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Healthcare is continually evolving to meet the changing needs of twenty-first century populations whilst striving to keeping pace with medical and technological advancements. Patients and clinicians remain the constants in this evolving environment, sitting at the cutting edge of new evidence and innovation and at the coalface of clinical services which need to address the increasingly challenging health priorities we face as a society. Patients and clinicians, positioned centre stage in this changing world, must adjust their relationships and partnerships to reduce the burden of illness and ensure that multifaceted care needs are all properly addressed. In rare diseases, this relationship between patients and professionals demands a new model of care, in which patients are active, valued partners in their own care and function not as ‘enlightened self-interested’ individuals but as experts by experience. The unique characteristics of rare diseases demand that care evolves beyond multidisciplinary team care to ‘Networked-care’, in which care is prescribed based upon the body of experience and expertise of a community of experts and patients (who are experts by experience). Healthcare models are being redrawn around a new norm of clinical practice based on true patient-clinical partnerships in care. A partnership with patients, when supported by proper investment, is a collaborative relationship that aligns both the medical and clinical perspectives of professionals with a holistic perspective of patients’ life experiences. Such partnerships can (i) ensure that decisions around care and design of services are needs-led, (ii) reduce the fog of uncertainty that surrounds rare diseases, (iii) amplify the success of new discoveries, and (iv) create breakthrough innovations: in these ways, patient-clinical partnerships increase the efficiency and effectiveness of our work and build a more sustainable future for our healthcare services.

Altres ajuts: This work and the IRDiRC Scientific Secretariat are supported by the European FP7 contract, "SUPPORT-IRDiRC" (No 305207). H.L. receives funding from the European Commission under FP7 through NeurOmics (No 305121) and RD-Connect (No 305444). C.P.A. contributed to this work in his capacity as Chair of the IRDiRC Consortium Assembly, not as Director of the NCATS. The remaining authors declare that they have no competing interests. The International Rare Diseases Research Consortium (IRDiRC) has agreed on IRDiRC Policies and Guidelines, following extensive deliberations and discussions in 2012 and 2013, as a first step towards improving coordination of research efforts worldwide. The 25 funding members and 3 patient umbrella organizations (as of early 2013) of IRDiRC, a consortium of research funders that focuses on improving diagnosis and therapy for rare disease patients, agreed in Dublin, Ireland in April 2013 on the Policies and Guidelines that emphasize collaboration in rare disease research, the involvement of patients and their representatives in all relevant aspects of research, as well as the sharing of data and resources. The Policies and Guidelines provide guidance on ontologies, diagnostics, biomarkers, patient registries, biobanks, natural history, therapeutics, models, publication, intellectual property, and communication. Most IRDiRC members-currently nearly 50 strong-have since incorporated its policies in their funding calls and some have chosen to exceed the requirements laid out, for instance in relation to data sharing. The IRDiRC Policies and Guidelines are the first, detailed agreement of major public and private funding organizations worldwide to govern rare disease research, and may serve as a template for other areas of international research collaboration. While it is too early to assess their full impact on research productivity and patient benefit, the IRDiRC Policies and Guidelines have already contributed significantly to improving transparency and collaboration in rare disease research.

Objectives Although one out of four persons affected by cancer in Europe has a rare cancer (RC), it is unknown to which extent they are addressed in National Cancer Control Plans (NCCPs) and National Rare Diseases Plans (NRDPs). The objective of this review was to analyse the content included in European NCCPs and NRDPs on RCs in adults. The working hypothesis is that RCs have a lower presence in NCCPs compared to more common cancers, and that NRDPs do not generally approach them. Methods A review based on a documentary analysis on the priorities and recommendations in the area of RCs was conducted in 15 European NCCPs and 18 NRDPs. After identifying the areas covered therein, we performed a thematic analysis to allow a narrative description of the status of RCs’ health policy. Results Rare cancers are hardly addressed in NCCPs and not addressed in NRDPs. Of the 15 NCCPs analysed, only 8 contained some elements on RCs, and only 3 of these described specific measures to address this disease group or took a comprehensive approach. The cross-cutting analysis of the 8 NCCPs allowed identifying 14 critical issues necessary to reach a comprehensive approach to RCs’ policy. Conclusions The scarce presence of RCs in most of NCCPs may indicate low visibility and limited political understanding of their specificities. The critical issues emerging from the analysis are intended to improving the national policy frameworks addressing RC challenges and to place the NCCPs as strategic documents that must play a key role in this process.

EURORDIS-Rare Diseases Europe was established in 1997 to gather all rare diseases at European level to gain visibility and create a new social space, and emerge as a civil society community able to voice the needs and expectations of 30 million people in the 48 European countries. The organization has helped establish most of the 67 disease-specific European Federations or Informal networks. The strategy is a triptych: Patient Empowerment; Patient Engagement; Patient Advocacy. Partnership with stakeholders strengthens the patient’s voice and shapes research, policies and patient services, and the expertise of experience, patient knowledge and contribution to healthcare. In this context, 24 European Reference Networks on rare diseases were established; EURORDIS led the organisation and structuring of patient involvement into these Networks.

