Progress in Rare Diseases Research 2010–2016: An IRDiRC Perspective

Rare diseases by definition are conditions that affect small numbers of people. The prevalence threshold that designates a disease as rare varies in different countries. Generally, diseases with prevalence fewer than 5 in 10,000 people are considered rare.1 Many rare diseases affect far fewer people worldwide, with some having a single identified case and others with cases numbering from tens to low hundreds of people.2 However, collectively, they are common. There are ∼6,000–8,000 rare diseases, with 250–280 new diseases described annually, affecting an estimated 6–8% of the human population.3-6 The rarity of these diseases individually creates significant challenges for affected patients, their families, and for clinicians attempting to achieve a confirmed diagnosis and implement best care.7, 8 Obtaining a correct diagnosis is frequently a difficult and lengthy process, as physicians and caregivers often lack appropriate expertise in a disease that they rarely encounter.4 Effective therapeutics are lacking for the large majority of these diseases, and when they exist, they are often very expensive because of scientific and manufacturing challenges, and small potential markets for such products; this creates barriers to access that are frequently difficult to resolve.3 Rare diseases are chronic and often severely disabling, thus treating these patients places a substantial burden on healthcare budgets. For example, one recent study from Western Australia concluded that in 2010 the state population affected by a limited cohort of only 467 rare diseases represented 2% of the population but 10.5% of in-patient hospital costs.9 Therefore, improved diagnostics and targeted therapeutics that keep these patients healthier and reduce their time in medical facilities would be highly beneficial. Many rare diseases resemble common ones and involve the same genetic pathways, but are generally more aggressive or severe in their presentation. Improved understanding of these diseases may therefore be relevant to improving or developing diagnostics and therapeutics for their more common counterparts. Most rare diseases are genetic in their etiology, thus research addressing them systematically begins with efforts to identify genetic variants that are causative for particular diseases.1, 5 Such research has been under way for decades and has been successful, with many links between genetic mutations and diseases identified. However, by the mid-2000s it became increasingly apparent that several factors were limiting success and needed to be addressed systematically on an international scale. Linking a genetic variant with a particular disease requires finding two or, preferably, more unrelated individuals who have a genetic variant in common, as well as exhibiting similar phenotypic characteristics. Identifying such matches can be facilitated by data sharing, but due to at times competitive academic framework and limitations in the consent obtained from research participants, data sharing among research groups working on the same disease was often limited or nonexistent. An additional problem was the lack of a standardized vocabulary to describe phenotypes, further complicating the identification of patients with similar symptoms.10 At the same time, the advent of next-generation genomic techniques, which dramatically increased throughput and lowered cost, provided the opportunity to drastically accelerate the discovery of gene–disease connections.11 However, with this promise came the additional technical challenges of storing, analyzing, sending, and comparing large sets of data. The introduction of regulatory and economic incentives (e.g., market exclusivity, fee waivers, protocol assistance) was also successful in attracting the biopharmaceutical industry, which was previously reluctant to invest in rare disease therapeutic development with little or limited return on investment.5 Prior to the introduction of the Orphan Drug Act in the US in 1983, only 10 orphan drugs were approved in a decade, compared with 247 drugs for over 200 rare diseases in the course of the 25 years postlegislation.12 In Europe, following the adoption of the European Commission (EC) Regulation 141/2000, 63 orphan medicinal products received marketing authorization by 2010, a decade after implementation.13 While a large increase in the number of orphan designations was seen on both sides of the Atlantic, the average combined number of orphan-designated products approved was about 15 per year and they addressed only a handful of rare diseases. By 2010, ∼400 orphan medicinal products were available for less than 300 rare diseases. Additionally, observations by the US Food and Drug Administration (FDA) of a slowdown instead of the expected acceleration in innovative medical therapies reaching patients were also reported in the mid-2000s.14 Attrition rate aside, therapy development for rare diseases faces a number of specific challenges, including small populations for clinical studies, difficulty in determining relevant outcome measures and endpoints, and poorly understood natural histories. The heterogeneous pathophysiology and dispersed nature of rare diseases means research and development efforts and patient populations are scattered around the world. A scarcity of expertise poses a huge challenge to patients who seek access to diagnostic testing and appropriate treatment. In this overall setting, following initial