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Journal of Community Genetics logoLink to Journal of Community Genetics
. 2021 Mar 18;12(2):231–239. doi: 10.1007/s12687-021-00520-9

Rare disease care pathways in the EU: from odysseys and labyrinths towards highways

Birute Tumiene 1,2,✉, Holm Graessner 3,4,5
PMCID: PMC8141079  PMID: 33738760

Abstract

Care pathways (CPW) are used worldwide to structure care processes within the patient-centered care concept. Rare diseases (RD), defined as those affecting less than 5 persons per 10,000 and including up to 10,000 different diseases, present unique challenges to CPW development due to their rarity and a large number of disease entities, chronic and frequently disabling nature, heterogeneous manifestation, multisystem involvement, and complexity in diagnostics and treatment. However, failure to develop RD CPWs eventually leads to long diagnostic odysseys, limited and unequal access to RD treatments, and a huge burden of complex care coordination that lies on the shoulders of patients and their families, imposing many personal, professional and social life difficulties, and diminishing their quality of life. In the development of RD CPW, there is a need to ensure smooth horizontal and vertical care integration, multiple transitions, and long-term care coordination across many geographically distant care providers and to find a fine balance between centralized expertise-based, complex, highly specialized services and possibilities for local care provision, patient empowerment and self-management, and digital healthcare. Established in 2017, European Reference Networks may have a high added value through an increase in accessibility and quality of services, economies of scale, scope and speed in the development of lacking evidence-based, educational and other resources for RD CPW, and speeding up innovation development and translation into RD CPW. However, their full benefits may only be reaped through a pan-European collaboration, universal acceptance of common European values and open-mindedness for sometimes disruptive innovation in the provision of healthcare across all Member States of the European Union.

Introduction

As compared to usual care pathways that are developed for common diseases, the development of rare disease care pathways presents unique challenges that stem out of unique features of rare diseases: rarity and large number of disease entities, chronic and frequently disabling nature, heterogeneous manifestation, multisystem involvement, and complexity in diagnostics and treatment. Moreover, as no one single country may solve all rare disease-related issues alone, these pathways are inevitably highly dependent on a pan-European cooperation of Member States. European Reference Networks (ERNs) have a high added value and may bring substantial benefits to the Member States and their citizens, however, they also add an additional layer of complexity onto rare disease care pathways. In addition, being the first of its scale example of a real European Union collaboration in healthcare, ERNs and their governing structures have a difficult obligation to establish new rules and practices that frequently involve disruptive innovations in healthcare provision. Hence, challenges experienced by ERNs in their efforts to meet high demands and expectations that we put onto them rise not only from the unique features of rare diseases but also from the necessity to establish a common pan-European organizational culture for rare disease management that has to take into account many legal, organizational, cultural, economic, social, and other factors in our highly diverse national systems. The task is deemed “mission-possible”; however, its implementation relies on a universal acceptance of common European values and open-mindedness for sometimes disruptive innovation.

Conceptual framework

Care pathways: definitions and models

Care pathways (CPWs) are used worldwide as one of the methods to structure care processes and improve them within the patient-centered care concept. Although definitions of CPW in literature may vary, an operational definition proposed for a Cochrane systematic review includes all four criteria: (1) the intervention is a structured multidisciplinary plan of care; (2) the intervention is used to translate guidelines or evidence into local structures; (3) the intervention details steps in a course of care (i.e., the intervention has timeframes or criteria-based progression); and (4) the intervention aims to standardize care for a specific population [Lawal et al. 2016]. The claim that is often repeated is that CPWs aim to have “the right person, in the right place, doing the right thing, at the right time, with the right outcome and all with attention to the patient experience.”

Care pathways are always based on evidence-based resources that may include clinical practice guidelines (CPG), algorithms, diagnostic flowcharts, protocols, etc. Evidence-based resources and CPWs may be developed for single diseases (e.g., Huntington disease (Bachoud-Lévi et al. 2019)) or groups of disorders that encompass multiple related etiologies (e.g., hereditary ataxias (De Silva et al. 2019)). Steps or constituents of every CPW include various combinations of diagnostic procedures, specific or symptomatic treatments, long-term care, surveillance or monitoring, rehabilitation, palliative services, self-management, etc. Whereas clinical guidelines provide generic standards and recommendations, CPWs take into account the local organization of services, available competencies and resources, healthcare provider (HCP) structures, and care systems (Rotter et al. 2012). Finally, the application of every step of a CPW in any given patient may also depend on his/her disease presentation, severity, and psychosocial circumstances.

By definition, CPWs are most required for chronic complex diseases where coordination of actions of multiple healthcare providers (HCP) has to be ensured over protracted timeframes (Plishka et al. 2016). For these diseases, the organization of CPWs inevitably includes horizontal and vertical care integration, transitions of care and care coordination, or case management. Horizontal integration links services that are on the same level in the process of care, e.g., multidisciplinary teams (MDT) in the center of expertise (CoE) or general practitioner, social care, and mental health care services at the local community level. Vertical integration brings together HCPs at different levels of a hierarchical structure, e.g., primary, secondary, and tertiary care (European Commission 2018). Transitions of care are a set of actions designed to ensure coordination and continuity of care (National Transitions of Care Coalition n.d.). Transitions are experienced by patients as they cross healthcare levels (e.g., to get a long-term care at a primary care level after an acute episode in a tertiary-level hospital) or confront with age-related changes of care (e.g., transition from pediatric to adult services). Care coordination ensures the provision of a combination of health services and information that meets patient’s needs and specifically means the connections within and across services and settings—putting them in the right order and appropriately using resources (McDonald et al. 2007). A case manager or care coordinator is a professional who coordinates every step in the CPW and responds to the needs of a patient during his/her clinical journey. In reality, the role of case managers is frequently assumed by general practitioners or one of the MDT members in CoE; however, physician-managers usually take care about medical issues only. A dedicated nurse practitioner or social worker trained as a case manager may successfully coordinate care across healthcare levels and across sectors. Moreover, formal and informal patient organizations also provide some guidance (Castro et al. 2017).

