Petra Kaufmann

International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases

Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their “diagnostic odyssey,” improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.

Down syndrome: national conference on patient registries, research databases, and biobanks.

A December 2010 meeting, Down Syndrome: National Conference on Patient Registries, Research Databases, and Biobanks, was jointly sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at the National Institutes of Health (NIH) in Bethesda, MD, and the Global Down Syndrome Foundation (GDSF)/Linda Crnic Institute for Down Syndrome based in Denver, CO. Approximately 70 attendees and organizers from various advocacy groups, federal agencies (Centers for Disease Control and Prevention, and various NIH Institutes, Centers, and Offices), members of industry, clinicians, and researchers from various academic institutions were greeted by Drs. Yvonne Maddox, Deputy Director of NICHD, and Edward McCabe, Executive Director of the Linda Crnic Institute for Down Syndrome. They charged the participants to focus on the separate issues of contact registries, research databases, and biobanks through both podium presentations and breakout session discussions. Among the breakout groups for each of the major sessions, participants were asked to generate responses to questions posed by the organizers concerning these three research resources as they related to Down syndrome and then to report back to the group at large with a summary of their discussions. This report represents a synthesis of the discussions and suggested approaches formulated by the group as a whole.

‘IRDiRC Recognized Resources’: a new mechanism to support scientists to conduct efficient, high-quality research for rare diseases

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.

Future of Rare Diseases Research 2017–2027: An IRDiRC Perspective

Christopher P. Austin1,∗, Christine M. Cutillo1, Lilian P.L. Lau2, Anneliene H. Jonker2, Ana Rath2,3, Daria Julkowska4, David Thomson5, Sharon F. Terry6, Béatrice de Montleau7, Diego Ardigò8, Virginie Hivert7, Kym M. Boycott9, Gareth Baynam10,11, Petra Kaufmann1, Domenica Taruscio12, Hanns Lochmüller13, Makoto Suematsu14, Carlo Incerti15, Ruxandra Draghia-Akli16,17, Irene Norstedt16, Lu Wang18 and Hugh J.S. Dawkins19 on behalf of the International Rare Diseases Research Consortium (IRDiRC)

Efficiency Perspectives on Adaptive Designs in Stroke Clinical Trials

An adaptive design allows the modifications of various features, such as sample size and treatment assignments, in a clinical study based on the analysis of interim data. The goal is to enhance statistical efficiency by maximizing relevant information obtained from the clinical data. The promise of efficiency, however, comes with a cost, per se, that is seldom made explicit in the literature. This article reviews some commonly used adaptive strategies in early-phase stroke trials and discusses their associated costs. Specifically, we illustrate the trade-offs in several clinical contexts, including dose-finding in the Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART), futility analyses and internal pilot in Phase 2 proof-of-concept trials, and sample size considerations in an imaging-based dose-selection trial. Through these illustrations, we demonstrate the potential tension between the perspectives of an individual investigator and that of the broader community of stakeholders. This understanding is critical to appreciate the limitations, as well as the full promise, of adaptive designs, so that investigators can deploy an appropriate statistical design--be it adaptive or not--in a clinical study.

Common data elements for clinical research in Friedreich's ataxia

To reduce study start‐up time, increase data sharing, and assist investigators conducting clinical studies, the National Institute of Neurological Disorders and Stroke embarked on an initiative to create common data elements for neuroscience clinical research. The Common Data Element Team developed general common data elements, which are commonly collected in clinical studies regardless of therapeutic area, such as demographics. In the present project, we applied such approaches to data collection in Friedreichs ataxia (FRDA), a neurological disorder that involves multiple organ systems. To develop FRDA common data elements, FRDA experts formed a working group and subgroups to define elements in the following: ataxia and performance measures; biomarkers; cardiac and other clinical outcomes; and demographics, laboratory tests, and medical history. The basic development process included identification of international experts in FRDA clinical research, meeting by teleconference to develop a draft of standardized common data elements recommendations, vetting of recommendations across the subgroups, and dissemination of recommendations to the research community for public comment. The full recommendations were published online in September 2011 at http://www.commondataelements.ninds.nih.gov/FA.aspx. The subgroups′ recommendations are classified as core, supplemental, or exploratory. Template case report forms were created for many of the core tests. The present set of data elements should ideally lead to decreased initiation time for clinical research studies and greater ability to compare and analyze data across studies. Their incorporation into new, ongoing studies will be assessed in an ongoing fashion to define their utility in FRDA.

