Sharing Individual Patient Data (IPD) from clinical trials is increasingly promoted to improve transparency, reproducibility, and scientific value. However, implementation remains challenging due to ethical, regulatory, and operational constraints, particularly in multinational studies. This study evaluates the implementation of IPD sharing strategies within three multinational COVID-19 vaccine trials (EU-COVAT-1 AGED, EU-COVAT-2 BOOSTAVAC, and EU-COVPT-1 CoVacc) conducted under the VACCELERATE platform, focusing on protocol integration, informed consent, anonymisation, and repository-based data governance. Data sharing strategies were prospectively integrated into all trial protocols. A harmonized informed consent template was developed to secure broad participant consent. Data collection followed Clinical Data Acquisition Standards Harmonization (CDASH) guidelines. A structured, risk-based anonymization methodology was applied to the IPD of the AGED trial, involving data minimization and transformation of quasi-identifiers. The anonymized IPD dataset and relevant trial metadata were prepared for deposition in the ECRIN Clinical Research Data Sharing Repository (crDSR), hosted within a secure trusted research environment, in a GDPR-compliant process. All three trials included IPD sharing provisions in their protocols. Full implementation was achieved only in the EU-COVAT-1 AGED trial, which obtained ethics approval for the harmonised consent template and completed anonymisation and repository submission. Operational constraints and national regulatory differences prevented full implementation in the other trials. The EU-COVAT-1 AGED dataset was successfully deposited in the repository, enabling secure long-term preservation and controlled secondary access. The VACCELERATE experience demonstrates that responsible IPD sharing is feasible when integrated early into trial design and supported by harmonised consent, robust anonymisation, and secure repository infrastructure. Persistent regulatory heterogeneity and resource limitations remain key barriers. Early planning and institutional support are essential to making FAIR data sharing routine in multinational clinical research. EudraCT 2021-004526-29; https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-004526-29/DE/; 2021-004889-35; https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2021-004889-35; and 2021-004526-29; https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2021-004526-29 RR2-https://doi.org/10.1016/j.ijid.2024.107161

This study examines the complex and often ambiguous conceptualization of consent in European health research, focusing on the relationship between informed consent to participate in research and consent as a legal basis for personal data processing. Differences between these two forms of consent may lead to inconsistent procedures and requirements, thereby generating legal and practical challenges for researchers, ethics committees, data protection authorities, and other oversight bodies. Drawing on two use cases involving observational retrospective studies, the paper compares consent requirements and oversight practices in Belgium, the Czech Republic, Finland, France, Germany, Italy, Poland, and Spain, highlighting persistent fragmentation and uneven institutional coordination across national research governance systems. The paper also distinguishes between 'monist' conceptions of consent, which view research and data protection consent as expressions of a single normative concept, and 'dualist' conceptions, which treat them as distinct forms of authorization grounded in different ethical and legal rationales. The paper concludes by reflecting on the implications of the upcoming European Health Data Space Regulation, arguing that its approach to secondary data use may further accentuate existing tensions and highlighting the need for greater conceptual clarity and institutional coordination in European health research governance.

The eCREAM project seeks to enhance emergency department (ED) care quality and research capacity by developing tools to extract and analyse electronic health record (EHR) data using artificial intelligence-based natural language processing. This involves creating interoperable databases for research and quality-of-care improvements across multiple European countries, which presents significant legal and ethical challenges due to the cross-jurisdictional processing of sensitive health information. A dedicated legal and regulatory task force was established to address these challenges. The methodological approach included the development of an ethical, legal, and social implications (ELSI) document, a legal and operational survey to map data flows and identify regulatory requirements, the creation of template documents for regulatory submissions, and multidisciplinary consultations with national experts. The main challenge was the legal classification of studies that did not fit the conventional clinical study categories. The data reuse was confirmed to rely on consent, but obtaining fresh consent was impracticable and incompatible with the study design. Varying national interpretations of the GDPR necessitated case-by-case analyses. Regulatory pathways primarily involved submissions to local ethics committees, which subsequently approved the approach under strict safeguards. This experience demonstrates that multinational ED research using EHR data can be conducted in a legally and ethically compliant manner through a proactive, tailored strategy to navigate the legal and regulatory landscape. Early engagement of a multidisciplinary legal and regulatory task force is critical. The framework developed provides a replicable model for future large-scale emergency care research initiatives within the EU while respecting patient privacy and regulatory requirements.