discussions between Dr Ruxandra Draghia-Akli of the Directorate-General for Research and Innovation (DG RTD) of the European Commission (EC) and Dr Francis Collins of the US National Institutes of Health (NIH), the International Rare Diseases Research Consortium (IRDiRC) was formed.15 A consortium that unites public and private sector funders of research, patient advocacy groups, and scientific researchers, IRDiRC is committed to a global partnership to advance rare diseases research. This is delivered by attracting further resources to the domain and facilitating better international collaboration and coordination among research groups. In 2011, at its inauguration, IRDiRC set two ambitious goals for the rare diseases research collective—to develop 200 new therapies and the means to diagnose most rare genetic diseases by the year 2020. Six years after its official launch, IRDiRC is reflecting on its progress and achievements toward these goals, and considers how best to move forward even more ambitiously in the coming years. In this context, we review the history and the key success factors, as they provide the best markers for our future success and overcoming the apparently insurmountable issues ahead for people living with rare diseases, rare diseases stakeholders, industry, and policy makers. The EC's DG RTD and the US NIH met in 2009 to discuss the need for expanded and further integrated efforts to address the global imperative for governments to collect public health data and provide solutions for patients affected with rare diseases. A preparatory workshop held in Reykjavík, Iceland, in October 2010 led to the creation of IRDiRC.15 Formally launched in 2011 to foster international research collaboration and investment in the field, IRDiRC had two aspirational goals: i) to contribute to the development of 200 new therapies, and ii) to develop the means to diagnose most rare diseases by the year 2020. At its launch, five public research funders committed to the IRDiRC mission. By the end of 2011, IRDiRC had expanded to 18 public funding members in addition to three international umbrella patient groups. The first private funders, i.e., companies, joined the effort in 2012. The Consortium has since expanded globally to include nearly 50 members across Europe, North America, Asia, Australia, and the Middle East (Figure 1), each—excepting the umbrella patient groups—committed to invest a minimum of USD 10 million in rare diseases research funding over 5 years.16 Through this global reach, with the cooperation of its public and private funders and patient groups, IRDiRC began to develop common scientific and policy frameworks to guide research and development in rare diseases under the leadership of Dr Ruxandra Draghia-Akli (Chair, 2011–2012), Dr Paul Lasko (Chair, 2013–2015), and Dr Christopher Austin (Chair, 2016–present). The work of IRDiRC and its committees is critical for the development of new rare diseases knowledge, which is in turn vital for governments to develop informed, collaborative, and evidence-based policy, and for academics and industry to be guided in the development of new diagnostics and therapies for rare diseases. While IRDiRC has a wide range of members, it is recognized that expertise in rare diseases, just as patients, is distributed around the world. In order to engage with international stakeholders in rare diseases research inside and outside of the Consortium, to assess the progress on the IRDiRC objectives, and to share acquired knowledge and competences, three international IRDiRC Conferences have been organized, to date. These conferences, held in Dublin, Ireland; Shenzhen, China; and Paris, France, respectively, advanced discussions on rare diseases research, and emphasized the utmost importance of collaborations among the global rare disease community to progress and success. IRDiRC is currently governed through a Consortium Assembly (formerly Executive Committee), three Scientific Committees, three Constituent Committees, an Operating Committee, ad hoc Task Forces, and a Scientific Secretariat (Figure 2). 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The years have been for the rare diseases research community and for rare disease progress has been toward improved diagnostics and patient research in this have in many and most in the US the and the However, the further has been the and collaboration between these public funders, industry, and the people living with rare diseases. 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IRDiRC has to several that are improving collaboration among and the of patients to engage as in research. While has been is a need to accelerate on the and to across to that new goals for the rare diseases community for the 10 years only be but This time this time this time one but that these which to be at that the from our that we to on in a different way when that which is a difficulty be the only common and way of at the of The the and of the IRDiRC Consortium and and members of the IRDiRC Scientific Committees, Task and Scientific Secretariat for their to this effort The IRDiRC Scientific Secretariat is by the European Commission and is by the European Commission has to this work in as of the IRDiRC Consortium in as of the National for The in this are the of the and the of their the European Commission on of the Commission is for the which be of the following in as of the IRDiRC Consortium in as the of the National for The of The is for the or of by the than be to the for the