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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.

Background Showing how engagement adds value for all stakeholders can be an effective motivator for broader implementation of patient engagement. However, it is unclear what methods can best be used to evaluate patient engagement. This paper is focused on ways to evaluate patient engagement at three decision‐making points in the medicines research and development process: research priority setting, clinical trial design and early dialogues with regulators and health technology assessment bodies. Objective Our aim was to review the literature on monitoring and evaluation of patient engagement, with a focus on indicators and methods. Search strategy and inclusion criteria We undertook a scoping literature review using a systematic search, including academic and grey literature with a focus on evaluation approaches or outcomes associated with patient engagement. No date limits were applied other than a cut‐off of publications after July 2018. Data extraction and synthesis Data were extracted from 91 publications, coded and thematically analysed. Main results A total of 18 benefits and 5 costs of patient engagement were identified, mapped with 28 possible indicators for their evaluation. Several quantitative and qualitative methods were found for the evaluation of benefits and costs of patient engagement. Discussion and conclusions Currently available indicators and methods are of some use in measuring impact but are not sufficient to understand the pathway to impact, nor whether interaction between researchers and patients leads to change. We suggest that the impacts of patient engagement can best be determined not by applying single indicators, but a coherent set of measures.

The International Rare Diseases Research Consortium (IRDiRC) has created a Guidebook to facilitate drug development for rare diseases by organizing available tools into a standardized framework. The International Rare Diseases Research Consortium (IRDiRC) has created a Guidebook to facilitate drug development for rare diseases by organizing available tools into a standardized framework.

The European orphan regulation incentivizes the development of medicines for conditions for which the pharmaceutical industry would be unwilling to develop medicines under normal market conditions. Defining an orphan condition is the starting point of every orphan designation, and it is also the entity used to determine prevalence, which must not be more than 5 in 10, 000 for orphan designation to be permitted. In practice, most orphan conditions can be easily identified ; recognized distinct medical entities would generally be considered as valid conditions, defined in terms of their specific characteristics . However, in certain areas, there may be challenges in defining orphan conditions such that a condition is in keeping with the regulatory framework and consistent across all applications that are presented to the European Medicines Agency (EMA)’s Committee for Orphan Medicinal Products (COMP).

Background Evidence-based clinical practice is challenging in all fields, but poses special barriers in the field of rare diseases. The present paper summarises the main barriers faced by clinical research in rare diseases, and highlights opportunities for improvement. Methods Systematic literature searches without meta-analyses and internal European Clinical Research Infrastructure Network (ECRIN) communications during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project. Results Barriers specific to rare diseases comprise the difficulty to recruit participants because of rarity, scattering of patients, limited knowledge on natural history of diseases, difficulties to achieve accurate diagnosis and identify patients in health information systems, and difficulties choosing clinically relevant outcomes. Conclusions Evidence-based clinical practice for rare diseases should start by collecting clinical data in databases and registries; defining measurable patient-centred outcomes; and selecting appropriate study designs adapted to small study populations. Rare diseases constitute one of the most paradigmatic fields in which multi-stakeholder engagement, especially from patients, is needed for success. Clinical research infrastructures and expertise networks offer opportunities for establishing evidence-based clinical practice within rare diseases. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2287-7) contains supplementary material, which is available to authorized users.

Human enhancer of filamentation 1 (HEF1) is a multi-domain docking protein of the p130 Cas family. HEF1 is present at focal adhesions and is involved in integrin signalling mediating cytoskeleton reorganization associated with cell migration, adhesion or apoptosis. HEF1 functions are regulated in part by phosphorylation on tyrosine residues. HEF1 is also phosphorylated on serines/threonines leading to two isoforms refered to as p105 and p115. In most cases, the serine/threonine kinase(s) responsible for HEF1 phosphorylation have not been identified. In the present study, we have investigated HEF1 ser/thr phosphorylation. In the HCT-116 cell line transiently overexpressing Flag-HEF1 we showed that Hesperadin, a synthetic indolinone displaying antiproliferative effect and described as an inhibitor of various kinases including Aurora-B, prevented HEF1 phosphorylation induced by the ser/thr phosphatase PP2A inhibitor: okadaic acid (OA). In addition we showed that conversion of endogenous HEF1 p105 to p115 in HaCaT cells was prevented upon treatment with Hesperadin, resulting in accumulation of p105HEF1. We also identified serine 369 as the target site of phosphorylation by this Hesperadin-inhibited kinase in HCT-116. Finally, we provide evidence that phosphorylation on serine 369 but not phosphorylation on serine 296, triggers HEF1 degradation by the proteasomal machinery. These data suggest that conversion of p105 to p115 results from a ser-369-dependent phosphorylation mediated by an Hesperadin-sensitive kinase and regulates the half-life of HEF1.

