How the new European data protection regulation affects clinical research and recommendations?

Clinical research on human subjects or their data is confronted with conflicting requirements with, on one hand, the principle of open science (transparency and data sharing), the possibilities offered by big data and the reuse of healthcare or research data, and on the other, changes to the regulatory and legislative framework, including the general data protection regulation (GDPR). A roundtable was organized in Giens, France in October 2018 to identify problem areas, the need for clarification and streamlining, and to make recommendations to promote clinical research while ensuring a high level of patient protection. After details were given about these developments, the roundtable participants were able to propose recommendations, primarily (1) to clarify: what is considered anonymized data, and what is "public interest" within the meaning of the GDPR; (2) for the French data protection authority (CNIL) to continue preparing reference methodologies to simplify the approval system; (3) to promote the secondary use of data by making it easier to inform patients and obtain broad patient consent, by specifying the circumstances under which their withdrawal and opposition rights apply, so as to limit the risk of bias; (4) to facilitate access to data warehouses by providing technological and methodological aids. The roundtable also recommends increasing discussions between authorities in Europe on research topics, encouraging French authorities to contribute to the preparation of codes of conduct and setting up a voluntary harmonization procedure to coordinate the opinions of data protection authorities, while ensuring that key documents are available in English.

Methods for Stratification and Validation Cohorts: A Scoping Review.

Personalized medicine requires large cohorts for patient stratification and validation of patient clustering. However, standards and harmonized practices on the methods and tools to be used for the design and management of cohorts in personalized medicine remain to be defined. This study aims to describe the current state-of-the-art in this area. A scoping review was conducted searching in PubMed, EMBASE, Web of Science, Psycinfo and Cochrane Library for reviews about tools and methods related to cohorts used in personalized medicine. The search focused on cancer, stroke and Alzheimer's disease and was limited to reports in English, French, German, Italian and Spanish published from 2005 to April 2020. The screening process was reported through a PRISMA flowchart. Fifty reviews were included, mostly including information about how data were generated (25/50) and about tools used for data management and analysis (24/50). No direct information was found about the quality of data and the requirements to monitor associated clinical data. A scarcity of information and standards was found in specific areas such as sample size calculation. With this information, comprehensive guidelines could be developed in the future to improve the reproducibility and robustness in the design and management of cohorts in personalized medicine studies.

Disclosure of investigators' recruitment performance in multicenter clinical trials: a further step for research transparency.

Rafael Dal-Ré and colleagues argue that the recruitment targets and performance of all site investigators in multi-centre clinical trials should be disclosed in trial registration sites before a trial starts, and when it ends.

[ECRIN (European clinical research infrastructures network), a pan-European infrastructure for clinical research]. / ECRIN (European clinical research infrastructures network) et la structuration de la recherche clinique en Europe.

Clinical research plays a key role both in the development of innovative health products and in the optimisation of medical strategies, leading to evidence-based practice and healthcare cost containment. ECRIN is a distributed ESFRI-roadmap pan-European infrastructure designed to support multinational clinical research, making Europe a single area for clinical studies, taking advantage of its population size to access patients, and unlocking latent scientific providing services to multinational. Servicing of multinational trials started during the preparatory phase, and ECRIN has applied for ERIC status in 2011. In parallel, ECRIN has also proposed an FP7 integrating activity project to further develop, upgrade and expand the ECRIN infrastructure built up during the past FP6 and FP7 projects, facilitating an efficient organization of clinical research in Europe, with ECRIN developing generic tools and providing generic services for multinational studies, and supporting the construction of pan-European disease-oriented networks that will in turn act as ECRIN users. This organization will improve Europe's attractiveness for industry trials, boost its scientific competitiveness, and result in better healthcare for European citizens. The three medical areas supported in this project (rare diseases, medical devices, and nutrition) will serve as pilots for other biomedical research fields. By creating a single area for clinical research in Europe, this structure will contribute to the implementation of the Europe flagship initiative 2020 'Innovation Union', whose objectives include defragmentation of research and educational capacities, tackling the major societal challenges (starting with healthy aging), and removing barriers to bringing ideas to the market.

Emotional hyper-reactivity in normothymic bipolar patients.

