaxCombo test, as the Cross-PhRMA working group recommends such decisions be based on the totality of data
该反驳继续了肿瘤卓越中心(2016-2017)发起的关于统计方法的讨论,以解决在存在非比例风险(NPH)的情况下评估治疗效果的问题(Duke-Margolis Workshop 2018;Lin et al. 2020a, Lin et al. 2020b;Roychoudhury et al. 2021)。该方法的发表引起了很多讨论,几篇评论文章(Freidlin and Korn 2019;Bartlett et al. 2020;Lin等。2020a;Magirr and Burman 2021;Roychoudhury等人,2021)和MaxCombo测试合著者的反驳(Lin等人,2020b)。在考虑了提议的方法并审查了相关的回应和反驳后,我们在文章中表达了我们对MaxCombo测试的看法,并就NPH预期时的设计问题提供了总体思路(Shen et al. 2021)。作为对我们文章发表的回应,Cross-PhRMA工作组(Lin et al. 2023)、Posch、Ristl和König(2022)发表了额外的评论,提供了进一步的澄清和观点。我们感谢监管统计界对NPH问题的极大兴趣,并希望借此机会提供额外的澄清和评论。正如Lin等人(2023)所指出的,尽管我们2021年文章的主要目标是关注MaxCombo测试,但许多问题更为普遍,在使用许多其他方法和测试统计数据时同样适用,例如,难以解释或未能纳入NPH的潜在原因。事实上,认识到更常用的测试(如log-rank测试等)的缺点,FDA发起了对话,并邀请PhRMA一起制定解决这一问题的方法。MaxCombo测试代表了一种灵活的测试程序,不受NPH下各种形状曲线的影响。跨phrma工作组提出了一种评估NPH预期治疗效果的三步法(Lin et al. 2020a, Lin et al. 2020b, Roychoudhury et al. 2021)。Lin等人(2023)澄清说,在这种情况下,不能仅仅根据MaxCombo测试的结果来宣称成功的治疗效果,因为Cross-PhRMA工作组建议基于整体数据做出此类决定
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引用次数: 0
Editor’s Note: Special Section on Estimands, Design and Analysis of Clinical Trials with Time-to-Event Outcomes 编者注:具有事件发生时间结果的临床试验的估计、设计和分析的特别部分
IF 1.8 4区 医学 Q3 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2023-04-03 DOI: 10.1080/19466315.2023.2200113
T. Hamasaki
In several disease areas, such as cardiovascular disease, oncology/cancer or HIV, clinical trials often collect and analyze multiple time-to-event (or survival) outcomes from patients to assess the effects of interventions. Methods for time-to-event outcomes are more complex than for binary or continuous outcomes. The design, monitoring, analysis and reporting of clinical trials with time-to-event outcomes (time-to-event clinical trials) will require considerable care. A common practice in time-to-event clinical trials is to first create a composite endpoint that combines several clinically relevant time-to-event outcomes (e.g., major adverse cardiovascular events (MACE), consisting of death, myocardial infarction, and stroke in cardiovascular disease; progression free survival (PFS) consisting of time-to-progression and overall survival), and then to perform a time-to-first-event analysis for the composite endpoint. The advantages and challenges of using composite endpoints are well known and have been discussed in the statistical and medical literature. Recently, many statisticians have attempted to redefine the estimand(s) of interest to capture the effects of interventions and the corresponding estimators of the estimand(s) (statistical methods) since the implementation of the estimand framework highlighted in the ICH-E9(R1) guideline (ICH 2019). Common survival analysis methods, such as Kaplan-Meier method, log-rank test, or Cox proportional hazards regression, have many strengths and are well accepted in practice. However, there are situations in which they may not be feasible or provide reliable results. The common methods are based
在一些疾病领域,如心血管疾病、肿瘤/癌症或艾滋病毒,临床试验通常收集和分析患者的多次事件(或生存)结果,以评估干预措施的效果。时间到事件结果的方法比二元或连续结果的方法更复杂。设计、监测、分析和报告具有事件发生时间结果的临床试验(事件发生时间临床试验)将需要相当谨慎。在事件发生时间临床试验中,一种常见的做法是首先创建一个复合终点,该终点结合了几个临床相关的事件发生时间结局(例如,心血管疾病中的主要不良事件(MACE),包括死亡、心肌梗死和中风;无进展生存期(PFS),包括进展时间和总生存期),然后对复合终点进行首次事件时间分析。使用复合终点的优点和挑战是众所周知的,并在统计和医学文献中进行了讨论。最近,自ICH- e9 (R1)指南(ICH 2019)中强调的估计框架实施以来,许多统计学家试图重新定义感兴趣的估计,以捕获干预措施的效果和相应的估计量(统计方法)。常见的生存分析方法,如Kaplan-Meier法、log-rank检验、Cox比例风险回归等,有很多优点,在实践中被广泛接受。然而,在某些情况下,它们可能不可行或不能提供可靠的结果。常用的方法是基于
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引用次数: 0
Comment on “Non-Proportional Hazards – an Evaluation of the MaxCombo Test in Cancer Clinical Trials” by the Cross-Pharma Non-Proportional Hazards Working Group 跨制药非比例风险工作组对“非比例风险——对MaxCombo试验在癌症临床试验中的评价”的评论