The data contained in the Orphanet "Orphan Drugs" database is extracted from official sources. This data includes a list of all substances which have been granted an orphan designation for a disease(s) considered as rare in Europe, whether further developed to become drugs with marketing authorisation (MA) or not. The Orphanet database also includes drugs without an orphan designation as long as they have been granted a MA with a specific indication for a rare disease. Orphanet also publishes a quarterly report ("Orphanet Report Series") listing orphan drugs on the European market with or without prior orphan designation. In order to improve access to Orphanet’s rich database of information and resources, the search engine has been recalibrated to render data more accessible. In addition to existing search options (by drug or disease), four new sub-tabs improve the visibility of information pertaining to orphan drugs, allowing users to search by a wider range of criteria. Several alphabetical lists of designated products, orphan-designated products with MA, substances and drug trade names are now available. New advanced search options allow users to refine their search by sponsor, MA holder and ATC (Anatomic, Therapeutic, Chemical) category. Substances are now clearly separated from trade names in the results pages: trade names are used solely for products granted MA, whereas substances with orphan designation status (prior to MA) are referred to by their active molecule. Additionally, each substance or trade name is linked to the "Clinical trials" sub-tab of the "Research and trials" tab. Users can retrieve clinical trial(s) that are (or have been) performed for a particular drug. These can also be searched by a wider range of criteria (disease concerned, principal investigator by country, sponsor or clinical trial category). These features are available in all five languages of the Orphanet website.

Background Academic-sponsored trials for rare diseases face many challenges; the present paper identifies hurdles in the set-up of six multinational clinical trials for drug repurposing, as use cases. Methods Six academic-sponsored multinational trials aiming to generate knowledge on rare diseases drug repurposing were used as examples to identify problems in their set-up. Coordinating investigators leading these trials provided feedback on hurdles linked to study, country, and site set up, on the basis of pre-identified categories established through the analysis of previous peer-reviewed publications. Results Administrative burden and lack of harmonization for trial-site agreements were deemed as a major hurdle. Other main identified obstacles included the following: (1) complexity and restriction on the use of public funding, especially in a multinational set up, (2) drug supply, including procurement tendering rules and country-specific requirements for drug stability, and (3) lack of harmonization on regulatory requirements to get trial approvals. Conclusion A better knowledge of the non-commercial clinical research landscape and its challenges and requirements is needed to make drugs—especially those with less commercial gain—accessible to rare diseases patients. Better information about existing resources like research infrastructures, clinical research programs, and counseling mechanisms is needed to support and guide clinicians through the many challenges associated to the set-up of academic-sponsored multinational trials.

Orphanet compiles 6500 research projects. This information been analysed to identify areas in need of collaborative research projects and to target future calls for proposals. The analysis of the distribution of number of diseases by number of treatments in development showed that most RD have no more than 3 orphan designations, whereas 53 RD have over three orphan designations. Similar results were obtained when clinical trials, marketed drugs, patient registries and preclinical/epidemiological/basic research were analysed. Some of the diseases which were over-represented upstream in the process of R&D (with a treatment on the market or drugs in development) are also well represented regarding ongoing research, like Cystic fibrosis, pulmonary arterial hypertension and some rare cancers. Diseases with a higher prevalence are anticipated to have more treatments in development: this assumption is not backed up by our data analysis. The best represented medical domain in terms of percentage of diseases with MA/OD is rare tumours, followed by Systemic and Rheumatologic diseases, Respiratory diseases, Immunological diseases, Metabolic diseases and Haematological diseases. It seems that the most mature fields keep on investing in research and are also the strongest ones regarding the products in development, and even in basic research for some of them. Other fields, however, like Neurology, seem to be essentially in development, since the percentage of diseases with MA is low compared to other domains and to the percentage of neurologic diseases with OD, clinical trials and research. The absence of orphan designations for some medical domains, like Cardiology, could be explained by the fact that the Cardiology rare diseases benefit from treatments already available for these diseases' common forms. This work was supported by the RareDiseasePlatform contract (RDPlatform), a three-year project which began in May 2008, financed by the European Union’s Seventh Framework Programme (HEALTH-F2-2008-2012).