General CPW models include chain, hub-and-spoke, and web models. Chain models are used for high predictability care processes with a high level of agreement between the team members, e.g., in processes leading to elective surgeries. For these processes, pathways may be embedded into time-task matrixes, also called Gantt Charts. Hub models are used for less predictable processes and involve a care coordinator who can use chain models for the high predictability sub-processes. Web models are used for unpredictable care, e.g., complex diagnostic pathways or pathways for patients with several important comorbidities. In hub and web models, the time-task matrix can be changed into a goal-task matrix (Overill 2003).

Challenges for RD CPW

Lack of CPWs for rare diseases

Failure to develop RD CPWs eventually leads to long diagnostic odysseys and labyrinths with an average duration of 5 to 6 years (Taruscio et al. 2017), limited and unequal across and within countries access to RD treatments (Nuti et al. 2017; Gatta et al. 2019), and a huge burden of complex care coordination that lies on the shoulders of patients and their families, imposing many personal, professional and social life difficulties, and diminishing their quality of life (Rare Barometer 2017). While the development of RD CPWs is a sole responsibility of countries and crucially depends on the will of policy-makers and health authorities, RD CPWs are still at an early stage of development in the majority of EU Member States (MS). However, even under appropriate recognition, the development of RD CPWs is a difficult endeavor due to unique features of RD that create unique challenges for RD CPWs in comparison to CPWs for common diseases.

Lack of evidence-based resources

Clinical practice guidelines (CPG) were developed for a small minority out of 6000 to 8000 RD: the usual producers of CPGs—professional organizations—seldom develop guidelines for RD (Pavan et al. 2017). Meanwhile, thousands of very rare and ultra-rare disorders lack any evidence-based resources except from single case reports in the medical literature; these patients confront with a so-called scientific uncertainty, when even the most experienced professionals are unable to provide information that is required by patients and their families. In some cases, CPGs are developed for several or several dozens of diseases grouped according to a predominating symptom (De Silva et al. 2019). In other cases, RD patients need individual care plans based on their disease symptoms and course.

Large scope and complexity of RD CPW

While CPWs for common diseases are usually comprised at a local or regional level, RD CPWs should be developed at a national level and cross not only regional but also national borders. When RD CPWs are restricted to regions, substantial unwarranted variations may arise due to the uneven distribution of expertise and resources across and within countries. Eventually, it may lead to “post-code lottery” situations, where chances of any RD patient to get services of sufficient quality depend on his/her residential location (Nuti et al. 2017; Harrison et al. 2015). Consequently, the organization of RD CPW involves multiple levels from primary care to tertiary level highly specialized settings and, eventually, cross-border healthcare. Multiple legal and organizational factors at all these levels have to be taken into account and introduce substantial complexities into RD CPWs.

Limited abilities to recognize RD at CPW entry level

There are approximately 6000 to 8000 RD and it is beyond human capacities to memorize signs and symptoms of every RD. Furthermore, many RD patients present with signs and symptoms that mimic those of common diseases, are non-specific, overlapping, and/or not fully blown in young patients (Tumienė et al. 2018). Finally, many currently practicing physicians got their medical education before RD concepts were even developed. Therefore, general practitioners or local HCPs possess limited knowledge on RD and limited abilities to recognize them (Vandeborne et al. 2019). Even when RD are suspected by local practitioners, they may have limited information on where to refer patients for diagnosis. Hence, it is very important to train medical students and healthcare professionals to recognize “red flags” of RD (i.e., unusual presentation or course of a disorder, multisystem involvement, positive family history), raise their index of suspicion for RD, and provide information about healthcare system organization for RD, including national CoEs and European Reference Networks (ERNs).

Lack of support and financial incentives

In some countries, highly specialized interventions (e.g., diagnostic investigations, complex treatments) are properly regulated and remunerated. However, many activities related to RD care and networking at a national and international level are not accounted for, regulated, and reimbursed, including collection and inclusion of data into RD patient registries or Clinical Patient Management System (CPMS) of ERNs, multiple administrative and organizational activities for networking and care coordination, and many more. Furthermore, additional costs are related to the education and training of professionals as they must have exceptional skills and knowledge that is usually not provided through regular medical training. For these reasons, hospitals may even incur financial losses due to the provision of services to RD patients and participation in ERN activities. A team of ERN hospital managers has been set up to try to identify and solve common problems, but a crucial role here is played by the health authorities responsible for the organization and legal regulation of care systems, funding of CoE, and reimbursement for services.

Need to benchmark and monitor national/regional CPWs

Performance of any CoE (e.g., numbers of patients or population coverage, care outcomes) is highly dependent on the organization of services along the whole RD CPW. Failure to establish robust referral systems to CoE, especially fast-tracking measures for treatable disorders, will increase time-to-diagnosis and time-to-treatment, while lack of care transition links (including navigation of data and communication measures between professionals) will preclude application of evidence-based resources and standardization of care with adverse effects on health outcomes. However, rare disease-specific ORPHA coding is implemented in some EU countries or regions only; therefore, the means to monitor RD CPWs in national systems across the EU are very limited (RD-ACTION: Data and policies for rare diseases n.d.). Currently, many ERNs are developing their own monitoring and peer-benchmarking processes through the creation of registries to collect health outcomes.

Specific components and characteristics of RD CPW

Substantial load onto highly specialized services

RD CPWs almost inevitably include highly specialized services that require expensive equipment and infrastructures, long-term experience, and high-level skills of professionals. RD diagnostics nearly always involve highly specialized investigations (e.g., genomic testing or specialized pathology). RD patients frequently require complex treatments (e.g., complex surgeries, transplantations, or gene therapy). Even surveillance or rehabilitation may be highly specialized in some RD (e.g., surveillance in genetic tumor risk syndromes (Vos et al. 2019) or rehabilitation in pulmonary arterial hypertension (Keusch et al. 2017)). In many cases, these services may only be provided in tertiary-level university hospitals.

Centralization of services

To ensure the safety, quality, and cost-efficiency of highly specialized services for RD, they have to be centralized at a national or even European level (Kalaiselvan et al. 2019; Derbel et al. 2017; Perrier et al. 2018). Centralization is usually achieved through accreditation and/or designation of RD centers of expertise (CoE). The natural inclination of top-level professionals and hospitals towards competition may create tensions and pressures in the healthcare systems. Hence, there is a need for a strong will of policy-makers and health authorities to keep the right balance between safety, quality, and cost-efficiency of highly specialized services versus the right to choose and competition of HCPs (Stordeur et al. 2016). Besides, centralization for RD introduces unusual tertiary—tertiary-level interconnections that may be ensured through national planning of RD CPWs and bilateral or multilateral agreements between HCPs (Peycelon et al. 2017).

Balance between highly specialized and less specialized, locally provided services

Due to the need for centralization, highly specialized services for RD are quite often provided far away from patient’s home and introduce long distances into RD CPWs. Hence, it is very important to identify those less specialized services that may be safely and with sufficient quality instituted by local HCPs or even at home. It may help to avoid long-term “exile due to illness,” frequent, and burdensome traveling of patients and their families, and may reduce costs of care. Fine-tuning of this balance is a difficult task that depends not only on the diagnosis but also on the capabilities and readiness of local HCPs to take responsibilities, links between highly specialized and local settings for data transfer and communication, care coordination, and patient empowerment.

Gatekeeping at the primary level

Mandatory primary care referrals to specialized care indicate strong gatekeeper systems in at least half of the EU MS. Moreover, strengthening of gatekeeper functions is a current trend that aims to reduce hospital usage in diseases that are amenable to care at the primary care level (European Commission 2017). However, unduly strict gatekeeping may be highly detrimental in RD CPWs due to prolonged diagnostic odysseys and reduced access to treatments. Hence, it is highly important to relax gatekeeping for confirmed or suspected RD and to ensure robust systems of referral and access to highly specialized services at all times where needed.

Importance of patient empowerment and self-management

RD patients and their caregivers often become “experts by experience”: in their long journeys towards diagnosis and treatment, with many health professionals on their way having limited knowledge on RD, patients and their caregivers are “forced” to accumulate knowledge by themselves (Le Cam and Bolz-Johnson 2019). Besides, RD patients and caregivers frequently get exceptional skills in self-management (e.g., home parenteral nutrition, oxygen and inhalation therapies, monitoring, and adjustment of complex dietary treatments). Although benefits of patient empowerment and self-management were emphasized in many chronic diseases (Coster et al. 2020), their current place and potential for application in RD CPWs are largely underinvestigated. Patient organizations and resource centers for RD and CoE have a special role in patient empowerment (Le Cam and Bolz-Johnson 2019, Castro et al. 2017), while the spread of digital healthcare technologies and applications may significantly empower self-management and self-monitoring applications.

Significance of ICT technologies

Due to long distances in RD CPWs, their complex structures, and cross-border nature, ICT technologies are indispensable. Examples of possible applications include referral systems, patient registries (Posset et al. 2019), disease monitoring and surveillance systems (Cialone et al. 2011), self-management applications (Hoogeveen et al. 2018; Donald et al. 2019), consultations through telemedicine given to patients or local professionals (Portaro et al. 2018), meetings and communication of multidisciplinary teams (MDT), and multiple others. Digital health services may support, complement or substitute usual healthcare services, or offer entirely new services. With digital technologies penetrating every sphere of our lives, eHealth, teleHealth, and mHealth will inevitably change the way healthcare is delivered in the future. However, currently, their use is severely hampered by a lack of legal, financial, and organizational base for these services, including the application of GDPR requirements for data privacy and reimbursement for digital services.

Links between healthcare and research

There are few medical areas where a strong link between healthcare and research is as important as in RD. In a substantial part of RD patients, etiological diagnosis may not be established even though application of all available diagnostic investigations currently used in clinical practice. Meanwhile, research methods (e.g., multiomics) may provide means to identify etiology in undiagnosed cases (Taruscio et al. 2017; Webb-Robertson et al. 2020). Moreover, currently, only 5% of RD has specific treatments, but hundreds of potential therapies are in the pipeline of clinical research. Hence, recruitment of every available patient for clinical trials may be highly important in some rare and ultra-rare diseases. Data and biological samples of RD patients are collected into registries and biobanks of CoE for RD and comprise highly important fuels for RD biomedical and clinical research. Besides, although clinical trials by no means may replace usual treatments, for many RD patients, it is the only option for specific treatments. Many CoE are based in university hospitals and provide all these crucial links between healthcare and research.

