RealiseD implements a collaborative and compRehensive mEthodological and operational Approach to cLinical trIalS in rarE Diseases enabling timely drug development and approval centred on patients’ needs with high level of evidence reachable in a limited environment. The core of RealiseD operational approaches includes the systematic procedures for patients’ referral, the certification of clinical sites and filling the gaps for successful development of rare and ultra rare diseases[(U)RD]’ clinical trials using 4 (U)RD diseases from 4 European Research Networks (ERNs). RealiseD methodological teams will optimise innovative statistical and quantitative approaches for design and analysis of (U)RD-CTs developed in the past 10 years and refined in the last years to facilitate the regulatory pathway for innovative drug development. RealiseD is implemented in a public private partnership consortium including regulators and HTA bodies representatives to co-create operational and methodological approaches in an iterative procedure using a multistakeholders’ agreement process. RealiseD will increase the incentives and motivation for the pharmaceutical industry by reducing many uncertainties on the path of drug development in (U)RD that will follow widely accepted rules. To achieve these innovative approaches, RealiseD will capitalise on an international multistakeholders effort as the problem in (U)RD drug development cannot be solved in a restricted geographical area. With the development and deployment of playbooks arising from the co-created developments, RealiseD will ascertain visibility and readiness of the innovations. The overall ambition of RealiseD is to change the paradigm of CT design for U(RD) by enlarging the spectrum of methodological and operational approaches and to establish a sustainable, innovative, and optimised CT paradigm for U(RD) medicinal product development programs, while maximizing the acceptance by all stakeholders.