Study on Rare Diseases

Table of Contents

• Tackling rare diseases 1
• Challenges, opportunities and gaps for action on rare diseases in the European Union 1
• DO NOT DELETE PAGE BREAK 2
• Tackling rare diseases 3
• Challenges, opportunities and gaps for action on rare diseases in the European Union 3
• Abstract 3
• There are around 36 million patients suffering from rare diseases in the EU. This in-depth analysis gives an overview of European actions for rare diseases to date and identifies opportunities and gaps for further EU level actions to improve diagnosis, care, and treatment for rare diseases. 3
• This document was provided by the Policy Department for Economic, Scientific and Quality of Life Policies at the request of the Committee on Public Health (SANT). 3
• This document was requested by the European Parliament's Subcommittee on Public Health (SANT). 4
• AUTHORS 4
• Bregtje KAMPHUIS, Technopolis B.V. 4
• Thyra DE JONGH, Health Insights 4
• Veerle BASTIAANSSEN, Technopolis B.V. 4
• ADMINISTRATOR RESPONSIBLE 4
• Christian KURRER 4
• EDITORIAL ASSISTANT 4
• Irene VERNACOTOLA 4
• LINGUISTIC VERSIONS 4
• Original: EN 4
• ABOUT THE EDITOR 4
• Policy departments provide in-house and external expertise to support European Parliament committees and other parliamentary bodies in shaping legislation and exercising democratic scrutiny over EU internal policies. 4
• To contact the Policy Department or to subscribe for email alert updates, please write to: 4
• Policy Department for Economic, Scientific and Quality of Life Policies 4
• European Parliament 4
• L-2929 - Luxembourg 4
• Email: Poldep-Economy-Science@ep.europa.eu 4
• Manuscript completed: June 2024 4
• Date of publication: June 2024 4
• © European Union, 2024 4
• This document is available on the internet at: 4
• http://www.europarl.europa.eu/supporting-analyses 4
• DISCLAIMER AND COPYRIGHT 4
• The opinions expressed in this document are the sole responsibility of the authors and do not necessarily represent the official position of the European Parliament. 4
• Reproduction and translation for non-commercial purposes are authorised, provided the source is acknowledged and the European Parliament is given prior notice and sent a copy. 4
• For citation purposes, the publication should be referenced as: Kamphuis, B. et Al., 2024, Tackling rare diseases, publication for the Subcommittee on Public Health, Policy Department for Economic, Scientific and Quality of Life Policies, European Parliament, Luxembourg. 4
• © Cover image used under licence from Adobe Stock. 4
• CONTENTS 5
• LIST OF BOXES 7 5
• LIST OF FIGURES 7 5
• LIST OF TABLES 7 5
• LIST OF ABBREVIATIONS 8 5
• EXECUTIVE SUMMARY 10 5
• 1. INTRODUCTION 14 5
• 1.1. Aim and structure of the study 15 5
• 2. EUROPEAN ACTION FOR RARE DISEASES 16 5
• 2.1. Overarching action 18 5
• 2.1.1. Legislation 18 5
• 2.1.2. Policy Programmes, Communications and Recommendations 21 5
• 2.1.3. Establishing national plans for rare diseases 22 5
• 2.1.4. Involvement of patient organisations in decision-making 24 5
• 2.1.5. Opportunities and gaps in overarching action for rare diseases 24 5
• 2.2. Addressing research and knowledge gaps 26 5
• 2.2.1. European expert groups on rare diseases 26 5
• 2.2.2. Dedicated research or project funding 28 5
• 2.3. Addressing issues around diagnosis and codification of rare diseases 29 5
• 2.3.1. Diagnosis through screening 30 5
• 2.3.2. Collaboration in diagnosis and treatment through European Reference Networks 31 5
• 2.3.3. Codification systems for rare diseases 33 5
• 2.3.4. Registries for rare diseases and biobanks 34 5
• 2.3.5. Opportunities and gaps in diagnosis and codification 35 5
• 2.4. Addressing market failure in product development 36 5
• 2.4.1. Key elements for orphan medicines in proposed pharmaceutical legislation 37 5
• 2.4.2. Funding for R&D 42 5
• 2.5. Addressing issues around patient access and market access 47 5
• 2.5.1. Marketing authorisation 47 5
• 2.5.2. National level pricing and reimbursement 48 5
• 2.6. Addressing high prices and lack of competition 50 5
• 2.6.1. Mechanism of Coordinated Access to Orphan Medicinal Products 50 5
• 2.6.2. New pharmaceutical legislation 51 5
• 2.6.3. Opportunities and gaps 51 5
• 3. CONCLUSIONS 53 5
• APPENDIX A: THE EVALUATION OF THE EU GENERAL PHARMACEUTICAL LEGISLATION 55 6
• REFERENCES 57 6
• LIST OF BOXES 7
• Box 2: Overview of EU expert groups on rare diseases 26 7
• Box 3: European Joint Actions 28 7
• Box 4: Examples of EU funded projects working to share data and knowledge 29 7
• Box 5: Overview of E-Rare programmes 43 7
• Box 6: Overview of the European Joint Programme on Rare Disease (EJP-RD) 44 7
• Box 7: Health Technology Assessment 47 7
• Box 8: External reference pricing 49 7
• LIST OF FIGURES 7
• Figure 1: Research questions and key challenges in the field of rare diseases 15 7
• LIST OF TABLES 7
• Table 1: Overview of actions taken by the European Union to address challenges in the field of rare diseases 11 7
• Table 2: Overview of instruments, tools and initiatives 16 7
• Table 3: Overview of main changes to rare disease incentives and provisions (non-exhaustive) 38 7
• Table 4: Summary of opportunities, gaps and concerns 53 7
• Table 5: 2023 Proposals for European Pharmaceutical Legislation 56 7
• Box 1: EUROPLAN 23 7
• LIST OF ABBREVIATIONS 8
• Belgium, the Netherlands, Luxembourg, Austria and Ireland 8
• BeneluxAI 8
• Childhood Cancer International (European branch) 8
• CCI Europe 8
• European Commission Expert Group on Rare Diseases 8
• CERGD 8
• Committee for Medicinal Products for Human Use 8
• CHMP 8
• Coordination Group for Mutual Recognition and Decentralised Procedures-Human 8
• CMDh 8
• Committee on Orphan Medicinal Products 8
• COMP 8
• European Economic Area 8
• EEA 8
• European Economic and Social Committee 8
• EESC 8
• European Federation of Pharmaceutical Industries and Associations 8
• EFPIA 8
• European Joint Programme on Rare Diseases 8
• EJP-RD 8
• European Medicines Agency 8
• EMA 8
• European Platform for Rare Disease Registries 8
• EPIRARE 8
• European Rare Disease Registry Infrastructure 8
• ERDRI 8
• European Reference Network 8
• ERN 8
• External Reference Pricing 8
• ERP 8
• European Union 8
• EU 8
• European Union Committee of Experts on Rare Diseases 8
• EUCERD 8
• European Alliance of Rare Disease Patient Organisations 8
• EURORDIS 8
• Framework Programme 8
• FP 8
• General Pharmaceutical Legislation 8
• GPL 8
• Health Technology Assessment 8
• HTA 8
• Health Technology Assessment Regulation (EU) 8
• HTAR 8
• High Unmet Medical Need 8
• HUMN 8
• 10th version of the International Classification of Diseases 9
• ICD-10 9
• French National Institute for Health and Medical Research 9
• INSERM 9
• International Rare Diseases Research Consortium 9
• IRDiRC 9
• Mechanism of Coordinated Access to Orphan Medicinal Products 9
• MoCA-OMP 9
• Joint Action 9
• JA 9
• Joint Action on integration of ERNs into national healthcare systems 9
• JARDIN 9
• Member States 9
• MS 9
• Rare Disease Task Force 9
• RDTF 9
• Research & Development 9
• R&D 9
• Orphan Medicinal Products 9
• OMPs 9
• Paediatric Investigation Plan 9
• PIP 9
• Pharmacovigilance Risk Assessment Committee 9
• PRAC 9
• European Society for Paediatric Oncology 9
• SIOP 9
• Steering Group on Health Promotion, Disease Prevention and Management of Non-Communicable Diseases 9
• SGPP 9
• Small and Medium Enterprise 9
• SMEs 9
• Treaty on the Functioning of the European Union 9
• TFEU 9
• Unmet Medical Need 9
• UMN 9
• EXECUTIVE SUMMARY 10
• Background 10
• Rare diseases affect around 36 million patients in the European Union, with extensive effects on their quality of life. Despite widespread recognition of the importance of tackling rare diseases, challenges remain around their diagnosis, care, and treatment. Problems around the diagnosis of rare diseases are exacerbated by continuing gaps in research and knowledge for rare diseases, and difficulties in the codification of rare diseases. And, even where diagnoses are given, patient access to care and treatment for these conditions varies across the European Member States. The development of suitable treatments is marked by market failure and requires stimulation. However, difficulties in clinical development and evidence generation, establishing the efficacy and effectiveness of treatments remain problematic even if research and development (R&D) is incentivised. And even when products for rare diseases (‘orphan medicines’) make it out of R&D stages and are available on the market, they are often characterised by high prices and a lack of competition, affecting patient access to these treatments. 10
• Aim 10
• The aim of this study is to seek answers to three research questions: 10
• 1. What does the European Union do to address the challenges in the field of rare diseases? 10
• 2. How successful are the actions taken by the European Union? 10
• 3. What do stakeholders think the European Union could do to further address the challenges in the field of rare diseases? 10
• This study answers these questions through a desk-based mapping of initiatives and review of peer-reviewed articles and other literature. 10
• Key Findings 10
• The European Commission, or other European bodies, have undertaken action to addressing the most salient challenges for rare diseases, namely: 10
•  A lack of data, information, and research into rare diseases; 10
•  Problems around diagnosis of rare diseases, and the codification of individual rare diseases in and across Member States; 10
•  Market failure in developing treatments for rare diseases; 10
•  Problems in establishing market or patient access to treatments for rare diseases; and 10
•  High prices for treatments for rare diseases 10
• Table 1 outlines the main actions. 10
• Table 1: Overview of actions taken by the European Union to address challenges in the field of rare diseases 11
• - The introduction of a definition for high unmet medical need 12
• - Amendments to market exclusivity periods and regulatory data protection periods 12
• - Amendments to the orphan designation 12
• - Reorganisation of the Committee on Orphan Medicinal products 12
• At a general level, stakeholders recommend the creation of a European policy framework to support, guide, and monitor national plans for rare diseases and a renewed European Action Plan for rare diseases to update older guidance. Across the board, stakeholders have also reiterated the need to increase patient engagement and empowerment by, for example, including patients in critical dialogue, initiatives, and design of care pathways, and supporting patient organisations. Embedding equal access to comprehensive care can also be supported by other EU policies and guidelines, such as the EU Disability Strategy. 12
• Issues around diagnosis should benefit from the improved use of existing and new technologies for diagnosis of rare diseases, extending to the development and equitable implementation of next generation sequencing and other new technologies for improved diagnosis. 12
• Stakeholders have noted that the ERN ecosystem can also be improved, notably by integrating ERNs into national systems. Also important are to continue efforts to improve interoperability and standardisation of health data, and use of the European Health Data Space to promote data sharing. 12
• The proposed revised pharmaceutical legislation seeks to address market failures in the research and development space, which could springboard wider prioritisation and collaboration in key areas of high unmet medical need. The proposal are in the process of being discussed by Member States, so bringing these provisions into force and monitoring their effects is key. Within this point, and if the proposals are brought into force as they are currently phrased, reflecting on both uncertainty around the definition of high unmet medical need and effects of launch incentives on SMEs and/or MS will be critical. 13
• R&D could also benefit from the prioritisation of patient participation, innovation, and collaboration in R&D by the EU, including the efficient use of resources, encouragement of patient-centred research, and fostering international research collaborations. It is also important to find mechanisms for R&D which are flexible, sustainable, and durable, and able to respond to emergent health threats. 13
• While pricing and reimbursement are national competencies in the EU, the use of the joint HTA assessment processes introduced by the HTA Regulation may be essential in bringing novel products with limited evidence to market more quickly for patients. Orphan medicinal products are notoriously expensive. Stakeholders have suggested the creation of a solidarity fund to pay for rare disease treatments would allow Member States to pool resources to pay for rare disease treatments. In the meantime, continue collaboration in price negotiation or procurement for rare disease treatments is an interim tool to address high prices, together with EU initiatives like the Mechanism of Coordinated Access to Orphan Medicinal Products (MoCA-OMP). 13
• 1. Introduction 14
• 1.1. Aim and structure of the study 15
