The Rare Disease Moonshot: Paradigms Shift, Translational Medicine, and Regulatory Science for the World's Rarest Conditions

The European Commission (EC) supports the rare diseases field extensively through public–private partnership (PPP) and its framework programs since 2005 and 2007, respectively. Notably, most recently with the proposed European Partnership on Rare Diseases (European Rare Diseases Research Alliance – ERDERA proposal) and the Innovative Health Initiative (IHI) topic 3 Call 4¹ project focusing on new ways of doing clinical trials for rare and ultra-rare diseases. Additionally, an Horizon Europe funding call on new therapies for rare diseases (RD) enabled 11 new projects to start in 2023 and 2024, two among these projects will deal with modeling and simulation to address regulatory needs in the development of orphan and pediatric medicines. While over the years these projects have shown the value of multistakeholders' collaboration, they are currently operating relatively independently of the others, yet for all these collaborative initiatives to be sustainable and successful it will require going far beyond what any one project could do alone.

This perspective presents the Rare Disease Moonshot initiative with its purpose, strategies, and priorities to find new treatments and cures for the world's rarest and most severe conditions that currently have no therapeutic options, and which often affect children. It presents the work that is still required to further stimulate the integration of high-quality regulatory science in research which is of particular importance for RD, support the development and organization of large-scale sustainable infrastructures and, de-risking investment to accelerate funding such as the need for a Regulatory Readiness Level scale.

The EC's evaluation² of the medicines for RDs and pediatric legislations published in 2020 acknowledged that the Orphan Regulation has not sufficiently managed to support development in areas where the need for innovative medicines is greatest. The main issues remaining for diseases with lower incidence being the most challenging ones, with the key to unlocking breakthroughs in diagnosis and treatment being fostering dynamic international partnerships and streamlined data sharing.³ Therefore, in December 2022 an informal coalition of the willing (The Critical Path Institute (C-Path), the European Infrastructure for Translational Medicine (EATRIS), the European Clinical Research Infrastructure Network (ECRIN), the Biobanking and Biomolecular Resources Research Infrastructure – European Research Infrastructure Consortium (BBMRI-ERIC), the European Federation of Pharmaceutical Industries and Associations (EFPIA), the European Confederation of Pharmaceutical Entrepreneurs (EUCOPE), EuropaBio, EURORDIS-Rare Diseases Europe, and the European Joint Programme for Rare Diseases (EJP-RD)) was initiated, the Rare Disease Moonshot.⁴ The mission of the initiative is to engage with external advisors and stakeholders to boost public–private collaborations with a focus on addressing the gaps and challenges in the therapeutic development for rare and ultra-RDs, to identify strategies and priorities that are published by the mean of recommendations. The aim of the recommendations is to inform funders of research programs at national, European and international levels from public and private sectors who plan projects in RD, such as the IHI Call 4 topic 3.¹ It defines how to develop, implement, and sustain complex systems with the full drug development lifecycle being considered. Three recommendations have already been published to support research projects aimed at developing new tools for diagnostics and treatments, and expediting clinical trial readiness.⁵ The recommendations should be contributing to enable regulatory approval and research that quickly yields safer and more effective medicinal products with affordable and sustainable access for patients. These have been developed with an iterative process deeply rooted in instrumental stakeholders collaboration critical to accelerating RD research.

One of the key challenges identified in the clinical trials research recommendations is the need for leveraging existing data, resources and infrastructure, with the integration of regulatory grade sources in research and development plans. Regulators have demonstrated that when engaging and boosting regulatory science, data collaboration strategies, and patient experience research into the design and planning at the earliest stages of development, the implementation of new methods and tools can be accelerated.⁶ Research Infrastructures constitute a powerful resource to integrate regulatory science and is a prerequisite for collaboration between regulators, patients, industry and academia contributing to, and directly accelerating the goals set by IRDiRC and its Orphan Drug Development Guidebook.⁷ Europe's Research Infrastructures are decisive for our capacity to deliver scientific breakthroughs and to foster innovation, they should facilitate cross-disciplinary research and the exploitation of data interoperability to produce new science while tackling remaining challenges in rare and ultra-rare disease. The impact of such infrastructure, combined with regulatory science can minimize risks, costs, and patients' burden; however, to be successful, it requires gathering knowledge and data collaboration from the patients, research, and industry communities that can foster project outcomes meeting regulators' standards and expectations. Yet the lack of integration of regulatory science in the plan, design, and conduct of projects still needs to be addressed.

