Periodic Reporting for period 3 - SIMCOR (In Silico testing and validation of Cardiovascular Implantable devices)
Période du rapport: 2024-01-01 au 2024-06-30
Cardiovascular implantable devices contribute to reducing mortality and enhancing patients’ quality of life. Validation represents a critical aspect in their development lifecycle, as inadequate validation can lead to warnings and recalls from regulatory authorities, which cost manufacturing companies millions of dollars, ruin their reputation and directly affect the share price.
In-silico methodologies for medical device testing and validation, such as virtual cohorts and computer-based simulation, represent a promising opportunity for enhancing the quality, safety and efficacy of medical devices, while reducing costs and time-to-market and minimising the need for live testing on animal and human subjects.
SIMCor (In-silico testing and validation of Cardiovascular Implantable devices) is a 3.5-year (2021-2024) Research and Innovation Action funded under the topic SC1-DTH-06-2020 (Accelerating the uptake of computer simulations for testing medicines and medical devices) of the European Commission’s Horizon 2020 Framework Programme.
The project implemented a computational platform for in-silico development, validation and regulatory approval of cardiovascular implantable devices. The platform supports device testing along the entire value chain, from device design and in-vitro experiments to virtual animal and clinical studies, by integrating in-silico testing solutions with traditional methodologies.
Particularly, SIMCor (1) provided proof-of-validation for in-silico testing solutions, such as virtual cohorts and computer-based simulation of cardiovascular device implantation and performance, focussing on two clinical use cases, transcatheter aortic valve implantation (TAVI) and pulmonary artery pressure sensors (PAPS), used for the treatment of aortic valve disease (AVD) and heart failure (HF); (2) developed standard operating procedures for in-silico testing and validation of cardiovascular devices; (3) quantified the benefits of in-silico testing for healthcare, industry and society as a whole; (4) engaged with regulatory authorities to accelerate the integration of in-silico testing into the medical device approval processes; (5) contributed with data, virtual cohorts, simulation models, methodologies, and standard operating procedures.
In-silico methodologies for medical device testing and validation, such as virtual cohorts and computer-based simulation, represent a promising opportunity for enhancing the quality, safety and efficacy of medical devices, while reducing costs and time-to-market and minimising the need for live testing on animal and human subjects.
SIMCor (In-silico testing and validation of Cardiovascular Implantable devices) is a 3.5-year (2021-2024) Research and Innovation Action funded under the topic SC1-DTH-06-2020 (Accelerating the uptake of computer simulations for testing medicines and medical devices) of the European Commission’s Horizon 2020 Framework Programme.
The project implemented a computational platform for in-silico development, validation and regulatory approval of cardiovascular implantable devices. The platform supports device testing along the entire value chain, from device design and in-vitro experiments to virtual animal and clinical studies, by integrating in-silico testing solutions with traditional methodologies.
Particularly, SIMCor (1) provided proof-of-validation for in-silico testing solutions, such as virtual cohorts and computer-based simulation of cardiovascular device implantation and performance, focussing on two clinical use cases, transcatheter aortic valve implantation (TAVI) and pulmonary artery pressure sensors (PAPS), used for the treatment of aortic valve disease (AVD) and heart failure (HF); (2) developed standard operating procedures for in-silico testing and validation of cardiovascular devices; (3) quantified the benefits of in-silico testing for healthcare, industry and society as a whole; (4) engaged with regulatory authorities to accelerate the integration of in-silico testing into the medical device approval processes; (5) contributed with data, virtual cohorts, simulation models, methodologies, and standard operating procedures.
The consortium elaborated protocols for the collection of clinical data and conduction of animal studies and obtained ethical clearance from local ethics committees and national authorities. Furthermore, ethical and legal assessment was performed to ensure the privacy and security of data collection, processing and usage. Clinical data collection was successfully finalised for both use cases, and the planned acute and chronic animal experiments related to the PAPS use case have been conducted.
The consortium defined the system requirements for its virtual research environment (VRE) and the procedures for data processing. It also identified the clinical and corresponding engineering properties related to the performance of the implants to be calculated using in-silico models. The project set up project management procedures and elaborated its engagement, communication and dissemination strategy.
The consortium deployed an initial VRE Drive for sharing of data between partners. The VRE was then continuously updated by including modules for virtual cohort generation, device implantation, and device effect simulations as well as statistical evaluation via a dedicated R-Statistical Environment. The project defined its methodology for generating and validating virtual cohorts, which was implemented and resulted in the publication of validated virtual cohorts for the PAPS and TAVI use cases and the integration of the virtual cohort generators into the VRE.
The consortium has leveraged the resources, models, and frameworks developed based on the requirements defined at the start of the project to facilitate the validation of the device effect models for PAPS and TAVI. Specifically, low- and high-fidelity validation of selected endpoints for safety and efficacy for the TAVI and PAPS use cases were finalised via animal experiments, bench tests, in-silico testing and comparison against real-world data from clinical trials.
Combining the different resources, including virtual cohorts and the device effect models, the consortium conducted 4 in-silico clinical trials (ISCTs), each 2 for the PAPS and TAVI use cases respectively. These ISCTs aimed to address specific device-related questions of interest and demonstrate the applicability of the SIMCor methodology. The ISCT design and results were used to inform the clinical and socio-impact assessment frameworks. In addition, a wide range of interviews with academic, industry and regulatory and notified body representatives was conducted, to further inform and refine the SIMCor impact assessment framework.
To foster awareness of in-silico testing technologies and support their regulatory acceptance, the consortium also conducted intense dissemination of its results and engagement with regulatory authorities and notified bodies. The consortium has been conducting extensive presentation of results via relevant conferences, through talks and posters, and peer-reviewed journal articles. The consortium will facilitate the exploitation of the project results via ongoing research, providing access to the VRE to external users, as well as listing available models and data in the EDITH catalogue.
The consortium defined the system requirements for its virtual research environment (VRE) and the procedures for data processing. It also identified the clinical and corresponding engineering properties related to the performance of the implants to be calculated using in-silico models. The project set up project management procedures and elaborated its engagement, communication and dissemination strategy.
The consortium deployed an initial VRE Drive for sharing of data between partners. The VRE was then continuously updated by including modules for virtual cohort generation, device implantation, and device effect simulations as well as statistical evaluation via a dedicated R-Statistical Environment. The project defined its methodology for generating and validating virtual cohorts, which was implemented and resulted in the publication of validated virtual cohorts for the PAPS and TAVI use cases and the integration of the virtual cohort generators into the VRE.
The consortium has leveraged the resources, models, and frameworks developed based on the requirements defined at the start of the project to facilitate the validation of the device effect models for PAPS and TAVI. Specifically, low- and high-fidelity validation of selected endpoints for safety and efficacy for the TAVI and PAPS use cases were finalised via animal experiments, bench tests, in-silico testing and comparison against real-world data from clinical trials.
Combining the different resources, including virtual cohorts and the device effect models, the consortium conducted 4 in-silico clinical trials (ISCTs), each 2 for the PAPS and TAVI use cases respectively. These ISCTs aimed to address specific device-related questions of interest and demonstrate the applicability of the SIMCor methodology. The ISCT design and results were used to inform the clinical and socio-impact assessment frameworks. In addition, a wide range of interviews with academic, industry and regulatory and notified body representatives was conducted, to further inform and refine the SIMCor impact assessment framework.
To foster awareness of in-silico testing technologies and support their regulatory acceptance, the consortium also conducted intense dissemination of its results and engagement with regulatory authorities and notified bodies. The consortium has been conducting extensive presentation of results via relevant conferences, through talks and posters, and peer-reviewed journal articles. The consortium will facilitate the exploitation of the project results via ongoing research, providing access to the VRE to external users, as well as listing available models and data in the EDITH catalogue.
SIMCor implemented a computational infrastructure that integrates preclinical, clinical and synthetic data resources, virtual cohorts, simulation models, methods, guidelines and SOPs to serve as a digital testing environment at the service of researchers, manufacturers and regulatory bodies. The SOPs have been made publicly available together with relevant information, models and data, allowing evaluation and adoption by other stakeholders.
The project defined a methodology for the generation of virtual cohorts for replacement of in-vitro, preclinical and human testing, reproducing a variety of geometries, pathophysiologic conditions and clinical features. SIMCor elaborated a framework for the virtual implantation of medical devices, as well as for the assessment of device performance in regard to safety, efficacy, and usability for its two use cases. Thus, the project demonstrated the robustness and reliability of in-silico testing methodologies for the evaluation and regulatory approval of cardiovascular devices. Based on results on TAVI and PAPS, SIMCor extrapolated best practices and guidelines for the development, validation and regulatory approval of any type of cardiovascular device.
Through a series of interviews, focus groups, literature research, and four dedicated ISCTs, SIMCor informed its frameworks to assess the impact of integrating in-silico testing solutions into traditional clinical trials, as well as to evaluate and quantify the benefits for the clinical research workflow, industry, market, and broader societal perspective. These analyses highlight strengths and relevant barriers to the adoption of in-silico testing solutions into routine workflow and therefore will be beneficial for accelerating this adoption of virtual cohorts and simulation models into the development, testing and regulatory approval process of cardiovascular devices.
The project defined a methodology for the generation of virtual cohorts for replacement of in-vitro, preclinical and human testing, reproducing a variety of geometries, pathophysiologic conditions and clinical features. SIMCor elaborated a framework for the virtual implantation of medical devices, as well as for the assessment of device performance in regard to safety, efficacy, and usability for its two use cases. Thus, the project demonstrated the robustness and reliability of in-silico testing methodologies for the evaluation and regulatory approval of cardiovascular devices. Based on results on TAVI and PAPS, SIMCor extrapolated best practices and guidelines for the development, validation and regulatory approval of any type of cardiovascular device.
Through a series of interviews, focus groups, literature research, and four dedicated ISCTs, SIMCor informed its frameworks to assess the impact of integrating in-silico testing solutions into traditional clinical trials, as well as to evaluate and quantify the benefits for the clinical research workflow, industry, market, and broader societal perspective. These analyses highlight strengths and relevant barriers to the adoption of in-silico testing solutions into routine workflow and therefore will be beneficial for accelerating this adoption of virtual cohorts and simulation models into the development, testing and regulatory approval process of cardiovascular devices.