Pathmanathan Pras, Aycock Kenneth, Badal Andreu, Bighamian Ramin, Bodner Jeff, Craven Brent A, Niederer Steven
Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, United States of America.
Medtronic, PLC., Minneapolis, Minnesota, United States of America.
PLoS Comput Biol. 2024 Aug 8;20(8):e1012289. doi: 10.1371/journal.pcbi.1012289. eCollection 2024 Aug.
In silico clinical trials (ISCTs) are an emerging method in modeling and simulation where medical interventions are evaluated using computational models of patients. ISCTs have the potential to provide cost-effective, time-efficient, and ethically favorable alternatives for evaluating the safety and effectiveness of medical devices. However, ensuring the credibility of ISCT results is a significant challenge. This paper aims to identify unique considerations for assessing the credibility of ISCTs and proposes an ISCT credibility assessment workflow based on recently published model assessment frameworks. First, we review various ISCTs described in the literature, carefully selected to showcase the range of methodological options available. These studies cover a wide variety of devices, reasons for conducting ISCTs, patient model generation approaches including subject-specific versus 'synthetic' virtual patients, complexity levels of devices and patient models, incorporation of clinician or clinical outcome models, and methods for integrating ISCT results with real-world clinical trials. We next discuss how verification, validation, and uncertainty quantification apply to ISCTs, considering the range of ISCT approaches identified. Based on our analysis, we then present a hierarchical workflow for assessing ISCT credibility, using a general credibility assessment framework recently published by the FDA's Center for Devices and Radiological Health. Overall, this work aims to promote standardization in ISCTs and contribute to the wider adoption and acceptance of ISCTs as a reliable tool for evaluating medical devices.
计算机模拟临床试验（ISCTs）是建模与仿真领域中一种新兴的方法，它利用患者的计算模型来评估医学干预措施。ISCTs有潜力为评估医疗器械的安全性和有效性提供具有成本效益、节省时间且符合伦理的替代方案。然而，确保ISCT结果的可信度是一项重大挑战。本文旨在确定评估ISCTs可信度时需要特别考虑的因素，并基于最近发表的模型评估框架提出一种ISCT可信度评估工作流程。首先，我们回顾文献中描述的各种ISCTs，这些文献经过精心挑选，以展示可用方法的范围。这些研究涵盖了各种各样的设备、进行ISCTs的原因、患者模型生成方法，包括特定受试者与“合成”虚拟患者、设备和患者模型的复杂程度、临床医生或临床结果模型的纳入，以及将ISCT结果与现实世界临床试验相结合的方法。接下来，考虑到所确定的ISCT方法的范围，我们讨论验证、确认和不确定性量化如何应用于ISCTs。基于我们的分析，我们随后使用美国食品药品监督管理局设备与放射健康中心最近发布的一般可信度评估框架，提出一个用于评估ISCT可信度的分层工作流程。总体而言，这项工作旨在促进ISCTs的标准化，并有助于更广泛地采用和接受ISCTs作为评估医疗器械的可靠工具。
