Model consent clauses for rare disease research

Background: Rare Disease research has seen tremendous advancements over the last decades, with the development of new technologies, various global collaborative efforts and improved data sharing. To maximize the impact of and to further build on these developments, there is a need for model consent clauses for rare diseases research, in order to improve data interoperability, to meet the informational needs of participants, and to ensure proper ethical and legal use of data sources and participants' overall protection. Methods: A global Task Force was set up to develop model consent clauses specific to rare diseases research, that are comprehensive, harmonized, readily accessible, and internationally applicable, facilitating the recruitment and consent of rare disease research participants around the world. Existing consent forms and notices of consent were analyzed and classified under different consent themes, which were used as background to develop the model consent clauses. Results: The IRDiRC-GA4GH MCC Task Force met in September 2018, to discuss and design model consent clauses. Based on analyzed consent forms, they listed generic core elements and designed the following rare disease research specific core elements; Rare Disease Research Introductory Clause, Familial Participation, Audio/Visual Imaging, Collecting, storing, sharing of rare disease data, Recontact for matching, Data Linkage, Return of Results to Family Members, Incapacity/Death, and Benefits. Conclusion: The model consent clauses presented in this article have been drafted to highlight consent elements that bear in mind the trends in rare disease research, while providing a tool to help foster harmonization and collaborative efforts

Recommendations for the design of small population clinical trials

Background Orphan drug development faces numerous challenges, including low disease prevalence, patient population heterogeneity, and strong presence of paediatric patient populations. Consequently, clinical trials for orphan drugs are often smaller than those of non-orphan drugs, and they require the development of efficient trial designs relevant to small populations to gain the most information from the available data. The International Rare Diseases Research Consortium (IRDiRC) is aimed at promoting international collaboration and advance rare diseases research worldwide, and has as one of its goals to contribute to 1000 new therapies for rare diseases. IRDiRC set up a Small Population Clinical Trials (SPCT) Task Force in order to address the shortcomings of our understanding in carrying out clinical trials in rare diseases. Results The IRDiRC SPCT Task Force met in March 2016 to discuss challenges faced in the design of small studies for rare diseases and present their recommendations, structured around six topics: different study methods/designs and their relation to different characteristics of medical conditions, adequate safety data, multi-arm trial designs, decision analytic approaches and rational approaches to adjusting levels of evidence, extrapolation, and patients’ engagement in study design. Conclusions Recommendations have been issued based on discussions of the Small Population Clinical Trials Task Force that aim to contribute towards successful therapy development and clinical use. While randomised clinical trials are still considered the gold standard, it is recommended to systematically take into consideration alternative trial design options when studying treatments for a rare disease. Combining different sources of safety data is important to give a fuller picture of a therapy’s safety profile. Multi-arm trials should be considered an opportunity for rare diseases therapy development, and funders are encouraged to support such trial design via international networks. Patient engagement is critical in trial design and therapy development, a process which sponsors are encouraged to incorporate when conducting trials and clinical studies. Input from multiple regulatory agencies is recommended early and throughout clinical development. Regulators are often supportive of new clinical trial designs, provided they are well thought through and justified, and they also welcome discussions and questions on this topic. Parallel advice for multiregional development programs should also be considered

Drug repurposing for rare: progress and opportunities for the rare disease community

Repurposing is one of the key opportunities to address the unmet rare diseases therapeutic need. Based on cases of drug repurposing in small population conditions, and previous work in drug repurposing, we analyzed the most important lessons learned, such as the sharing of clinical observations, reaching out to regulatory scientific advice at an early stage, and public-private collaboration. In addition, current upcoming trends in the field of drug repurposing in rare diseases were analyzed, including the role these trends could play in the rare diseases’ ecosystem. Specifically, we cover the opportunities of innovation platforms, the use of real-world data, the use of artificial intelligence, regulatory initiatives in repurposing, and patient engagement throughout the repurposing project. The outcomes from these emerging activities will help progress the field of drug repurposing for the benefit of patients, public health and medicines development

Embodiment and Presence in Virtual Reality After Stroke. A Comparative Study With Healthy Subjects

[EN] The ability of virtual reality (VR) to recreate controlled, immersive, and interactive environments that provide intensive and customized exercises has motivated its therapeutic use after stroke. Interaction and bodily presence in VR-based interventions is usually mediated through virtual selves, which synchronously represent body movements or responses to events on external input devices. Embodied self-representations in the virtual world not only provide an anchor for visuomotor tasks, but their morphologies can have behavioral implications. While research has focused on the underlying subjective mechanisms of exposure to VR on healthy individuals, the transference of these findings to individuals with stroke is not evident and remains unexplored, which could affect the experience and, ultimately, the clinical effectiveness of neurorehabilitation interventions. This study determined and compared the sense of embodiment and presence elicited by a virtual environment under different perspectives and levels of immersion in healthy subjects and individuals with stroke. Forty-six healthy subjects and 32 individuals with stroke embodied a gender-matched neutral avatar in a virtual environment that was displayed in a first-person perspective with a head-mounted display and in a third-person perspective with a screen, and the participants were asked to interact in a virtual task for 10 min under each condition in counterbalanced order, and to complete two questionnaires about the sense of embodiment and presence experienced during the interaction. The sense of body-ownership, self-location, and presence were more vividly experienced in a first-person than in a third-person perspective by both healthy subjects (p < 0.001, eta(2)(p) = 0.212; p = 0.005, eta(2)(p) = 0.101; p = 0.001, eta(2)(p) = 0.401, respectively) and individuals with stroke (p = 0.019, eta(2)(p) = 0.070; p = 0.001, eta(2)(p) = 0.135; p = 0.014, eta(2)(p) = 0.077, respectively). In contrast, no agency perspective-related differences were found in any group. All measures were consistently higher for healthy controls than for individuals with stroke, but differences between groups only reached statistical significance in presence under the first-person condition (p < 0.010, eta(2)(p) = 0.084). In spite of these differences, the participants experienced a vivid sense of embodiment and presence in almost all conditions. These results provide first evidence that, although less intensively, embodiment and presence are similarly experienced by individuals who have suffered a stroke and by healthy individuals, which could support the vividness of their experience and, consequently, the effectiveness of VR-based interventions.This study was funded by Ministerio de Economía y Competitividad of Spain (Project RTC-2017-6051-7 and Grant BES-2014-068218), Fundació la Marató de la TV3 (Grant 201701-10), and Universitat Politècnica de València (Grant PAID-10-18). We acknowledge the support of NVIDIA Corporation with the donation of the Titan Xp GPU used for this research.Borrego, A.; Latorre, J.; Alcañiz Raya, ML.; Llorens Rodríguez, R. (2019). Embodiment and Presence in Virtual Reality After Stroke. A Comparative Study With Healthy Subjects. Frontiers in Neurology. 10:1-8. https://doi.org/10.3389/fneur.2019.01061S1810Berlucchi, G., & Aglioti, S. (1997). 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Consciousness and Cognition, 36, 277-288. doi:10.1016/j.concog.2015.07.008Kilteni, K., Maselli, A., Kording, K. P., & Slater, M. (2015). Over my fake body: body ownership illusions for studying the multisensory basis of own-body perception. Frontiers in Human Neuroscience, 9. doi:10.3389/fnhum.2015.00141Clark, A., Kiverstein, J., & Vierkant, T. (Eds.). (2013). Decomposing the Will. doi:10.1093/acprof:oso/9780199746996.001.0001Frith, C. D., Blakemore, S.-J., & Wolpert, D. M. (2000). Abnormalities in the awareness and control of action. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 355(1404), 1771-1788. doi:10.1098/rstb.2000.0734Bermúdez i Badia, S., Fluet, G. G., Llorens, R., & Deutsch, J. E. (2016). Virtual Reality for Sensorimotor Rehabilitation Post Stroke: Design Principles and Evidence. Neurorehabilitation Technology, 573-603. doi:10.1007/978-3-319-28603-7_28Perez-Marcos, D., Sanchez-Vives, M. V., & Slater, M. (2011). Is my hand connected to my body? The impact of body continuity and arm alignment on the virtual hand illusion. Cognitive Neurodynamics, 6(4), 295-305. doi:10.1007/s11571-011-9178-5IJsselsteijn, W. A., de Kort, Y. A. W., & Haans, A. (2006). Is This My Hand I See Before Me? The Rubber Hand Illusion in Reality, Virtual Reality, and Mixed Reality. Presence: Teleoperators and Virtual Environments, 15(4), 455-464. doi:10.1162/pres.15.4.455Banakou, D., Groten, R., & Slater, M. (2013). Illusory ownership of a virtual child body causes overestimation of object sizes and implicit attitude changes. Proceedings of the National Academy of Sciences, 110(31), 12846-12851. doi:10.1073/pnas.1306779110Yee, N., & Bailenson, J. (2007). The Proteus Effect: The Effect of Transformed Self-Representation on Behavior. Human Communication Research, 33(3), 271-290. doi:10.1111/j.1468-2958.2007.00299.xSteed, A., Frlston, S., Lopez, M. M., Drummond, J., Pan, Y., & Swapp, D. (2016). An ‘In the Wild’ Experiment on Presence and Embodiment using Consumer Virtual Reality Equipment. IEEE Transactions on Visualization and Computer Graphics, 22(4), 1406-1414. doi:10.1109/tvcg.2016.2518135Colomer, C., Llorens, R., Noé, E., & Alcañiz, M. (2016). Effect of a mixed reality-based intervention on arm, hand, and finger function on chronic stroke. Journal of NeuroEngineering and Rehabilitation, 13(1). doi:10.1186/s12984-016-0153-6Laver, K. E., Lange, B., George, S., Deutsch, J. E., Saposnik, G., & Crotty, M. (2017). Virtual reality for stroke rehabilitation. Cochrane Database of Systematic Reviews. doi:10.1002/14651858.cd008349.pub4Llorens, R., Borrego, A., Palomo, P., Cebolla, A., Noé, E., i Badia, S. B., & Baños, R. (2017). Body schema plasticity after stroke: Subjective and neurophysiological correlates of the rubber hand illusion. Neuropsychologia, 96, 61-69. doi:10.1016/j.neuropsychologia.2017.01.007Zeller, D., Gross, C., Bartsch, A., Johansen-Berg, H., & Classen, J. (2011). Ventral Premotor Cortex May Be Required for Dynamic Changes in the Feeling of Limb Ownership: A Lesion Study. Journal of Neuroscience, 31(13), 4852-4857. doi:10.1523/jneurosci.5154-10.2011Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). «Mini-mental state». Journal of Psychiatric Research, 12(3), 189-198. doi:10.1016/0022-3956(75)90026-6Romero, M., Sánchez, A., Marín, C., Navarro, M. D., Ferri, J., & Noé, E. (2012). Clinical usefulness of the Spanish version of the Mississippi Aphasia Screening Test (MASTsp): validation in stroke patients. Neurología (English Edition), 27(4), 216-224. doi:10.1016/j.nrleng.2011.06.001Latorre, J., Llorens, R., Colomer, C., & Alcañiz, M. (2018). Reliability and comparison of Kinect-based methods for estimating spatiotemporal gait parameters of healthy and post-stroke individuals. Journal of Biomechanics, 72, 268-273. doi:10.1016/j.jbiomech.2018.03.008Lloréns, R., Noé, E., Naranjo, V., Borrego, A., Latorre, J., & Alcañiz, M. (2015). Tracking Systems for Virtual Rehabilitation: Objective Performance vs. Subjective Experience. A Practical Scenario. Sensors, 15(3), 6586-6606. doi:10.3390/s150306586Slater, M., & Steed, A. (2000). A Virtual Presence Counter. Presence: Teleoperators and Virtual Environments, 9(5), 413-434. doi:10.1162/105474600566925Slater, M., Spanlang, B., Sanchez-Vives, M. V., & Blanke, O. (2010). First Person Experience of Body Transfer in Virtual Reality. PLoS ONE, 5(5), e10564. doi:10.1371/journal.pone.0010564Petkova, V. I., Khoshnevis, M., & Ehrsson, H. H. (2011). The Perspective Matters! Multisensory Integration in Ego-Centric Reference Frames Determines Full-Body Ownership. Frontiers in Psychology, 2. doi:10.3389/fpsyg.2011.00035Maselli, A., & Slater, M. (2013). The building blocks of the full body ownership illusion. Frontiers in Human Neuroscience, 7. doi:10.3389/fnhum.2013.00083Debarba, H. G., Molla, E., Herbelin, B., & Boulic, R. (2015). 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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

Létalité synthétique et Métabolisme dans le Sarcome d'Ewing : connaissance grâce au Silence

Ewing sarcoma, the second most commonly occurring pediatric bone tumor, is most often characterized by a chromosomal translocation between EWSR1 and FLI1. The gene fusion EWS-FLI1 accounts for 85% of all Ewing sarcoma and is considered the major oncogene and master regulator of Ewing sarcoma. EWS-FLI1 is a transcriptional modulator of targets, both directly and indirectly. Ewing sarcoma is aggressively treated with chemotherapy, localized surgery and radiation and has an overall survival of about 70%, however, survival for metastasis or relapsed cases remains low. One of the cancer hallmarks, metabolic deregulation, is most likely partly dependent on EWS-FLI1 in Ewing sarcoma cells. In order to get a better understanding of Ewing sarcoma biology and oncogenesis, it might be of high interest to investigate the influence of EWS-FLI1 in Ewing sarcoma cells. We therefore performed a global metabolic profiling of Ewing sarcoma cells with or without inhibition of EWS-FLI1. Several changes in the energy metabolism were observed throughout this study; the observed changes were consistent with an energy profile that moved from a cancer cell energy metabolism towards the energy metabolism of a more normal cell upon EWS-FLI1 inhibition, primarily based on the TCA cycle. Levels of TCA intermediates, glycosylation precursors, methionine pathway metabolites and amino acids, especially changes in the tryptophan metabolic pathway, were altered upon EWS-FLI1 inhibition. Parallel to this study, we performed a high-throughput synthetic lethality screen, in order to not only identify essential genes for cell survival and proliferation, but also to identify new synthetic lethal targets that could specifically target Ewing sarcoma cells carrying the EWS-FLI1 fusion gene.Le sarcome de Ewing est la seconde tumeur pédiatrique de l’os la plus fréquente. Elle est caractérisée par une translocation chromosomique résultant à la fusion de EWSR1 avec un membre de la famille ETS. Chez 85% des patients, cette fusion conduit à l’expression de la protéine chimérique EWS-FLI1 qui est l’oncogène majeur de ce sarcome. Ce dernier agit principalement par son action transcriptionelle sur des cibles qui lui sont propres. Au niveau thérapeutique, le sarcome d’Ewing est traité par chimiothérapie, chirurgie locale et par radiothérapie. La survie à long terme des patients est de l’ordre de 70%, mais beaucoup plus basse pour les patients métastatiques et quasi nulle lors d’une récidive. Parmi maintes caractéristiques, certains cancers présentent une dérégulation énergétique. L’influence d’EWS-FLI1 sur cet aspect n’a fait l’objet d’aucune étude dans le contexte du sarcome d’Ewing. Nous avons donc étudié par profilage métabolomique des cellules de sarcome d’Ewing en présence ou en absence d’EWS-FLI1. En comparant ces deux conditions, des modulations du profil énergétique relatif au cycle de Krebs, des précurseurs de le glycosylation ainsi que des métabolites de la voie de la méthionine et du tryptophane ont été observés. En parallèle, grâce à un crible de banque de shRNAs réalisé dans des conditions expérimentales similaires à l’étude métabolomique (lignée d’Ewing avec ou sans EWS-FLI1), nous avons pu identifier des gènes présentant des caractéristiques « synthétique létales », c'est-à-dire tuant uniquement les cellules du sarcome d’Ewing en présence de son oncogène

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

Recommendations for the design of small population clinical trials

Background: Orphan drug development faces numerous challenges, including low disease prevalence, patient population heterogeneity, and strong presence of paediatric patient populations. Consequently, clinical trials for orphan drugs are often smaller than those of non-orphan drugs, and they require the development of efficient trial designs relevant to small populations to gain the most information from the available data. The International Rare Diseases Research Consortium (IRDiRC) is aimed at promoting international collaboration and advance rare diseases research worldwide, and has as one of its goals to contribute to 1000 new therapies for rare diseases. IRDiRC set up a Small Population Clinical Trials (SPCT) Task Force in order to address the shortcomings of our understanding in carrying out clinical trials in rare diseases. Results: The IRDiRC SPCT Task Force met in March 2016 to discuss challenges faced in the design of small studies for rare diseases and present their recommendations, structured around six topics: different study methods/designs and their relation to different characteristics of medical conditions, adequate safety data, multi-arm trial designs, decision analytic approaches and rational approaches to adjusting levels of evidence, extrapolation, and patients' engagement in study design. Conclusions: Recommendations have been issued based on discussions of the Small Population Clinical Trials Task Force that aim to contribute towards successful therapy development and clinical use. While randomised clinical trials are still considered the gold standard, it is recommended to systematically take into consideration alternative trial design options when studying treatments for a rare disease. Combining different sources of safety data is important to give a fuller picture of a therapy's safety profile. Multi-arm trials should be considered an opportunity for rare diseases therapy development, and funders are encouraged to support such trial design via international networks. Patient engagement is critical in trial design and therapy development, a process which sponsors are encouraged to incorporate when conducting trials and clinical studies. Input from multiple regulatory agencies is recommended early and throughout clinical development. Regulators are often supportive of new clinical trial designs, provided they are well thought through and justified, and they also welcome discussions and questions on this topic. Parallel advice for multiregional development programs should also be considered

How to START? Four pillars to optimally begin your orphan drug development

Abstract Drug development is a complex, resource intensive and long process in any disease area, and developing medicines to treat rare diseases presents even more challenges due to the small patient populations, often limited disease knowledge, heterogeneous clinical manifestations, and disease progression. However, common to all drug development programs is the need to gather as much information as possible on both the disease and the patients’ needs ahead of the development path definition. Here, we propose a checklist named START, a tool that provides an overview of the key pillars to be considered when starting an orphan drug development: STakeholder mapping, Available information on the disease, Resources, and Target patient value profile. This tool helps to build solid foundations of a successful patient-centered medicines development program and guides different types of developers through a set of questions to ask for guidance through the starting phase of a rare disease therapeutic pathway