The research and innovation (R&I) action (project) to be funded under this topic is expected to transform the clinical research landscape and boost drug development for rare diseases by enhancing patient access to clinical trials and trial preparedness of investigational sites, increasing acceptability of new tools and methods, and preventing research fragmentation across Europe.

It will have a direct impact not only on patients with rare and ultra-rare¹ diseases but also on all stakeholders involved in drug development. More specifically, the expected impact will include the following:

• New pathways co-created by all interested parties and new rules / best practices for early engagement will facilitate clinical development in ‘white spot’ areas² and increase the likelihood that pharmaceutical and biotech companies will test drugs originally intended for common diseases in rare/ultra-rare disease populations with a plausible disease-modifying mechanism of action (MOA).
• Patients with rare/ultra‑rare diseases will benefit from cutting-edge clinical development of new health innovations in Europe (impacting the current situation of 95% of underserved rare diseases).
• By fostering the use of alternative innovative designs for randomised clinical trials, patients will have a higher probability of being assigned to active treatment, whether in Phase 2 and/or in Phase 3 registrational trials (especially critical for rare paediatric genetic diseases where the window of therapeutic intervention may be relatively narrow).
• Continuum of evidence generation accelerates authorisation and patient access / treatment / deployment.
• In line with the Accelerating Clinical Trials in EU³ (ACT-EU) initiative, proactive delivery of patient‑oriented medicines across populations including patients with rare/ultra-rare diseases will be increased. Europe is becoming more attractive for the clinical development of medicines for rare/ultra-rare diseases thanks to the uptake of innovative methodological approaches for conducting successful clinical trials for rare/ultra-rare diseases.
• Optimised and predictable referral of patients (physically and virtually) to expert centres, facilitated through incentives, while avoiding patients’ disadvantages/burdens (e.g., travel etc.) and inconsistency between healthcare providers would help sponsors in their clinical development where appropriate.

Overall, the success of the project should be determined by measuring an increase in the use of innovative trials, including complex trials, designed to target selected populations with rare/ultra-rare diseases, and in the use and dissemination of playbooks⁴, which will optimise the current situation⁵ and increase the number of new approved medicines targeting rare/ultra-rare diseases that are currently underserved.

_{1 Ultra-rare diseases: diseases with a prevalence <1 per 50 000 persons (https://err.ersjournals.com/content/29/156/200195)}

_{2 ‘White spot’: conditions for which there is no approved treatment option and where development is not currently commercially viable.}

_{3 https://www.ema.europa.eu/en/human-regulatory/research-development/clinical-trials/accelerating-clinical-trials-eu-act-eu}

_{4 Playbook: a book/guide including comprehensive guide on a technical topics, describing both overarching strategy and tactical approaches, and including all information relevant to the design, conduct, implementation and analyses of innovative CTs.}

_{5 https://www.nature.com/articles/d41573-022-00019-z / https://irdirc.org/resources-2/rd-metrics/}

The project generated from the topic should not only develop capacities and capabilities to execute innovative trial designs, but also plan to identify solutions to address scientific gaps as well as technical and operational challenges, and to collaborate / find synergies with relevant existing initiatives to establish a new, dedicated, rare disease specific and sustainable infrastructure. The project is expected to support innovation and optimise drug development for rare diseases with high unmet medical needs by focusing on clinical trials conducted for small populations and clusters of diseases with commonalities.

With a focus on addressing ‘white spots¹’ in a subset of the 95% of underserved rare diseases, the R&I action to be supported under this topic should:

1. Deliver novel rare/ultra-rare disease-specific methodological approaches² to transform the way treatments are developed with a view towards accelerating approval and access.
2. Pressure-test new clinical trial designs by using the playbooks co-created with stakeholders through case studies and modelling, addressing up to four selected paediatric / rare disease (or clusters of ultra‑rare diseases with commonalities) case studies, and different types of interventions (at least one for advanced therapy medicinal products (ATMP)).

In more detail, all the following outcomes are expected to be delivered:

• Playbooks³ for designing novel clinical trials (CT) for rare diseases / clusters of diseases that can also be used for education and training. Jointly created with and validated by regulators, health technology assessment (HTA) bodies, these playbooks should include:
  • good practice recommendations for multinational innovative studies, electronic health records (EHRs) driven registries and longitudinal natural history studies;
  • standardised processes across all disease areas, countries and sites for fast and reliable feasibility processes, allowing – for example – for early feasibility assessment to support the design of feasible development programmes. Effectiveness assessment of optimised CT designs as compared to the ‘gold-standard’ CT design for rare diseases;
  • study protocols co-created by expert network(s) with regulators, HTA bodies, patients, and industry;
  • agreement on a minimum set of data variables to be included in every registry / newly designed real‑world data (RWD) source (baseline patient characteristics, disease-related information, etc.) to ensure usability for regulatory decision-making and study planning;
  • information to support clinical research network set-up for conducting innovative trials including, for example, real world evidence (RWE), remote elements etc;
  • guidance from expert advice to developers on specific aspects when designing CTs.
• Alignment and complementarity with the European Partnership on Rare Diseases (in particular the ‘Clinical Research Network’) co-funded by Horizon Europe and Member States and Associated countries, to create synergies and avoid overlaps.
• Certified/qualified clinical trial sites scientifically and operationally (especially in the areas of ATMPs) with readily available pools of patients ready to be recruited into CTs where appropriate; working to agreed site standards along comparable process and quality standards.
• Structured and predictable system for referral of patient (physically and virtually) to expert centres, facilitated through incentives and avoiding patient disadvantages (travel etc.) and incongruity amongst healthcare providers.