BACKGROUND: Normothymic states in bipolar disorders are generally considered to be devoid of severe symptoms. However, bipolar patients present subsyndromal symptoms for half of their lives, and often have comorbid psychiatric disorders. If we go beyond the concept of temperamental features, can we identify certain emotional characteristics distinguishing normothymic bipolar patients from normal controls? We previously showed, using self-completed questionnaires, that normothymic bipolar patients display higher levels of emotional lability and intensity than controls. OBJECTIVES: The aim of this study was to assess the emotional reactivity of normothymic bipolar patients, comparing such patients with a normal control group during an experimental mood induction procedure. METHOD: We evaluated the subjective emotional reactivity of 145 subjects (90 control subjects and 55 normothymic bipolar patients), using an emotional induction method based on the viewing of a set of 18 pictures (6 positive, 6 negative, 6 neutral) extracted from the International Affective Picture System. Subjective valence and arousal were recorded with the Self-Assessment Manikin. We also recorded startle reflexes, triggered by a tone occurring during the viewing of two-thirds of the pictures. We controlled for confounding factors, such as concurrent treatments, in all analyses. RESULTS: Normothymic bipolar patients and normal controls assessed valence and arousal similarly for positive and negative images. However, neutral images were considered more pleasant [F(1,143) = 8.4; p = 0.004] and induced a higher level of arousal [F(1,143) = 12.3; p = 0.001] in normothymic bipolar patients than in control subjects. Neutral pictures also triggered a stronger startle reflex in normothymic bipolar patients compared to controls [F(3,123) = 3.1; p = 0.03]. CONCLUSION: Normothymic bipolar patients displayed emotional hyper-reactivity, mostly evidenced in neutral situations. This feature may be linked to emotional dysregulation and is a potential endophenotype and/or a risk factor for bipolar disorders. This trait may be responsible for vulnerability to minor stressful events in everyday life. These findings have potential implications for the daily management of bipolar disorder between crises.

Evaluation of repositories for sharing individual-participant data from clinical studies.

BACKGROUND: Data repositories have the potential to play an important role in the effective and safe sharing of individual-participant data (IPD) from clinical studies. We analysed the current landscape of data repositories to create a detailed description of available repositories and assess their suitability for hosting data from clinical studies, from the perspective of the clinical researcher. METHODS: We assessed repositories that enable storage, sharing, discoverability, re-use of the IPD and associated documents from clinical studies using a pre-defined set of 34 items and publicly available information from April to June 2018. For this purpose, we developed an indicator set to capture the maturity of the repositories' procedures and their suitability for the hosting of IPD. The indicators cover guidelines for data upload and data de-identification, data quality controls, contracts for upload and storage, flexibility of access, application of identifiers, availability of metadata, and long-term preservation. RESULTS: We analysed 25 repositories, from an initial set of 55 identified as possibly relevant. Half of the included repositories were generic, i.e. not limited to a specific disease or clinical area and 13 were launched in the last 8 years. The sample was extremely heterogeneous and included repositories developed by research funders, infrastructures, universities, and editors. All but three repositories do not apply a fee for uploading, storage or access to data. None of the repositories completely demonstrated all the items included in the indicator set, but three repositories (Dryad, Drum, EASY) met - fully or partially - all items. Flexibility of data-access modalities appears to be limited, being lacking in half of the repositories. CONCLUSIONS: Our evaluation, though often hampered by the lack of sufficient information, can help researchers to find a suitable repository for their datasets. Some repositories are more mature because of their support for clinical dataset preparation, contractual agreements, metadata and identifiers, different modalities of access, and long-term preservation of data. Further work is now required to achieve a more robust and accurate system for evaluation, which in turn may encourage the sharing of clinical study data. TRIAL REGISTRATION: Study protocol available at https://zenodo.org/record/1438261#.W64kW9Egrcs .

European mental health research resources: Picture and recommendations of the ROAMER project.

