To fulfil the above aim, the proposal should:

• identify good practices for the design, use and implementation of innovative clinical trial (e.g., basket trials, platform trials, in silico trials) and of tools/methods (e.g., RWD, digital health technologies, quantitative approaches, trial with remote elements) developed for small populations and clusters of diseases, while also addressing scientific and statistical challenges with the generation and interpretation of small, incomplete and/or heterogenous data sets to help support CT and product approval;
• identify good practices to address knowledge gaps including the collection of natural history data, the development of relevant new endpoints and patient reported outcomes (PROs) which should be incorporated into the CT design;
• benchmark new clinical trial designs (i.e. basket, platform CTs, shared control arm trials between different sponsors…) that should be assessed and compared to the existing ‘gold standard’ CT model for rare diseases (i.e. single arm);
• focus on paediatric and adult rare diseases (‘white spots’);
• develop appropriate capacity and capability for innovative clinical trials as well as education and training programmes based on lessons learnt from existing initiatives and developers’ experience so that best practices to optimise drug development in rare diseases can be shared and disseminated, and playbooks deployed;
• develop a virtual platform for knowledge and tool sharing, which could be also used for playbook deployment;
• identify clinical trial sites which are certified/qualified scientifically and operationally (especially in the areas of ATMPs) with readily available pools of patients ready to be recruited into CTs where appropriate. Taking into account the cohort size of such clinical trials it will be quite important to ensure the cultural and geographical distribution of the CT at EU level;

To be successful and deliver according to the objectives, it is important:

• to capitalise on past public investments and collaborate with relevant stakeholders, e.g. with the European Reference Networks (ERNs) and their registries, the European Joint Programme on Rare Diseases (EJP RD2) and the future European partnership on rare diseases (RDP) to foster a more cost-effective pathway for the development of treatments for patients with rare diseases in Europe. The ERNs3 are being established under the Directive on patients’ rights in cross-border healthcare, with their registries under the supervision of the Member States4 and therefore any plan for collaboration between ERNs and industry should be compatible with the principles5set up by the ERN Board of Member States and the Commission services. Hence the need to identify solutions to unlock industry collaboration with ERNs (e.g., leveraging on ERNs’ clinical expertise, ERN registries, etc.) should be in line with these principles;
• to utilise the European Commission’s infrastructure for the RD registry data and clinical cohorts ecosystem, namely the European Platform on Rare Disease Registration (EU RD Platform) for clinical data management;
• to leverage key learnings from existing ongoing initiatives, e.g., the Bespoke Gene Therapy Consortium6 IMI EU-PEARL7 EUnetHTA218 or of the IRDIRC “Orphan Drug Development Guidebook” project9 which aims at creating a simple guidebook for academic and industrial drug developers describing the available tools and initiatives specific for rare disease development and how best to use them; etc. (see the Funding&Tenders).