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). The Consortium Assembly is composed of one representative per IRDiRC member, and the Chairs and Vice Chairs of each of the three Scientific Committees. The Consortium Assembly acts as the primary forum to exchange information on issues that influence IRDiRC goals and activities, coordinates scientific and policy efforts in addressing research priorities to advance IRDiRC goals, adopts policies and guidelines, and provides strategic vision to foster rare diseases research. IRDiRC members of the Consortium Assembly further subdivide into three Constituent Committees, one each for Funders, Companies, and Patient Advocates, which each identify common priorities, roadblocks, and gaps across their respective constituent space, and coordinate activities to address those needs. The three Scientific Committees, one each for Diagnostics, Interdisciplinary, and Therapies, advise the Consortium Assembly on research priorities and progress made from a scientific viewpoint, identify bottlenecks and funding gaps in rare diseases research, and agree on actions in their scientific areas that will bring IRDiRC closer to its goals. The Operating Committee—consisting of the Chairs and Vice Chairs of the Consortium Assembly, the Constituent Committees and the Scientific Committees, and the Scientific Secretariat—is the key working committee that monitors and manages progress of IRDiRC activities and processes, provides information to the Consortium Assembly, and enables a more effective management of the Consortium. In order to push policy changes forward and provide technical solutions to specific, prioritized topics, ad hoc Task Forces—each consisting of topically relevant experts—are proposed and set up by the Scientific and Constituent Committees. The organizational, secretarial, reporting, and communications support to IRDiRC and its various members are provided by the Scientific Secretariat. Together, the Consortium contributes to the acceleration of rare diseases research, diagnostics and therapeutics development, reinforces international research cooperation and coordination, and maximizes the impact of investments made in the field of rare diseases research, all in order to bring diagnoses and therapies to rare disease patients throughout the world. To meet IRDiRC's goals, collaborative actions and overarching policies are needed to address the challenges encountered as well as streamlining access to relevant data and patient populations. Research in rare diseases is urgently needed, as many rare disease patients still lack an accurate and confirmed diagnosis and appropriate treatment. Funding of rare diseases research should not be carried out in isolation; appropriate coordinated effort through a network of funders will ensure that the impact of research investment is maximized through deduplication of research projects, generation of knowledge in lesser studied diseases, creation of common frameworks and infrastructures to facilitate data and patient sample sharing, and translation of basic research into preclinical and clinical studies. Collaborative funding mechanisms also enable the financing of large, transnational projects that require resources beyond what can be provided by individual, national research programs. The IRDiRC Scientific Secretariat, in collaboration with Orphanet,17 collects information pertaining to the projects funded by IRDiRC members. Data from IRDiRC public research funding members (excluding data from the NIH National Cancer Institute, from which data collection is ongoing) illustrate the financing of over 3,000 projects since 2010. A majority of them are basic and preclinical research projects, accounting for about 87% of funded projects, while clinical research (including observational studies and clinical trials) represents ∼8% of the total number of awarded projects, and epidemiological, health economics and social sciences studies account for 4% of funded research (Figure 3). Collectively, the basic and preclinical research projects covered nearly 1,200 rare diseases, while the clinical trials covered ∼220 rare diseases. The former mainly focused on rare neurological diseases (including neuromuscular diseases) and developmental disorders (including conditions associated with dysmorphology and congenital anomalies), whereas clinical trials were mainly oriented towards rare cancers and rare neurological diseases (Figures 4, 5). The prevalence and intersection of these disorder groupings in diagnostic and therapeutic domains reflect the biological and clinical overlaps between developmental disorders and cancer.18 This also reflects the reciprocal opportunities between and within rare syndromic diseases, rare cancers, and their intersections for insights into new therapies and for drug repurposing.19 Drug clinical trials constitute the overwhelming majority of trials (Figure 6), with more than half of them in earlier phases of development (phases I to II), 31% in phase III and 5% in phase IV (Figure 7). Approximately half of all clinical trials were funded by companies (48%), the others supported by public institutions. These data serve as the foundation for much of the new work of the Constituent Committees aimed at identifying areas of need, prioritizing, and addressing those gaps via coordinated implementation activities,20 while taking into consideration the promising21 bedside-to-bench translational approach to increase the likelihood of success in drug development and clinical translation. Data received from public funders also demonstrated strong research investments and increasing number of collaborative calls on rare diseases, a sign of global commitment toward advancing rare diseases research and thus a commitment to bring diagnoses and treatments to rare disease patients. The EC, an IRDiRC cofounder, through its Framework Programme 7 (2007–2013) and Horizon 2020 Programme (2014–2020), invested around €762M in 135 rare diseases projects between 2010 and 2015,22 and expect to finance more projects in the coming years. The US NIH, another IRDiRC cofounder, has invested around US$10B between 2011 and 2016 via seven institutes and centers that are member organizations of IRDiRC, and the National Center for Advancing Translational Sciences' Office of Rare Diseases Research (ORDR) alone has invested over US$100M in around 180 rare diseases projects between 2010 and 2015. E-Rare, a joint transnational funding network, grew from 15 funding partners in 2010 to 26 funding partners in 2017.23 Between 2011 and 2016, E-Rare funded 77 projects with a budget of €67.5M;24 the largest research funding call took place in 2015 when 19 projects were financed through an investment of €19.2M. Funders at the national level play an equally important role in financing rare diseases research. As an example, in Spain, the National Institute of Health Carlos III spent a total of €43.4M in the period of 2010–2016 to finance around 45–60 projects each year, while additionally earmarking an average of €5M per year to support the Centre of Biomedical Research Network for Rare Diseases (CIBERER). The Japan Agency for Medical Research and Development (AMED), established in April 2015, set up a dedicated Division of Rare/Intractable Disease Research. In 2 years, AMED has disbursed ¥20B (€153M/US$176M) and funded over 350 research projects. The Canadian Institutes of Health Research's (CIHR) Institute of Genetics has invested over CA$110M between 2011 and 2016. In recent years, patient organizations have also been making impressive investments in rare diseases research in order to develop diagnostic tools and therapeutics for their patients. Telethon Italia, for example, funded 337 extramural research projects in 2010–2016, as well as other intramural research activities and support initiatives, for a total budget close to €235M. A comprehensive data collection and analysis of rare diseases research funding, including the number and types of projects, and number and categories of rare diseases studied, for 2010–2016, is currently under way; the report is expected to be published in late 2017 to complement the State of Art of Research in Rare Diseases report. Advances in diagnostics and therapeutics in the rare disease space over the past 6 years are attributed to a combination of factors and many players. IRDiRC monitors a number of metrics to quantify the progress made towards its key objectives. Progress in the diagnostics field relies on the identification of rare diseases and their underlying cause, often genetic in origin, and the development and availability of associated analytical tests. In this setting, the IRDiRC Diagnostics and Interdisciplinary Scientific Committees, in collaboration with Orphanet, analyzed the number of diseases for which a clinical test is available; at present, a genetic test is available for around 3,600 rare diseases, compared with 2,200 in 2010. Based on data curated by Orphanet and Online Mendelian Inheritance in Man (OMIM), an average of about 260–280 rare genetic diseases are discovered per year.4 In recent years, the majority of novel genes were discovered through exome sequencing approaches, with decreased use of previous discovery methods such as positional cloning. However, the discovery rate of exome sequencing over the past couple of years appears to be declining—this may be attributed to the fact that most of the simpler, monogenic rare diseases that are tractable to current techniques have been discovered, leaving the more complex cases to be solved. Nonetheless, in the last 5 years diagnostic efficiency has increased from ∼10% to a forward for rare disease a number of bottlenecks to be to the of and of genes and In the past two several have policies dedicated to orphan drug development and others are currently following with specific policies for their To better the number of therapies available for rare disease patients, IRDiRC the number of of medicinal products with a marketing authorization and orphan since 2010 via data from the European Agency and the An increase has been in the number of drug that the market in both and the and more are expected to as the number of orphan designations has as Between 2010 and 2016, over new drugs have the over diseases. The in the number of orphan drug designations a promise for the future of rare disease drug development, and for rare disease patients. the addition of new members, and