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.

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 .

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.

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.

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.

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.

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.

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.

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.

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.

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.

Mental health research priorities for Europe.

Mental and brain disorders represent the greatest health burden to Europe-not only for directly affected individuals, but also for their caregivers and the wider society. They incur substantial economic costs through direct (and indirect) health-care and welfare spending, and via productivity losses, all of which substantially affect European development. Funding for research to mitigate these effects lags far behind the cost of mental and brain disorders to society. Here, we describe a comprehensive, coordinated mental health research agenda for Europe and worldwide. This agenda was based on systematic reviews of published work and consensus decision making by multidisciplinary scientific experts and affected stakeholders (more than 1000 in total): individuals with mental health problems and their families, health-care workers, policy makers, and funders. We generated six priorities that will, over the next 5-10 years, help to close the biggest gaps in mental health research in Europe, and in turn overcome the substantial challenges caused by mental disorders.

Fostering EMA's transparency policy.

The European Medicines Agency has opened a window to access clinical trial data. This is an important step forward which deserves attention, support, and advice from all the stakeholders. Regulatory agencies are the most comprehensive repositories of clinical trial data on drugs and can also promote and develop standard practices for data sharing. The release of the EMA draft policy on publication and access to clinical trial data in 2013 has fueled a lively debate among academia, industry, and the public in general that is still ongoing. As clinical researchers and producers and users of clinical trial data, we endorse the European Medicines Agency's opening and offer a few suggestions for complete, safe, and effective data sharing.

ROAMER: roadmap for mental health research in Europe.

Despite the high impact of mental disorders in society, European mental health research is at a critical situation with a relatively low level of funding, and few advances been achieved during the last decade. The development of coordinated research policies and integrated research networks in mental health is lagging behind other disciplines in Europe, resulting in lower degree of cooperation and scientific impact. To reduce more efficiently the burden of mental disorders in Europe, a concerted new research agenda is necessary. The ROAMER (Roadmap for Mental Health Research in Europe) project, funded under the European Commission's Seventh Framework Programme, aims to develop a comprehensive and integrated mental health research agenda within the perspective of the European Union (EU) Horizon 2020 programme, with a translational goal, covering basic, clinical and public health research. ROAMER covers six major domains: infrastructures and capacity building, biomedicine, psychological research and treatments, social and economic issues, public health and well-being. Within each of them, state-of-the-art and strength, weakness and gap analyses were conducted before building consensus on future research priorities. The process is inclusive and participatory, incorporating a wide diversity of European expert researchers as well as the views of service users, carers, professionals and policy and funding institutions.

European Network of Bipolar Research Expert Centre (ENBREC): a network to foster research and promote innovative care.

Bipolar disorders rank as one of the most disabling illnesses in working age adults worldwide. Despite this, the quality of care offered to patients with this disorder is suboptimal, largely due to limitations in our understanding of the pathology. Improving this scenario requires the development of a critical mass of expertise and multicentre collaborative projects. Within the framework of the European FP7 programme, we developed a European Network of Bipolar Research Expert Centres (ENBREC) designed specifically to facilitate EU-wide studies. ENBREC provides an integrated support structure facilitating research on disease mechanisms and clinical outcomes across six European countries (France, Germany, Italy, Norway, Spain and the UK). The centres are adopting a standardised clinical assessment that explores multiple aspects of bipolar disorder through a structured evaluation designed to inform clinical decision-making as well as being applicable to research. Reliable, established measures have been prioritised, and instruments have been translated and validated when necessary. An electronic healthcare record and monitoring system (e-ENBREC©) has been developed to collate the data. Protocols to conduct multicentre clinical observational studies and joint studies on cognitive function, biomarkers, genetics, and neuroimaging are in progress; a pilot study has been completed on strategies for routine implementation of psycho-education. The network demonstrates 'proof of principle' that expert centres across Europe can collaborate on a wide range of basic science and clinical programmes using shared protocols. This paper is to describe the network and how it aims to improve the quality and effectiveness of research in a neglected priority area.