European Academy of Neurology guidance for developing and reporting clinical practice guidelines on rare neurological diseases.

BACKGROUND AND PURPOSE: Rare diseases affect up to 29 million people in the European Union, and almost 50% of them affect the nervous system or muscles. Delays in diagnosis and treatment onset and insufficient treatment choices are common. Clinical practice guidelines (CPGs) may improve the diagnosis and treatment of patients and optimize care pathways, delivering the best scientific evidence to all clinicians treating these patients. Recommendations are set for developing and reporting high-quality CPGs on rare neurological diseases (RNDs) within the European Academy of Neurology (EAN), through a consensus procedure. METHODS: A group of 27 experts generated an initial list of items that were evaluated through a two-step Delphi consensus procedure and a face-to-face meeting. The final list of items was reviewed by an external review group of 58 members. RESULTS: The consensus procedure yielded 63 final items. Items are listed according to the domains of the AGREE instruments and concern scope and purpose, stakeholder involvement, rigour of development, and applicability. Additional items consider reporting and ethical issues. Recommendations are supported by practical examples derived from published guidelines and are presented in two tables: (1) items specific to RND CPGs, and general guideline items of special importance for RNDs, or often neglected; (2) items for guideline development within the EAN. CONCLUSIONS: This guidance aims to provide solutions to the issues specific to RNDs. This consensus document, produced by many experts in various fields, is considered to serve as a starting point for further harmonization and for increasing the quality of CPGs in the field of RNDs.

An Objective Approach to Identify Priority Rare Diseases for the Development of Solutions Reducing the Diagnostic Delay Based on French Data.

A timely diagnosis is a critical step to ensure a proper access to expert clinical management for patients. However, diagnosing rare diseases (RD) is a major challenge, as they are not only numerous but also extremely diverse in their expression and cause. This generates a long lag time between first symptoms and diagnosis, unanimously thought to be unacceptably long in many cases, and amenable to improvement. Digital technologies offer new opportunities for improving diagnosis and care in a sector with urgent needs. However, developing and testing digital solutions would only be possible for a limited number of rare diseases (RD). The approach presented here aims at proposing an objective way of defining a subset of "priority" RD to focus on for the development and test of new solutions to reduce the time to diagnosis. An approach which is relevant not only when developing and testing new digital solutions but also organizational solutions in the field of RDs. The priority RDs presented herein have been highlighted using two objective criteria: the existence of a well-defined and established standard of care management, defined as the availability of a medicinal product specifically targeting the disease; and / or the existence of authoritative clinical guidelines. Our approach, based on French data, led to the establishment of a list of 251 RD for which a delayed diagnosis would be especially detrimental for the patient. This work demonstrates the feasibility of identifying objectively a subset of RD at urgent needs for the development of solutions to reduce the delay to diagnosis, if choices have to be made, based on publicly and well-established available data. The proposed list needs to be updated and adapted to the local situation, and validated by experts to establish if the delay to diagnosis can be reduced.

Common Elements in Rare Kidney Diseases: Conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Rare kidney diseases encompass at least 150 different conditions, most of which are inherited. Although individual rare kidney diseases raise specific issues, as a group these rare diseases can have overlapping challenges in diagnosis and treatment. These challenges include small numbers of affected patients, unidentified causes of disease, lack of biomarkers for monitoring disease progression, and need for complex care. To address common clinical and patient issues among rare kidney diseases, the KDIGO Controversies Conference entitled, Common Elements in Rare Kidney Diseases, brought together a panel of multidisciplinary clinical providers and patient advocates to address five central issues for rare kidney diseases. These issues encompassed diagnostic challenges, management of kidney functional decline and progression of chronic kidney disease, challenges in clinical study design, translation of advances in research to clinical care, and provision of practical and integrated patient support. Thus, by a process of consensus, guidance for addressing these challenges was developed and is presented here.

Reaching multidisciplinary consensus on classification of anaphylaxis for the eleventh revision of the World Health Organization's (WHO) International Classification of Diseases (ICD-11).

