The READI European project: Enhancing inclusivity in clinical research.

Although the risk of developing cardiovascular disease (CVD) is reduced by the Mediterranean diet,1 CVD prevalence in Spain is rising. CVD is a major cause of mortality and morbidity in this country, and there is a growing awareness in the scientific community of the need for advances in knowledge, diagnosis, and therapy. Spain has a strong tradition of basic research in molecular biology, immunology, development, neuroscience, and oncology, but historically there have been few research groups dedicated to basic cardiovascular research, and this has been reflected in limited funding. Over the last 20 years, a national strategy to address this situation has seen the creation of a cardiovascular center of excellence and research networks focused on CVD. This significant boost to Spanish cardiovascular research has generated closer collaboration between the clinical and basic research communities, with already tangible beneficial results for patients. Here, we outline current trends in cardiovascular research in Spain, highlighting achievements, opportunities, and challenges. ### Grants and Funding Despite increasing CVD incidence and prevalence, public research funding in Spain has decreased over the last decade. This cut in funds follows a general trend in Spain in the wake of the global financial crisis. In 2016, the Ministry of Economy and Competitiveness, which is the main public funding body in Spain, spent around 380 million euros on different project grants, mainly in the so-called Excellence, Societal Challenges, and Health Research Projects programs. The Excellence call funded >700 grants (42% success rate), averaging around 100 000 euros per project. The Societal Challenges awarded 1500 grants (49% success rate) with 145 000 euros each on average. The Health Research Projects scheme funded >600 projects with an average of 95 000 euros each (36% success rate). These projects are 3 to 4 years long and were awarded to 1, or sometimes 2, principal investigators. Over the last …

The need for performing clinical trials to develop well-studied and appropriate medicines for inherited neurometabolic disease patients faces ethical concerns mainly raising from four aspects: the diseases are rare; include young and very young patients; the neurological impairment may compromise the capability to provide ‘consent’; and the genetic nature of the disease leads to further ethical implications. This work is intended to identify the ethical provisions applicable to clinical research involving these patients and to evaluate if these cover the ethical issues. Three searches have been performed on the European regulatory/legal framework, the literature and European Union-funded projects. The European legal framework offers a number of ethical provisions ruling the clinical research on paediatric, rare, inherited diseases with neurological symptoms. In the literature, relevant publications deal with informed consent, newborn genetic screenings, gene therapy and rights/interests of research participants. Additional information raised from European projects on sharing patients’ data from different countries, the need to fill the gap of the regulatory framework and to improve information to stakeholders and patients/families.Conclusion: Several recommendations and guidelines on ethical aspects are applicable to the inherited neurometabolic disease research in Europe, even though they suffer from the lack of a common ethical approach.What is Known:• When planning and conducting clinical trials, sponsors and researchers know that clinical trials are to be performed according to well-established ethical rules, and patients should be aware about their rights.• In the cases of paediatric patients, vulnerable patients unable to provide consent, genetic diseases’ further rules apply.What is New:• This work discusses which ethical rules apply to ensure protection of patient’s rights if all the above-mentioned features coexist.• This work shows available data and information on how these rules have been applied.

The European Health Data Space (EHDS) initiative was launched to create a unified framework for health data exchange across Europe. Central to this initiative is the European Electronic Health Record Exchange Format, designed to achieve interoperability of electronic health record data across Europe. Despite these advancements, the readiness of current guidelines and implementations, such as the European Patient Summary, to support secondary use in clinical research, particularly in cardiology, remains underexplored. This study aims to evaluate the European Patient Summary guidelines and their implementations, specifically the HL7 FHIR International Patient Summary Implementation Guide, to determine their suitability for secondary use in clinical research. The focus is on identifying gaps and extensions needed to enhance the utility of the European Patient Summary for building artificial intelligence models in assisting heart failure management. We selected two European Union-funded research projects, DataTools4Heart and AI4HF, that aim to reuse electronic health record data to develop artificial intelligence models for personalized decision support services for heart failure patients. We analyzed their clinical use cases and the specific data items required, and we compared these with the current European Patient Summary guidelines and provided a detailed gap analysis indicating similarities and required extensions. In our gap analysis, we also compared the needs of DataTools4Heart and AI4HF with the HL7 FHIR International Patient Summary Implementation Guide to assess the extensions needed to support clinical research. The EHDS is a transformative initiative to establish a European health data ecosystem that supports healthcare delivery and clinical research. Our comparative analysis demonstrates that, with minor extensions, these guidelines have significant potential to facilitate access to electronic healthcare record data for the secondary use, particularly in training AI models. We advocate for the adoption of an International Patient Summary format as a semantically interoperable core set of data elements, which will enhance global clinical research efforts and improve patient outcomes through precision medicine.