• Rare diseases are defined in the EU as conditions that affect no more than 1 in 2,000 individuals; while one rare disease may only affect a handful of patients in the EU, others may affect around 200,000. While the patient populations per rare disease are considered small in comparison to more common ailments, there are around 6,000 to 8,000 distinct rare diseases3. All in all, this means that there are around 36 million patients suffering from rare diseases in the EU3 and that rare diseases affect about 4% of the population during their lifetime. An estimated 80% of rare diseases arise due to genetics4. Rare diseases are often chronically debilitating and/or life-threatening: about 70% of these conditions manifest in childhood as life-long and disabling conditions and give rise to complex needs4. EURORDIS, the European alliance of rare disease patient organisations, indicates that “the quality of life of a person living with a rare disease is affected by lack or loss of autonomy due to chronic, progressive, degenerative, and frequently life-threatening aspects of the disease”5. As the prevalence of each disease is low, there is also limited medical expertise and overall knowledge on the disease as well as limited research. This is why rare diseases are also referred to as orphan diseases and rare disease patients as the ‘orphans of the health systems’ as they often can’t attain diagnosis, treatments, or the benefits of research5. There are often no existing effective cures for rare diseases5, as 90% of rare diseases currently do not have any approved therapies. 14
• Rare diseases are considered a pressing public health concern both in Europe and globally given the aggregate number of patients suffering from them, the limited treatment options, and the impact of rare diseases on individual patients. Despite widespread recognition of the importance of tackling rare diseases, several important challenges remain. For example, the small patient populations mean that the pharmaceutical industry is not inherently interested in these diseases as the industry expects high costs for research and development but low revenues due to small case numbers. Patients suffering from rare diseases also often deal with delayed diagnosis, with large amounts of patients having to wait multiple years for diagnosis and large amounts of patients having received an initial wrong diagnosis with inappropriate surgery, medication, or psychological care as a result. Individual rare diseases are also not always seen as a research priority by government, pharmaceutical companies, or charities, which means that researcher can struggle to access the funds needed to adequately study rare diseases. These challenges sit within broader economic, social, political and technological trends which can cause difficulties, such as demographic changes, greater variation in access to treatments and increased strain on healthcare budgets, as well as opportunities, such as the increased use and potential for data and AI solutions and a rise in patient-led research. 14
• Addressing the gaps and issues around rare diseases requires efforts at both Member State and European level. The rare diseases field is particularly relevant for European action, given issues around the small patient populations, limits in knowledge and experience for rare diseases, and the often-remaining variation across the EU Member States in aspects of diagnosis, care, and treatment for rare diseases. Rather than trying to battle these medical conditions at a national level, bringing together resources and knowledge across EU Member States can address some of these issues and provide major added value,. 15
• The aim of this study is to seek answers to three research questions across key challenges for the diagnosis, treatment, and care of rare diseases (see Figure 1). For each major challenge, we identify the main actions undertaken by the European Commission, discuss their successes or limitations, and identify opportunities and gaps that remain. 15
• Figure 1: Research questions and key challenges in the field of rare diseases 15
• / 15
• Source: Authors’ own elaboration. 15
• This study seeks to answer these questions through a desk-based mapping of initiatives and review of peer-reviewed articles and other literature. A limitation of this method is that that secondary data alone is not sufficient in order to identify all opportunities and gaps, especially for currently ongoing or future activities. 15
• 2. European action for rare diseases 16
• 2.1. Overarching action 18
• 2.1.1. Legislation 18
• a. Orphan Regulation No 141/2000 18
• 2.1.2. Policy Programmes, Communications and Recommendations 21
• a. Community Action Programme on Rare Diseases 21
• b. 2008 Communication COM/2008/679 on rare diseases and challenges for Europe 21
• c. 2009 Council Recommendation 2009/C151/02 on action in the field of rare disease 21
• 2.1.3. Establishing national plans for rare diseases 22
• 2.1.4. Involvement of patient organisations in decision-making 24
• 2.1.5. Opportunities and gaps in overarching action for rare diseases 24
• 2.2. Addressing research and knowledge gaps 26
• 2.2.1. European expert groups on rare diseases 26
• Box 2: Overview of EU expert groups on rare diseases 26
• Box 3: European Joint Actions 28
• 2.2.2. Dedicated research or project funding 28
• Box 4: Examples of EU funded projects working to share data and knowledge 29
• a. Opportunities and gaps in area of research and knowledge 29
• 2.3. Addressing issues around diagnosis and codification of rare diseases 29
• 2.3.1. Diagnosis through screening 30
• 2.3.2. Collaboration in diagnosis and treatment through European Reference Networks 31
• 2.3.3. Codification systems for rare diseases 33
• 2.3.4. Registries for rare diseases and biobanks 34
• 2.3.5. Opportunities and gaps in diagnosis and codification 35
• 2.4. Addressing market failure in product development 36
• 2.4.1. Key elements for orphan medicines in proposed pharmaceutical legislation 37
• 2.4.2. Funding for R&D 42
• a. Closed funding mechanisms and collaborative projects for R&D 42
• Box 5: Overview of E-Rare programmes 43
• Box 6: Overview of the European Joint Programme on Rare Disease (EJP-RD) 44
• b. Current funding mechanisms and collaborative projects for R&D 44
• c. Opportunities, gaps and uncertainties for market failure for rare diseases 45
• 2.5. Addressing issues around patient access and market access 47
• 2.5.1. Marketing authorisation 47
• 2.5.2. National level pricing and reimbursement 48
• a. Opportunities, gaps and uncertainties 49
• 2.6. Addressing high prices and lack of competition 50
• 2.6.1. Mechanism of Coordinated Access to Orphan Medicinal Products 50
• 2.6.2. New pharmaceutical legislation 51
• 2.6.3. Opportunities and gaps 51
• This section outlines actions taken by the European Commission or other European bodies in addressing the most salient challenges for rare diseases, namely: 16
•  A lack of data, information, and research into rare diseases (Section 2.2); 16
•  Problems around diagnosis of rare diseases, and the codification of individual rare diseases in and across Member States (Section 2.3); 16
•  Market failure in developing treatments for rare diseases (Section 2.4); 16
•  Problems in establishing market or patient access to treatments for rare diseases (Section 2.5); and 16
•  High prices for treatments for rare diseases (Section 2.6) 16
• Section 2.1 outlines overarching actions, including dedicated legislation, communications, or those which address a number of issues at once. Table 2 provides an overview of the instruments, tools, and initiatives discussed across each of these sections. 16
• Table 2: Overview of instruments, tools and initiatives 16
• Source: Authors’ own elaboration. 17
• While the large unmet need of rare disease patients had been recognised earlier and funding was allocated for rare diseases from the Fourth Framework Programme for Research and Technological Development (1994-1998) onward, the real start of European action on Rare Diseases came through the development of the Orphan regulation. 18
• Several Member States begun introducing national measures and policies to increase knowledge of rare diseases and improve detection, diagnosis, prevention, and treatment in the 1990s. This action trailed the introduction of the Orphan Drug Act in the United States (US) a decade earlier in 1983. Under this Act, manufacturers were given access to funding and tax relief for clinical trials, as well as a 7-year period of market exclusivity to incentivise the development of orphan medicines. Early signs of success from this US-based example, alongside national actions by European Member States, triggered a reflection on the need for concerted EU action on rare diseases. In 1995, the Council of the European Union called upon the European Commission, in close cooperation with the Member States, “to look into the situation of ‘orphan’ medicines in Europe and, if necessary, make appropriate proposals with a view to improving access to medicinal products intended particularly for people suffering from rare diseases”. This call helped create the momentum for a legislative proposal for the introduction of an EU Orphan Regulation. 18
• An ‘orphan’ medicine is intended for the diagnosis, prevention, or treatment of rare diseases. 18
• In April 1999, the European Commission adopted Regulation (EC) No 141/2000 on Orphan Medicinal Products (the Orphan Regulation). The Regulation was the first piece of European legislation that dealt directly with issues around rare diseases and orphan medicinal products. Similar to the US Orphan Drug Act, this legislation was intended to incentivise pharmaceutical companies to develop medicines for rare diseases. The Commission recognised that, under normal market conditions, companies may not be able to recoup the investment for R&D for diseases with very small patient populations but that patients who suffer from such rare diseases are entitled to the quality of treatment afforded to more common diseases19,. 18
• Mirroring many of the features of the US Orphan Drug Act, the EU Orphan Regulation introduced a series of incentives and made these available to sponsors of products (typically pharmaceutical companies or researchers) deemed eligible for an “orphan designation”. Specifically, the orphan designation provides applicants access to protocol assistance and to theEuropean Medicines Agency (EMA) centralised marketing authorisation procedure, and offers fee reductions or fee waivers for the costs of EMA applications., Most importantly, though, if an orphan designation is confirmed at the time of marketing authorisation, the sponsor is entitled to a ten-year period of market exclusivity. Market exclusivity is a form of regulatory protection that ensures that, during this period, no other similar products for the same indication may be placed on the market. Since the introduction of the Paediatric Regulation in 2006, this period can be extended by a further two years if the sponsor has complied with all the requirements laid down in a ‘Paediatric Investigation Plan’ (PIP). To support the implementation of the Regulation, a dedicated Committee for Orphan Medicinal Products (COMP) was created. This Committee examines applications for the medicinal product to be considered an orphan medicinal product, advises on policy on orphan medicinal products and assists the EMA and Commission in drawing up guidelines. 18
• In 2006, the European Commission published a review of the first five years of experience with the EU Orphan Regulation. This review concluded that the incentives provided by the Regulation had already had a positive effect: between 2000 and 2005, 268 products had received an orphan designation, covering over 200 different rare diseases. Of these, 22 had already received a marketing authorisation and the number of authorisations had increased each year28. These initial results suggested that the Regulation had helped to stimulate industrial activity and innovativeness in orphan medicine development28. The review concluded that there had not been any major difficulties in implementing the Orphan Regulation but deemed it too early to assess its impact on public health. 19
• In 2019, the Commission published a joint evaluation of the Regulations on medicinal products for paediatric use and orphan medicinal products. The evaluation concluded that the EU Orphan Regulation has been important in contributing to the development and availability of new orphan medicines through the use of incentives,. 19
• The 2019 evaluation of the Orphan Regulation indicates that around 21 additional orphan medicines are thought to have come to market because of the Regulation. Some estimations suggest that over half of the orphan medicinal products would not have been economically viable without the Regulation. However, the 2019 evaluation also found that the Regulation did not sufficiently address areas of greatest unmet medical need and has increased costs for healthcare systems. 19
• A 2020 report commissioned by the European Federation of Pharmaceutical Industries and Associations (EFPIA) added that patients are often unlikely to benefit from the developments the Regulation inspires because the marketplace remains immature and the financial vulnerability that exists in the field of orphan medicines, especially for small and medium enterprises (SMEs). 20
