OBJECTIVE: The European Health Data Space (EHDS) shapes the digital transformation of healthcare in Europe. The EHDS regulation will also accelerate the use of health data for research, innovation, policy-making, and regulatory activities for secondary use of data (known as EHDS2). The Integration of heterogeneous Data and Evidence towards Regulatory and HTA Acceptance (IDERHA) project builds one of the first pan-European health data spaces in alignment with the EHDS2 requirements, addressing lung cancer as a pilot. METHODS: In this study, we conducted a comprehensive review of the EHDS regulation, technical requirements for EHDS2, and related projects. We also explored the results of the Joint Action Towards the European Health Data Space (TEHDAS) to identify the framework of IDERHA's alignment with EHDS2. We also conducted an internal webinar and an external workshop with EHDS experts to share expertise on the EHDS requirements and challenges. RESULTS: We identified the lessons learned from the existing projects and the minimum-set of requirements for aligning IDERHA infrastructure with EHDS2, including user journey, concepts, terminologies, and standards. The IDERHA framework (i.e., platform architecture, standardization approaches, documentation, etc.) is being developed accordingly. DISCUSSION: The IDERHA's alignment plan with EHDS2 necessitates the implementation of three categories of standardization for: data discoverability: Data Catalog Vocabulary (DCAT-AP), enabling semantics interoperability: Observational Medical Outcomes Partnership (OMOP), and health data exchange (DICOM and FHIR). The main challenge is that some standards are still being refined, e.g., the extension of the DCAT-AP (HealthDCAT-AP). Additionally, extensions to the Observational Health Data Sciences and Informatics (OHDSI) OMOP Common Data Model (CDM) to represent the patient-generated health data are still needed. Finally, proper mapping between standards (FHIR/OMOP) is a prerequisite for proper data exchange. CONCLUSIONS: The IDERHA's plan and our collaboration with other EHDS initiatives/projects are critical in advancing the implementation of EHDS2.