in particular Japan in 2015, IRDiRC to data from specific from 2017 IRDiRC will be by the and Medical Agency in Japan and more globally as other significant regulatory are to the Consortium. In order to i) collaborations in rare diseases research, ii) increase the of patients and their in all relevant of research, and the sharing of data and IRDiRC has a set of that address such common The and were by the Scientific Committees to serve as for research funders and to provide on key that include patient natural history studies, and These policies and have been by the IRDiRC members through their intramural rare diseases research and extramural rare diseases research funding and provide for the rare diseases research and bottlenecks in diagnostic and therapeutic research the by rare diseases patients. The Constituent and Scientific Committees identify and for Task to and to policy and Obtaining a diagnosis for rare disease patients is in order to disease of the advance genetic and provide important to patients and their At present, the causative is still for half of all rare diseases and only of rare genetic diseases have an available diagnostic test in the of the Orphanet The and Interdisciplinary Scientific Committees the issues discovery and diagnostics of rare genetic diseases, and areas and for the use of for clinical the development of tools and resources to facilitate genomic and phenotypic data and the development of best and in data discovery and the use of genetic and for and the increased of novel disease successful discovery will not only a potential diagnostic but also has the potential to contribute to and therapeutic opportunities for the rare for this patient Therefore, such genetic to rare diseases are important and have potential for rare disease patients. A further consideration is that therapeutic and global also require the and implementation of genomic and phenotypic for those currently in such including across Europe, Asia, the and in and is that this new knowledge will also insights for currently more populations. development is a and process, and often rare disease patients not have the to the means to access therapies, The Scientific the the drug development process, from identification to drug by the regulatory and a set of that further foster therapeutic development of orphan medicinal products with scientific and regulatory key were emphasized as important to up the protocol from at of and with all stakeholders to ensure are and with health and to ensure that therapies to market are to patients. The Scientific is also of the need to best among the regulatory in order to bring about a in the development of new rare disease by to and are and IRDiRC to and support such and collaborative actions between and In order to specific of rare diseases research, and to further contribute to the IRDiRC objectives, Task are Task current to and effective research and solutions through policy technical including and These Task may as IRDiRC initiatives, or with groups that to and address similar are also of members to ensure that different are to and new a network of and which for rare disease is a collaborative between IRDiRC, the for and Health and other IRDiRC also partners with on the and Task to develop a standardized way to consent and other conditions of clinical data making the information and available for and sharing and on the Task which was set up to develop on the and technical of in rare diseases research, and a technical for deduplication of research in data sets knowledge of their IRDiRC Task i) the International Consortium of which provided the community with to achieve between by the of and for rare ii) the Task which made on methods to support the development of outcome measures for rare diseases in order to the of future trials and to provide data of to the patient the Task which for and innovative clinical relevant to small often the of rare disease clinical scientific from and the Data and Task which identified opportunities to the research and patient data to the potential of data and drug As new issues and areas of are Task are set to further contribute to and development, and the global rare diseases research rare disease patients, the who study rare diseases are often and As resources and tools available to further their work are not to To address this need, IRDiRC set up an to available resources that in the rare diseases community have were to be more may accelerate the of rare diseases To this resources are via a by IRDiRC Scientific members and in the are on a To resources have received the five guidelines, five three two and an IRDiRC with several to develop global policies and technical solutions for specific rare disease or joint projects and These but are not limited Orphanet,17 the Collaborative the European the US Office of Rare Diseases Research (ORDR) with its Rare Diseases Research Network at the National Center for Advancing Translational and the Diseases Network International Through these collaborative have been in disease and with a of and development of policies for and data sharing for rare and genetic This is by significant in knowledge and which are

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