As part of the Roamer project, we sought to have a picture of the available mental health research (MHR) funding, capacity-building and infrastructures resources and to establish consensus-based recommendations that would allow an increase of European MHR resources and enable better use and accessibility to them. The methods fell into three sections (i) a review of the literature, (ii) a mental health-related keywords search within the Cordis®, On-Course® and Meril® databases which contain information on European research funding, training and infrastructures. These reviews provided an overview that was presented to (iii) two experts workshops with 28 participants drawn from academic which identified gaps and produced recommendations. The literature review illustrates the debates in the scientific community on funding, training and infrastructures. The database searches estimated the fraction of health research resources available for mental health. Eight overarching goals for MHR resources were identified by the workshops; each of them was carried out with several practical recommendations. Resources for MHR are scarce considering the burden of mental disorders, the high rate of return of MHR and the under-investment of the field. The recommendations are urgently warranted to increase resources and their optimal access and use.

Therapeutic hypothermia for acute ischaemic stroke. Results of a European multicentre, randomised, phase III clinical trial.

INTRODUCTION: We assessed whether modest systemic cooling started within 6 hours of symptom onset improves functional outcome at three months in awake patients with acute ischaemic stroke. PATIENTS AND METHODS: In this European randomised open-label clinical trial with blinded outcome assessment, adult patients with acute ischaemic stroke were randomised to cooling to a target body temperature of 34.0-35.0°C, started within 6 h after stroke onset and maintained for 12 or 24 h , versus standard treatment. The primary outcome was the score on the modified Rankin Scale at 91 days, as analysed with ordinal logistic regression. RESULTS: The trial was stopped after inclusion of 98 of the originally intended 1500 patients because of slow recruitment and cessation of funding. Forty-nine patients were randomised to hypothermia versus 49 to standard treatment. Four patients were lost to follow-up. Of patients randomised to hypothermia, 15 (31%) achieved the predefined cooling targets. The primary outcome did not differ between the groups (odds ratio for good outcome, 1.01; 95% confidence interval, 0.48-2.13; p = 0.97). The number of patients with one or more serious adverse events did not differ between groups (relative risk, 1.22; 95% confidence interval, 0.65-1.94; p = 0.52). DISCUSSION: In this trial, cooling to a target of 34.0-35.0°C and maintaining this for 12 or 24 h was not feasible in the majority of patients. The final sample was underpowered to detect clinically relevant differences in outcomes. CONCLUSION: Before new trials are launched, the feasibility of cooling needs to be improved.

Bioavailability and urinary excretion of isoflavones in humans: effects of soy-based supplements formulation and equol production.

Soy isoflavones (IF) are of particular interest for their possible estrogenic effects on the symptoms of menopause. The bioavailability of IF is clearly a factor influencing their biological activity. The first aim of this study was to elucidate the impact of the matrix process and especially the formulation of soy-based capsules on IF bioavailability. Twelve healthy volunteers were recruited for a randomized, double-blind, two-way crossover trial and received a single dose of the two soy-based formulations, one containing a pure soy standardized extract of IF, and the other containing soy flour in addition to the standardized extract of IF. Using a new and validated ELISA method, we measured the plasma and urinary concentrations of genistein, daidzein and its metabolite equol. Based on European Medicine Evaluation Agency recommendations, the main pharmacokinetic parameters allowed us to demonstrate the bioequivalence of the two formulations, indicating that the presence or absence of soy flour did not alter either the absorption or the elimination of daidzein and genistein. As bioequivalence was demonstrated, we pooled data collected during the two study-periods to address another original issue: Did the ability to produce equol affect the bioavailability of daidzein? We demonstrated that daidzein excretion was significantly lower in equol producers compared with equol non producers over the entire elimination period of the soy IF. This difference disappeared when equol excretion was added to daidzein excretion in equol producers. Our results indicated that the production of equol could partly explain the difference in daidzein bioavailability after IF ingestion.

Barriers to the conduct of randomised clinical trials within all disease areas.

BACKGROUND: Randomised clinical trials are key to advancing medical knowledge and to enhancing patient care, but major barriers to their conduct exist. The present paper presents some of these barriers. METHODS: We performed systematic literature searches 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: The following barriers to randomised clinical trials were identified: inadequate knowledge of clinical research and trial methodology; lack of funding; excessive monitoring; restrictive privacy law and lack of transparency; complex regulatory requirements; and inadequate infrastructures. There is a need for more pragmatic randomised clinical trials conducted with low risks of systematic and random errors, and multinational cooperation is essential. CONCLUSIONS: The present paper presents major barriers to randomised clinical trials. It also underlines the value of using a pan-European-distributed infrastructure to help investigators overcome barriers for multi-country trials in any disease area.