• Calls for further action in rare diseases have been made by other European bodies. In 2023, the European Economic and Social Committee (EESC) published an Opinion on ‘ensuring strong European solidarity for rare disease patients’, repeating concerns raised in its 2009 opinion that pleaded for a comprehensive European approach to address the challenges that people with rare diseases face. The Opinion notes that the 2009 Recommendations are ‘still being addressed with varying degrees of success’ and calls for a European action plan attainable by 2030, focusing on equal opportunities for diagnosis, treatment, and integrated care. Similarly, the European Parliament called for an EU action plan on rare and neglected diseases in a 2020 Resolution. 20
• The findings of the 2019 joint evaluation of the Orphan and Paediatric Regulations helped to inform the development of the European Commission’s Pharmaceutical Strategy for Europe, which was adopted in 2020. The Strategy explicitly aims to address the 95% of rare diseases which continue to have no treatment options and instigated a reflection on the incentives used to stimulate innovation for these diseases. In April 2023, the Commission adopted proposals for a new general pharmaceutical legislation (GPL), accompanied by an impact assessment for the GPL. Elements of the revised pharmaceutical legislation relevant to orphan medicines and rare diseases are discussed in Section 2.4. Appendix A provides more detail on the evaluation of the GPL. 20
• Alongside the adoption of the Orphan Regulation, the European Parliament and Council issued a 1999 Decision on “adopting a programme of Community action on rare diseases within the framework for action in the field of public health”. 21
• These bodies reasoned that EU-level action was necessary as Member States may struggle to undertake individual action in rare diseases given the low prevalence of these diseases, a lack of information, and that, when taken together, these diseases affect a significant population41. The Decision also set out that those affected by a rare disease were not benefiting from the health resources and services they needed, while they and their families experience serious difficulties as a result of their condition41. The ‘Community Action Programme on Rare Diseases’ introduced by the 1999 Decision aimed to i) set up a coherent and complementary European information network on rare diseases, ii) enhance training and ongoing education of professionals, focusing on early detection, recognition, intervention, and prevention of rare diseases, iii) promote transnational collaboration and iv) provide community level support for monitoring rare diseases in Member States and establishing early warning systems. The programme funded several initiatives, of which several have been continued in later programmes. Such initiatives included Orphanet, an online reference portal that centralises various resources for the diagnosis, care, and treatment of patients with rare diseases (see Section 2.3.3), and EUROCAT, a network that brings population-based registries for congenital disorders and structural or functional anomalies together (see Section 2.3.4). 21
• Building on the recommendations from these reports, in November 2008 the Commission adopted Communication COM/2008/679 on rare diseases and challenges for Europe. In it, the Commission outlined an EU strategy for addressing rare diseases to tackle remaining challenges, giving direction to Community activities to further improve the access and equity to prevention, diagnosis and treatment for patients suffering from a rare disease43. Objectives included improving research and patient involvement, improving the recognition and visibility of rare diseases, supporting Member States’ policies on rare diseases, and developing European cooperation, coordination, and regulation for rare diseases. The Communication prioritised the infrastructure of information sharing networks by developing national and regional centres of excellence through European Reference Networks (ERN). 21
• The 2008 Communication was closely followed by Council Recommendation 2009/C151/02 on action in the field of rare diseases. This Recommendation set up a plan and strategy in the field of rare diseases, aiming to ensure that those suffering from rare diseases have access to high-quality care by facilitating the early diagnosis and treatment of rare diseases, and, if possible, access to effective orphan medicines44. 21
• The Recommendation aimed to support national plans and strategies by setting up the European Union Committee of Experts on Rare Diseases (EUCERD) joint action programme, helping EU governments in developing their own national strategies. The Recommendation underlined the importance of databases such as Orphanet and the funded research projects in the field of rare diseases. Echoing the 2006 recommendations of the Rare Disease Task Force (RDTF) and the 2008 Communication, the 2009 Council Recommendation furthermore called for the creation of European Reference Networks for rare diseases, recognising that the limited number of rare diseases patients requires gathering expertise at European level to ensure access to accurate information and high-quality care44. 22
• In 2014, an Implementation Report on the Communication concluded that, in the years following the 2008 Communication and 2009 Recommendation, the EU had made great improvements and set-up important initiatives in the field of rare diseases. Close to 120 collaborative research projects had been funded with a budget of over €620 million46. The Commission concluded that most action points from these two documents had been reached. However, the EESC was more cautious and found that the degree of success achieved varied. 22
• The 2009 Council Recommendation on action in the field of rare diseases (2009/C151/02), recommended that Member States establish and implement plans or strategies for rare diseases to ensure patients with rare diseases have access to high-quality care and, if possible, to effective orphan medicines48. At the time of the Recommendation, only four Member States (Bulgaria, France, Portugal, and Spain) had national plans for rare diseases. 22
• EUROPLAN, the European Project for Rare Diseases National Plans Development, was specifically created to provide guidelines and recommendations for Member States to develop a plan or strategy for rare diseases and linking these with a common framework at the European level (see Box 1 for more information) . 22
• This "double level" approach respected national competencies and was intended to ensure coherent and consistent progress in EU rare diseases care50. EUROPLAN was supported by the EUCERD Joint Action supporting Member States in the development of strategies, integrating rare diseases into other social policies, and implementing a coding and classification system for rare diseases. 22
• Box 1: EUROPLAN 23
• EUROPLAN was seen as an effective way to stimulate expertise sharing and consensus building. The project helped ensure that activities implemented by Member States for rare diseases were consistent and coherent with both the best practices at the time and related EU policy. Sources differ on which Member States created a plan: the European Commission website (no date) shows national plans for 22 Member States, RD-ACTION (2018) reports 25 Member States have a plan, and EURORDIS (no date) reports that 26 Member States have a national plan or strategy for rare diseases. 23
• RD-ACTION reported that, out of the 25 national Member State plans in existence in 2018, 19 were for a fixed period of time59. Many of these plans are now out of date, with end dates around 2020, 2018 or even 201358. 23
• The Rare 2030 project concluded national plans should be updated to be action-oriented, sustainable, long-term, and integrated with other (national) social policies such as those for cancer, research and data, access to medicines, and social rights. 24
• Patient organisations empower patients, a particularly important role in the context of rare diseases as these can be overlooked by the research or medical community and policy makers. These organisations are also important stakeholders when developing new therapies and policies from which patients should benefit. They can provide valuable involvement in every stage of drug development and commercialisation, as well as in setting research priorities and in post-authorisation communication and advocacy. These activities are particularly important in the rare diseases space: as rare diseases are defined by small patient populations, understanding, and including their experiences in decision-making processes is important for patient access. See Section 2.4.1. for more information on how the proposed pharmaceutical legislation aims to involve patient organisations in marketing authorisation decisions. 24
• The EC consults patient organisations in the development of rare disease policies and promotes their activities. The EC has called upon Member States to do similarly. There are many patient organisations for rare diseases in Europe, reflecting the extensive number of rare diseases in existence, of which almost 1,100 are members of EURORDIS, the European Organisation for Rare Diseases, a non-governmental and non-profit alliance of rare disease patient organisations from 74 countries aiming to improve the lives of people living with rare diseases globally. 24
• 1. Creation of a European policy framework to support national plans for rare diseases 24
• The 2008 EUROPLAN project supported Member States in developing national action plans. A large proportion of these were for a fixed period of time and are now out of date. The first recommendation of the Rare 2030 project finds that a policy framework to guide and monitor national plans is needed, with a focus on sustainable funding, long-term and action-oriented visions, and integrated with other social policies for related topics. The European Commission could also foster informal dialogue between national representatives or bodies to assist with knowledge and best practice sharing in the field69. 24
• 2. Creation of a European Action Plan for rare diseases 25
• There have also been calls for the development of a European Action Plan,, or suggestions for the revised EU general pharmaceutical legislation to be supplemented by a new Council Recommendation on rare diseases. Given almost 15 years have passed since similar publications, and considering the advancements in the field, guidance from the European Commission could reflect on existing and new challenges for rare disease and provide a vision for the direction of how to address these to Member States and other European bodies. EURORDIS suggest that the inclusion of the creation of an Action Plan as a priority in the EC 2024 – 2029 work plan would be a significant development for European rare disease policy71. 25
• 3. Increased patient engagement and empowerment 25
• There are many patient associations bringing together patients, practitioners and other stakeholders addressing individual rare diseases, as well as European and international organisations aimed at consolidating efforts and knowledge for rare diseases. However, there may be space to empower patients and patient organisations further. Embedding patient voices in policy making and planning will help to make sure actions for improvements in diagnosis, treatment, and care benefit those who need it. This can take place through organisations such as the EESC, which aims to provide a voice to civil society in political dialogue72 or patient representation through associations. EURORDIS, which identified partnerships with patients as one of the main recommendations out of Rare 2030 (Recommendations 4 and 5), suggests focusing on communication with patients, involvement in initiatives, and support for European or global patient initiatives. The revised pharmaceutical legislation proposes to remove the EMA Committee on Orphan Medicinal Products (COMP), which is responsible for recommending which medicines are eligible to receive orphan designation from the EMA. This change may also affect patient representation: since its inception as part of the Orphan Regulation, the COMP has had three patient representative members in its composition. The revised pharmaceutical legislation proposes to include patient representatives in the Committee for Medicinal Products for Human Use (CHMP) and the Pharmacovigilance Risk Assessment Committee (PRAC) (see Section 2.4.1). Generally welcomed by stakeholders, questions do remain around appropriate compensation, training, and the definition of patient organisations. 25
• Knowledge of and research into rare diseases is often limited by a lack of data and information. The sheer number of distinct rare diseases that exist, as well as their low prevalence, means that many have not been extensively researched. Accompanied by a lack of funding and prioritisation of rare disease research, much remains unknown about the underlying causes of many rare diseases or how they manifest. The limited availability of data on natural histories of diseases, genetic profiles and clinical patient information forms a barrier to the development of diagnostic tests and treatments. In recent years, there have been multiple initiatives at EU level to increase the collection and sharing of such data and knowledge, thereby helping to build a more conducive research environment. Still, rare diseases are comparatively poorly understood. 26
• The European Union appointed dedicated expert groups on rare diseases from 2004 to 2018. As part of the 2003 – 2008 Public Health Programme (now referred to as the first EU health programme), the Rare Diseases Task Force (RDTF) was established to instigate collaborative initiatives and dialogue around research and policy for rare diseases in Europe in 2004,. The RDTF was replaced by other iterations of expert groups: the European Union Committee of Experts on Rare Diseases (EUCERD) in 2009 and the European Commission Expert Group on Rare Diseases (CERGD) in 2013 (see Box 2). 26
• The objectives of EUCERD included monitoring and evaluation of rare disease measures in the EU, assisting with the preparation of reports for the EC, and assisting in international cooperation. 26
• These objectives were further supported by two dedicated EU Joint Actions: EUCERD JA and RD-ACTION (See Box 3 for more information). Importantly, the Committee’s activities did not overlap with those covered by the EU Orphan Regulation and, correspondingly, of the COMP. Rather, EUCERD focused on providing a broader expertise and support on rare diseases at policy level79. 26
• EUCERD adopted five different Recommendations and one Opinion during its term,, which are seen as valuable instruments in guiding and instructing stakeholders on ensuring access to (integrated) care for patients of rare diseases. 27
• The Recommendations helped to accelerate the adoption of national plans for rare diseases throughout Europe. The subsequently appointed CERGD covered the same actions as the EUCERD, in broad lines. The possibility to exchange experiences and follow the activities of other Member States was seen as very important, as CERGD enabled and encouraged countries to continue the development of a framework for rare diseases80. In setting up CERGD, the Commission highlighted the valuable work done by EUCERD and indicated that there was a continuing need for a group of experts in the area80. However, while the European Commission set up other expert groups after CERGD ended, these groups no longer had an exclusive focus on rare diseases: the 2018 – 2022 ‘Steering Group on Health Promotion, Disease Prevention and Management of Non-Communicable Diseases’ (also known as the SGPP) and the 2022 established ‘Commission Expert Group on Public Health’ had a broader focus of non-communicable diseases (including rare diseases). The Expert Group on Public Health aims to continue the work initiated in earlier expert groups by working on several areas, and as defined in the different sub-groups within this expert group. 27
• The work conducted by the expert groups was supported by European Joint Actions (JA) (see Box 3). 27
• In general, the experience and results of the expert groups and committees have shown to improve the coordination among Member States by sharing and implementing best practices, guiding, and developing coordinated actions, which has contributed to reducing the burden of non-communicable diseases in the EU89. However, the European Commission expert groups on rare diseases have been disbanded and are now integrated in expert groups with much wider remits which may be attributable to a wider trend of disbanding European expert groups. The result is that there has no longer been an EU forum dedicated to bringing together representatives or experts specifically on rare diseases or integrating other stakeholders, or to monitor or assess the state of rare diseases within the Union since 201891. It is not clear whether the current Expert Group on Public Health still provides a forum for these issues, or whether the ERNs are meant to fill this potential gap. A 2018 report by RD-ACTION suggested that the ERNs will not be able to replace these expert groups in full91. 28
• The European Commission has sought to support research in this field, both by making funds available through the Framework Programmes and by making rare diseases a priority area within the programmes. The Community Action Programme was succeeded by the 2003 – 2008 Public Health Programme (now referred to as the first EU health programme). The focus of this programme was similar to its predecessor, continuing existing work in rare diseases. 28
• This programme made the exchange of information on rare diseases using existing European networks a priority action. Through the Health Programmes, the Framework Programmes, ERA-Net and EJP RD, the European Union has consistently supported research in rare diseases both through direct funding and by providing structure for Member States to pool money. The Public Health Programme was succeeded by the Public Health Programme (2003-2008), the Health programme (2008-2013), the 3rd Health Programme (2014-2020) and EU4Health (2021-2027). 28
• Solve-RD (solving the unsolved rare diseases) is a research project funded by the European Commission that ran between 2018 and 2022, fully integrated with the European Reference Networks (ERNs) for rare diseases (four ERNs formed the core of Solve-RD but the project involved patient cohorts all across the ERNs). The research project claims to be the first time in Europe that hundreds of rare disease experts teamed up to actively share and jointly analyse existing data from unsolved rare disease patients. 29
• RD-Connect Project was a multidisciplinary project funded under a framework programme (FP) 7 grant that ran between 2012 and 2018 that aimed to create an integrated global infrastructure for Rare Disease Research. The project created a Genome-Phenome Analysis Platform (a collaborative platform to accelerate rare disease diagnosis and gene discovery), a Registry and Biobank Finder and a Sample Catalogue (intended to facilitate the discovery of samples and sample data from Rare Disease biobanks). 29
• No specific opportunities or gaps around research and knowledge gaps have been identified in the literature or in stakeholder communications. The continuation of the efforts described in this section is advisable. The European Reference Networks also touch on issues around research and knowledge gaps, and will be discussed in detail in Section 2.3.2. 29
• The average time between onset of symptoms and diagnosis of rare diseases is 4 to 5 years and, in certain instances, it can take decades for a patient to get clarity on their condition. Difficulties in diagnosis are exacerbated by the very small patient population affected by rare diseases: most health professionals will have very little exposure to them in their clinical practice, and may therefore have difficulties recognising symptoms and issuing an accurate diagnosis. A lack of diagnostic tests and the absence of clear, accepted diagnostic criteria and coding systems to identify rare diseases further contribute to low rates of detection. 29
• The 2008 EC Communication and 2009 Council Recommendation spurred on several actions aimed at addressing issues that make diagnosing rare diseases difficult. These actions are related to screening (see Section 2.3.1), the European Reference Networks (see Section 2.3.2), the codification of rare diseases (see Section 2.3.3), and patient registries and biobanks (see Section 2.3.4). 30
• While it is possible to identify some rare diseases at a very early stage, or even prenatally through genetic screening, it is not feasible to do so routinely for all conditions. 30
• There is currently no harmonised legislation or guidance across the EU on which diseases should be included in national screening programmes. While certain Member States prioritise (primary) prevention measures of rare diseases, such as new-born screening, the use and implementation of such measures varies across the EU. The number of medical conditions included in screening plans differs from one Member State to another. Addressing this variation has been a focal point since 2013, when EUCERD adopted an opinion on potential areas of European collaboration in the field of new-born screening107. However, as these screening programmes fall fully under the competency of Member States, there was no major EU-level action at this stage. The European Commission commissioned a report on new-born screening in the Member States in 2016 to understand this variation and seeks to provide complementary action such as through Member State collaboration through the ERNs, and the European Platform on Rare Disease Registration (see Section 2.3.4) to address a lack of data and the small sample sizes which can hinder the development of new-born screening programmes. While new-born screening programmes improved between 2010 and 2020, disparities continue to remain106,. 30
• In 2022, the EESC highlighted the importance of ‘rare disease diagnosis during perinatal or neonatal screening or as soon as possible after the onset of health or developmental problems’. There is now a public-private partnership between the European Commission (through Horizon2020), EFPIA and the Innovative Medicines Initiative to fund the Screen4Care project, which runs from 2021 until 2027. The project has a dual approach to shorten the time taken for diagnosis of rare diseases by i) the exploration of next-generation sequencing for new-born screening, with the possibility to shorten the path to diagnosis, and ii) the use of digital solutions to improve accuracy and speed of patient diagnosis, such as the use of AI algorithms in electronic health records to identify rare disease patients,. 30
• As individual rare diseases affect only small groups, most health professionals will have had very little exposure to them in their clinical practice and may not be able to recognise symptoms or to make an accurate, timely diagnosis. The European Commission has made efforts to address these issues around diagnosis through the European Reference Networks (ERNs). The 2009 Council Recommendation gave the impulse for the creation of European Reference Networks and encouraged Member States to identify centres of expertise within their own countries and foster the participation of these centres in the ERNs. The mandate for the ERNs was provided by the EU Cross-Border Health Care Directive (Directive 2011/24/EU) adopted in 2011,. 31
• The ERNs are virtual, voluntary cross-border networks aimed at bringing healthcare providers from across Europe together to help diagnose and treat patients with rare diseases that require highly specialised healthcare and pooling of knowledge and resources. They hold significant potential to address rare disease issues at the pan-European level, seeking to reduce inequities and create high-quality healthcare for any rare disease patient throughout the EU. They provide economies of scale to do research, produce educational content and develop clinical trials for rare diseases, also well as hosting an exchange programme to stimulate knowledge transfers118,. 31
• A Clinical Patient Management System allows the expertise to travel, not the patient, reducing the need for ill patients to travel to seek medical advice. Membership of ERNs has expanded over the years: as of the 1st of January 2022, there are 1,450 full healthcare providers and 155 affiliated partners. 31
• In March 2021, a research consortium under Horizon2020 called the ‘European Rare Disease Research Coordination and support Action’ (ERICA) started its work to create an integrated platform for the research and innovation capacity of the ERNs. The project is planned to finish in February 2025. 32
• There is an ongoing EC evaluation of the ERNs (2014/287/EU) which has not yet published its findings as of the writing of this report. 32
• In March 2024, the European Commission launched a new joint action – Joint Action on integration of ERNs into national healthcare systems (JARDIN) – to improve the diagnosis, care, and treatment of people with rare diseases by integrating the ERNs into national health systems. 32
• In 2018, a Commission Report on the operation of the Cross-Border Health Care Directive touched upon the ERNs, finding them to be successful. The report found 165 virtual panels on patient cases had been started by June 2018, with more virtual panels operating daily and that patients were directly benefitting from these panels. 32
• The evaluation of the third Health Programme (see Section 2.2.2.) also found that stakeholders deemed the ERNs to be a successful action under the Programme. The 2023 evaluation of the ERNs found that its ecosystem delivers highly specialised care for patients through medical consultations, the production of clinical guidelines, and specialised training. A 2024 European Commission evaluation of the 24 ERNs was positive. An assessment of the 836 healthcare providers issued 733 providers with a positive evaluation, 72 providers requiring improvement, and 25 providers being terminated129,. 32