Bridge to psychosocial and community care

RD are usually chronic and often whole-life conditions that induce disabilities and complex needs; therefore, patients and their families need support and empowerment, social services, psychological care, and community support. Failure to address these needs results in social exclusion, diminished mental health and quality of life, negatively affect personal and professional lives, and socioeconomic status of patients and their families (Castro et al. 2017; Rare Barometer 2017). Resource centers for RD are a highly important part of RD CPWs that may provide integrated care and one-stop-shop services, including rehabilitation, therapeutic, social and support services, patient empowerment, guidance, and education (Castro et al. 2017).

European reference networks in RD CPW: challenges and opportunities

In 2017, more than 900 CoE for RD across Europe joined their forces into 24 ERNs, while in 2019, more than 200 Affiliated Partners were linked to existing ERNs. A current number of ERN Full Members and Affiliated Partners exceeds 1200 CoE. With a further expansion of ERNs in 2021, direct participation in ERNs may reach close to 2000 CoE. All these CoE provide crucial hubs for national and pan-European CPWs for RD, and their networking has a high added value for national systems and across Europe.

Accessibility to knowledge, expertise, and highly specialized services

ERNs may provide access to expertise and high-quality services for any patient with a RD in any MS; there is a huge potential to reduce inequities across Europe. A patient may gain benefits directly (through a consultation in the Clinical Patient Management System, CPMS) or indirectly (e.g., through expertise gained by a local professional or application of ERN-developed clinical practice guidelines and standards in national systems).

Economies of scale, scope, and speed

Through the networking of top-level experts, ERNs may ensure economies of scale, scope, and speed for any task that is performed in collaboration (e.g., development of clinical practice guidelines, collection of RD patients’ cohorts and data, biomedical and clinical RD research). ERN Full Members and Affiliated Partners spread the knowledge and resources generated by ERNs into national systems.

ERN logo—a European quality label

ERN Full Membership is achieved through a gradual and lengthy process: firstly, national health authorities perform an accreditation and/or designation of RD CoE. Through the national endorsement procedure, RD CoE may be endorsed to apply for ERN Full Membership. Applications of candidates are evaluated by ERN Boards and get their positive or negative opinions. The main aims of this peer-review process are to check for compliance with the field-specific criteria, including patients’ volumes, available infrastructures for highly specialized services, composition of MDT, professionals’ expertise, and skills. Further assessment of candidates is performed by the Independent Assessment Body (IAB) through evaluation of documentation and direct on-site visits. Eventually, Full Membership of ERNs is approved by the ERN Board of Member States (BoMS) that also has a right to overrule decisions of both ERN Boards and the IAB (European Commission 2019). Moreover, continuous ERN monitoring ensures that ERN Full Members execute required activities that are of sufficient quality at all times; non-compliance procedure may be executed to exclude HCPs that no longer conform to the criteria. This complex interplay of national and European quality assurance processes have to ensure that the ERN logo remains a European quality label for the highest standards in RD care.

Expertise travels, not the patient: CPMS

CPMS is one of the main instruments that EC developed for ERNs to execute their functions. ICT system for virtual consultations ensures smooth and safe traveling of knowledge and patients’ data across Europe and may help MS to save funds that would be otherwise spent on physical cross-border healthcare services. Besides, participation in CPMS consultations may increase the expertise of all participating professionals and clinical advice may be used in similar clinical situations later on.

ERN members as the doors and gatekeepers for cross-border RD CPWs

Although Directive 2011/24/EU on the application of patients’ rights in cross-border healthcare ensure access to healthcare across the European Economic Area (EEA) for all EEA citizens, its Article 8 defines healthcare that may be subject to prior authorization (European Parliament and the Council of the European Union 2011). Services for RD patients usually “require the use of highly specialized and cost-intensive medical infrastructure or medical equipment” (European Parliament and the Council of the European Union 2011); hence, many EU MS execute their right to prior authorization procedures for planned cross-border services for RD patients. Prior authorization helps MS to save resources that were previously allocated to the development of expensive infrastructures and building of professionals’ expertise. ERN Full Members and Affiliated Partners are in the best position to help health authorities in their decisions on prior authorization: being experts in the field, they know well both national and European resources. Besides, as the means to ensure the most rational decisions in every clinical situation, ERN Coordinators propose a “CPMS-first” approach where every RD patient gets CPMS consultation prior to the decision on referral for cross-border healthcare.

Knowledge generation for RD CPWs

One of the main functions of ERNs that was recently supported by EC is the development of CPGs for RD. ERNs intensively prepare CPGs (De Silva et al. 2019; Kyrklund et al. 2020) and other resources for RD CPWs (Bolz-Johnson et al. 2020). While networks of top-level experts in ERNs create “theoretical models” for RD CPWs, their “operational versions” may be adapted and developed by RD CoE and other national stakeholders. These operational resources for RD CPWs take into account national capacities and preferences and fine-tune the balance between highly specialized and local services. Other ERN-generated knowledge resources may also be used by national systems: e.g., specific criteria developed by ERNs for Full Membership may be applied for national accreditation or designation of RD CoE.