Specific barriers to the conduct of randomised clinical trials on medical devices.

BACKGROUND: Medical devices play an important role in the diagnosis, prevention, treatment and care of diseases. However, compared to pharmaceuticals, there is no rigorous formal regulation for demonstration of benefits and exclusion of harms to patients. The medical device industry argues that the classical evidence hierarchy cannot be applied for medical devices, as randomised clinical trials are impossible to perform. This article aims to identify the barriers for randomised clinical trials on medical devices. METHODS: Systematic literature searches without meta-analysis and internal European Clinical Research Infrastructure Network (ECRIN) communications taking place during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project. RESULTS: In addition to the barriers that exist for all trials, we identified three major barriers for randomised clinical trials on medical devices, namely: (1) randomisation, including timing of assessment, acceptability, blinding, choice of the comparator group and considerations on the learning curve; (2) difficulties in determining appropriate outcomes; and (3) the lack of scientific advice, regulations and transparency. CONCLUSIONS: The present review offers potential solutions to break down the barriers identified, and argues for applying the randomised clinical trial design when assessing the benefits and harms of medical devices.

Evidence-based practice within nutrition: what are the barriers for improving the evidence and how can they be dealt with?

BACKGROUND: Evidence-based clinical research poses special barriers in the field of nutrition. The present review summarises the main barriers to research in the field of nutrition that are not common to all randomised clinical trials or trials on rare diseases and highlights opportunities for improvements. METHODS: Systematic academic literature searches 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: Many nutrients occur in multiple forms that differ in biological activity, and several factors can alter their bioavailability which raises barriers to their assessment. These include specific difficulties with blinding procedures, with assessments of dietary intake, and with selecting appropriate outcomes as patient-centred outcomes may occur decennia into the future. The methodologies and regulations for drug trials are, however, applicable to nutrition trials. CONCLUSIONS: Research on clinical nutrition should start by collecting clinical data systematically in databases and registries. Measurable patient-centred outcomes and appropriate study designs are needed. International cooperation and multistakeholder engagement are key for success.

A systematic literature review of evidence-based clinical practice for rare diseases: what are the perceived and real barriers for improving the evidence and how can they be overcome?

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.

Sharing and reuse of individual participant data from clinical trials: principles and recommendations.

OBJECTIVES: We examined major issues associated with sharing of individual clinical trial data and developed a consensus document on providing access to individual participant data from clinical trials, using a broad interdisciplinary approach. DESIGN AND METHODS: This was a consensus-building process among the members of a multistakeholder task force, involving a wide range of experts (researchers, patient representatives, methodologists, information technology experts, and representatives from funders, infrastructures and standards development organisations). An independent facilitator supported the process using the nominal group technique. The consensus was reached in a series of three workshops held over 1 year, supported by exchange of documents and teleconferences within focused subgroups when needed. This work was set within the Horizon 2020-funded project CORBEL (Coordinated Research Infrastructures Building Enduring Life-science Services) and coordinated by the European Clinical Research Infrastructure Network. Thus, the focus was on non-commercial trials and the perspective mainly European. OUTCOME: We developed principles and practical recommendations on how to share data from clinical trials. RESULTS: The task force reached consensus on 10 principles and 50 recommendations, representing the fundamental requirements of any framework used for the sharing of clinical trials data. The document covers the following main areas: making data sharing a reality (eg, cultural change, academic incentives, funding), consent for data sharing, protection of trial participants (eg, de-identification), data standards, rights, types and management of access (eg, data request and access models), data management and repositories, discoverability, and metadata. CONCLUSIONS: The adoption of the recommendations in this document would help to promote and support data sharing and reuse among researchers, adequately inform trial participants and protect their rights, and provide effective and efficient systems for preparing, storing and accessing data. The recommendations now need to be implemented and tested in practice. Further work needs to be done to integrate these proposals with those from other geographical areas and other academic domains.

Public-private partnership models in France and in Europe.

