This document was developed to provide a standard operating procedure (SOP) on the generation of virtual cohorts and their validation for use in in-silico trials. It aims to establish a systematic approach to building and validating virtual cohorts, for immediate use in device-effect simulation and thereby facilitate the in-silico trials. Considering the wide possibilities of ‘context(s) of use’ for virtual cohorts, we present a broad set of recommendations, building on the advances and the specific learnings from the two SIMCor use cases: transcatheter aortic valve implantation (TAVI) and pulmonary artery pressure sensors (PAPS). The SOP presents the cycle of development, validation, and application of virtual cohorts of pigs and humans, as applied to the above-mentioned use cases. Moreover, in theOutlook section, we sketch the broad perspectives on critical factors that need to be considered while attempting to generate virtual cohorts. Also, highlighted are the nuances related to their validation for different ‘context(s) of use’. This deliverable also includes two tangible applications of virtual cohorts, on the aortic valve and the pulmonary artery, for predicting patient-specific treatment outcomes like leakage post-implantation or device migration. 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.