Innovation development and translation

Every ERN has a triple obligation of highly specialized healthcare services, research, and education in RD. This triangle creates a highly efficient pipeline for clinical research and innovation translation that is further fueled by ERN registries. Moreover, with hundreds of CoE across the EU, ERNs create the largest RD research and innovation platform to date, while their participation in the European Joint Programme for Rare Diseases n.d. effectively embeds them into the European and global ecosystem for RD research (European Joint Programme for Rare Diseases n.d.). Eventually, ERNs will ensure that state-of-the-art innovations are introduced into CPGs and are implemented in clinical practice.

Education and training

Supported by EC and MS, all ERNs develop and provide RD education and training, for example, training programs and fellowships (European Joint Programme for Rare Diseases n.d.), schools (European Reference Network Neurological Diseases (ERN-RND) n.d. webinars (The European Rare Kidney Disease Network (ERKNet) (n.d.)), online modules for students, curricula, and many other educational activities. Many online educational materials are open-resource and are highly actively used by stakeholders from Europe and across the globe. As the majority of ERN Members are CoE based in teaching university hospitals, ERN-developed education and training on RD effectively spread into national systems.

Indeed, the potential of ERNs to bring multiple breakthroughs into the RD field was widely recognized. Unfortunately, many still unsolved challenges may preclude reaping the full benefits of ERNs and endanger their long-term sustainability (European Court of Auditors 2019).

Disruptive innovations call for innovative legal, organizational, and financial solutions

ERNs were a novel and unprecedented formation in the EU and even globally. Despite several years of discussions among MS that took place in the ERN BoMS (European Commission website n.d.), some issues of ERN governance, day-to-day functioning, and sustainability were not foreseen and solved in time (European Court of Auditors 2019). Indeed, many ERN concepts, functions, and services are disruptive innovations per se that not only create “new networks and new organizations based on a new set of values, involving new players, which makes it possible to health improve outcomes and other valuable goals, such as equity and efficiency,” but also “displaces older systems and ways of doing things” (European Commission 2016). Unfortunately, it may take some time to change a mindset, overcome inertia, and conservativeness, and to identify unforeseen bottlenecks and solutions on how to remove them.

Lack of EU powers to solve EU-wide issues

Although EC provides a considerable administrative and financial support to many ERN functions and services including administration, ICT system, development of ERN registries, CPGs, education and training, and every ERN Coordinator, Full Member, and Affiliated Partner are embedded into its national system and crucially depend on decisions taken at the national level. According to Article 168 of the Treaty on the Functioning of the European Union, the organization and finance of healthcare is a responsibility of every MS and EU’s work in public health and healthcare shall be restricted to helpful coordinating measures only (Council of the European Union 2012; Greer et al. 2019). Consequently, a principle of “voluntary participation” in ERNs is set out in Article 12 of the Directive on the application of patients’ rights in cross-border healthcare (European Parliament and the Council of the European Union 2011), while a mandate of ERN BoMS includes only assessment, approval, and termination of ERN membership and Networks (Commission Implementing Decision 2014) and a “forum for exchanging information and expertise in order to steer the development of the ERNs, provide guidance to the Networks and to the Member States and advise the Commission on matters related to the establishment of the Networks” (Commission Implementing Decision 2019), and may not have a power on many national processes that are important for ERN functioning. As a result, many EU-wide issues that are important for the day-to-day functioning, governance, and sustainability of ERNs remain unsolved (European Court of Auditors 2019), while over-reliance on the political will of national policy-makers and health authorities may finally endanger ERN performance and sustainability.

ERN integration into national systems

Performance and functioning of any ERN unit (Full Member or Affiliated Partner) crucially depend on the organization of national systems, while reaping of ERN benefits relies on proper national integration of these units. ERN Working Group on ERN Integration into National Systems (WGEIN) identified five strategic areas for interventions, including legal frameworks, development of RD CPWs and referral systems, support to ERNs, and dissemination of information, along with a list of proposed actions that were supported by ERN BoMS (ERN Board of Member States 2019). While some MS take decisive steps to integrate their ERN Members into national systems, ERN BoMS Statement does not have any legally binding powers and its implementation is subject to autonomic decisions of national authorities.

Gaps in ERN quality assurance

Although complex interplay of national and European quality assurance processes should ensure that every ERN Member conforms to the highest attainable standards, several gaps in these processes remain. While some MS have stringent procedures of accreditation and endorsement, only “soft” quality assurance measures are applied in other MS. Moreover, due to unexpectedly high numbers of applicants for ERN Membership, only approximately 20% of candidates were eventually evaluated through on-site visits of IAB during the inaugural stage of ERN creation and up to 20% more in subsequent years. Fortunately, these gaps in ERN quality assurance may be rectified through ERN monitoring and termination of membership of ERN Members that no longer conform to the criteria, but it takes time.

Support for ERN research

Being “born” from the Directive on the application of patients’ rights in cross-border healthcare, ERNs have their “home and patronage” in DG SANTE. RD research comprises a substantial part of ERN activities; however, the development of EU research strategies and instruments is not in the competencies of DG SANTE. Although European Joint Programme on Rare Diseases effectively embeds ERNs into the whole RD research ecosystem, it is not in the current capacities of this programme to fulfill the needs of ERNs in RD research. Either a substantial increase in EJP RD capacities or a separate strategy and instruments for ERN research would be required to use their whole potential.

