The advancement of sciences and technologies, economic challenges, increasing expectations, and consumerism result in a radical transformation of health and social care around the globe, characterized by foundational organizational, methodological, and technological paradigm changes. The transformation of the health and social care ecosystems aims at ubiquitously providing personalized, preventive, predictive, participative precision (5P) medicine, considering and understanding the individual's health status in a comprehensive context from the elementary particle up to society. For designing and implementing such advanced ecosystems, an understanding and correct representation of the structure, function, and relations of their components is inevitable, thereby including the perspectives, principles, and methodologies of all included disciplines. To guarantee consistent and conformant processes and outcomes, the specifications and principles must be based on international standards. A core standard for representing transformed health ecosystems and managing the integration and interoperability of systems, components, specifications, and artifacts is ISO 23903:2021, therefore playing a central role in this publication. Consequently, ISO/TC 215 and CEN/TC 251, both representing the international standardization on health informatics, declared the deployment of ISO 23903:2021 mandatory for all their projects and standards addressing more than one domain. The paper summarizes and concludes the first author's leading engagement in the evolution of pHealth in Europe and beyond over the last 15 years, discussing the concepts, principles, and standards for designing, implementing, and managing 5P medicine ecosystems. It not only introduces the theoretical foundations of the approach but also exemplifies its deployment in practical projects and solutions regarding interoperability and integration in multi-domain ecosystems. The presented approach enables comprehensive and consistent integration of and interoperability between domains, systems, related actors, specifications, standards, and solutions. That way, it should help overcome the problems and limitations of data-centric approaches, which still dominate projects and products nowadays, and replace them with knowledge-centric, comprehensive, and consistent ones.