BACKGROUND: Although currently misclassified in the International Classification of Diseases (ICD) and still not officially listed as a rare disease, anaphylaxis is a well-known clinical emergency. Anaphylaxis is now one of the principal headings in the "Allergic and hypersensitivity conditions" section recently compiled for the forthcoming 11th Revision of ICD (ICD-11). We here report the building process used for the pioneering "Anaphylaxis" subsection of ICD-11 in which we aimed for transparency as recommended in the ICD-11 revision guidelines. RESULTS: During an online intensive scientific and technical discussions with ICD-11 Topic Advisory Groups and Expert Working Groups, we drafted a total of 35 proposals for the classification of anaphylaxis. From all the 35 proposals, 77% were implemented, 20% remain to be implemented, and the others being partially implemented (1.5%) or rejected (1.5%). CONCLUSION: For the first time, anaphylaxis is now properly classified and has attained greater visibility within ICD. In addition to all the benefits expected from the actions we have undertaken in updating the terminology, definitions and classification of allergic and hypersensitivity conditions for ICD-11, we strongly believe that anaphylaxis should be a public health priority and that it should therefore be formally added into the list of rare diseases in order to support awareness and quality clinical management of patients.

Recommendations from the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL).

Rare diseases are an important public health issue with high unmet need. The introduction of the EU Regulation on orphan medicinal products (OMP) has been successful in stimulating investment in the research and development of OMPs. Despite this advancement, patients do not have universal access to these new medicines. There are many factors that affect OMP uptake, but one of the most important is the difficulty of making pricing and reimbursement (P&R) decisions in rare diseases. Until now, there has been little consensus on the most appropriate assessment criteria, perspective or appraisal process. This paper proposes nine principles to help improve the consistency of OMP P&R assessment in Europe and ensure that value assessment, pricing and funding processes reflect the specificities of rare diseases and contribute to both the sustainability of healthcare systems and the sustainability of innovation in this field. These recommendations are the output of the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL), a collaboration between rare disease experts, patient representatives, academics, health technology assessment (HTA) practitioners, politicians and industry representatives. ORPH-VAL reached its recommendations through careful consideration of existing OMP P&R literature and through a wide consultation with expert stakeholders, including payers, regulators and patients. The principles cover four areas: OMP decision criteria, OMP decision process, OMP sustainable funding systems and European co-ordination. This paper also presents a guide to the core elements of value relevant to OMPs that should be consistently considered in all OMP appraisals. The principles outlined in this paper may be helpful in drawing together an emerging consensus on this topic and identifying areas where consistency in payer approach could be achievable and beneficial. All stakeholders have an obligation to work together to ensure that the promise of OMP's is realised.

Fatal anaphylaxis registries data support changes in the who anaphylaxis mortality coding rules.

Anaphylaxis is defined as a severe life-threatening generalized or systemic hypersensitivity reaction. The difficulty of coding anaphylaxis fatalities under the World Health Organization (WHO) International Classification of Diseases (ICD) system is recognized as an important reason for under-notification of anaphylaxis deaths. On current death certificates, a limited number of ICD codes are valid as underlying causes of death, and death certificates do not include the word anaphylaxis per se. In this review, we provide evidences supporting the need for changes in WHO mortality coding rules and call for addition of anaphylaxis as an underlying cause of death on international death certificates. This publication will be included in support of a formal request to the WHO as a formal request for this move taking the 11th ICD revision.

The Human Phenotype Ontology in 2017.

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.

The collective impact of rare diseases in Western Australia: an estimate using a population-based cohort.

PURPOSE: It has been argued that rare diseases should be recognized as a public health priority. However, there is a shortage of epidemiological data describing the true burden of rare diseases. This study investigated hospital service use to provide a better understanding of the collective health and economic impacts of rare diseases. METHODS: Novel methodology was developed using a carefully constructed set of diagnostic codes, a selection of rare disease cohorts from hospital administrative data, and advanced data-linkage technologies. Outcomes included health-service use and hospital admission costs. RESULTS: In 2010, cohort members who were alive represented approximately 2.0% of the Western Australian population. The cohort accounted for 4.6% of people discharged from hospital and 9.9% of hospital discharges, and it had a greater average length of stay than the general population. The total cost of hospital discharges for the cohort represented 10.5% of 2010 state inpatient hospital costs. CONCLUSIONS: This population-based cohort study provides strong new evidence of a marked disparity between the proportion of the population with rare diseases and their combined health-system costs. The methodology will inform future rare-disease studies, and the evidence will guide government strategies for managing the service needs of people living with rare diseases.Genet Med advance online publication 22 September 2016.

Rare diseases in ICD11: making rare diseases visible in health information systems through appropriate coding.