Conclusions

As compared to usual CPWs that are developed for common diseases, the development of RD CPWs presents unique challenges that stem out of unique features of RD. Moreover, as no one single country may solve all RD-related issues alone, RD CPWs are inevitably highly dependent on a pan-European cooperation of MS. ERNs have a high added value and may bring substantial benefits to MS and their citizens; however, they also add an additional layer of complexity onto RD CPW. In addition, being the first of its scale example of a real EU collaboration in healthcare, ERNs and their governing structures have a difficult obligation to establish new rules and practices that frequently involve disruptive innovations in healthcare provision. Hence, challenges experienced by ERNs in their efforts to meet high demands and expectations that we put onto them rise not only from the unique features of RD but also from the necessity to establish a common pan-European organizational culture for RD management that has to take into account many legal, organizational, cultural, economic, social, and other factors in our highly diverse national systems. The task is deemed “mission-possible”; however, its implementation relies on a universal acceptance of common European values and open-mindedness for sometimes disruptive innovation.

Acknowledgments

This work is supported (not financially) by the European Reference Network for Rare Neurological Diseases, ERN-RND.

Funding

ERN-RND is partly co-funded by the European Union within the framework of the Third Health Programme “ERN-2016—Framework Partnership Agreement 2017–2021.”

Declarations

Research involving human participants and/or animals

This article does not contain any studies with human participants or animals performed by any of the authors.

