Examining the Effect of Missing Data and Unmeasured Confounding on External Comparator Studies: Case Studies and Simulations.

IF 4 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Safety Pub Date : 2024-12-01 Epub Date: 2024-08-05 DOI:10.1007/s40264-024-01467-9
Gerd Rippin, Héctor Sanz, Wilhelmina E Hoogendoorn, Nicolás M Ballarini, Joan A Largent, Eleni Demas, Douwe Postmus, Theodor Framke, Lukas M Aguirre Dávila, Chantal Quinten, Francesco Pignatti
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引用次数: 0

Abstract

Background and objective: Missing data and unmeasured confounding are key challenges for external comparator studies. This work evaluates bias and other performance characteristics depending on missingness and unmeasured confounding by means of two case studies and simulations.

Methods: Two case studies were constructed by taking the treatment arms from two randomised controlled trials and an external real-world data source that exhibited substantial missingness. The indications of the randomised controlled trials were multiple myeloma and metastatic hormone-sensitive prostate cancer. Overall survival was taken as the main endpoint. The effects of missing data and unmeasured confounding were assessed for the case studies by reporting estimated external comparator versus randomised controlled trial treatment effects. Based on the two case studies, simulations were performed broadening the settings by varying the underlying hazard ratio, the sample size, the sample size ratio between the experimental arm and the external comparator, the number of missing covariates and the percentage of missingness. Thereby, bias and other performance metrics could be quantified dependent on these factors.

Results: For the multiple myeloma external comparator study, results were in line with the randomised controlled trial, despite missingness and potential unmeasured confounding, while for the metastatic hormone-sensitive prostate cancer case study missing data led to a low sample size, leading overall to inconclusive results. Furthermore, for the metastatic hormone-sensitive prostate cancer study, missing data in important eligibility criteria led to further limitations. Simulations were successfully applied to gain a quantitative understanding of the effects of missing data and unmeasured confounding.

Conclusions: This exploratory study confirmed external comparator strengths and limitations by quantifying the impact of missing data and unmeasured confounding using case studies and simulations. In particular, missing data in key eligibility criteria were seen to limit the ability to derive the external comparator target analysis population accurately, while simulations demonstrated the magnitude of bias to expect for various settings.

Abstract Image

检验缺失数据和未测量混杂因素对外部比较研究的影响:案例研究与模拟
背景和目的:缺失数据和无法测量的混杂因素是外部参照研究面临的主要挑战。这项工作通过两个案例研究和模拟,评估了缺失和未测量混杂的偏差和其他性能特征:方法:通过从两项随机对照试验和一个外部真实世界数据源中提取治疗臂,构建了两项案例研究。随机对照试验的适应症是多发性骨髓瘤和转移性激素敏感性前列腺癌。总生存期是主要终点。通过报告外部参照物与随机对照试验治疗效果的估计值,评估了缺失数据和未测量混杂因素对病例研究的影响。在两个案例研究的基础上,通过改变基本危险比、样本量、实验臂与外部参照物之间的样本量比、缺失协变量数量和缺失百分比,扩大了模拟设置。因此,偏差和其他性能指标可以根据这些因素进行量化:在多发性骨髓瘤外部参照研究中,尽管存在缺失和潜在的未测量混杂因素,但结果与随机对照试验一致,而在转移性激素敏感性前列腺癌病例研究中,缺失数据导致样本量较少,从而导致总体结果不确定。此外,在转移性荷尔蒙敏感性前列腺癌研究中,重要资格标准数据的缺失导致了进一步的局限性。我们成功地应用了模拟方法,从数量上了解了缺失数据和未测量混杂因素的影响:这项探索性研究通过案例研究和模拟,量化了缺失数据和未测量混杂因素的影响,从而确认了外部参照系统的优势和局限性。特别是,关键资格标准中的缺失数据被认为限制了准确推导外部参照系统目标分析人群的能力,而模拟则显示了不同环境下的预期偏差程度。
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来源期刊
Drug Safety
Drug Safety 医学-毒理学
CiteScore
7.60
自引率
7.10%
发文量
112
审稿时长
6-12 weeks
期刊介绍: Drug Safety is the official journal of the International Society of Pharmacovigilance. The journal includes: Overviews of contentious or emerging issues. Comprehensive narrative reviews that provide an authoritative source of information on epidemiology, clinical features, prevention and management of adverse effects of individual drugs and drug classes. In-depth benefit-risk assessment of adverse effect and efficacy data for a drug in a defined therapeutic area. Systematic reviews (with or without meta-analyses) that collate empirical evidence to answer a specific research question, using explicit, systematic methods as outlined by the PRISMA statement. Original research articles reporting the results of well-designed studies in disciplines such as pharmacoepidemiology, pharmacovigilance, pharmacology and toxicology, and pharmacogenomics. Editorials and commentaries on topical issues. Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in Drug Safety Drugs may be accompanied by plain language summaries to assist readers who have some knowledge of, but not in-depth expertise in, the area to understand important medical advances.
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