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Toward trustworthy medical device in silico clinical trials: a hierarchical framework for establishing credibility and strategies for overcoming key challenges

Kenneth I. Aycock, Tom Battisti, Ashley Peterson, Jiang Yao, Steven Kreuzer, Claudio Capelli, Sanjay Pant Orcid Logo, Pras Pathmanathan, David M. Hoganson, Steve M. Levine, Brent A. Craven

Frontiers in Medicine, Volume: 11

Swansea University Author: Sanjay Pant Orcid Logo

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    © 2024 Aycock, Battisti, Peterson, Yao, Kreuzer, Capelli, Pant, Pathmanathan, Hoganson, Levine and Craven. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).

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DOI (Published version): 10.3389/fmed.2024.1433372

Abstract

Computational models of patients and medical devices can be combined to perform an in silico clinical trial (ISCT) to investigate questions related to device safety and/or effectiveness across the total product life cycle. ISCTs can potentially accelerate product development by more quickly informin...

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Published in: Frontiers in Medicine
ISSN: 2296-858X 2296-858X
Published: Frontiers Media SA 2024
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URI: https://cronfa.swan.ac.uk/Record/cronfa67610
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ISCT submodels can include those for the medical device, the patient, the interaction of the device and patient, generating virtual patients, clinical decision making and simulating an intervention (e.g., device implantation), and translating acute physics-based simulation outputs to health-related clinical outcomes (e.g., device safety and/or effectiveness endpoints). Establishing the credibility of each ISCT submodel is challenging, but is nonetheless important because inaccurate output from a single submodel could potentially compromise the credibility of the entire ISCT. The objective of this study is to begin addressing some of these challenges and to identify general strategies for establishing ISCT credibility. Most notably, we propose a hierarchical approach for assessing the credibility of an ISCT that involves systematically gathering credibility evidence for each ISCT submodel in isolation before demonstrating credibility of the full ISCT. Also, following FDA Guidance for assessing computational model credibility, we provide suggestions for ways to clearly describe each of the ISCT submodels and the full ISCT, discuss considerations for performing an ISCT model risk assessment, identify common challenges to demonstrating ISCT credibility, and present strategies for addressing these challenges using our proposed hierarchical approach. 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spelling 2024-10-25T12:18:50.3807344 v2 67610 2024-09-09 Toward trustworthy medical device in silico clinical trials: a hierarchical framework for establishing credibility and strategies for overcoming key challenges 43b388e955511a9d1b86b863c2018a9f 0000-0002-2081-308X Sanjay Pant Sanjay Pant true false 2024-09-09 ACEM Computational models of patients and medical devices can be combined to perform an in silico clinical trial (ISCT) to investigate questions related to device safety and/or effectiveness across the total product life cycle. ISCTs can potentially accelerate product development by more quickly informing device design and testing or they could be used to refine, reduce, or in some cases to completely replace human subjects in a clinical trial. There are numerous potential benefits of ISCTs. An important caveat, however, is that an ISCT is a virtual representation of the real world that has to be shown to be credible before being relied upon to make decisions that have the potential to cause patient harm. There are many challenges to establishing ISCT credibility. ISCTs can integrate many different submodels that potentially use different modeling types (e.g., physics-based, data-driven, rule-based) that necessitate different strategies and approaches for generating credibility evidence. ISCT submodels can include those for the medical device, the patient, the interaction of the device and patient, generating virtual patients, clinical decision making and simulating an intervention (e.g., device implantation), and translating acute physics-based simulation outputs to health-related clinical outcomes (e.g., device safety and/or effectiveness endpoints). Establishing the credibility of each ISCT submodel is challenging, but is nonetheless important because inaccurate output from a single submodel could potentially compromise the credibility of the entire ISCT. The objective of this study is to begin addressing some of these challenges and to identify general strategies for establishing ISCT credibility. Most notably, we propose a hierarchical approach for assessing the credibility of an ISCT that involves systematically gathering credibility evidence for each ISCT submodel in isolation before demonstrating credibility of the full ISCT. Also, following FDA Guidance for assessing computational model credibility, we provide suggestions for ways to clearly describe each of the ISCT submodels and the full ISCT, discuss considerations for performing an ISCT model risk assessment, identify common challenges to demonstrating ISCT credibility, and present strategies for addressing these challenges using our proposed hierarchical approach. Finally, in the Appendix we illustrate the many concepts described here using a hypothetical ISCT example. Journal Article Frontiers in Medicine 11 Frontiers Media SA 2296-858X 2296-858X In silico clinical trial, ISCT, model credibility, computational modeling and simulation, hierarchical verification and validation 12 8 2024 2024-08-12 10.3389/fmed.2024.1433372 COLLEGE NANME Aerospace, Civil, Electrical, and Mechanical Engineering COLLEGE CODE ACEM Swansea University Another institution paid the OA fee The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was funded in part by the U.S. FDA Center for Devices and Radiological Health (CDRH) Critical Path program. 