Conflict of interest

Dr. Graessner receives/has received research support from the Deutsche Forschungsgemeinschaft (DFG), the Bundesministerium für Bildung und Forschung (BMBF), the Bundesministerium für Gesundheit (BMG), and the European Union (EU). He has received consulting fees from Roche. He has received a speaker honorarium from Takeda. Dr. Birute Tumiene receives/has received research support from the European Union.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. Bachoud-Lévi AC, Ferreira J, Massart R, et al. International guidelines for the treatment of Huntington’s disease. Front Neurol. 2019;10:710. doi: 10.3389/fneur.2019.00710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Rare Barometer (2017) Juggling care and daily life: the balancing act of the rare disease community. Available at: http://download2.eurordis.org.s3.amazonaws.com/rbv/2017_05_09_Social%20survey%20leaflet%20final.pdf
  3. Bolz-Johnson M, Meek J, Hoogerbrugge N. “Patient Journeys”: improving care by patient involvement. Eur J Hum Genet. 2020;28(2):141–143. doi: 10.1038/s41431-019-0555-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Castro R, Senecat J, de Chalendar M, et al. Bridging the gap between health and social care for rare diseases: key issues and innovative solutions. Adv Exp Med Biol. 2017;1031:605–627. doi: 10.1007/978-3-319-67144-4_32. [DOI] [PubMed] [Google Scholar]
  5. Cialone J, Augustine EF, Newhouse N, Vierhile A, Marshall FJ, Mink JW. Quantitative telemedicine ratings in Batten disease: implications for rare disease research. Neurology. 2011;77(20):1808–1811. doi: 10.1212/WNL.0b013e3182377e29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Commission Implementing Decision (2014) of 10 March setting out criteria for establishing and evaluating European Reference Networks and their Members and for facilitating the exchange of information and expertise on establishing and evaluating such Networks. 2014. Available at: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=OJ%3AJOL_2014_147_R_0007
  7. Commission Implementing Decision (2019) 2014/287/EU of 26 July amending Implementing Decision 2014/287/EU setting out criteria for establishing and evaluating European Reference Networks and their Members and for facilitating the exchange of information and expertise on establishing and evaluating such Networks. 2019. Available at: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32019D1269&from=EN
  8. Coster S, Li Y, Norman IJ. Cochrane reviews of educational and self-management interventions to guide nursing practice: a review [published online ahead of print, 2020 Jul 2] Int J Nurs Stud. 2020;110:103698. doi: 10.1016/j.ijnurstu.2020.103698. [DOI] [PubMed] [Google Scholar]
  9. Council of the European Union. Consolidated versions of the Treaty on European Union and the Treaty on the Functioning of the European Union (2012) Consolidated versions of the Treaty on European Union and the Treaty on the Functioning of the European Union. Official Journal C 326 1–12. Available at: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:12012E/TXT&from=EN
  10. De Silva R, Greenfield J, Cook A, et al. Guidelines on the diagnosis and management of the progressive ataxias. Orphanet J Rare Dis. 2019;14(1):51. doi: 10.1186/s13023-019-1013-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Derbel O, Heudel PE, Cropet C, et al. Survival impact of centralization and clinical guidelines for soft tissue sarcoma (A prospective and exhaustive population-based cohort) PLoS One. 2017;12(2):e0158406. doi: 10.1371/journal.pone.0158406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Donald A, Cizer H, Finnegan N, Collin-Histed T, Hughes DA, Davies EH. Measuring disease activity and patient experience remotely using wearable technology and a mobile phone app: outcomes from a pilot study in Gaucher disease. Orphanet J Rare Dis. 2019;14(1):212. doi: 10.1186/s13023-019-1182-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. ERN Board of Member States (2019) Statement of the ERN Board of Member States on Integration of the European Reference Networks to the healthcare systems of Member States. Available at: https://ec.europa.eu/health/sites/health/files/ern/docs/integration_healthcaresystems_en.pdf;https://ec.europa.eu/health/sites/health/files/ern/docs/integration_healthcaresystems_annex_en.pdf
  14. European Commission (2016) Report of the Expert Panel on effective ways of investing in Health (EXPH) on Disruptive Innovation. Considerations for health and health care in Europe Available at: https://ec.europa.eu/health/sites/health/files/expert_panel/docs/012_disruptive_innovation_en.pdf
  15. European Commission . State of Health in the EU: Companion Report 2017. Luxembourg: Publications Office of the European Union; 2017. [Google Scholar]
  16. European Commission . Health system performance assessment – Integrated Care Assessment (20157303 HSPA) Luxembourg: Publications Office of the European Union; 2018. [Google Scholar]
  17. European Commission (2019) ERN Assessment Manual for Applicants. Description and Procedures Available at: https://ec.europa.eu/health/sites/health/files/ern/docs/call2019_assesmanual_en.pdf
  18. European Commission website (n.d.) European Reference Networks. Board of Member States. Available at: https://ec.europa.eu/health/ern/board_member_states_en
  19. European Court of Auditors (2019) EU actions for cross-border healthcare: significant ambitions but improved management required. Available at: https://www.eca.europa.eu/Lists/ECADocuments/SR19_07/SR_HEALTH_CARE_EN.pdf
  20. European Joint Programme for Rare Diseases (n.d.) website. Available at: https://www.ejprarediseases.org/
  21. European Parliament and the Council of the European Union (2011) Directive 2011/24/EUof the European Parliament and of the Council of 9 March on the application of patients’ rights in cross-border healthcare. Available at: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex%3A32011L0083
  22. European Reference Network Neurological Diseases (ERN-RND) (n.d.) Available at: http://www.ern-rnd.eu/
  23. Gatta G, Trama A, Capocaccia R. RARECARENet Working Group. Epidemiology of rare cancers and inequalities in oncologic outcomes. Eur J Surg Oncol. 2019;45(1):3–11. doi: 10.1016/j.ejso.2017.08.018. [DOI] [PubMed] [Google Scholar]
  24. Greer SL, Fahy N, Rozenblum S, et al. Everything you always wanted to know about European Union health policies but were afraid to ask. 2nd ed., 2019. European Observatory on Health Systems and Policies. Available at: https://apps.who.int/iris/bitstream/handle/10665/328267/9789289051767-eng.pdf?sequence=1&isAllowed=y. [PubMed]
  25. Harrison M, Birch S, Eden M, Ramsden S, Farragher T, Payne K, Hall G, Black GCM. Variation in healthcare services for specialist genetic testing and implications for planning genetic services: the example of inherited retinal dystrophy in the English NHS. J Community Genet. 2015;6(2):157–165. doi: 10.1007/s12687-014-0210-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hoogeveen IJ, Peeks F, De Boer F, Lubout CMA, de Koning TJ, te Boekhorst S, Zandvoort RJ, Burghard R, van Spronsen FJ, Derks TGJ. A preliminary study of telemedicine for patients with hepatic glycogen storage disease and their healthcare providers: from bedside to home site monitoring. J Inherit Metab Dis. 2018;41(6):929–936. doi: 10.1007/s10545-018-0167-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kalaiselvan R, Malik AK, Rao R, Wong K, Ali N, Griffin M, Chandrasekar CR, Fenwick SF, Poston GJ, Malik H. Impact of centralization of services on outcomes in a rare tumour: retroperitoneal sarcomas. Eur J Surg Oncol. 2019;45(2):249–253. doi: 10.1016/j.ejso.2018.06.032. [DOI] [PubMed] [Google Scholar]