Neuroscience Networking: Linking Discovery to Drugs

Discoveries in the pre-clinical neurosciences have set the stage for bringing new therapies to patients affected by neurological disorders. The National lnstitute of Neurological Disorders and Stroke (NINDS) is dedicated to promoting the development of new therapies through its funding programs that range from basic neuroscience to translational research and finally clinical research to test the most promising new therapies in patients. In an effort to accelerate the translation of new discoveries to clinical practice, NINDS is piloting novel organizational strategies. In translational research, NINDS is taking the lead on the establishment of a ‘virtual pharma’ structure, through which researchers will partner with the NIH to accelerate the progress of drug development from early hit discovery through phase 1 clinical trials. In clinical research, the new Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) aims to promote the efficient implementation of scientifically sound, biomarker-informed phase 2 clinical trials that can be initiated by academic or industry investigators.

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.

The TREAT-NMD advisory committee for therapeutics (TACT): an innovative de-risking model to foster orphan drug development.

Despite multiple publications on potential therapies for neuromuscular diseases (NMD) in cell and animal models only a handful reach clinical trials. The ability to prioritise drug development according to objective criteria is particularly critical in rare diseases with large unmet needs and a limited numbers of patients who can be enrolled into clinical trials. TREAT-NMD Advisory Committee for Therapeutics (TACT) was established to provide independent and objective guidance on the preclinical and development pathway of potential therapies (whether novel or repurposed) for NMD.We present our experience in the establishment and operation of the TACT. TACT provides a unique resource of recognized experts from multiple disciplines. The goal of each TACT review is to help the sponsor to position the candidate compound along a realistic and well-informed plan to clinical trials, and eventual registration. The reviews and subsequent recommendations are focused on generating meaningful and rigorous data that can enable clear go/no-go decisions and facilitate longer term funding or partnering opportunities. The review process thereby acts to comment on viability, de-risking the process of proceeding on a development programme.To date TACT has held 10 review meeting and reviewed 29 program applications in several rare neuromuscular diseases: Of the 29 programs reviewed, 19 were from industry and 10 were from academia; 15 were for novel compounds and 14 were for repurposed drugs; 16 were small molecules and 13 were biologics; 14 were preclinical stage applications and 15 were clinical stage applications. 3 had received Orphan drug designation from European Medicines Agency and 3 from Food and Drug Administration. A number of recurrent themes emerged over the course of the reviews and we found that applicants frequently require advice and education on issues concerned with preclinical standard operating procedures, interactions with regulatory agencies, formulation, repurposing, clinical trial design, manufacturing and ethics.Over the 5xa0years since its establishment TACT has amassed a body of experience that can be extrapolated to other groups of rare diseases to improve the community’s chances of successfully bringing new rare disease drugs to registration and ultimately to market.

Carotid Intervention Is It Warranted in Asymptomatic Individuals if Risk Factors Are Aggressively Managed

It is estimated that 2% to 12% of adults have >50% stenosis of the carotid arteries. Carotid stenosis is a strong indicator of systemic atherosclerotic disease with subsequent adverse health outcomes including myocardial infarction, stroke, and renal and peripheral arterial disease. The risk of stroke, usually resulting from carotid embolism to the middle cerebral artery or its branches, is low in asymptomatic carotid stenosis but spikes once persons experience ischemic symptoms (ipsilateral transient ischemic attack or stroke). The principal health objective is to prevent conversion to symptomatic stenosis. Even greater public health impact can be achieved with risk factor reduction that attenuates associated myocardial infarction, strokes from noncarotid causes, and peripheral arterial disease. Direct vascular intervention, carotid endarterectomy (CEA), or carotid artery stent/angioplasty (CAS) can reduce stroke risk in persons with symptomatic carotid stenosis, but evidence for their absolute value in improving health for the millions with asymptomatic stenosis is less firm. The Carotid Revascularization using Endarterectomy or Stenting Trial-2 (CREST2) team is embarking on an ambitious clinical …