1. IntroductionThe 200th ENMC workshop hosted a group of 18 participants including neuromuscular clinicians, scientists, and patients’ representatives. Representatives of pilot European Reference Networks (ERNs) in the field of rare anaemias and metabolic diseases, as well as industry, were also present. They represented different groups and centres from Belgium, France, Germany, Hungary, Italy, the Netherlands, Spain, Sweden, and the United Kingdom.As with other rare diseases, the rarity and diversity of Neuromuscular Diseases (NMD) pose specific challenges for healthcare provision and research as well as for the development and marketing of therapies. Patients with NMD often lack a timely and accurate diagnosis, which has an influence on quality of life, prognosis and in some cases survival. Rare Diseases (RD) are a priority area in the EU Public Health Programme (2008–2013). Patient registries, biobanks and bioinformatics support, along with quality criteria for Centres of Expertise (CoEs), are the tools which the EC has put in place ahead of the establishment of ERNs. The neuromuscular field has the opportunity to utilise these specific instruments to help solve some fundamental problems, such as providing better care for patients and developing research.The aims of this workshop were the exchange of knowledge and expertise in processes for the delivery of neuromuscular care, the assessment of existing resources both national and international, the identification of gaps which need to be addressed, and to decide on a guideline document for the implementation of ERN/ERNs in the neuromuscular field.2. BackgroundIn Europe a RD is defined as a disease which affects no more than 1 per 2000 people. Rare diseases affect 8% of the European Union (EU) population (27–36 million) and 80% of rare diseases are of genetic origin [[1]Cassiman J.J. EuroGentest – a European Network of Excellence aimed at harmonizing genetic testing services.Eur J Hum Genet. 2005; 13: 1103-1105Crossref PubMed Scopus (40) Google Scholar]. Neuromuscular diseases are amongst these rare diseases. They are complex, progressive, multi-system disorders, mostly of genetic origin but also acquired, and they can present from childhood to adulthood. Most of the Neuromuscular Diseases (NMD) require multidisciplinary care and this is frequently provided in a rather scattered and uncoordinated way. In 1991 a survey of world literature, including more than 150 studies, estimated that 1 in 3500 of the general population was expected to be affected by a disabling neuromuscular disease, presenting in childhood or in later life. Data included in this paper concerned the most common neuromuscular diseases [[2]Emery A.E.H. Population frequencies of inherited neuromuscular diseases – a world survey.Neuromuscular Disord. 1991; 1: 19-29Abstract Full Text PDF PubMed Scopus (1146) Google Scholar]. Another study on inherited neuromuscular disease prevalence was carried out in Northern Ireland between February 1993 and June 1994, and the authors estimated an overall prevalence of 1 in 2900 of general population [[3]Hughes M.I. Hicks E.M. Nevin N.C. Patterson V.H. The prevalence of inherited neuromuscular disease in Northern Ireland.Neuromuscular Disord. 1996; 6: 69-73Abstract Full Text PDF PubMed Scopus (72) Google Scholar]. In 2012 according to NEUROMICS (Integrated European Project on Omics Research of rare Neuromuscular and Neurodegenerative Diseases) (http://rd-neuromics.eu) researchers, it is estimated that about 500,000–600,000 patients are suffering from rare Neurodegenerative diseases/Neuromuscular diseases in Europe. The majority of surveys currently published deal with the prevalence of a single disease and they do not address the rarest conditions. Advances in diagnostics also quickly make most of the published data on prevalence of neuromuscular conditions outdated. The same is true for the increased awareness of the general population on this issue. The number of diagnosed patients tends to increase as a result of the former and also due to better care.There have been many efforts at EU level to improve the profile of rare diseases and to develop mechanisms which will allow care for patients with RD to be organised more effectively. At a policy level, this includes the establishment of both CoEs and ERNs. CoEs and ERNs in the field of rare diseases are priorities of EU health policy as stated in the 2004 and 2005 Reports of the High Level Group on Health Services and Medical Care (HLG) [[4]HLG on Health Services and Medical Care. Available from: <http://ec.europa.eu/health/ph_overview/co_operation/mobility/high_level_hsmc_en.htm>.Google Scholar], the Council Recommendation on an action in the field of rare diseases (08.06.09) (http://eur-lex.europa.eu/JOIndex.do) [[5]Council Recommendation of 8 June 2009 on an action in the field of rare diseases. EN C 151/8 Off J Eur Union; 03.07.2009.Google Scholar], and in the Cross-Border Healthcare Directive (09.03.2011) (http://eur-lex.europa.eu/JOIndex.do) [[6]Directive 2011/24/EU of the European Parliament and of the Council of 9 March 2011 on the application of patients’ rights in cross-border healthcare. Off J Eur Union 2011; L 88/45. Available from: <http://www.eur-lex.europa.eu>.Google Scholar]. In addition, via funding available from the framework research programmes and the DG Sanco health programmes, there have been many years of investment to promote networking and collaborative research in the field of rare diseases. The neuromuscular field has been very successful in this regard, securing several major awards, including the Network of Excellence TREAT-NMD (FP6), and several associated research projects including NMD-CHIP, BIO-NMD (FP7) and CARE-NMD (DG Sanco) as well as leadership in additional broader projects such as RD Connect, the EUCERD Joint Action and Neuromics. These projects which extend into a broad range of activities including implementation of care guidelines and innovative techniques and strategies aimed at establishing molecular diagnosis and omic platforms for gene and biomarkers discovery demonstrate the broad added value that the ability to develop and maintain networks has brought to the field. The TREAT-NMD network of excellence and now Alliance represents European excellence for NMD, for care, diagnosis and research.The aim of establishing European Reference Networks (ERNs) is to facilitate the concentration of efforts and resources to assist in the diagnosis and management of patients with RD, thereby reducing in the long run the burden on healthcare systems.This workshop was structured in order to provide the participants with background information about EU policies regarding rare diseases, followed by an overview of existing national and international initiatives in the neuromuscular field, the experience of pilot ERNs in other fields of expertise and the role of learned societies in the context of an ERN. The last session was devoted to the discussion of the different aspects regarding the implementation of an ERN in the neuromuscular field.3. The background to EU plans for ERNs3.1 Overview of EU policy and legislation on RD and ERNs for public health and research, plans for applications and criteria for assessmentKate Bushby presented an overview on the aim, legislative process and content of the RD ERNs. ERNs are not projects, but rather an infrastructure focussed on care with the aim of improving access to highly specialized healthcare services. Unlike previously supported networks in the NM field, ERNs will not specifically address research, though the delivery of research via centres of expertise who are the partners in an ERN is foreseen (http://www.eucerd.eu). While ERNs will not be limited to RD, this group of conditions is particularly suited to this model of collaboration, and the EUCERD has published recommendations on the specific scope of RD ERNs [[7]EUCERD Recommendations on Quality Criteria for Centres of Expertise for Rare Diseases in Member States. Available from: <http://www.eucerd.eu>, (24.10.12).Google Scholar].The eligibility to become an ERN is a dual process that depends both on Member State and EU approval via an assessment body. Networks will be legal entities and they will be licensed to use a Logo. ERNs will be subjected to an evaluation process every five years through an independent evaluation body. The Commission will support the Member States in the development of RD ERNs, with the understanding that healthcare providers’ participation will be voluntary and those wishing to participate must fulfil all the required conditions and criteria. The expected timeline for the various processes involved in establishing the first ERNs is as follows: adoption of the Legal Acts by March 2014, selection of Independent Bodies by October 2014, first call by February 2015 and the establishment of the first ERNs by October 2015.In Paragraph 4, Article 12 of Directive 2011/24/EU [[6]Directive 2011/24/EU of the European Parliament and of the Council of 9 March 2011 on the application of patients’ rights in cross-border healthcare. Off J Eur Union 2011; L 88/45. Available from: <http://www.eur-lex.europa.eu>.Google Scholar], the EU propose 6 criteria and conditions for Networks: have the knowledge and expertise to diagnose, follow-up and manage patients with evidence of good outcomes; to follow a multi-disciplinary approach; to offer a high level of expertise and to have the capacity to produce good practice guidelines and to implement outcome and quality control measures; to make a contribution to research; to organise teaching and training activities; and to collaborate closely with other centres of expertise and networks at national and international level.All members in an ERN shall have in common: the expertise they specialise in; certain treatment(s) offered; or disease(s) or health condition(s) they focus on. They shall contribute to the objectives and the conditions and criteria of the Networks: patients’ empowerment and centred care; organisational, management and business continuity of the CoEs; research and training capacity; exchange of expertise, information systems and e-health tools; and expertise, good practice, quality, patient safety and evaluation.3.2 Patient empowerment within RD policiesFlaminia Macchia presented the views of EURORDIS (http://www.eurordis.org/) on the role and expectations of patients’ organizations regarding an ERN for RD.EURORDIS is a patient-driven, non-governmental alliance that represents 593 different patient organizations in 54 different countries. They represent more than 4000 separate diseases and around 30 million people in Europe. EURORDIS is primarily concerned with networking, dissemination of information, increasing awareness, rare diseases policy, and patients’ services.EURORDIS is in favour of establishing a limited number of ERNs, 20–30, which should collectively cover all rare disease patients by each addressing a broad range of diseases instead of a single disease; this way, patients suffering from ultra-rare diseases would not be left outside an ERN. They also see an ERN as a structured healthcare pathway in a field where relevant knowledge is scattered.According to EURORDIS, the most important characteristics for ERNs to embody are the multidisciplinarity, the broad coverage of all RD, a flexible structure able to evolve over time, and a high level of interoperability between and within a network.The participation of relevant patient organizations in the management and evaluation of an ERN should be one of the criteria of eligibility. Patient organisations should participate in the governance of the Networks and be members of the Steering and Executive Committees.3.3 EUCERD work on CoEs and ERNs for RD and their definitionKate Bushby gave a brief overview of the European Union Committee of Experts on Rare Diseases (EUCERD) composition, aim and work, with special emphasis on the sets of recommendations that have been produced. Some of the past opportunities encompassed by the EU strategies for RD were also reviewed, in particular the EU-funded projects related to NMD. EUCERD was established in 2009 and elaborated a series of recommendations (www.eucerd.eu) to help MS in their process of designating CoEs and in the elaboration of NP. The aim was to introduce harmonious standards of quality of practices, as CoEs are a key component and the building blocks of future ERNs. In reality, there is an enormous heterogeneity across Europe in the way CoE are designated. EUCERD produced 45 recommendations in 4 main areas (www.eucerd.eu): Mission and scope of CoEs; Criteria for designation; Process for designation; and European dimension.The EUCERD recommendations on RD ERNs were also discussed, which point out that the main mission of RD ERNs is to provide a framework for healthcare pathways for RD patients. ERNs should be flexible structures able to work with different national health policies. They should cover core tools and activities, and envisage adequate and long term funding. Funding is supposed to be provided by the EU as well as the MS and ERNs should deliver added value in at least 3 of the objectives of the Cross-Border Healthcare Directive. The recommendations state that the number of RD ERNs should be limited and priority shall be given to existing formal/informal networks of experts, to those with patient organization cooperation and to those with sufficient existing research activity. A brief presentation on the ERNs section of the draft Horizon 2020 call was also discussed.3.4 Current status of National Plans/Strategies for rare diseasesIn this session Teresinha Evangelista informed about the background work concerning the establishment of National Plans/Strategies (NP) for RD and gave an overview of the European situation in 2013 with respect to NP and CoEs. The implementation of a NP by each Member State by the end of 2013 is one of the Council Recommendations towards an action in the field of rare diseases [[5]Council Recommendation of 8 June 2009 on an action in the field of rare diseases. EN C 151/8 Off J Eur Union; 03.07.2009.Google Scholar]; however, an RD planning process is not exclusive as long as RD are covered in other public health strategies. NP should integrate current and future initiatives in the RD field at local, regional and national levels. They should have a limited number of priority actions and should take into account guidelines and recommendations that were expected to be developed. Other key issues addressed in the Council Recommendation include the need to create and implement a common identification system by all Member States and the need to gather expertise at the European level and ensure equal access to information, diagnosis and high quality care through the implementation of ERNs. The identification, at a national level, of CoEs with a multidisciplinary approach to care, the empowerment