Public health relies on technologies to produce and analyse data, as well as effectively develop and implement policies and practices. An example is the public health practice of epidemiology, which relies on computational technology to monitor the health status of populations, identify disadvantaged or at risk population groups and thereby inform health policy and priority setting. Critical to achieving health improvements for the underserved population of people living with rare diseases is early diagnosis and best care. In the rare diseases field, the vast majority of diseases are caused by destructive but previously difficult to identify protein-coding gene mutations. The reduction in cost of genetic testing and advances in the clinical use of genome sequencing, data science and imaging are converging to provide more precise understandings of the 'person-time-place' triad. That is: who is affected (people); when the disease is occurring (time); and where the disease is occurring (place). Consequently we are witnessing a paradigm shift in public health policy and practice towards 'precision public health'.Patient and stakeholder engagement has informed the need for a national public health policy framework for rare diseases. The engagement approach in different countries has produced highly comparable outcomes and objectives. Knowledge and experience sharing across the international rare diseases networks and partnerships has informed the development of the Western Australian Rare Diseases Strategic Framework 2015-2018 (RD Framework) and Australian government health briefings on the need for a National plan.The RD Framework is guiding the translation of genomic and other technologies into the Western Australian health system, leading to greater precision in diagnostic pathways and care, and is an example of how a precision public health framework can improve health outcomes for the rare diseases population.Five vignettes are used to illustrate how policy decisions provide the scaffolding for translation of new genomics knowledge, and catalyze transformative change in delivery of clinical services. The vignettes presented here are from an Australian perspective and are not intended to be comprehensive, but rather to provide insights into how a new and emerging 'precision public health' paradigm can improve the experiences of patients living with rare diseases, their caregivers and families.The conclusion is that genomic public health is informed by the individual and family needs, and the population health imperatives of an early and accurate diagnosis; which is the portal to best practice care. Knowledge sharing is critical for public health policy development and improving the lives of people living with rare diseases.

'Adaptive' approaches to bringing drugs to market have been widely discussed in recent years. Here, we describe the evolution of the adaptive approach and of concepts developed by ADAPT SMART, a multi-stakeholder consortium funded by the European Innovative Medicines Initiative. 'Adaptive' approaches to bringing drugs to market have been widely discussed in recent years. Here, we describe the evolution of the adaptive approach and of concepts developed by ADAPT SMART, a multi-stakeholder consortium funded by the European Innovative Medicines Initiative.

Public health relies on technologies to produce and analyse data, as well as effectively develop and implement policies and practices. An example is the public health practice of epidemiology, which relies on computational technology to monitor the health status of populations, identify disadvantaged or at risk population groups and thereby inform health policy and priority setting. Critical to achieving health improvements for the underserved population of people living with rare diseases is early diagnosis and best care. In the rare diseases field, the vast majority of diseases are caused by destructive but previously difficult to identify protein-coding gene mutations. The reduction in cost of genetic testing and advances in the clinical use of genome sequencing, data science and imaging are converging to provide more precise understandings of the ‘person-time-place’ triad. That is: who is affected (people); when the disease is occurring (time); and where the disease is occurring (place). Consequently we are witnessing a paradigm shift in public health policy and practice towards ‘precision public health’.

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. Electronic supplementary material The online version of this article (doi:10.1186/s13023-017-0601-9) contains supplementary material, which is available to authorized users.

The International Rare Diseases Research Consortium (IRDiRC) has created a quality label, ‘IRDiRC Recognized Resources', formerly known as ‘IRDiRC Recommended'. It is a peer-reviewed quality indicator process established based on the IRDiRC Policies and Guidelines to designate resources (ie, standards, guidelines, tools, and platforms) designed to accelerate the pace of discoveries and translation into clinical applications for the rare disease (RD) research community. In its first year of implementation, 13 resources successfully applied for this designation, each focused on key areas essential to IRDiRC objectives and to the field of RD research more broadly. These included data sharing for discovery, knowledge organisation and ontologies, networking patient registries, and therapeutic development. ‘IRDiRC Recognized Resources' is a mechanism aimed to provide community-approved contributions to RD research higher visibility, and encourage researchers to adopt recognised standards, guidelines, tools, and platforms that facilitate research advances guided by the principles of interoperability and sharing.

Patients’ organisations call for an assessment of the clinical added value of orphan drugs at the time of the marketing authorisation evaluation. The European Commission has commissioned Ernst & Young to explore the feasibility of a new Committee at the European Medicines Agency1. A new drug candidate faces a number of hurdles on its journey to reach the patient. Regulators are the first, and right after are the Health Technology Agencies and payers. Things can turn sour, from a political point of view, when that second scenario happens, when the regulators say “yes this drug is safe and effective” and the payers say “Oh well but we won’t reimburse it”. Regulators and health technology assessment experts have recently started to harmonise their respective methodologies to avoid some degree of redundancy and contradictions in their respective opinions. Patients are participating in the decision making at the European Medicines Agency, and work closely with some national regulatory agencies. More systematic involvement with health technology assessment agencies is only beginning. This paper illustrates some of the issues patients are discussing with health technology assessment bodies.