141st ENMC International Workshop Inaugural Meeting of the EURO-Laminopathies Project Nuclear Envelope-linked Rare Human Diseases: From Molecular Pathophysiology towards Clinical Applications 10–12 March 2006, Naarden, The Netherlands

Integration profiles collaboratively developed by CDISC and IHE for integrating data from Electronic Health Records (EHRs) with clinical research and pharmacovigilance are limited to resolving lexical/syntactic data integration issues and do not address semantic barriers. This paper describes the collaboration between two European projects – EHR4CR and SALUS – in implementing ISO/IEC 11179-based metadata registries (MDRs) and semantically integrated cross-platform data access. A common “semantic MDR” provides a framework for bidirectional/cross-MDR mapping and federated queries are enabled using the newly-defined IHE Data Exchange (DEX) profile. In the pilot implementation, mappings for 178 EHR4CR and 199 SALUS metadata elements were persisted in the semantic MDR. The DEX profile was then used to access semantically equivalent data elements in SALUS or EHR4CR participating EHR systems. ISO/IEC 11179-based MDRs and DEX integration profile address the goal of developing pan-EU computable semantic integration of data from clinical care, clinical research, and patient safety platforms.

EHRs can now be adapted to integrate seamlessly with existing research platforms. However, key challenges need to be overcome in order to provide a platform that functions across many EHR systems.TheIHE Quality, Research and Public Health (QRPH)domain addresses the information exchange standards necessary to share information relevant to quality improvement in patient care and clinical research. In collaboration with CDISC’s Healthcare Link initiative, IHE QRPH has developed a set of integration profiles that specifically address EHR-enabled research.The panel participants from three European projects will present how subsets of existing IHE QRPH profiles can be pulled together (and extended when necessary) to form a super profile which will standardize and automate the clinical trial process flow.TheEHR4CRproject is providing adaptable, reusable and scalable tools and services for reusing data from hospital EHRs for Clinical Research.TRANSFoRmis developing an informatics infrastructure to support the learning healthcare system in European Primary Care.SALUSproject is providing scalable, standard based interoperability framework for sustainable proactive post market safety studies. Overall, the panel will discuss the key steps towards realizing a jointEHR4CR/TRANSFoRm/SALUS European projectathondemonstrating EHR-enabled clinical research across Europe using standard-based integration and content profiles.

Cost-benefit assessment of using electronic health records data for clinical research versus current practices: Contribution of the Electronic Health Records for Clinical Research (EHR4CR) European Project

Background: The new technological platform developed by the Electronic Health Records for Clinical Research (EHR4CR) European research project (2011-2016) has been specially designed to enable the trustworthy reuse of health data contained in hospital-based electronic health records (EHR) for enhancing and speeding up clinical research scenarios. In particular, protocol feasibility assessments, patient identification for recruitment, and clinical data exchange for study conduct, in accordance with data privacy, ethical and legal requirements. The objective of our study was to assess the financial impact of adopting these advanced solutions compared to current practices, from the perspective of the primary sponsors of clinical trials in Europe. Methods: Considering a scalable implementation of EHR4CR solutions in up to 5-10% of Phase II, III and IV clinical trials to be commercially sponsored in Europe over 5 years, two potential market sizes were defined. The first has a European initial scope (i.e., for European clinical trials only), and the second has a European subsequent broader scope (also including European arms of global studies). Based on expert opinions, the EHR4CR initial scope target market was estimated to be 30% of the broader scope. Direct costs to clinical research sponsors were estimated under current practices, and with the EHR4CR platform. Uncertainty was managed using 100,000 Monte Carlo simulations. Results: Compared to current practices, the potential average 5-year savings with EHR4CR solutions for Phase II, III and IV commercially sponsored clinical trials in Europe were estimated at €175.5 m for the European initial scope market, and at €585.3 m for the European broader scope market. These results were confirmed by robust probabilistic sensitivity analyses. Conclusions: Compared to current practices, EHR4CR solutions appear cost-saving for primary sponsors of clinical trials. These results suggest that the potential for savings would increase with a broader adoption of EHR4CR solutions in Europe, and beyond.