• At the same time, the ERNs have been subject to some criticism. The European Court of Auditors reported in 2019 that there was no clear vision regarding the ERNs financial sustainability, or as to how to integrate the ERNs in the national healthcare systems. 32
• The ambitious and innovative nature of ERNs also means that the implementation has faced challenges. One of these is related to their complex governance arising out of international and intersectoral features of the network. A 2023 Opinion also outlined a number of factors which required attention, including around reimbursement of healthcare providers, interoperability of systems, and integration of ERNs into national healthcare systems to guarantee the promotion of their existence and accessibility. Other perceived challenges include a lack of legal status for ERNs, insufficient exploitation of the potential of ERNs in rare disease research, difficulties engaging with patient representatives, and lack of clarity about the role of ERNs in the rare disease and digital ecosystem133. 32
• Coding systems codifying diseases by describing when a condition can be considered the same based on characteristics such as symptoms and genetic markers. The lack of firmly established coding systems for capturing data on rare diseases plays a large role in issues around diagnosis of these conditions. 33
• Orphanet was launched in 1997 by the INSERM (French National Institute for Health and Medical Research) and became a European endeavour in 2000,. 33
• Since then, Orphanet has gradually grown and now covers a network of 41 countries both within Europe and across the globe136. 33
• The database contains information on a wide range of RDs, including their clinical characteristics, epidemiology, genetic basis, and the available resources for treatment. 33
• The platform aims to provide high-quality information to various stakeholders to aid in research and 33
• Patient registries are another important tool for the collation of information across patients suffering from the same disease. Patient registries aim to collect uniform data on a population defined by a particular disease, condition, or exposure over time. 34
• Registries provide insight into clinical practice, treatment and patient outcomes, and the appropriateness of care. As such, they help address the difficulties in diagnosis of patients. The number and focus of national disease registries vary across Member States, as some countries have higher capacity and expertise to develop these registries, or different patient populations and resulting needs. As of 2021, there are 639 national and regional rare disease-related registries across the Member States, 97 larger European registries and 76 international registries. 34
• EUROCAT is a network that brings population-based registries together, seeking to provide key epidemiological information on congenital anomalies by serving as an early warning system, acting as a central resource, evaluating prevention effectiveness, assessing prenatal screening impact, fostering collaborative research, and promoting the establishment of data registries across Europe. 34
• Originally set up in 1974, EUROCAT has undergone changes over the years. In 2000, it became funded through European funds from the Programme of Community Action on Rare Diseases. Since 2015, the EC JRC has been responsible for the European level coordination activities. A 2014 evaluation found that stakeholders indicated EUROCAT as a much-needed resource for epidemiological data on congenital anomalies and evaluating the potential risks of medicines taken by pregnant women149. Constructive feedback focused on increasing engagement with the lay community and recommendations for emerging areas in the field of congenital anomalies. In general, users of EUROCAT emphasised the need for the continuation of the network, and the network has been considered an invaluable resource in the field of RDs149,. 34
• From 2011 to 2014, the European Commission funded EPIRARE (European Platform for Rare Disease Registries) through Health Programme, which aimed to build consensus and synergies to address regulatory ethical and technical issues associated with the registration of RD patients and to create an EU platform for the collection of RD patients and their communications151. Research papers indicated that the definition of common data elements (CDE) for rare diseases under this project was a first step in the promotion of the use of common tools for the collection of comparable data. 34
• The European Commission’s Joint Research Centre developed the European Platform on Rare Diseases Registration in 2019 to provide a central access point for information on rare disease patient registries for all stakeholders. The Platform made rare disease registries’ data searchable and findable, through the European Rare Disease Registry Infrastructure (ERDRI) that supports existing registries as well as the creation of new registries. Broader lack of interoperability of health systems and data infrastructures remains an issue. 35
• Biobanks contain DNA and samples of cells and tissues that can enable research and can also help facilitate easier diagnosis. Under the umbrella of the RD-Connect Project,, the first operating network of biobanks was developed: EuroBioBank. This biobank is specifically focused on rare disease research and provides DNA and cell and tissue samples to the scientific community conducting research on rare diseases. The EuroBioBank was initially supported by the EU, but since 2012 has been funded by the Italian non-profit Fondazione Telethon159. 35
• 1. Improved use of existing and new technologies for diagnosis of rare diseases 35
• One of the recommendations of the Rare 2030 Project highlights the need for earlier and accurate diagnosis of rare diseases156. Outside of necessary improvements in knowledge on specific rare diseases and care delivery, improved diagnosis also extends to the development and equitable implementation of next generation sequencing and other new technologies for improved diagnosis. It is also important that patients are involved in the design of care pathways, allowing them to navigate the healthcare system with more ease to access the care they need. EURORDIS has also identified consistent implementation of new-born screening across the EU Member States as critical to improving diagnosis of rare diseases. Another recommendation from the Rare 2030 project highlights the need for earlier, faster, and more accurate diagnosis. This requires a focus on new technologies and diagnostic tools driven by the needs of the rare disease community. The patient organisation EURORDIS calls for improved diagnostic tools to be accompanied by a coordinated care approach for undiagnosed individuals160. Improvements in this space may be directed, for example, at healthcare professional training to assist in identifying when referrals to specialist centres should be made. 35
• 2. Integration of ERNs into national systems 36
• The 2023 EESC Opinion and EURORDIS have both indicated that improvement around the organisation of the centres of expertise that form the basis of the ERNs is needed. This focus is also in line with the third recommendation from the Rare 2030 project: establishing access to high quality healthcare at European, national and regional levels. Local and national systems need to be aware of the centres of expertise available to them and integrate access to these centres into their care systems. This would require the creation of criteria to define a centre of expertise, identification of all centres of expertise, and support for Member States to integrate these centres into their national systems. This would need to be supported by ‘sustainable and proportionate investment’ for Centres of Expertise and the ERNs from both national and EU budgets161. The JARDIN Joint Action will be pivotal in achieving these objectives. EURORDIS has identified securing EU co-funding for the next budgetary period as an essential component for achieving JARDIN’s goals160. 36
• 3. Improved interoperability and standardisation of health data 36
• The RARE 2030 foresight study indicates that there is a need for an interoperable infrastructure with a fully-fledged data strategy for rare diseases to enable both the collection and use of the health-related data with appropriate safeguards (Recommendations 2, 3, and 7)161. The lack of interoperability in data infrastructure had previously been established with regard to patient registries and steps were undertaken to at least make the data from different registries accessible and searchable161. Better interoperability of these registries as well as other health systems would allow for digital healthcare pathways and could accelerate the development and uptake of treatment options for rare diseases as well as facilitate European-wide clinical research161. EURORDIS also highlights the need to promote data sharing through the European Health Data Space to drive innovation and improve care for those with rare diseases160. 36
• Identifying molecules which are effective as medicines is difficult. Most medicines function by interfering with biological processes in the body, such as by blocking specific receptors, activating an immune response, or replacing missing chemicals. Depending on the nature of the disease and the mechanism of action of the medicine, the treatment may then allow for the body to be restored to a healthy state and the patient to be cured. However, the majority of rare diseases are rooted in genetic factors. Conventional medicines do not interfere at the genetic level. Thus, whilst such medicines may help to alleviate or suppress symptoms of genetic diseases, they cannot address their underlying causes. Treatment to manage the disease will then typically be lifelong. Newer types of treatment, such as gene therapies, do hold promise, in particular for monogenetic diseases that are caused by mutations in a single gene. At the moment, however, most medicines for rare diseases are non-curative. 36
• Even when the cause of a rare disease is known and promising drug targets have been identified, the further development into effective treatments is still an uphill battle. Just like for other medicines, medicines for the treatment of rare diseases, also known as orphan medicinal products (OMPs), require demonstration of safety and efficacy before they can be approved for placement on the market, often involving a lengthy and costly process of preclinical and clinical testing. This process also carries a high risk of failure: most candidate medicines that enter clinical development never make it to market, and orphan drug development is even more expensive, complex, and risky than for those medicines intended for more common conditions. The total development costs for both successful and unsuccessful products can thus only be recouped through the profitable sale of approved medicines. However, in the case of orphan medicines any sales volumes are inherently low, meaning that these medicines offer limited opportunity for developers to recover their costs. As a result, pharmaceutical companies have tended to focus their product pipelines on medical conditions with a higher prevalence, where there is more commercial potential. 36
• Even though in the last three decades dedicated research funding and policy measures have helped drive more product development into the rare disease space, the field remains characterised by a large unmet need for effective treatments. Roughly only 6% of people affected by rare diseases receive a specific diagnosis and prognosis-changing treatment, the majority of which is related to rare cancers,. 37
• The proposed revision of the EU general pharmaceutical legislation (see Appendix A for more detail) is driven by concerns over insufficient patient access to medicinal products, including the differing levels of access across the Member States, supply issues and pharmaceutical shortages in EU/EEA countries, and a lack of focus on unmet medical need in R&D. 37
• These concerns impact the quality of treatment available to patients in the European Union and place an unnecessary burden on healthcare systems and professionals to identify suitable alternative treatments167. In this context, the proposed legislative reforms aim to promote both a) research, development, and innovation in, b) access to affordable medicines and c) improvements in the security of the supply of medicines. The proposals recognise that rare diseases (and paediatric medicine) will still require specific requirements and incentives to stimulate R&D167. The proposals aim at balancing the stimulation of innovation in the EU pharmaceutical industry with faster market entry for generic and biosimilar products. Table 3 provides an overview of the main features of changes for orphan medicines between the current and the newly proposed pharmaceutical legislation. 37
• Table 3: Overview of main changes to rare disease incentives and provisions (non-exhaustive) 38
• Source: Authors’ own elaboration based on the current pharmaceutical legislation, the proposed pharmaceutical legislation, Bogaert, P. et al., 2023 and European Parliament, 2023. 38