Six thousand to nine thousand different rare diseases according to different classifications have been identified to date and new conditions appear each month as reported in the scientific literature. Although each rare disease affects very few people, when all > 6000 diseases are taken collectively, 30 million people are affected in Europe alone. Each rare disease impacts not only the person suffering, but also entire families, communities, and our society as a whole. This is the paradox of rarity we face today.

Background In the past few years there has been a political imperative driving the creation of European Reference Networks as these are considered a promising way to achieve equity in access to the most up to date medical care across Europe. The right to equity in the access to care was established by the directive of the European Parliament and of the Council on the application of patients' rights in cross-border healthcare. The particular situation for Rare Diseases whereby sharing of expertise can be regarded as especially valuable, as well as the work that is already in place in the networking of Rare Diseases experts means that Rare Diseases are considered excellent models for the development of European Reference Networks. Discussion To be effective, a Rare Disease network should be based on the common effort of different stakeholders and be built on what is present in the community. European Reference Networks are an excellent model to overcome some of the specificities of rare diseases: scarcity of patients, resources and expertise. European Reference Networks with broad scope will allow the rare disease community the possibility of reaching a larger number of patients and more diversified rare diseases. The practical value of grouping rare diseases in broad networks is well demonstrated in different grouping systems present in Europe (EURORDIS grouping of diseases, “Les filières de santé maladies rares”, Orphanet classification and the UK Research Model). Summary In this paper the authors, partners of EUCERD Joint Action, address some of the questions that surround the establishment of European Reference Networks. We will focus on how Rare Diseases could be efficiently grouped in order to constitute European Reference Networks and how they might be structured to allow each and every disease to benefit from networking.

In many European Union (EU) Member States (MS), rare disease (RD) patients are subject to marginalisation in classic healthcare systems designed for non-rare diseases. As a result they do not experience equal access to timely, high quality health services they deserve. The restructuring of healthcare systems to better reflect the values of equity and solidarity amongst RD patients, professionals, and policy makers across Europe can be accomplished through the establishment of Centres of Expertise (CoE). Although no official definition of CoE exists, some MS have established physical expert structures for the management and care of RD patients at the national level. Specialising in a single RD or a group of RDs, CoE are ideally care centres that bring together a group of multidisciplinary, specialised competencies and ensure timely diagnosis and appropriate follow-up care by aiming to improve the continuity and coordination of care through the implementation of healthcare pathways. In addition to providing an added value to the quality of local healthcare services, CoE are also key determinants for research on rare diseases, and support the optimisation of healthcare spending in the current economic climate. Stakeholders across Europe in the rare disease community have worked together to establish several key policy elements synthesized in the Eurordis Policy Factsheet on CoE. In order to best establish, manage, and sustain long-term functioning of CoE, monitoring systems must be established appropriate for each disease and national context. Building on the previous work of many stakeholders in this discussion, MS across Europe should work toward the establishment of CoE as possibly the most crucial elements in the context of national plans and strategies. Although much success has been observed in the establishment of CoE in several MS, several challenges for future national strategies on CoE remain and are identified here.

The goal of this paper is to study the immersion property through its links with credit risk modelling. The construction of a credit model by the enlargement of a reference filtration with the progressive knowledge of a credit event occurrence has become a standard for reduced form modelling. It is known that such a construction rises mathematical difficulties, mainly relied to the properties of the random time. Whereas the invariance of the property of semi-martingale in the enlargement is implied by the absence of arbitrage, we address in this paper the question of the invariance of the martingale property.

The preservation of the semi-martingale property in progressive enlargement of filtrations has been studied by many authors. Most of them focus on progressive enlargement with a honest time, allowing for semi-martingale invariance and simple decomposition formulas. However, times allowing for semi-martingale invariance in initial enlargements preserve as well this property in progressive enlargements. This paper is devoted to the related canonical decomposition of the martingales in the reference filtration as semi-martingales in the enlarged filtration. Examples are given in credit risk modelling.

In the context of arbitrage-free modelling of financial derivatives, we introduce a novel calibration technique for models in the affine- quadratic class for the purpose of contingent claims pricing and risk- management. In particular, we aim at calibrating a stochastic volatility jump diffusion model to the whole market volatility surface at any given time. We numerically implement the algorithm and show that the proposed approach is both stable and accurate.

There is growing recognition that the current research-and-development (R&D) and innovation-regulation ecosystem could be made more efficient to stimulate and support access to innovative therapies for those patients with rare, life-threatening diseases for which there are no adequate licensed therapies. New and progressive thinking on the principles and processes of drug development and regulation are needed in rare disease settings in order to ensure developments are financially sustainable. This paper presents perspectives on the current and emerging schemes for accelerating development of and access to medicines for rare diseases in the European Union.