BackgroundInformed consent (IC) is essential in defending the autonomy of potential participants in clinical research. Despite the advances in research ethics, particularly in IC, the different guidelines and codes have not been fully implemented. Several studies have presented consent deficiencies that have resulted in unethical practices or poor understanding of the IC.Main bodyThis article reviews the evolution of IC, from its philosophical origins and initial use in the Ottoman Empire (16th century) to its use in clinical research today. It also presents the vision of the European project i-CONSENT (Grant Agreement number: 741856), whose main purpose is to improve the understanding of ICs in research and identifies the key components of a new paradigm to develop patient-centred ICs.ConclusionsIn many cases, the IC has served to protect the investigator or sponsor from complaints. Different ethical guidelines have sought to make the IC a more useful tool, with little success. Today’s IC is mainly a bureaucratic and legal process that fails to consider the patient’s point of view. In this context, the Guidelines for Tailoring the Informed Consent Process in Clinical Studies provide alternatives to the current IC process, focusing on the patient’s opinions and making them part of the process, thereby improving clinical research quality.

Electronic health records in hospitals contribute to improving the quality of care by enabling better management of clinical information. The databases thus constituted facilitate the exchange of health information with healthcare providers and optimize multidisciplinary coordination for better therapeutic results. The EHR4CR (Electronic Health Records for Clinical Research) European project has developed an innovative pilot platform enabling the reuse of this digital information for clinical research. By enhancing and speeding up clinical research procedures, this innovative approach makes it possible to conduct clinical trials more efficiently, faster, and more economically.

Dear Sir, The European Organisation for Rare Diseases -EURORDIS- is a non-governmental patient-driven alliance of patient organisations and individuals active in the field of rare diseases. EURORDIS represents over 600 rare disease organisations in 58 countries (including 26 EU Member States) covering more than 4,000 rare diseases. More information is available on www.eurordis.org1. Since 2004, EURORDIS has been involved in different discussions at European and national levels on shaping Centres of Expertise and European Reference Networks (ERNs) for rare diseases with a view to improve timely access to appropriate diagnosis and care for people living with a rare disease. Over almost a decade, EURORDIS has gathered the opinions of its members on these topics through its Annual Membership Meetings as well as through surveys and workshops organised within the European co-funded projects RAPSODY and POLKA2. The opinions of our members have informed relevant EURORDIS position papers, which thus reflect the expectations of patients and their families regarding the organisation of care and delivery of treatments for their diseases. Why are ERNs important for patients with rare diseases? Due to the low prevalence of each rare disease, expertise is by essence scarce and scattered throughout Europe. The best way to accelerate access to a proper, timely diagnosis, as well as appropriate care, is to share expertise by linking at European level the national Centres of Expertise, healthcare providers, diagnostic laboratories, other relevant services and patients’ organisations. ERNs are also intended to gather a critical mass of patients and data to support rare disease registries and clinical research. The national Centres of Expertise are seen to constitute the nodes of ERNs for rare diseases. EURORDIS, through its representatives, contributed to the Recommendation of the European Committee of Experts on Rare Diseases (EUCERD) on the “quality criteria for Centres of Expertise for Rare Diseases in Member States”, which was adopted on 24 October 2011. To date, the EU Member States are developing criteria based on this Recommendation for designated Centres of Expertise for RDs in their territory within their national plans/strategies for rare diseases. The European Directive 2011/24/EU3 on the “application of patients’ rights in cross-border healthcare” has delineated for the first time the legal framework for European reference networks. This has been a success in translating a concept into a real healthcare framework with an added value for patients. In addition, Article 13 of this Directive is specifically dedicated to rare diseases: “The Commission shall support Member States in cooperating in the development of diagnosis and treatment capacity in particular by aiming to make health professionals aware of the tools available to them at Union level to assist them in the correct diagnosis of rare diseases, in particular the Orphanet database, and the European Reference Networks”. In this evolving context, EURORDIS adopted in May 2012 a position to outline its vision and strategy for ERNs for rare diseases; what they should comprise and how they should function based on the patient’s real life experience. EURORDIS rejects the logic of selecting priorities amongst rare diseases; all patients affected with a rare disease should be covered by at least one ERN in the long run. As it will not be possible to fund numerous ERNs, EURORDIS recommends that a limited number of ERNs for RDs (20 to 30) should be created by diagnostic and therapeutic areas in order to cover a wide range of rare diseases. EURORDIS also emphasises that a high-level of multi-disciplinarity and inter-operability among ERNs are absolutely necessary. The successful development of ERNs for RDs will rely on a step-wise approach aimed at establishing progressively the various activities of the ERN, such as experts’ opinions, good practice guidelines on medical care as well as social care, training, patient registries, e-health. The ERNS should remain flexible in order to evolve over time. The EURORDIS representatives in the EUCERD voiced the patients’ perspectives during the consultations on the elaboration of the Recommendation on European Reference Networks for Rare Diseases. This EUCERD Recommendation4 was adopted on 31 January 2013 and integrates many elements of the rare disease patients’ position. The new Health for Growth Programme of the European Commission, adopted in March, shall cover a period of seven years, from 2014 to 2020. We are aware that there will not be enough funding for European reference networks. Therefore, we need to be creative and seek other sources of funding, for instance from the Horizon 2020 programme and possibly structural funds for health. Tonio Borg, European Commissioner for Health, has recently emphasised that research on rare diseases is a priority for the European Commission and where there is an opportunity to offer a better service to citizens, the principle of subsidiarity applies; hence this principle applies to Cross-Border Healthcare for Rare Diseases.

