Credibility assessment of in silico clinical trials for medical devices.

Abstract

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.