This reprint addresses healthcare transformation towards personalized, participative, preventive, predictive, and precision medicine (5P Medicine) with the support of new technologies such as micro-, nano-, and bio-techniques, as well as artificial intelligence and learning systems. These technologies offer big opportunities, but also bear big challenges regarding ethics including security, privacy, and related policies to be managed. The resulting multidisciplinary, highly dynamic, and context-sensitive 5PM ecosystems shall enable consistent and comprehensive interoperability between all actors, domains, specifications, and work products based on the understanding of the real-world business system and its development process viewpoints. This requires the representation and management of knowledge from different domains and their actors, using their methodologies and languages, but also individual skills and experiences. The outcome is a system-oriented, architecture-centric, ontology-based, policy-driven approach allowing for the formal representation and management of health ecosystems, including their standardized integration and interoperability in ISO 23903 Interoperability and integration Reference Architecture. The reprint describes the principles, methodologies, and standards needed for successfully managing the transformation of health and social care, exemplified by practical projects and solutions. The reprint is based on papers published in the context of the pHealth 2022 Conference in Oslo, Norway, which have been strongly extended regarding their focus and size.