Adolescent urology

From the Early Emergence of Psychiatry to Stem Cells and Neural Organoids.

An increasing number of European research projects return, or plan to return, individual genomic research results (IRR) to participants. While data access is a data subject’s right under the General Data Protection Regulation (GDPR), and many legal and ethical guidelines allow or require participants to receive personal data generated in research, the practice of returning results is not straightforward and raises several practical and ethical issues. Existing guidelines focusing on return of IRR are mostly project-specific, only discuss which results to return, or were developed outside Europe. To address this gap, we analysed existing normative documents identified online using inductive content analysis. We used this analysis to develop a checklist of steps to assist European researchers considering whether to return IRR to participants. We then sought feedback on the checklist from an interdisciplinary panel of European experts (clinicians, clinical researchers, population-based researchers, biobank managers, ethicists, lawyers and policy makers) to refine the checklist. The checklist outlines seven major components researchers should consider when determining whether, and how, to return results to adult research participants: 1) Decide which results to return; 2) Develop a plan for return of results; 3) Obtain participant informed consent; 4) Collect and analyse data; 5) Confirm results; 6) Disclose research results; 7) Follow-up and monitor. Our checklist provides a clear outline of the steps European researchers can follow to develop ethical and sustainable result return pathways within their own research projects. Further legal analysis is required to ensure this checklist complies with relevant domestic laws.

This review is based on the debates held in Barcelona from 3 July 2012 to 4 July 2012 with the active participation of all authors. The debates were organized by B-Debate (an initiative of Biocat and Obra Social ‘La Caixa’) and Universitat Pompeu Fabra (Barcelona). The event was held within the framework of the European INBIOMEDvision project (funded by the EU Seventh Framework Programme for Research and Technological Development (FP7) under grant agreement no. 270107). In addition, we received support from EU FP7 project no. 200754 (GEN2PHEN) and the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115002 (eTOX) and no. 115191 (Open PHACTS), resources of which are composed of financial contribution from the EU FP7 and in kind contributions from companies of the European Federation of Pharmaceutical Industries and Associations. L.I.F received support from Instituto de Salud Carlos III Fondo Europeo de Desarollo Regional (CP10/00524).