• Stakeholder responses to the proposed pharmaceutical legislation have varied: while EURORDIS (the European organisation for rare diseases) has welcomed the changes and suggested the proposed legislation could go even further, industry has met the proposals with apprehension and concerns over the effects on the investment climate in Europe,. A report commissioned by EFPIA warns that the proposed changes will undermine the previous two decades of progress in the rare diseases field. The concerns raised by industry relate to three primary components: the introduction of a (high) unmet medical need criterion, changes to the market exclusivity and regulatory data periods, and the introduction of a cap on orphan designation. 38
• The proposals seek to direct R&D to where it is most needed and where investment may be less likely under regular market forces, i.e. where there is high unmet medical need (HUMN),. The European Society for Paediatric Oncology (SIOP Europe) and Childhood Cancer International (CCI Europe) have endorsed the inclusion of unmet medical need (UMN) and HUMN in the proposals, together with the involvement of patient stakeholders in these processes. However, industry stakeholders have indicated that a fixed definition may be difficult given that the effectiveness of orphan medicines varies across patients and for diseases where symptom severity fluctuates and may not reflect the needs of individual patients173,. The nature of R&D means that it may be difficult to provide proof of a ‘meaningful reduction’ during the early stages of development, to be sure investment will eventually address (H)UMN, and that definitions for (H)UMN will not change over the duration of the R&D period179,. 39
• These factors may mean that the effects are difficult to predict for the industry at the time of early-stage R&D investment (e.g. they may not be eligible for additional data protection periods), possibly weakening the incentives attached to these definitions179,. 39
• One of these incentives to stimulate R&D of medicinal products addressing HUMN is established through a proposed modular approach to market exclusivity for orphan medicines, which differs from how non-orphan medicines will be addressed in the new legislation. The current 10-year term of orphan market exclusivity is proposed to be reduced to nine years, but with additional 1-year periods available for certain situations, such as an EU-wide patient access. The Commission has indicated that the proposed market exclusivity periods add up to a maximum of 13 years of protection (the ‘modular approach’). This approach seeks to reward innovation in disease areas with no current treatment or medicinal products that are exceptional advances, while promoting faster generic/biosimilar competition where possible to improve access and affordability of orphan medicines. 39
• EURORDIS has welcomed the modular aspect, finding that it will encourage R&D in areas of unmet need. However, critics have said the proposed duration is a limitation when compared to the current standards, especially as the extension requirements are seen as strict. Potential difficulties include requirements around launching a product in all Member States in a given time period, requirements for a sufficient supply of the products and the impact of the definitions of UMN/HUMN186,. It is thus unclear whether the maximum 13-year protection period is attainable at this point. Market exclusivity will be further affected by the change which allows regulators to accept and assess applications for generics and biosimilars within the last two years of the market exclusivity period186. The inclusion of this provision will, however, facilitate earlier market entry of competitor products which is generally considered to be a positive step towards price competition and lower prices for products. 40
• The proposals would also reduce the period of regulatory data protection from eight to six years with options for extension in specific circumstances, such as an EU-wide launch. 40
• A reduction in this period is aimed at reducing the time taken for generic or biosimilar entry, which can have positive impacts for the affordability of medicines. SIOP Europe and CCI Europe found that the additional data protection terms awarded when a product experiences an EU-wide launch will establish more equality across the European Union. 40
• On the other hand, the proposed regulatory data protection has been criticised by EFPIA, who suggest that reducing regulatory data protection has a direct impact on companies’ ability to launch and/or obtain a return on investment in all EU Member States. EFPIA also indicates that these effects will be more profound for SMEs. 41
• The proposals furthermore introduce an expiration date to the validity of the orphan designation: after seven years, the product would lose the designation and the associated benefits. Validity may be extended if evidence is provided to show the relevant studies are ongoing and promising. The Commission expects this provision to ‘stimulate timely product development’ and improve availability and access for patients. While the aim of this provision is to stimulate faster development, some stakeholders have suggested that companies already reduce the duration of R&D as far as possible within the requirements of the regulatory system and that companies will simply apply for orphan designation at a later stage193,. A 2023 EFPIA commissioned report suggest that the 7-year cap, together with the modular market exclusivity, would decrease innovation by 12%. 41
• Lastly, the proposals suggest the removal of the dedicated Committee on Orphan Medicinal Products, responsible for recommending which medicines are eligible to receive orphan designation by the EMA. The Committee is made up of one representative for each Member State, three patient representatives, and three members nominated by the European Commission. The expertise of COMP is proposed to be reorganised into working groups or expert pools which assist the EMA CHMP, PRAC, and the Coordination Group for Mutual Recognition and Decentralised Procedures-Human (CMDh). Instead, for the first time, there are plans to appoint patient representatives to the CHMP. 41
• A one-year pilot of this involvement ran in 2014, during which two patients participates in benefit-risk assessments requiring patient participation, primarily in cases where the CHMP was likely to issue a negative opinion. 41
• The European Commission will perform an impact assessment of the revised pharmaceutical legislation to inform legislators of the expected and possible effects of the legislation if it comes into force. The proposals suggest a 15-year period should pass before a meaningful evaluation of the new legislation can be conducted. However, given the importance of addressing rare diseases and the major changes that are proposed for the rare disease field, the European Commission may need to closely observe the implementation and effects of aspects of the legislation. 41
• Pharmaceutical R&D requires large financial investments, and many products which enter R&D stages are ultimately deemed unsuccessful. The small patient populations associated with rare diseases mean that recouping those costs is difficult for companies, and that they therefore tend to focus on R&D for medical conditions with a higher prevalence and more commercial potential. The European Union has allocated dedicated research funding and implemented policy measures to drive more product development into the rare disease space over the past 25 years. 42
• Despite these efforts, the field remains characterised by a large unmet medical need for effective treatments. Evaluations of the current legislation on medicines for rare diseases and children have found that the medical need of these groups is insufficiently met, unequal access across the European Union remains, affordability remains challenging, and that the regulatory system does not cater for innovation and, at times, creates unnecessary administrative burdens. 42
• The Rare 2030 foresight study also concluded that ‘available, accessible, and affordable treatments’ and ‘innovative and needs-led R&D’ remain key focal point for the European Union. 42
• Market failure is exacerbated by the fact that R&D for medicines is expensive. The EU seeks to address this by offering multiple funding mechanisms for research on rare diseases. 42
• As previously indicated (see Section 2.2.2), the EU Health Programmes have been important vehicles for supporting such research. Rare diseases were an explicit priority under both the second (2008-2013) and third (2014-2020) Health Programmes, and the 7th framework programme (FP7) (2007-2013). The European Commission reports that, under FP7 and Horizon2020 (2014-2020), €2.4 billion was made available for research on rare diseases across 440 multinational research projects,. The current programme, EU4Health, has a €5.3 billion budget for 2021 to 2027 across four general objectives. EU4Health is set to support research into rare diseases, improving the ERN ecosystem (including creating new ERNs where needed), and securing basic care for patients with chronic or rare diseases,. 42
• Following the 2009 Council Recommendation that research resources should be identified and that coordination of community, national and regional programmes for rare diseases research should be improved, another stream of funding was established through ERA-Net201,,. ERA-Net was developed as a Framework-wide scheme aimed at developing and strengthening the coordination of national and regional research programmes207. Under this scheme were three partnerships focused on rare diseases: E-Rare-1; E-Rare-2 and E-Rare-3 (see Box 5 for more information)207. 43
• In essence, these programmes pooled resources and coordination of different regional and national instruments focused on facilitating research in the area of rare diseases. 43
• In 2019, the funding activities of E-Rare were integrated in Pillar 1 of the European Joint Programme of Rare Diseases (EJP RD)208. The EJP RD ran from 2019 – 2023 and was funded by Horizon2020 and was considered a major milestone by the European Commission, as it encouraged 130 institutions from 35 countries to work together to ensure a better integrated and cross-sectoral approach to health challenges (see Box 6 for more information,208. 43
• EJP RD involved research funders, universities, research organisations, research infrastructures, hospitals, and patient organisations from 35 countries, including 26 out of the 27 EU Member States. The EU contributed €55 million, out of a total investment of over €100 million. The EJP RD was a hybrid scheme, combining the scheme for joint calls of E-Rare with in-house research activities208. EJP-RD intended to create a research and innovation pipeline "from bench to bedside", aiming for a rapid translation of research results into clinical applications and uptake in health care for the benefit of patients. The programme brought together research funders, ministries, research institutes and universities, hospitals, EU research infrastructures, foundations, and patient organisations. Also, all 24 European Reference Networks were part of EJP RD. The programme integrated existing infrastructures, trainings, funding programmes and tools, expanding existing ones and developing new essential ones208. 44
• The European Union also supported the International Rare Diseases Research Consortium (IRDiRC) through the European Joint Programme on Rare Disease (EJP-RD) under the Horizon 2020 programme. The Consortium was officially launched in 2011 with the goal of contributing to the development of 200 new therapies and the means to diagnose most rare diseases by the year 2020. The first goal, to deliver 200 new therapies was achieved in early 2017, three years earlier than expected. After this success, the IRDiRC devised a new set of global rare disease goals for 2027: 1) For all patients coming to medical attention with a suspected rare disease to be diagnosed within one year if their disorder is known in the medical literature; and for all the currently undiagnosable individuals to enter a globally coordinated diagnostic and research pipeline and; 2) for 1000 new therapies for rare diseases to be approved, the majority of which will focus on diseases without approved options and lastly to develop methodologies to assess the impact of diagnoses and therapies on rare disease patients216. In general, IRDiRC has been key in raising public awareness of rare diseases and has subsequently led to an increase in investments into research on rare diseases. ‘ 44
• Current European funding is offered through Horizon Europe for the period of 2021 to 2027 with a budget of €95 million. Most of the funding under Horizon Europe is used for collaborative research projects within the health research policy areas: including ‘basic and translational research to understand the causes and characteristics of rare diseases; proof-of-concept of pre-clinical and clinical validation of new therapies and new diagnostics tools and technologies; [and] clinical research (clinical trials, natural history and cohort’ across all medical areas’. 44
• Beyond the project funding available under Horizon Europe, the Commission will guide funding into priority areas through a specific implementation tool: European Partnerships. These partnerships aim to bring the European Commission together with private and public partners to support research and innovation, in line with Horizon Europe’s Strategic Plan for 2021-2024. One of these European Partnerships will be the European Partnership for Rare Diseases (RD Partnership) ,. The RD Partnership is expected to respond to a need for coordination and alignment in research funding, integration with national plans, address a gap in translation of research to usable treatment, and reduce fragmentation of knowledge and data. The RD Partnership’s mission will be to “to provide a suitable infrastructural and regulatory-compliant environment enabling an improved European competitiveness in RD research and health care” 218. 44
• The general objectives of the RD partnership is to generate and translate knowledge into meaningful and accessible health interventions responding to patient needs and access the full potential of healthcare and research data. These objectives will contribute to ‘timely, equitable access to innovative, sustainable and high-quality healthcare’ and better outcomes from different types of collaborations in the rare diseases field218. The work related to the Partnership was open for as a funding opportunity through Horizon Europe until September 2023. The communication of the result of this call is expected in Q1 2024223. 45
• 1. Addressing market failure through the revised pharmaceutical legislation 45
• The newly proposed pharmaceutical legislation, seeking to address the issues around linking R&D efforts to areas of highest unmet need, will be a major component of the EU’s vision for rare diseases. The proposed pharmaceutical legislation requests that the EMA creates a network of experts and stakeholders (academic experts, medicine developers, patients etc.) to discuss priorities in medicine development across all areas, but specifically on unmet medical need in children. This effort could be a springboard for wider prioritisation and collaboration in key areas of high unmet medical need. However, as neither is currently in force, the true impact of the proposals remains to be seen. 45
• 2. Reflecting on uncertainty around the definition of high unmet medical need in the revised pharmaceutical legislation 45
• The proposals for the revision of the general pharmaceutical legislation seek to direct research and development into areas of high need and where investment may be less likely under regular market forces through the use of incentives. The incentives for R&D stimulation in the proposals link to the concept of (high) unmet medical need. While this concept is recognised as a priority by many stakeholders, the limited information on exactly what the definition will be raises concerns whether a fixed definition will work for the heterogeneity seen in rare disease patient populations, whether the factors used for the definition can be seen during the early stages of development, and whether definitions will change over the long periods for R&D. The uncertainty around the definition of HUMN may weaken the incentives attached to these definitions, given industry players will be limited in assessing the likelihood of a product in R&D addressing HUMN down the line,. The proposals indicate that the EMA should set out scientific guidelines for orphan medicines which address a high unmet medical need. It is important that these scientific guidelines are set out in a timely fashion, and possibly with a stakeholder consultation in order to capture an accurate and feasible definition. The Rare 2030 project suggests joint identification of unmet needs, and priority areas for investment may be needed to ensure affordable treatment. 45
• 3. Prioritisation of innovation and collaboration in R&D 46
• EURORDIS has called for the EU to encourage the efficient use of resources and prioritise innovative and patient-centred research. The European Partnership is an opportunity to minimize the market failures observed in the rare disease market by promoting collaboration in the research field. The work for the Partnership has not been publicly awarded as of the date of this study. It thus remains to be seen what form this Partnership will take or what actions it will prioritise. The Rare 2030 project and 2023 EESC Opinion also highlight the need to foster cross-border or international research collaborations like the IRDiRC,227. 46
• 4. Prioritisation of patient participation and focus in R&D 46
• EURORDIS has identified more patient participation as a key element in innovative, patient-centred research and patient-focused infrastructure228. Both EURORDIS and the Rare 2030 project highlight the need to see a R&D model linked to patient needs – closely related to the focus on high unmet medical need in the revised pharmaceutical legislation (see above) 227,228. 46
• 5. Finding mechanisms for R&D which are flexible, sustainable, and durable 46
• EURORDIS also highlights the need for a flexible framework which can respond to emergent health challenges and ensure treatment development remains feasible and prioritise in light of global changes. 46
• At present, all medicines that have been designated as an ‘orphan medicinal product’ in the EU must go through the EMA centralised procedure to obtain a marketing authorisation. This procedure ensures that any authorised medicine can in principle be placed on the market in any EU country. 47
• Orphan medicines are often approved by regulators on the basis of a more limited evidence base than is the case for non-orphan medicines. The clinical development for orphan medicines is challenged by the inherent low disease prevalence of rare diseases. 47
• As previously highlighted, before a medicine can be placed on the market, it must go through rigorous clinical testing. In the initial stages of clinical development, the candidate medicine is tested on healthy volunteers to demonstrate safety, but in later stages efficacy must be assessed in actual patients. For this, a sufficiently large number of trial participants is needed to show that any effects observed are statistically significant. In the case of trials involving rare disease patients, it can be challenging to find enough trial candidates. This challenge is compounded by the fact that rare diseases typically are severe and progressive, meaning that there may be ethical concerns about the use of placebo’s and withholding or delaying other forms of treatment from trial participants. Rare diseases furthermore often already manifest in childhood. 47
• Medical research on children is very strictly regulated, particularly since minors are themselves legally unable to give informed consent. The important additional safeguards that apply to paediatric clinical studies can make the process of patient enrolment very complex and lengthy. 47
• Marketing approval may be conditional, contingent on the further collection and review of evidence 47
• Box 7: Health Technology Assessment 47
• Health Technology Assessment (HTA) summarises information about medical, economic, social, and ethical issues related to the use of a health technology (which can be medicinal products, medical equipment, and prevention methods) in a systematic manner to provide national authorities with making reimbursement decisions for such technologies. 47
• There are very substantial differences in the availability of and access to orphan medicines across EU Member States. These differences can arise because, under the Treaty on the Functioning of the European Union (TFEU), matters of public health are a shared competence between the EU and its Member States,. 48
• This arrangement means that Member States retain full autonomy over the financing and organisation of health care. This includes the implementation of policies on pricing and reimbursement of medicines that can affect the market attractiveness from the perspective of the authorisation holder,. 48
• While R&D into treatments for rare diseases is stimulated by funding and regulatory incentives at European level and marketing authorisation is granted for all Member States at once by the EMA, subsequent pricing and reimbursement processes occur at a national level. Variation in these processes (e.g. the type of evidence accepted, the effects of company launch strategies which may elect to launch products in specific countries first) together with other market factors can affect the attractiveness of the national market for companies, or the availability of and access to orphan medicine products. 48
• For instance, countries may differ in how they assess the value of new medicines or in their willingness to accept uncertainty in the clinical evidence submitted, leading to divergent decisions on what price a country is willing to accept. 48
• The European Union introduced a Regulation on Health Technology Assessment (HTAR, Regulation (EU) 2021/2282) in 2022, outlining rules for joint clinical assessments (JCAs) and establishing a coordination group for national or regional HTA authorities. The Regulation sets out that, among other product categories, joint clinical assessments are appropriate for OMPs and will commence in 2028. 48
• The involvement of patient representatives in HTA or pricing and reimbursement also differs per country: patient advocacy is crucial for rare diseases by giving a voice to a small number of patients suffering from these conditions. Companies, for their part, often make strategic decisions on where and when to launch products based on the existence of a system known as External Reference Pricing (ERP, see Box 8),. 48
• Box 8: External reference pricing 49
• External reference pricing is a system where the price set in a given country is based on an average or median price in a ‘basket’ of reference countries. Because the system relies on referencing prices in different jurisdictions, company strategies (such as delays in launch, or adopting a particular sequence of countries to launch in) can have an impact on availability of products241. 49
• Combined with inherent disparities between Member States in other market factors (e.g. patient population, diagnostic capacity, standard of care), these aspects heavily influence the availability of and access to orphan medicines across the EU. 49
• 1. Reflect on effects of launch incentives proposed in the revised pharmaceutical legislation on SMEs and/or MS 49
• EURORDIS indicates more policies for access to complex therapies may be necessary in order to secure timely access to medicines, and transitions from R&D to patient access need to be made smoother. The proposals revising the European pharmaceutical legislation seek to address differences in patient access across Member States, in part, by awarding additional time for market exclusivity or regulatory data protection if market placement is established in all Member States. Whilst the industry may feel the one-year reduction of the base market exclusivity term (from 10 to 9 years) is in some form detrimental to the overall incentive, this period is still longer than comparable markets (e.g. 7-year market exclusivity term in the US). While the proposals have are clear intentions to a) ensure patient access is established and to b) avoid strategizing or avoidance of unattractive markets by the pharmaceutical industry, these requirements may disproportionally affect SMEs (due to a lack of infrastructure and resources) and depend on suitable infrastructure and knowledge within the Member States to support such a launch. The success of this component of the proposals in achieving wider patient access thus remains to be seen. Further activity to build capability and flexibility in response to these incentives may be necessary for those Member States who require it. 49
• 2. Establishment of equal access to comprehensive care through EU policies and guidelines 49
• EURORDIS identifies the establishment of equal access to care across the EU Member States as a key point of action. This may occur through the integration of health policies, disseminating multidisciplinary care practices, and the creation of EU guidelines within the EU Disability Strategy framework242. 49
• 3. Use of the joint HTA assessment processes 49
• The European HTA framework will be essential in the assessment of novel treatments. The Rare 2030 project also finds that joint HTA assessments should be incentivised in the interim, while working towards a fully function HTA framework. This will need to be supported by continuous evidence generation throughout the development of a product and once it comes to market. 49
• From the perspective of health systems, providing access to orphan medicines poses a significant challenge. Whereas for high-volume medicines the development costs can be more easily absorbed, resulting in a lower price per unit, for orphan medicines this is typically not the case. Consequently, orphan medicines are often very expensive, with some treatments costing over a million euros per patient,. At the same time, the aforementioned challenges surrounding clinical development and evidence generation can mean that there is only limited substantiation of claims about effectiveness. This leaves payers in a difficult position to decide whether the medicine should be reimbursed from the public budget when faced with limited resources and a need for prioritisation. 50