BACKGROUND: Because of their individual rarity, genetic diseases and other types of rare diseases are under-represented in healthcare coding systems; this contributes to a lack of ascertainment and recognition of their importance for healthcare planning and resource allocation, and prevents clinical research from being performed. METHODS: Orphanet was given the task to develop an inventory of rare diseases and a classification system which could serve as a template to update International terminologies. When the World Health Organization (WHO) launched the revision process of the International Classification of Diseases (ICD), a Topic Advisory Group for rare diseases was established, managed by Orphanet and funded by the European Commission. RESULTS: So far 5,400 rare diseases listed in the Orphanet database have an endorsed representation in the foundation layer of ICD-11, and are thus provided with a unique identifier in the Beta version of ICD-11, which is 10 times more than in ICD10. A rare disease linearization is also planned. The current beta version is open for public consultation and comments, and to be used for field testing. The adoption by the World Health Assembly is planned for 2017. CONCLUSIONS: The overall revision process was carried out with very limited means considering its scope, ambition and strategic significance, and experienced significant hurdles and setbacks. The lack of funding impacted the level of professionalism that could be attained. The contrast between the initially declared goals and the currently foreseen final product is disappointing. In the context of uncertainty around the outcome of the field testing and the potential willingness of countries to adopt this new version, the European Commission Expert Group on Rare Diseases adopted in November 2014 a recommendation for health care coding systems to consider using ORPHA codes in addition to ICD10 codes for rare diseases having no specific ICD10 codes. The Orphanet terminology, classifications and mappings with other terminologies are freely available at www.orphadata.org.

Rare disease policies to improve care for patients in Europe.

Rare diseases are those with a particularly low prevalence; in Europe, diseases are considered to be rare when they affect not more than 5 in 10000 persons in the European Union. The specificities of rare diseases make the area a veritable public health challenge: the limited number of patients and scarcity of knowledge and expertise single rare diseases out as a distinctive domain of high European added-value. The Orphan Medicinal Product Regulation of 1999 was the first European legislative text concerning rare diseases, followed by many initiatives, including recommendations by the Council of Ministers of the European Union in 2009. These initiatives contributed to the development of rare diseases policies at European and national level aimed at improving care for patients with rare diseases. A review of the political framework at European level and in European countries is provided to demonstrate how legislation has created a dynamic that is progressively improving care for patients with rare diseases. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)".

Pfizer-sponsored satellite symposium at the European Haemophilia Consortium (EHC) Congress: changing the policy landscape: haemophilia patient involvement in healthcare decision-making.

The annual European Haemophilia Consortium (EHC) Conference 2013, held in Bucharest, Romania, 4-5 October, was attended by over 200 patient advocates, policy makers and healthcare professionals from across Europe. Pfizer sponsored a satellite symposium at the conference entitled: 'Changing the policy landscape: haemophilia patient involvement in healthcare decision making', drawing on expertise from a panel specialising in the field of rare disease. The symposium, chaired by Declan Noone (Irish Haemophilia Society) on behalf of Brian O'Mahony (Irish Haemophilia Society), examined the current policy and economic landscape in Europe and how pressures on healthcare budgets are impacting haemophilia care. The symposium also discussed the importance of representing the 'patient voice' in key policy decisions through identification of opportunities for patient advocacy group engagement. Alastair Kent (Genetic Alliance UK) opened the session by highlighting that the downturn in the global economy has refocused decision-making in healthcare, moving cost-effectiveness of healthcare interventions higher up the agenda for decision-makers and payers. In light of this, patient engagement is more important than ever, particularly in healthcare technology assessments (HTAs), to ensure that patient and family opinions are represented. Ségolène Aymé (Orphanet) built upon this in her session discussing the rare disease policy landscape and regional initiatives taking place in Europe, including the EUROPLAN process, for which the participation of the haemophilia community is critical. Finally, Declan Noone provided an example of how the EHC, through its survey of 35 countries, demonstrated not only the considerable differences in the quality of care available for people with haemophilia across Europe, but also how the data from the survey could be used as a powerful advocacy tool to initiate change in countries with lower gross domestic product (GDP) that face healthcare spending challenges. The meeting closed with a 'call to action' for patient advocacy groups, focusing on avenues by which patients can become involved in the decision-making for policies that will ultimately affect access to, and quality of, haemophilia care in their country.

The European Union Committee of Experts on Rare Diseases: three productive years at the service of the rare disease community.

The European Union Committee of Experts on Rare Diseases was entrusted with aiding the European Commission in a number of tasks, ranging from the monitoring of initiatives, to recommending improvements and actions to be pursued in the future, in addition to helping strengthen liaison at both European and International levels in the field of rare diseases. The three-year mandate of the EUCERD drew to a close in July 2013 with an impressive record. The EUCERD has laid down the foundations for future work so as to continue to advance in the key areas that have been identified as of interest for the rare disease community at large: centres of expertise, European Reference Networks, patient registries and databases, newborn screening, and indicators for national rare disease plans/strategies. The work of the Committee should now be continued by the newly formed European Commission Expert Group on Rare Diseases.