Sustainable approaches for drug repurposing in rare diseases: recommendations from the IRDiRC Task Force

Drug repurposing represents a real opportunity to address unmet needs and improve the lives of rare disease patients. It is often presented as a faster, safer and cheaper path for bringing drugs into new indications. However, several economic, regulatory and scientific barriers can impede the successful repurposing of drugs for rare diseases. The International Rare Diseases Research Consortium (IRDiRC) set up the Task Force on Sustainable Models in Drug Repurposing with the objective of identifying key factors for achieving sustainable repurposing approaches in rare diseases. In order to help inform expert opinion, the Task Force investigated six cases of medicinal products repurposed into new rare indications and four cases of ongoing development programs. A questionnaire addressing the major steps of the repurposing approach was developed by the Task Force and sent to contact points of the organizations. In addition, interviews were conducted with the relevant organization representatives to conduct a deeper dive into the sustainability of the repurposing approach for each of the selected cases. Based on the collective experience of the members of the Task Force and the output from the questionnaires/interviews, we have identified ten key factors that should be considered by those embarking on repurposing projects. These factors include the identification of unmet patient needs and partnership with patients, collection of evidence concerning disease prevalence, patient numbers, drug pharmacology and disease etiology, drug industrial property status, off-label or compounding use, data from past clinical studies and needs for extended non-clinical and clinical studies. The development of a collaborative funding framework and early discussion with regulators and payers are additional factors to implement early in the development of sustainable drug repurposing projects

Research on rare diseases:ten years of progress and challenges at IRDiRC

The International Rare Diseases Research Consortium (IRDiRC) is a global collaborative initiative launched in 2011, aimed at tackling rare diseases through research. Here, we summarize IRDiRC’s vision and goals and highlight achievements and prospects after its first decade.</p

European expert recommendations on clinical investigation and evaluation of high‐risk medical devices for children

Several high-risk medical devices for children have become unavailable in the European Union (EU), since requirements and costs for device certification increased markedly due to the EU Medical Device Regulation. The EU-funded CORE-MD project held a workshop in January 2023 with experts from various child health specialties, representatives of European paediatric associations, a regulatory authority and the European Commission Directorate General Health and Food Safety. A virtual follow-up meeting took place in March 2023. We developed recommendations for investigation of high-risk medical devices for children building on participants' expertise and results of a scoping review of clinical trials on high-risk medical devices in children. Approaches for evaluating and certifying high-risk medical devices for market introduction are proposed

European expert recommendations on clinical investigation and evaluation of high-risk medical devices for children.

Several high-risk medical devices for children have become unavailable in the European Union (EU), since requirements and costs for device certification increased markedly due to the EU Medical Device Regulation. The EU-funded CORE-MD project held a workshop in January 2023 with experts from various child health specialties, representatives of European paediatric associations, a regulatory authority and the European Commission Directorate General Health and Food Safety. A virtual follow-up meeting took place in March 2023. We developed recommendations for investigation of high-risk medical devices for children building on participants' expertise and results of a scoping review of clinical trials on high-risk medical devices in children. Approaches for evaluating and certifying high-risk medical devices for market introduction are proposed

IRDiRC: 1000 new rare diseases treatments by 2027, identifying and bringing forward strategic actions

In 2017, the International Rare Diseases Research Consortium (IRDiRC) set out ambitious goals, one of which specifically aimed to stimulate the development and approval of 1000 new therapies for rare diseases by 2027. This goal was part of IRDiRC’s concerted efforts to foster research and provide better diagnostics and care options for the estimated 400 million patients suffering from the more than 6000 rare diseases (RD) worldwide. Lack of therapeutic options for rare disease patients is an urgent issue. Treatments are estimated to be available for less than 6% of RD conditions, and fewer than 50 new therapies per year are approved by regulatory agencies worldwide, leaving a major discrepancy between patient needs and therapeutic solutions. This paper describes the recent key steps the IRDiRC Therapies Scientific Committee (TSC) has taken to support the future approval of 1000 new therapies, namely Step 1 (conducting a gap analysis of the rare diseases drug development landscape) and Step 2 (developing strategic themes to advance IRDiRC Goal 2 and act upon them). The IRDiRC TSC created a multi-stakeholder group to run a gap analysis of the RD drug development field. The analysis identified four main priority needs: (1) the definition of a new master plan for RD medicines suitable for all developers (large and small pharmaceutical companies, academics, and not-for-profit organizations) incorporating stakeholders’ perspectives and best practices in the field to increase efficiency in the development and registration of innovative drugs and generate more value for patients and the healthcare system; (2) the elicitation of a research framework and business model for repurposing of existing drugs for RD indications to enact a quantum enlargement of the existing therapeutic armamentarium; (3) the definition of standards and practices for data collection in healthcare practice and their implementation in drug development to provide real-world evidence; and (4) the re-focusing of the current international RD research agenda pushing for concentrated research efforts and funding in support of the development of future treatments. In addition to identifying where efforts should be put, the TSC has concretely contributed to advance the IRDiRC goal by creating tools (e.g., the Orphan Drug Development Guidebook) and recommendations and making them available to the whole RD community. However, much remains to be done, and the TSC has refined its approach to incorporate progress made and reflect on new challenges

The International Rare Diseases Research Consortium : Policies and Guidelines to maximize impact

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

The International Rare Diseases Research Consortium: Policies and Guidelines to maximize impact

© 2017 European Society of Human Genetics. 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

Chimeric oncogene regulates the EGR2 sarcoma susceptibility gene via a GGAA-microsatellite

International audienceDeciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging. Ewing sarcoma is characterized by fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs. A recent genome-wide association study identified susceptibility variants near EGR2. Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and spheroidal growth in vitro and induced regression of Ewing sarcoma xenografts. Targeted germline deep sequencing of the EGR2 locus in affected subjects and controls identified 291 Ewing-associated SNPs. At rs79965208, the A risk allele connected adjacent GGAA repeats by converting an interspaced GGAT motif into a GGAA motif, thereby increasing the number of consecutive GGAA motifs and thus the EWSR1-FLI1-dependent enhancer activity of this sequence, with epigenetic characteristics of an active regulatory element. EWSR1-FLI1 preferentially bound to the A risk allele, which increased global and allele-specific EGR2 expression. Collectively, our findings establish cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesi