The objective of this deliverable is to define and develop a framework for estimating the impact of in-silico methods and technologies on clinical and preclinical trials, laying the basis for the assessment of broader effects on patient safety, animal welfare and industry workflow. In the introductory part a status view on this area is given. The document starts with basic terminology and definitions related to in-silico approaches. Thereafter, existing standards, guidelines and frameworks relevant for in-silico trials are referenced. Examples and use cases of published in-silico trials are presented as well as existing tools to support in-silico trials described. The introductory part of the deliverable closes with a selection of projects and programs dedicated to in-silico approaches and relevant for SIMCor. The approach for executing an in-silico trial in SIMCor will be based on the methodology provided by Bodner and Kaul (Proceedings of the ASME 2021 Verification and Validation Symposium, V001T02A0012021) for in-silico clinical trials for medical devices. This framework heavily relies on ideas already developed for model verification, validation, and uncertainty quantification. The process starts with the computational model, which is developed upstream of the in-silico trial. The next step is to establish baseline credibility evidence with the goal that the model is ready to use for the in-silico trial. After this step, clinical trial planning starts with developing the in-silico trial protocol. Thereafter, the in-silico trial is designed as follows: a virtual cohort following the specifications of the human cohort is generated and a final model validation will be performed using human data. If the model is adequate the model predictions to the target population can be performed and the clinical endpoints can be evaluated. An important aspect in applying in-silico trials is the transfer from engineering outputs to clinical endpoints. To support this process, transfer functions based upon available data will be considered in SIMCor.

SIMCor (In-Silico testing and validation of Cardiovascular IMplantable devices) has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 101017578.