of patients and patients’ representatives, and the development of sustainable research and healthcare infrastructures were also crucial aspects in the Council Recommendation. Developing guidelines and recommendations for the elaboration of NP/S in the field of RD was the task of the “European Project for Rare Diseases National Plans Development” (EUROPLAN) (http://www.europlanproject.eu) and further developed through the EUCERD Joint Action (http://www.eucerd.eu). According to EUROPLAN, a NP should consist of a set of integrated and comprehensive health and social policy actions for RD, with identified objectives achievable within a specified timeframe. Appropriate instruments and resources should be allocated for the development and implementation, and a monitoring system should be in place to ensure the efficacy. Europlan indicators were presented and the full set of indicators can be found at www.europlanproject.eu. By end of the first phase of the Europlan project, an analysis of the existing NP (Bulgaria, France, Greece, Portugal and Spain) was conducted and all NP had identified general objectives and specific areas where initiatives were needed. These specific areas were similar across all the existing NP, revealing that independently of the country, rare diseases share common needs.To date 13 countries have had their NP approved and 4 others are expected to adopt by the end of 2013. As for the remaining countries, NP are still under development or are being submitted to public consultation without a date for approval. Several countries already have designated CoEs for rare diseases in the context of a national policy for RD – such is the case for Bulgaria, Denmark, France, Italy, Spain and Sweden. Other countries have official centres of reference outside a national policy for rare diseases like Belgium, Czech Republic, Finland, Greece, Ireland, and the United Kingdom. Many centres around Europe already fulfil EUCERD and the Commission criteria for CoEs and can be eligible to apply for membership of an ERN as long as the participation is approved by the MS. Indeed the latest indications on the designations of ERNs include the term “healthcare provider” rather than CoEs.4. The neuromuscular context – an overview4.1 Current status of specialized neuromuscular centres in EuropeAs part of the preparatory work the organizers distributed a brief questionnaire with the aim of ascertaining the situation of specialized neuromuscular centres in the different European countries represented at the workshop. The major conclusions around this questionnaire are that NP are already approved or pending approval for most of the represented countries. There is also however a sense that despite approval most of the NP are not in fact implemented and that specific funding for RD plans is lacking in most MS. Only Belgium and France currently have CoEs officially appointed by the relevant ministry. In several countries patients’ organizations have a crucial role in recognizing CoEs, as well as academic institutions. When inquiring about the organization of neuromuscular clinics it was consensual among the participants that most clinics are involved in the care of all groups of NMD; nevertheless, many of them also have a super-specialized area of expertise. The inclusion of motor neuron disease/amyotrophic lateral sclerosis within NMD services varies from country to country. Planned transition from paediatrics to adult clinics, although contemplated in NP, is not universally implemented. Most countries have registries/networks in place for NMD and there is a strong association between national networks and the TREAT-NMD Alliance [8Bladen C.L. et al.The TREAT-NMD Duchenne muscular dystrophy registries: conception, design and utilisation by industry and academia.Hum Mutat. 2013; 34: 1449-1457Crossref PubMed Scopus (83) Google Scholar, 9Bladen CL, et al. Mapping the differences in care for 5000 spinal muscular atrophy patients, a survey of 24 national registries in North America, Australasia and Europe. J Neurol 2013. doi: 10.1007/s00415-013-7154-1.Google Scholar].4.2 National experiences: Belgian, French, Italian, Dutch and SpanishThe participants briefly summarised the current situation in their countries, where NMD are concerned. Peter Van den Bergh explained that after 1999 the Belgian National Institute for Health and Disability Insurance (NIHDI) recognized 6 reference centres for NMD and set the following criteria: a recognised expertise in neuromuscular diseases; care for adequate numbers of patients (>100); the existence of a multidisciplinary team; and the ability to provide optimal care to patients and their relatives at all disease stages. The Belgian reference centres for NMD should be able to offer medical and paramedical care as well as psychological, social and rehabilitation care. A positive result of the networking between these centres was the development of Activlim [[10]Vandervelde L. Van den Bergh P.Y. Goemans N. Thonnard J.L. ACTIVLIM: a Rasch-built measure of activity limitations in children and adults with neuromuscular disorders.Neuromuscular Disord. 