• Traditionally, the pharmaceutical market has been characterised by a balance between a period of market protection extended to innovators and a subsequent opening of the market to generic competition. 50
• This balance has provided important incentives for innovation whilst also offering a way to contain health expenditure, as the entry of generic competition normally leads to a sharp decrease in price. In the case of orphan medicines, however, this balance has been shifted. To incentivise product development, new exclusivity rights have been introduced – including in the EU, as described further in Section 2.4.1– to give marketing authorisation holders more opportunity to recoup their investment. At the same time, the market for orphan medicines is, by its very nature, already small and therefore less interesting for competitors to enter. For these reasons, in general, generic competition for orphan medicines has often been smaller and slower than for non-orphan medicines. 50
• The absence of a strong competitive market means that prices for orphan medicines may remain relatively high, even once market protections have expired,. 50
• The Mechanism of Coordinated Access to Orphan Medicinal Products (MoCA-OMP) was established in 2010, as part of the European Commission’s ‘Process on Corporate Responsibility in the Field of Pharmaceuticals’. One of the three pillars of this Process focused on access to medicines in Europe, specifically referencing how national pricing and reimbursement mechanisms determined the availability of medicines in Europe. MoCA-OMP seeks to increase collaboration between Member States, decision makers and other stakeholders to improve access to orphan medicines and to exchange information to assist with informed decisions on pricing and reimbursement at Member State level. In 2013, as part of the conclusions and reporting on the Process, MoCA-OMP recommended the development of a coordinated mechanism between volunteering Member States and developers of orphan medicines to examine and evaluate the potential value of an orphan medicine based on a transparent value framework they developed249. 50
• MoCA-OMP continues to exist as a platform where developers can request an informal, non-binding dialogue with MoCA-OMP and other stakeholders (‘a MoCA pilot’) about a specific orphan medicine in their development pipeline. MoCA assesses whether a pilot is necessary based on whether there is a need to discuss the optimisation of access to the product. Topics can cover all aspects of the development lifecycle, such as study endpoints, data requirements, identification of knowledge gaps, or potential novel payment models (pricing and reimbursement issues are not covered). Up to 2023, 47 meetings have taken place over 23 different orphan medicines249. A 2017 survey conducted by the platform itself reported that MoCA-OMP participants found MoCA-OMP to be a unique forum for informal dialogue between key stakeholders in the rare diseases field, with patient representatives, payers, medicine developers, and regulatory bodies all reporting benefits. MoCA-OMP Steering Group members have recommended that MoCA-OMP should move to a permanently supported platform to optimise payer’s resources251. 51
• The proposals for a new EU general pharmaceutical legislation seek to encourage more and earlier generic or biosimilar entry. These products are identical at a chemical level (or in the case of biosimilars, highly similar), and their entry stimulates price competition and provides healthcare providers with alternatives to prescribe. The proposals’ modular market exclusivity approach, together with allowing the assessment applications for generics and biosimilars within the last two years of the market exclusivity period, seek to promote faster generic/biosimilar competition. Earlier generic or biosimilar entry increases product choice which often results in price competition and lower prices as a result. 51
• However, for the period where market protections are still in place, national pricing, HTA, and reimbursement processes will continue to determine the affordability of orphan medicines. 51
• 1. Create a solidarity fund to pay for rare disease treatments 51
• Creation of a solidarity or special financial fund to pay for rare disease treatments, as proposed by the EESC Opinion, could reduce health inequality, address the unequal economic situations across Member States and facilitate the access to cross-border health care, and facilitate European cooperation for public health challenges252. Such a fund could draw inspiration, for example, from the 2002 EU Solidarity Fund (EUSF) for natural disasters and the lessons already learned from its implementation. The Rare 2030 Project also recommends that an EU fund for evidence generation across Member States for treatment for ultra-rare diseases should be explored. 51
• 2. Support MoCA-OMP in becoming a permanently supported forum 52
• Steering Group members of MoCA-OMP, a platform which brings key stakeholders together for informal and confidential discussions, have suggested the platform should move to a permanently supported forum to continue dialogue on issues around access to orphan medicines based on a survey of participants251. 52
• 3. Continue collaboration in price negotiation or procurement for rare disease treatments 52
• Collaborative pricing strategies are mentioned by EURORDIS as part of one of the eight key areas for action (‘timely access to affordable and innovative treatments’). Such collaboration has been seen when Member States join together for price negotiations or joint procurement of orphan medicines, sometimes extended to other activities like horizon scanning, or HTA. Examples include i) the BeneluxAI initiative, which brings together Belgium, the Netherlands, Luxembourg, Austria, and Ireland for a value-chain perspective (across the lifecycle of a medicine) to address issues around orphan medicines,, ii) steps towards joint clinical assessments of orphan medicinal products through the introduction of the HTA Regulation (Regulation (EU) 2021/2282), and iii) the revised pharmaceutical legislation’s proposal to discuss priorities in medicine development at EU level. The European Commission recognised the potential for joint procurement efforts in rare diseases in 2021, suggesting that those interested could come together on a voluntary basis. The International Association of Mutual Benefit Societies has proposed a model to calculate fair and transparent prices for medicines (the Fair Pricing Calculator). 52
• 3. Conclusions 53
• While many efforts have been made to improve the diagnosis, treatment, and care of patients with rare diseases, opportunities for further action remain. As it stands, 95% of rare diseases do not have any treatment at all, and variation across Member States remains for the quality-of-care that patients receive,. The preceding sections each discussed the opportunities and gaps identified by industry, patient, or other stakeholders. Table 4 provides an overview of these opportunities and gaps. 53
• Table 4: Summary of opportunities, gaps and concerns 53
• Opportunities and gaps 53
• Main topic or challenge 53
• Creation of a European policy framework to support national plans for rare diseases 53
• Overarching action 53
• Creation of a European Action Plan for rare diseases 53
• Increase patient engagement and empowerment 53
• Challenge 1: research and knowledge gaps 53
• N/A 53
• Improved use of existing and new technologies for diagnosis of rare diseases 53
• Challenge 2: diagnosis and codification 53
• Integration of ERNs into national systems 53
• Improved interoperability and standardisation of health data 53
• Addressing market failure through the revised pharmaceutical legislation 53
• Reflecting on uncertainty around the definition of high unmet medical need in the revised pharmaceutical legislation 53
• Challenge 3: market failure 53
• Prioritisation of innovation and collaboration in R&D 53
• Prioritisation of patient participation in R&D 53
• Finding mechanisms for R&D which are flexible, sustainable, and durable 53
• Reflect on effects of launch incentives proposed in the revised pharmaceutical legislation on SMEs and/or MS 53
• Challenge 4: Market access and patient access 53
• Establishment of equal access to comprehensive care through EU policies and guidelines 53
• Streamlining of regulatory, pricing and reimbursement policies 53
• Create a solidarity fund to pay for rare disease treatments 53
• Support MoCA-OMP in becoming a permanently supported forum 53
• Challenge 5: High prices 53
• Continue collaboration in price negotiation or procurement for rare disease treatments 53
• Source: Authors’ own elaboration. 53
• Stakeholders have identified where opportunities and gaps remain across almost all of the key challenges identified. These range from improvements on existing actions, reflections on planned actions, and identification of additional needs, yet to be addressed. The European Union has been active in the rare disease field since 2000, and more recent efforts, such as the European Reference Networks, aim to consolidate experiences and decrease variations in care and treatment across the EU Member States where possible. Across the board, stakeholders have reiterated the need to ensure patient engagement and empowerment and patient-centered approaches to care – these are important representation goals for any health conditions, but the nature of rare diseases and the small patient populations means the experiences and impacts on patients are often unknown or unrecognised. As such, amplification of and support to the patient voice is essential in the rare disease context. Where there are planned or future actions (such as the revised pharmaceutical legislation) which are expected to have significant impact for stakeholders, these need to be closely monitored and reviewed to ensure they achieve their intended outcome. The European Commission has room to guide European policy for rare diseases more closely, with stakeholders calling for a European policy framework to support, guide, and monitor national plans for rare diseases and a renewed European Action Plan for rare diseases to update older guidance. The Commission could also consider the creation of a solidarity fund to pay for rare disease treatments which would allow Member States to pool resources to cope with the high prices of OMPs and achieve greater equity among patients from different MS across the EU. 54
• Appendix A: The evaluation of the EU General Pharmaceutical Legislation 55
• A key action under the Pharmaceutical Strategy for Europe has been the evaluation of the current EU General Pharmaceutical Legislation (GPL). This legislation governs, among other things, the assessment and authorisation of all medicines placed on the EU market. The evaluation found that the GPL was successful at upholding quality, safety, and efficacy of medicinal products to the largest extent, but that the legislation’s provisions were limited in ensuring access to medicines, and only moderate in ensuring a competitive internal market and promoting the EU market globally. Alongside these observations, the evaluation found that problems persisted around addressing unmet medical need, equal access, affordability of medicines, and shortages, as well as environmental impacts of medicine residues263. Based on the findings of the evaluation and the subsequent outcomes of an impact assessment of various options for reform of the legislation, in April 2023 the Commission adopted proposals for a new GPL, accompanied by an impact assessment. Under these proposals, the existing EU Orphan Regulation will be repealed in its entirety and replaced by provisions contained within the GPL. The same applies to the Paediatric Regulation. In the explanatory memorandum to the proposals, the Commission argues that merging the Orphan and Paediatric Regulations with provisions for general pharmaceutical products will simplify the regulatory space and increase coherence264. The proposed new legislation would work closely with other pieces of EU legislation such as the Clinical Trials Regulation (Regulation 536/2014) and the Health Technology Assessment Regulation (Regulation 2021/2282) and is consistent with the aims of other actions such as Horizon Europe. Table 5 presents the proposed legislation and the existing instruments which will be repealed. 55
• Table 5: 2023 Proposals for European Pharmaceutical Legislation 56
• Source: Adapted from: European Commission (2023). Explanatory Memorandum. Proposal for a Regulation of The European Parliament And Of The Council laying down Union procedures for the authorisation and supervision of medicinal products for human use and establishing rules governing the European Medicines Agency, amending Regulation (EC) No 1394/2007 and Regulation (EU) No 536/2014 and repealing Regulation (EC) No 726/2004, Regulation (EC) No 141/2000 and Regulation (EC) No 1901/2006. 56
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