Estimands and their Estimators for Clinical Trials Impacted by the COVID-19 Pandemic: A Report from the NISS Ingram Olkin Forum Series on Unplanned Clinical Trial Disruptions

IF 1.5 4区医学 Q3 MATHEMATICAL & COMPUTATIONAL BIOLOGY

Statistics in Biopharmaceutical Research Pub Date : 2023-01-02 DOI:10.1080/19466315.2022.2094459

Kelly Van Lancker, S. Tarima, J. Bartlett, M. Bauer, Bharani Bharani-Dharan, F. Bretz, N. Flournoy, Hege Michiels, Camila Olarte Parra, J. L. Rosenberger, S. Cro

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引用次数: 7

Abstract

Abstract The COVID-19 pandemic continues to affect the conduct of clinical trials globally. Complications may arise from pandemic-related operational challenges such as site closures, travel limitations and interruptions to the supply chain for the investigational product, or from health-related challenges such as COVID-19 infections. Some of these complications lead to unforeseen intercurrent events in the sense that they affect either the interpretation or the existence of the measurements associated with the clinical question of interest. In this article, we demonstrate how the ICH E9(R1) Addendum on estimands and sensitivity analyses provides a rigorous basis to discuss potential pandemic-related trial disruptions and to embed these disruptions in the context of study objectives and design elements. We introduce several hypothetical estimand strategies and review various causal inference and missing data methods, as well as a statistical method that combines unbiased and possibly biased estimators for estimation. To illustrate, we describe the features of a stylized trial, and how it may have been impacted by the pandemic. This stylized trial will then be revisited by discussing the changes to the estimand and the estimator to account for pandemic disruptions. Finally, we outline considerations for designing future trials in the context of unforeseen disruptions.

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受COVID-19大流行影响的临床试验的估计及其估计:NISS英格拉姆奥尔金论坛系列关于计划外临床试验中断的报告

摘要新冠肺炎大流行继续影响全球临床试验的进行。并发症可能源于与流行病相关的操作挑战，如研究产品的现场关闭、旅行限制和供应链中断，或与健康相关的挑战，如新冠肺炎感染。其中一些并发症会导致不可预见的并发事件，因为它们会影响与感兴趣的临床问题相关的测量的解释或存在。在这篇文章中，我们展示了ICH E9（R1）关于估计和敏感性分析的附录如何为讨论潜在的与大流行相关的试验中断提供了严格的基础，并将这些中断嵌入研究目标和设计元素的背景中。我们介绍了几种假设的估计策略，并回顾了各种因果推断和缺失数据方法，以及一种结合无偏和可能有偏估计量进行估计的统计方法。为了说明这一点，我们描述了程式化试验的特点，以及它可能如何受到疫情的影响。然后，将通过讨论估计需求和估计量的变化来重新审视这一程式化试验，以解释疫情的干扰。最后，我们概述了在不可预见的中断情况下设计未来试验的考虑因素。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Statistics in Biopharmaceutical Research MATHEMATICAL & COMPUTATIONAL BIOLOGY-STATISTICS & PROBABILITY

CiteScore

3.90

自引率

16.70%

发文量

期刊介绍： Statistics in Biopharmaceutical Research ( SBR), publishes articles that focus on the needs of researchers and applied statisticians in biopharmaceutical industries; academic biostatisticians from schools of medicine, veterinary medicine, public health, and pharmacy; statisticians and quantitative analysts working in regulatory agencies (e.g., U.S. Food and Drug Administration and its counterpart in other countries); statisticians with an interest in adopting methodology presented in this journal to their own fields; and nonstatisticians with an interest in applying statistical methods to biopharmaceutical problems. Statistics in Biopharmaceutical Research accepts papers that discuss appropriate statistical methodology and information regarding the use of statistics in all phases of research, development, and practice in the pharmaceutical, biopharmaceutical, device, and diagnostics industries. Articles should focus on the development of novel statistical methods, novel applications of current methods, or the innovative application of statistical principles that can be used by statistical practitioners in these disciplines. Areas of application may include statistical methods for drug discovery, including papers that address issues of multiplicity, sequential trials, adaptive designs, etc.; preclinical and clinical studies; genomics and proteomics; bioassay; biomarkers and surrogate markers; models and analyses of drug history, including pharmacoeconomics, product life cycle, detection of adverse events in clinical studies, and postmarketing risk assessment; regulatory guidelines, including issues of standardization of terminology (e.g., CDISC), tolerance and specification limits related to pharmaceutical practice, and novel methods of drug approval; and detection of adverse events in clinical and toxicological studies. Tutorial articles also are welcome. Articles should include demonstrable evidence of the usefulness of this methodology (presumably by means of an application). The Editorial Board of SBR intends to ensure that the journal continually provides important, useful, and timely information. To accomplish this, the board strives to attract outstanding articles by seeing that each submission receives a careful, thorough, and prompt review. Authors can choose to publish gold open access in this journal.