  28. Keusch S, Turk A, Saxer S, et al. Rehabilitation in patients with pulmonary arterial hypertension. Swiss Med Wkly. 2017;147:w14462. doi: 10.4414/smw.2017.14462. [DOI] [PubMed] [Google Scholar]
  29. Kyrklund K, Sloots CEJ, De Blaauw I, et al. ERNICA guidelines for the management of rectosigmoid Hirschsprung’s disease. Orphanet J Rare Dis. 2020;15(1):164. doi: 10.1186/s13023-020-01362-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lawal AK, Rotter T, Kinsman L, et al. What is a clinical pathway? Refinement of an operational definition to identify clinical pathway studies for a Cochrane systematic review. BMC Med. 2016;14:35. doi: 10.1186/s12916-016-0580-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Le Cam Y, Bolz-Johnson M (2019) Expert by Experience: valuing patient engagement in healthcare. In: M.-P. Pomey et al. (eds.), Patient engagement, organizational behaviour in healthcare, Springer Nature Switzerland AG. doi:10.1007/978-3-030-14101-1_9
  32. McDonald KM, Sundaram V, Bravata DM, Lewis R, Lin N, Kraft S, McKinnon M, Paguntalan H, Owens DK. Care Coordination. Vol 7 of. In: Shojania KG, KM MD, Wachter RM, Owens DK, editors. Closing the quality gap: a critical analysis of quality improvement strategies. Technical Review 9 (Prepared by the Stanford University-UCSF Evidence-based Practice Center under contract 290-02-0017). AHRQ Publication No. 04(07)-0051-7. Rockville, MD: Agency for Healthcare Research and Quality; 2007. [PubMed] [Google Scholar]
  33. National Transitions of Care Coalition (n.d.) Available at: www.ntocc.org
  34. Nuti S, Seghieri C, Niccolai F, Vasta F, Grazzini G. Comparing regional models of congenital bleeding disorders: preliminary steps in the Italian context. BMC Res Notes. 2017;10(1):229. doi: 10.1186/s13104-017-2552-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Overill S (2003) The development, role, and integration of integrated care pathways in modern day health care. In: Ellershaw J, Wilkinson S (eds.). Care for the dying: A pathway to excellence. Oxford University Press
  36. Pavan S, Rommel K, Mateo Marquina ME, Höhn S, Lanneau V, Rath A. Clinical practice guidelines for rare diseases: the Orphanet Database. PLoS One. 2017;12(1):e0170365. doi: 10.1371/journal.pone.0170365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Perrier L, Rascle P, Morelle M, et al. The cost-saving effect of centralized histological reviews with soft tissue and visceral sarcomas, GIST, and desmoid tumors: the experiences of the pathologists of the French Sarcoma Group. PLoS One. 2018;13(4):e0193330. doi: 10.1371/journal.pone.0193330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Peycelon M, Faraj S, Leclair MD, Bonnard A. French Connection between specialized and routine pediatric surgical care. Eur J Pediatr Surg. 2017;27(5):410–415. doi: 10.1055/s-0037-1606636. [DOI] [PubMed] [Google Scholar]
  39. Plishka C, Rotter T, Kinsman L, et al. Effects of clinical pathways for chronic obstructive pulmonary disease (COPD) on patient, professional and systems outcomes: protocol for a systematic review. Syst Rev. 2016;5(1):135. doi: 10.1186/s13643-016-0311-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Portaro S, Calabrò RS, Bramanti P, Silvestri G, Torrisi M, Conti-Nibali V, Caliri S, Lunetta C, Alagna B, Naro A, Bramanti A. Telemedicine for facio-scapulo-humeral muscular dystrophy: a multidisciplinary approach to improve quality of life and reduce hospitalization rate? Disabil Health J. 2018;11(2):306–309. doi: 10.1016/j.dhjo.2017.09.003. [DOI] [PubMed] [Google Scholar]
  41. Posset R, Garbade SF, Boy N, Burlina AB, Dionisi-Vici C, Dobbelaere D, Garcia-Cazorla A, de Lonlay P, Teles EL, Vara R, Mew NA, Batshaw ML, Baumgartner MR, McCandless SE, Seminara J, Summar M, Hoffmann GF, Kölker S, Burgard P, Additional individual contributors of the UCDC and the E‐IMD consortium. Berry SA, Burrage L, Coughlin C, Diaz GA, Gallagher RC, Gropman A, Harding CO, Lee B, le Mons C, Lawrence Merritt J, II, Nagamani SCS, Schulze A, Stricker T, Tuchman M, Waisbren S, WeisfeldAdams J, Wong D, Yudkoff M, Arnoux JB, Bari&cacute I, Bosch AM, Chabrol B, Chakrapani A, CortèsSaladefont E, Couce ML, Eyskens F, Laet C, Meirleir L, Freisinger P, Gleich F, Grünewald S, Häberle J, Hwu WL, Jalan A, Karall D, Lindner M, Lund AM, Martinelli D, Murphy E, Mühlhausen C, Olivieri G, Ottolenghi C, Rodrigues E, Rubert L, Sarajlija A, Schiff M, Sokal E, SykutCegielska J, Walter JH, Williams M, Zeman J. Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders-a successful strategy for clinical research of rare diseases. J Inherit Metab Dis. 2019;42(1):93–106. doi: 10.1002/jimd.12031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. RD-ACTION: Data and policies for rare diseases (n.d.) Workpackage 5: Steering, maintaining and promoting the adoption of Orphacodes across MS. Available at: http://www.rd-action.eu/workpackage/workpackage-5/
  43. Rotter T, Kinsman L, James E, Machotta A, Steyerberg EW. The quality of the evidence base for clinical pathway effectiveness: room for improvement in the design of evaluation trials. BMC Med Res Methodol. 2012;12:80. doi: 10.1186/1471-2288-12-80. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Stordeur S, Vrijens F, Leroy R. Reference centres for adults with rare and complex cancers - policy recommendations to improve the organisation of care in Belgium. Rev Epidemiol Sante Publique. 2016;64(1):1–6. doi: 10.1016/j.respe.2015.11.006. [DOI] [PubMed] [Google Scholar]
  45. Taruscio D, Floridia G, Salvatore M, Groft SC, Gahl WA. Undiagnosed diseases: Italy-US collaboration and international efforts to tackle rare and common diseases lacking a diagnosis. Adv Exp Med Biol. 2017;1031:25–38. doi: 10.1007/978-3-319-67144-4_2. [DOI] [PubMed] [Google Scholar]
  46. The European Rare Kidney Disease Network (ERKNet) (n.d.) Available at: https://www.erknet.org/index.php?id=home
  47. Tumienė B, Maver A, Writzl K, Hodžić A, Čuturilo G, Kuzmanić-Šamija R, Čulić V, Peterlin B. Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice. Clin Genet. 2018;93(5):1057–1062. doi: 10.1111/cge.13203. [DOI] [PubMed] [Google Scholar]
  48. Vandeborne L, van Overbeeke E, Dooms M, De Beleyr B, Huys I. Information needs of physicians regarding the diagnosis of rare diseases: a questionnaire-based study in Belgium. Orphanet J Rare Dis. 2019;14(1):99. doi: 10.1186/s13023-019-1075-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Vos JR, Giepmans L, Röhl C, Geverink N, Hoogerbrugge N. ERN GENTURIS. Boosting care and knowledge about hereditary cancer: European Reference Network on Genetic Tumour Risk Syndromes. Familial Cancer. 2019;18(2):281–284. doi: 10.1007/s10689-018-0110-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Webb-Robertson BM, Stratton KG, Kyle JE, et al. Statistically driven metabolite and lipid profiling of patients from the undiagnosed diseases network. Anal Chem. 2020;92(2):1796–1803. doi: 10.1021/acs.analchem.9b03522. [DOI] [PMC free article] [PubMed] [Google Scholar]

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