_{1 ‘White spots’ - conditions for which there is no approved treatment option and where development is not currently commercially viable}

_{2 Framework defined as structured processes and methodologies}

_{3 Refer to footnote 67 (playbook).}

Developing medicines for rare diseases involves complexities and challenges beyond those typically seen for common conditions, in particular:

• for most rare diseases, disease aetiology, biology and natural history are insufficiently understood, while there are often no established endpoints for use in clinical trials;
• enrolling, engaging and retaining patients, including patients who may be far apart geographically;
• designing and evaluating clinical trials, including using/identifying relevant outcome measures;
• ensuring the quality of patient data, and enabling re-use of data (e.g. registries);
• underdeveloped and fragmented clinical trial infrastructure for the conduct of clinical studies, including those using ATMPs and for cell and gene therapies;
• an evolving and internationally fragmented global regulatory and landscape.

The evaluation of the regulations on Orphan Medicinal Products and Paediatric Medicines by the European Commission has concluded that those regulations have boosted the development of new therapies for rare diseases but have not yet adequately managed to direct research and innovation towards the areas of greatest unmet medical need. There is clearly a need for holistic and inclusive solutions to address the persisting root causes of these unmet medical needs and to deliver more medicines for patients with rare diseases. This topic, which contributes to the Rare Disease MOONSHOT Initiative¹ is expected to be an important catalyst for innovation for patients affected by some of the 95% of rare diseases without treatment options. Importantly, the project selected under this call would also align with the identified strategic priorities of the Horizon Europe co-funded Partnership on Rare Diseases that is expected to start in mid-2024 and to consolidate the Rare Disease (RD) research and innovation ecosystem.

The topic aims to unravel roadblocks on the current clinical development pathways and deliver methodological solutions for innovative clinical trial designs and analyses, including regulatory considerations.

To fulfil this 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;
• to build upon the results of Horizon 2020 (H2020) research projects such as the European Rare disease research Coordination and support Action (ERICA) and FP7 projects developing methodologies for clinical trials for small populations¹⁰ namely IDEAL¹¹, InSPiRe¹² or ASTERIX¹³. It will be crucial to optimise their findings (if necessary) based on new scientific/technological progress and find synergies with other existing projects, whether completed or ongoing;
• to build synergies with the new cluster of Horizon Europe projects on developing new effective therapies for RD with no approved options (expected to start in Q3 2023) and to partner with existing projects/initiatives, e.g., IMI (Innovative Medicines Initiative) Screen4Care¹⁴, IMI conect4children (c4c)¹⁵, Remedi4All¹⁶, C-Path RDCA-DAP¹⁷;
• to help overcome the fragmentation of the clinical trial environment across Europe;
• to identify solutions to overcome hurdles in the implementation of cross-border patient participation in clinical trials;
• to develop best practices to support the development of innovative and ‘regulatory-grade’ clinical trials and generate the appropriate evidence for regulatory and HTA decision-making.

Once developed and established, the playbooks and related infrastructures will be pressure-tested through case studies and modelling, using up to four selected paediatric/rare diseases (with at least one ultra-rare disease or clusters of diseases) and different types of interventions (at least one being an ATMP).

^{1 https://www.eurordis.org/rare-disease-moonshot/}

^{2 EJP RD (European Joint Programme on Rare Diseases): https://www.ejprarediseases.org/}

^{3 https://health.ec.europa.eu/european-reference-networks/overview_en}

^{4 https://health.ec.europa.eu/european-reference-networks/board-member-states_en}

^{5 https://health.ec.europa.eu/system/files/2020-03/statement_industry_conflictofinterest_en_0.pdf}

^{6 https://ncats.nih.gov/programs/BGTC}

^{7 https://eu-pearl.eu/}

^{8 https://www.eunethta.eu/eunethta-21/}

^{9 https://irdirc.org/activities/task-forces/orphan-drug-development-guidebook-task-force/}

^{10 https://cordis.europa.eu/search?q=contenttype%3D%27project%27%20AND%20programme%2Fcode%3D%27HEALTH.2013.4.2-3%27&p=1&num=10&srt=/project/contentUpdateDate:decreasing}

^{11 IDEAL – Integrated DEsign and AnaLysis of clinical trials in small population groups (rwth-aachen.de): https://www.ideal.rwth-aachen.de https://cordis.europa.eu/project/id/602552}

^{12 InSPiRe (Innovative methodology for small populations research): https://cordis.europa.eu/project/id/602144}

^{13 ASTERIX (Advances in Small Trials designs for Regulatory Innovation and eXcellence): http://www.asterix-fp7.eu/}

^{14 https://screen4care.eu/}

^{15 https://conect4children.org/}

^{16 https://remedi4all.org/}

^{17 https://portal.rdca.c-path.org/}