2007; 17: 459-469Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar] which is a measure of activity limitations for patients with upper and/or lower limb impairments. In 2008 they officially launched the Belgian Neuromuscular Disease Registry which aims to facilitate research, to evaluate and promote quality of care and to support political decision-making. This registry is linked to the National registry and includes approximately 4000 patients. The accreditation not only gives recognition but also allows these centres to have funding.Jean Pouget focused on France, which is already on its 2nd NP. France has 13 designated centres for NMD and they aim to develop French clinical networks.Anna Ambrosini presented the Italian Neuromuscular Network (as AIM, Italian Association of Myology) and gave a brief overview on how it coordinates the work of the neuromuscular field at a national level. The 3 main priorities of the Italian NMD network are the development of registries, the promotion of clinical trials, and the education and training of professionals. The network comprises two large groups – the myology group with 20 centres and the peripheral neuropathy group with 10 centres (mostly academic-based). These centres are self-reported and are subjected to a regular critical analysis of performance.Alessandra Ferlini explained that from the perspective of the organisation of health care in Italy the Regions have their own plans, which are dictated by National rules, including the plans for RDs. The health organisation at the Regional level is organised in networks. Hubs (reference centres) are the central excellence centres to whom spokes refer. Many (not all) Regions are monitoring the patients managing accordingly to these network, especially for RDs.Jan Verschuuren explained the structure and functioning of the Dutch national network for NMD, ISNO (www.isno.nl), and the connection with the international TREAT-NMD consortium, the ENMC and other international research networks. There are 7 centres designated by the Netherlands Federation of University Medical Centres, all based in one of the university hospitals in the Netherlands. The ISNO forms a platform whereby representatives from these centres have regular meetings and discuss issues pertaining to care and research. Netherlands has invested considerable effort into designating expert centres and there is a strong involvement and cooperation with the patients’ organizations. The quality criteria for the CoEs were established by ISNO, the NP on rare diseases and the Dutch patient organization and are mostly in accordance with the EUCERD recommendations.Carmen Paradas gave an overview of the Spanish situation. Spain started to identify expert centres in 2007, taking a National approach, and in 2013 they published the criteria for centres of expertise. These criteria are mostly in accordance with EUCERD recommendations although the Spanish NP does not foresee any additional funding for these centres of expertise. In 2008 the NMD group of the Spanish Neurological Society set-up a pilot project named “Registro Nacional de Enfermedades Musculares” (RENEM) which is a registry for 7 different NMD that has collected complete and reliable data on about 4700 patients. The information collected is homogeneous, guided towards specific purposes that help both in health planning and research. The main restriction and challenge facing this project relates to funding – as it was funded originally through EU grants, it was not made sustainable and it receives no funding from the Spanish government.4.3 Experience in the neuromuscular field on networking activities and BiobanksThe ENMC mission and structure were explained by Baziel van Engelen and Marita Pohlschmidt – they are primarily concerned with encouraging and facilitating collaborative research in Europe in the area of neuromuscular diseases. This is managed through small workshops uniting representative leaders in a specific field. These workshops are a starting point for new consortia, a breeding ground and a facilitator in topics such as diagnostic criteria, characterization of disease genes, clinical trials protocols and practical care standards. ENMC is a neutral, open and non-political organization which should position itself as a think-tank or ‘incubator’ and should be functioning as a virtual platform for interactions between different stakeholder groups. It is strongly supported by patient organizations and it is a member of the TREAT-NMD Alliance. Volker Straub gave a brief overview of the constitution of MD-NET as a neuromuscular network 12 years ago in Germany and also presented the EU FP6 funded TREAT-NMD Network, now constituted as the TREAT-NMD Alliance. This network for the neuromuscular field had very well-defined objectives designed to provide an