IF 1.8 4区 医学 Q3 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2023-04-03 DOI: 10.1080/19466315.2022.2103180
Ray S. Lin, P. Mukhopadhyay, Satrajit Roychoudhury, K. Anderson, Tianle Hu, Bo Huang, L. F. León, J. Liao, Ji Lin, Rong Liu, Xiaodong Luo, Yabing Mai, R. Qin, K. Tatsuoka, Yang Wang, Jiabu Ye, Jian Zhu, Tai-Tsang Chen, R. Iacona
aGenentech/Roche, South San Francisco, CA; bOtsuka America Pharmaceuticals, Inc, Rockville, MD, 20850; cPfizer Inc, New York, NY; dMerck & Co., Inc, Kenilworth, NJ; eSarepta Therapeutics, Cambridge, MA; fPfizer Inc, Groton, CT; gIncyte Corporation, Wilmington, DE; hSanofi US, Cambridge, MA; iBristolMyers Squibb, Berkeley Heights, NJ; jSanofi US, Bridgewater, NJ; kBoehringer Ingelheim, Shanghai, China; lJanssen Research & Development, LLC, Raritan, NJ; mSanten Pharmaceuticals, Emeryville, CA; nZ&W Consulting, Chester Springs, PA; oServier Pharmaceuticals, Boston, MA; pGSK, Collegeville, PA; qAstra Zeneca, Washington, DC; rThe Cross-Pharma NPH working group includes all the authors of this manuscript as listed above and the following members who have contributed tremendously to this work: Prabhu Bhagavatheeswaran, Julie Cong, Margarida Geraldes, Dominik Heinzmann, Yifan Huang, Zhengrong Li, Honglu Liu, Jane Qian, Xuejing Wang, Li-an Xu, Luping Zhao
aGenentech/Roche,南旧金山,加利福尼亚州;bOtsuka America Pharmaceuticals, Inc ., Rockville, MD, 20850;纽约cpizer公司;d默克公司,新泽西州凯尼尔沃斯;eSarepta Therapeutics, Cambridge, MA;辉瑞公司,格罗顿,康涅狄格州;gIncyte Corporation, Wilmington, DE;赛诺菲美国,剑桥,马萨诸塞州;bristol myers Squibb,伯克利高地,新泽西;赛诺菲美国,布里奇沃特,新泽西;勃林格殷格翰,上海,中国;janssen Research & Development, LLC, NJ;santen制药公司,加利福尼亚州埃默里维尔;nZ&W咨询公司,切斯特斯普林斯,宾夕法尼亚州;oServier Pharmaceuticals, Boston, MA;pGSK,学院维尔,宾夕法尼亚州;qAstra Zeneca,华盛顿特区;rcross - pharma NPH工作组包括上述手稿的所有作者以及以下对这项工作做出巨大贡献的成员:Prabhu Bhagavatheeswaran, Julie丛婧,Margarida Geraldes, Dominik Heinzmann,黄一凡,李正容,刘洪路,钱简,王学静,徐丽安,赵鲁平
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引用次数: 1
We Need Subject Matter Expertise to Choose and Identify Causal Estimands: Comment on “Estimands for Recurrent Event Endpoints in the Presence of a Terminal Event” 我们需要主题专业知识来选择和识别因果估计:评论“在终端事件存在的情况下对重复事件终点的估计”
IF 1.8 4区 医学 Q3 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2023-04-03 DOI: 10.1080/19466315.2022.2108138
Matias Janvin, Jessica G. Young, M. J. Stensrud
Abstract We summarize what we consider to be the two main limitations of the “Estimands for Recurrent Event Endpoints in the Presence of a Terminal Event” (Schmidli et al. 2022). First, the authors did not give detailed guidance on how to choose an appropriate estimand in light of subject-matter considerations. Reasoning about the mechanism by which treatment affects different types of events is central when selecting a causal estimand, and such reasoning can be grounded in the interventionist mediation literature. Second, the article also did not discuss the crucial task of identification when the aim is to study a causal question. Thereby, the authors omit important differences in the uncertainty of the assumptions needed to target each estimand by particular statistical methods. These assumptions have crucial implications for the confidence that can be placed in a given effect estimate, and for the planning and collection of relevant variables in the study design.
摘要我们总结了我们认为的“在终端事件存在的情况下对重复事件终点的估计”的两个主要限制(Schmidli et al. 2022)。首先,作者没有就如何根据主题事项考虑选择适当的估计给出详细的指导。在选择因果估计时,关于治疗影响不同类型事件的机制的推理是核心,这种推理可以在干预主义调解文献中建立基础。其次,本文也没有讨论识别的关键任务,当目的是研究一个因果问题。因此,作者通过特定的统计方法忽略了针对每个估计所需的假设不确定性中的重要差异。这些假设对于给定效果估计的置信度以及研究设计中相关变量的规划和收集具有至关重要的意义。
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引用次数: 1
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Statistics in Biopharmaceutical Research
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