Rare diseases face fundamental research and implementation challenges driven by small, scattered patient populations, incomplete natural history data, limited trial methodologies adapted to ultra-rare conditions, diagnostic delays, data fragmentation, lack of validated outcome measures, inconsistent integration of patient preferences, and economic barriers to therapy development and access. IMI and IHI projects on rare diseases (or with a rare disease angle) transform the European research and innovation ecosystem by accelerating diagnosis, pioneering adaptive and platform trial methodologies, strengthening paediatric and ultra-rare trial networks, integrating patient-generated and real-world data, and embedding patient preferences into decision-making. These public-private partnerships address the structural bottlenecks of rare disease research and improve Europe’s capacity to deliver timely, patient-centred and evidence-based therapies for rare and ultra-rare conditions.

1. Transforming clinical trial design for rare (and ultra-rare) diseases

The IMI/IHI projects below collectively make it feasible to conduct scientifically robust, efficient and ethically appropriate trials in small populations, accelerating therapy development where traditional designs are impractical.

• RealiseD develops practical playbooks and tools for ultra-rare disease trials, co-created with regulators, HTA bodies and patient groups. It also supports European Reference Networks and site certification to improve trial readiness.
• EU-PEARL constructed a European platform trial infrastructure, enabling adaptive, multi-arm, multi-indication studies under harmonised protocols. Recently, The Children’s Tumor Foundation and the Global Coalition for Adaptive Research built on the project’s outputs using the EU-PEARL’s model for a platform trial for patients with neurofibromatosis-1 (NF-1) and schwannomatosis (SWN) into a reality (link).
• AIMS-2-Trials advances innovative methodologies such as Bayesian designs, adaptive randomisation and master protocols, while aligning these approaches with regulatory and HTA expectations. The project focuses on autism and although it is not a rare disease, rare diseases are an integral part of this project. Several rare diseases such as Phelan-McDermid syndrome, Fragile X, TSC1, and SHANK-related disorders present an autism phenotype and have been included in the project. In addition more than half the individuals registered on the EAGER registry, developed under AIMS-2-Trials, have a rare disease.
• CONNECT4Children (C4C) strenghted Europe’s paediatric clinical trial network, critical for rare diseases with childhood onset, by harmonising standards and facilitating multinational recruitment. Following the project completion, a dutch-based foundation C4C Stichting is now supporting academia and industry in paediatric clinical research (about half of them in rare diseases), also as part of European Rare Disease Research Alliance (ERDERA), involving 180 organisations from 36 countries to help make Europe a world leader in rare diseases research and innovation.

2. Shortening time to diagnosis and enabling early detection

Screen4Care aims to accelerate rare disease diagnosis through a dual approach combining genetic newborn screening and digital technologies. By combining early genetic screening with data-driven digital tools, Screen4Care generates new knowledge and diagnostic pathways in areas where scientific evidence and translational capacity remain limited, helping illuminate rare disease “white spots” (link). Screen4Care addresses this urgent need by building a more systematic, technology-enabled diagnostic framework:

• The first pillar focuses on genetic newborn screening to enable earlier detection of rare diseases, particularly relevant as over 70% are genetic and nearly 90% affect children.
• The second pillar deploys digital tools, including the Screen4Care Meta-Symptom Checker and Virtual Clinic. Through predictive algorithms, federated machine learning, and integration with Electronic Health Records (EHRs), the project aims to flag at-risk patients and shorten time to diagnosis. The Meta-Symptom Checker supports individuals navigating unclear symptoms, while the Virtual Clinic guides patients from suspicion to diagnosis and provides ongoing post-diagnosis support.

3. Building interoperable, patient-centred data ecosystems

Rare disease research suffers from fragmented registries and disconnected data sources and the projects below are tackling these structural barriers.

• PaLaDIn integrates registries, real-world data, wearable data and patient-reported outcomes into harmonised platforms for neuromuscular diseases.
• The Med Safety App was created under the WEB-RADR project, to explore and utilise the powers of social media and new technologies for pharmacovigilance purposes. Through collaboration between the WEB-RADR project, the World Health Organisation (WHO), the Uppsala Monitoring Centre (UMC), and the MHRA, the Med Safety mobile app was launched in 2017 to support direct electronic reporting of suspected adverse reactions. Originally designed as a mobile app, Med Safety is an electronic reporting tool that empowers health professionals and members of the public to easily submit suspected adverse reaction reports for medicines and vaccines. Med Safety facilitates direct and structured reporting of suspected ADRs to National Centres. Users can also access up-to-date information and news alerts for selected products of interest.

4. Embedding patient voice and preference into research and decisions

Research outcomes and benefit–risk assessments increasingly reflect what matters most to patients and caregivers, improving relevance and trust.

• PREFER published evidence-based recommendations on how and when to include patient perspectives on benefits and risks of medicinal products aiming at supporting the development of guidelines for industry, Regulatory Authorities and HTA bodies.
• PaLaDIn and RealiseD co-create tools with patients to ensure endpoints reflect real-world priorities.
• Paediatric networks such as C4C ensure age-appropriate design and ethical standards.

5. Strengthening Europe’s rare disease research infrastructure

Beyond individual projects, the portfolio builds durable European capacity to become a more attractive and coordinated environment for rare disease R&D, reducing duplication, increasing efficiency and supporting equitable access to innovation.

Across the portfolio, IMI and IHI public private partnerships:

• Address the core structural bottlenecks of rare disease research (small populations, trial feasibility, fragmented data).
• Pioneer adaptive and platform trial methodologies suited for rare contexts.
• Accelerate genetic and AI-enabled diagnosis.
• Build interoperable, patient-centred data ecosystems.
• Strengthen paediatric and advanced therapy readiness.
• Integrate patient preferences and real-world evidence into decision frameworks.

More information on these projects can be found here.