The workshop entitled "Public-Private partnerships models in Europe-- comparison between France and European countries" brought together representatives of academia and industry, of national or European health research programs, of regional or national public-private partnership (PPP) initiatives, and of biotechnology with the following objectives: sharing a common vision on the needs, expectations and challenges of public-private partnership, based on the analysis of actual and original cases, and of new initiatives on public-private partnership, drawing conclusions and identifying key success factors, identifying trails for progress and drawing recommendations. The major event in this field is a European public-private partnership initiative between pharmaceutical industry (European Federation of Pharmaceultical Industry and Associations, EFPIA) and the European Commission (DG Research--health priority) resulting in the European Technology Platform project "Innovative Medicines Initiative" (IMI). Its architecture is based on the identification of the main bottlenecks to the development of innovative treatments (predictive pharmacology and toxicology, identification and validation of biomarkers, patients' recruitment, risk evaluation, and cooperation with the regulatory authorities). Simultaneously, initiatives both at the national and regional levels also foster PPP in the therapeutic field. Regional competitivity clusters acting in the biomedical sector, and national PPP calls such as the ANR (National Research Agency) RIB (Research and Innovation in Biotechnology) call are incentives for PPP projects. These regional and national PPP levels help public and private partners to further build consortia able to compete for EU-level calls, thus acting as incubators for EU PPP projects. In spite of incentives and of the regional and national structuring of PPP, weaknesses in the French system are linked to its fragmentation--multiple transfer agencies, multiple research organisations (operator or funding agency)--making contracts more difficult. This requires a simplified organisation, with a single referent per area (health, technology...). Improvement may also result from adaptation in the carreer, recruitment and mobility, from support to scientists in the management of projects, and from consistent support (without maintaining them artificially alive) to emerging companies from concept through clinical development. Pathways have been proposed to improve the efficiency of clinical research in France and Europe, involving the public hospital sector, and this requires the connection of disease-oriented networks and integrated infrastructures in Europe. As stated in the IMI strategic research agenda on efficacy, the quality of public infrastructures in Europe will be a key factor for its competitiveness and attractiveness for both academic and industry projects.

A European multi-language initiative to make the general population aware of independent clinical research: the European Communication on Research Awareness Need project.

BACKGROUND: The ECRAN (European Communication on Research Awareness Needs) project was initiated in 2012, with support from the European Commission, to improve public knowledge about the importance of independent, multinational, clinical trials in Europe. METHODS: Participants in the ECRAN consortium included clinicians and methodologists directly involved in clinical trials; researchers working in partnership with the public and patients; representatives of patients; and experts in science communication. We searched for, and evaluated, relevant existing materials and developed additional materials and tools, making them freely available under a Creative Commons licence. RESULTS: The principal communication materials developed were: 1. A website ( http://ecranproject.eu ) in six languages, including a Media centre section to help journalists to disseminate information about the ECRAN project 2. An animated film about clinical trials, dubbed in the 23 official languages of the European Community, and an interactive tutorial 3. An inventory of resources, available in 23 languages, searchable by topic, author, and media type 4. Two educational games for young people, developed in six languages 5. Testing Treatments interactive in a dozen languages, including five official European Community languages 6. An interactive tutorial slide presentation testing viewers' knowledge about clinical trials CONCLUSIONS: Over a 2-year project, our multidisciplinary and multinational consortium was able to produce, and make freely available in many languages, new materials to promote public knowledge about the importance of independent and international clinical trials. Sustained funding for the ECRAN information platform could help to promote successful recruitment to independent clinical trials supported through the European Clinical Research Infrastructure Network.

Evidence-based clinical practice: Overview of threats to the validity of evidence and how to minimise them.

Using the best quality of clinical research evidence is essential for choosing the right treatment for patients. How to identify the best research evidence is, however, difficult. In this narrative review we summarise these threats and describe how to minimise them. Pertinent literature was considered through literature searches combined with personal files. Treatments should generally not be chosen based only on evidence from observational studies or single randomised clinical trials. Systematic reviews with meta-analysis of all identifiable randomised clinical trials with Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment represent the highest level of evidence. Even though systematic reviews are trust worthier than other types of evidence, all levels of the evidence hierarchy are under threats from systematic errors (bias); design errors (abuse of surrogate outcomes, composite outcomes, etc.); and random errors (play of chance). Clinical research infrastructures may help in providing larger and better conducted trials. Trial Sequential Analysis may help in deciding when there is sufficient evidence in meta-analyses. If threats to the validity of clinical research are carefully considered and minimised, research results will be more valid and this will benefit patients and heath care systems.