infrastructure that ensures the most promising new therapies are reaching patients as quickly as possible. Its focus has been on the development of tools which industry, clinicians and scientists can use and on the establishment of best-practice of care for neuromuscular patients worldwide. Much of the work of the TREAT-NMD network has been sustained following the EU funding period via a patchwork of funding mechanisms. For example, the “Care and Trial Site Registry” (CTSR) (http://www.treat-nmd.eu/industry/trial-sites-and-patients/ctsr/) is one of the key dimensions of TREAT-NMD, enjoying multi-stakeholder involvement and functioning as a platform for trial readiness [[11]Rodger S. et al.The TREAT-NMD care and trial site registry: an online registry to facilitate clinical research for neuromuscular diseases.Orphanet J Rare Dis. 2013; 8: 171Crossref PubMed Scopus (26) Google Scholar]. It contains information about patient population, local infrastructures and their previous experience and training in clinical trials. Neuromics is a research project funded in FP7 by the European Commission to study 10 rare neurodegenerative and neuromuscular diseases with the aim of finding novel disease-causing genes, improve diagnostics and develop novel therapies for these disorders, and is building on the work of the CTSR. Janbernd Kirschner, who led the CARE-NMD project which also used this infrastructure, explained that the main objective was to evaluate current care practice across Europe for DMD, identify reasons for non-compliance with recommendations, and assess impact on the quality of life of patients with DMD. The project also aimed to disseminate and train different stakeholders on best care practices and establish a reference network of care centres. They used the CTSR infrastructure to identify the care centres specialised in the treatment of DMD and to perform a survey on care and quality of life of DMD patients. Jan Verschuuren’s overview on TREAT-NMD as an infrastructure project focused on the new developments around “Global Patients’ Registries”. For the global registry, a mandatory data set was defined and a flexible structure allowing the different National registries to connect with the global registry is in place. There is a particular focus on the reliability of the data collected, for which an annual training of curators is organized. Third parties (industry/academics) can access the global registry following approval by the TREAT-NMD oversight committee. In 2012 the number of patients in the registries for Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA) respectively were >13,500 over 40 countries and >2000 over 33 national SMA registries. Registries for other diseases (either global or at a National level) are also in place (http://www.treat-nmd.eu/resources/patient-registries/what/). Alessandra Ferlini cited that in Italy there are two main registries for NMDs, managed by Parents Associations, the Duchenne Parent project and the UILDM. On the other hand, the National registry of RD and several disease-specific registries are managed via ISS (D. Taruscio), which is partner of the RD-connect project. As in many other countrie, in the long run a way for disease specific registries, often supported by patient groups, and national initiatives to communicate, will need to be defined.Anna Ambrosini provided an overview on the current European panorama on biobanks, more precisely Telethon Network of Genetic Biobanks (TNGB), EuroBioBank (EBB) and RD-Connect. Telethon Genetic Biobanks are focused on diseases of genetic origin – the samples are available for research purposes and a portion of the samples is preserved for the patients’ advantage to allow retrospective analyses. Telethon has been funding Biobanks since 1993 and in 2008 merged its biobanks into a Network of high quality biobanks undergoing yearly assessments by an independent body (Telethon Scientific Committee) and maintaining a strong interaction with patient organizations. The EBB Network was established in 2001 by two patient organizations: AFM and EURORDIS. EBB received EC support from 2007 to 2011 within the European Network of Excellence TREAT-NMD in FP6. As of January 2012 Telethon has undertaken the EBB coordination. The EBB Network is currently composed of 23 members (including all TNGB biobanks) from 8 European countries. Over 440,000 samples are available and can be requested via the online catalogue. RD-Connect is a recently approved project aimed at the development of an integrated platform connecting databases, registries, biobanks and clinical bioinformatics for rare disease research. It aims to contribute to the IRDiRC objectives of delivering 200 new therapies for rare diseases and means to diagnose most rare diseases by the year 2020. It also aims to develop an integrated, quality-assured and comprehensive platform in which complete clinical profiles are combined with-omics dat
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