The draft Strategic Research & Innovation Agenda⁸ of ERDERA identifies the generation of regulatory-compliant research results in academia-driven development for novel therapeutics as a challenge which is often compromised by the lack of interaction beforehand with regulators and timely scientific advice. Factors have been identified that can contribute to the failure to develop and implement a properly informed regulatory strategy, are for example, a lack of understanding of regulatory science, resources and requirements among academic researchers, and a gap in communication and engagement between key stakeholders.⁹ The Moonshot multidisciplinary ecosystem aims to facilitate access to state-of-the-art infrastructures, combined with expertise in RD that are integrating regulatory science and hence are accelerating the discovery and development of novel therapies. Leveraging and developing such research infrastructures can lead to reducing failure rates of therapeutic developments by providing sustainable solutions that are fit for regulatory purposes and support data collaboration. For example, when integrated into the research project, regulatory science and data collaboration help to create new tools, such as Drug Development Tools (DDTs)¹⁰ and technologies, to get fundamentally better answers about how the safety and effectiveness of new products can be demonstrated, something that any one project could not do alone. Increased public availability of qualified DDTs is anticipated to benefit public health through (1) increased availability of effective drugs, (2) earlier access to medical therapies, (3) enhanced knowledge of the drug under development, and (4) increased quality of research and acceptability of its results. Investing in multistakeholders collaborations can be successful and sustainable; however, resources and infrastructures needed are often beyond the capabilities of a single entity, particularly because generating, collecting, analyzing and protecting data and information, and making it available to different users is fraught with hurdles.

Furthermore, the journey of translating scientific findings into patient benefit involves the need for a clear, viable, commercialization pathway which combined with unknown regulatory requirements, may deter some companies from development of drugs with small markets that may not be seen as economically viable targets. This often leads to a lower interest of investors due to the perceived risk of developing new treatment for RDs. To achieve the development of an infrastructure ecosystem that strives for scientific excellence, with impact and provides transnational services that may de-risk investments requires to have a systematic and consistent framework on the main regulatory requirements expected. In return, delivering projects in RD research and development that are contributing to regulatory approvals and access would result in decreased time, risk and cost associated with new medicines in rare disease. It is therefore essential that the investigators, their organizations and their funders have an adequate understanding of the various steps and tools necessary to navigate regulatory pathways and deliver outcomes that can enable regulatory approval and access. In 2020, the development of such tools was initiated by Mc Gowran et al.,¹¹ in the form of a Regulatory Readiness (RRL) tool. As an example of sponsors developing innovative medicines for marketing authorization (MA), Table 1 exemplifies how the RRL complemented by regulatory interactions can be a potential framework correlating regulatory pathways to facilitate the development and conduct of regulatory strategies. In the PPPs context, however, outcomes are often new end points, biomarkers, technologies (e.g., nanotechnologies and artificial intelligence-based technologies), and new scientific approaches (e.g., new approach methodologies to reduce animal use, modeling and simulation, and complex clinical trial methodology) which may also influence regulatory decision-making on MA. Similarly to a medicinal product, the potential regulatory impact of these projects should be considered at an early stage and require regulatory engagement through formal pathways. To undertake this approach, IHI has recently revisited its regulatory considerations guidance¹² on aspects to be considered when preparing a proposal and during project implementation. Applicants and consortia are expected to consider the potential impact of their projects' results on the regulatory framework to ensure that the type and level of evidence generated during their projects will meet the regulators' standards and expectations. These tasks will require time, work, resources and access to sustainable infrastructures.

The RD Moonshot was set up to boost public–private collaborations to address the gaps and challenges in therapeutic development for rare and ultra-rare diseases. After its first 2 years, the Moonshot partners have identified an urgent need for public–private collaborative work that further stimulate the integration of regulatory science in research and support the organization of large-scale sustainable infrastructures particularly for data collaboration. Investing in PPPs helps organizations and stakeholders to share the risks of innovation in high unmet need areas, the cost of infrastructures, and the work required to acquire relevant scientific expertise with large data sets that translate discoveries into treatments. Combined, with the development of an RRL framework consolidated by a broad consultation process at European level would allow for projects at all stages of the development to contribute to regulatory approvals and access. This would result in more efficient synergies and direction between various European and national sources of funding where significant resources have been invested. The Moonshot partners will continue to engage with external advisors and stakeholders to identify strategies and priorities for the successful implementation of their recommendations, the RRL development and will ensure their broad dissemination, application, and adoption to maximize their benefits so that projects at all stages can deliver sustainable research that quickly yields more safe, effective, medical products for people everywhere with RDs in a timely manner.

No funding was received for this work.

The authors declared no competing interests for this work.