2024-10-25T12:18:50.3807344 2024-09-09T15:03:29.2771734 Faculty of Science and Engineering School of Aerospace, Civil, Electrical, General and Mechanical Engineering - Mechanical Engineering Kenneth I. Aycock 1 Tom Battisti 2 Ashley Peterson 3 Jiang Yao 4 Steven Kreuzer 5 Claudio Capelli 6 Sanjay Pant 0000-0002-2081-308X 7 Pras Pathmanathan 8 David M. Hoganson 9 Steve M. Levine 10 Brent A. Craven 11 67610__31285__0083e652563f461c9bdb99f01c6c76e1.pdf 67610.VOR.pdf 2024-09-09T16:20:47.4384419 Output 2207029 application/pdf Version of Record true © 2024 Aycock, Battisti, Peterson, Yao, Kreuzer, Capelli, Pant, Pathmanathan, Hoganson, Levine and Craven. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). true eng http://creativecommons.org/licenses/by/4.0/
title Toward trustworthy medical device in silico clinical trials: a hierarchical framework for establishing credibility and strategies for overcoming key challenges
spellingShingle Toward trustworthy medical device in silico clinical trials: a hierarchical framework for establishing credibility and strategies for overcoming key challenges
Sanjay Pant
title_short Toward trustworthy medical device in silico clinical trials: a hierarchical framework for establishing credibility and strategies for overcoming key challenges
title_full Toward trustworthy medical device in silico clinical trials: a hierarchical framework for establishing credibility and strategies for overcoming key challenges
title_fullStr Toward trustworthy medical device in silico clinical trials: a hierarchical framework for establishing credibility and strategies for overcoming key challenges
title_full_unstemmed Toward trustworthy medical device in silico clinical trials: a hierarchical framework for establishing credibility and strategies for overcoming key challenges
title_sort Toward trustworthy medical device in silico clinical trials: a hierarchical framework for establishing credibility and strategies for overcoming key challenges
author_id_str_mv 43b388e955511a9d1b86b863c2018a9f
author_id_fullname_str_mv 43b388e955511a9d1b86b863c2018a9f_***_Sanjay Pant
author Sanjay Pant
author2 Kenneth I. Aycock
Tom Battisti
Ashley Peterson
Jiang Yao
Steven Kreuzer
Claudio Capelli
Sanjay Pant
Pras Pathmanathan
David M. Hoganson
Steve M. Levine
Brent A. Craven
format Journal article
container_title Frontiers in Medicine
container_volume 11
publishDate 2024
institution Swansea University
issn 2296-858X
2296-858X
doi_str_mv 10.3389/fmed.2024.1433372
publisher Frontiers Media SA
college_str Faculty of Science and Engineering
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hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Aerospace, Civil, Electrical, General and Mechanical Engineering - Mechanical Engineering{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Aerospace, Civil, Electrical, General and Mechanical Engineering - Mechanical Engineering
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description Computational models of patients and medical devices can be combined to perform an in silico clinical trial (ISCT) to investigate questions related to device safety and/or effectiveness across the total product life cycle. ISCTs can potentially accelerate product development by more quickly informing device design and testing or they could be used to refine, reduce, or in some cases to completely replace human subjects in a clinical trial. There are numerous potential benefits of ISCTs. An important caveat, however, is that an ISCT is a virtual representation of the real world that has to be shown to be credible before being relied upon to make decisions that have the potential to cause patient harm. There are many challenges to establishing ISCT credibility. ISCTs can integrate many different submodels that potentially use different modeling types (e.g., physics-based, data-driven, rule-based) that necessitate different strategies and approaches for generating credibility evidence. ISCT submodels can include those for the medical device, the patient, the interaction of the device and patient, generating virtual patients, clinical decision making and simulating an intervention (e.g., device implantation), and translating acute physics-based simulation outputs to health-related clinical outcomes (e.g., device safety and/or effectiveness endpoints). Establishing the credibility of each ISCT submodel is challenging, but is nonetheless important because inaccurate output from a single submodel could potentially compromise the credibility of the entire ISCT. The objective of this study is to begin addressing some of these challenges and to identify general strategies for establishing ISCT credibility. Most notably, we propose a hierarchical approach for assessing the credibility of an ISCT that involves systematically gathering credibility evidence for each ISCT submodel in isolation before demonstrating credibility of the full ISCT. Also, following FDA Guidance for assessing computational model credibility, we provide suggestions for ways to clearly describe each of the ISCT submodels and the full ISCT, discuss considerations for performing an ISCT model risk assessment, identify common challenges to demonstrating ISCT credibility, and present strategies for addressing these challenges using our proposed hierarchical approach. Finally, in the Appendix we illustrate the many concepts described here using a hypothetical ISCT example.
published_date 2024-08-12T08:28:26Z
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