In May 2022, the European Commission issued the Proposal for a Regulation on the European Health Data Space (EHDS), with the aims of granting citizens increased access to and control of their (electronic) health data across the EU, and facilitating health data re-use for research, innovation, and policymaking. As the first in a series of European domain-specific "data spaces", the EHDS is a high-stakes development that will transform health data governance in the EU region. As an international consortium of experts from health policy, law, ethics and the social sciences, we are concerned that the EHDS Proposal will detract from, rather than lead to the achievement of, its stated aims. We are in no doubt on the benefits of using health data for secondary purposes, and we appreciate attempts to facilitate such uses across borders in a carefully curated manner. Based on the current draft Regulation, however, the EHDS risks undermining rather than enhancing patient control over data; hindering rather than facilitating the work of health professionals and researchers; and eroding rather than increasing the public value generated through health data sharing. Therefore, significant adjustments are needed if the EHDS is to realize its promised benefits. Besides analyzing the implications for key groups and European societies at large who will be affected by the implementation of the EHDS, this contribution advances targeted policy recommendations to address the identified shortcomings of the EHDS Proposal.

In pediatric clinical research, it is essential to implement ethical and regulatory requirements, training, and facilities to grant the proper management of specimens, considering that blood sampling may be difficult, the number of specimens is usually limited, and all efforts should be made to minimize sample volumes. In the context of the Pediatric Clinical Research Infrastructure Network (PedCRIN) project, an easy-to-use tool has been developed to guide investigators and sponsors in managing specimens and associated data in compliance with the applicable European rules in the context of pediatric clinical trials. Key topics and research questions to properly manage biosamples and related data in the context of pediatric trials were identified by PedCRIN partners; the current European regulatory/ethical and legal resources were searched for and analyzed; the items/measures/procedures to ensure regulatory compliance of a pediatric trial with regards to biosamples were defined. A checklist of the key items to be considered for the management of biological samples in pediatric clinical trials in compliance with the European applicable rules and legislation, was prepared. It is publicly available on the PedCRIN website https://ecrin.org/projects/pedcrin. Five different topics were covered: consent and assent; minimizing harm and maximizing welfare; sampling volume; skills, training and facilities required for sampling; and long-term storage of biological material. This exercise addressed a specific need in the field of pediatric research to implement ad hoc procedures for specimen handling. In fact, specific guidance on the management of biosamples in pediatrics is not available.

The Horizon 2020 project EOSC-Life brings together the 13 Life Science 'ESFRI' research infrastructures to create an open, digital and collaborative space for biological and medical research. Sharing sensitive data is a specific challenge within EOSC-Life. For that reason, a toolbox is being developed, providing information to researchers who wish to share and/or use sensitive data in a cloud environment in general, and the European Open Science Cloud in particular. The sensitivity of the data may arise from its personal nature but can also be caused by intellectual property considerations, biohazard concerns, or the Nagoya protocol. The toolbox will not create new content, instead, it will allow researchers to find existing resources that are relevant for sharing sensitive data across all participating research infrastructures (F in FAIR). The toolbox will provide links to recommendations, procedures, and best practices, as well as to software (tools) to support data sharing and reuse. It will be based upon a tagging (categorisation) system, allowing consistent labelling and categorisation of resources. The current design document provides an outline for the anticipated toolbox, as well as its basic principles regarding content and sustainability.

Background Informed consent forms for clinical research are several and variable at international, national and local levels. According to the literature, they are often unclear and poorly understood by participants. Within the H2020 project CORBEL-Coordinated Research Infrastructures Building Enduring Life-science Services-clinical researchers, researchers in ethical, social, and legal issues, experts in planning and management of clinical studies, clinicians, researchers in citizen involvement and public engagement worked together to provide a minimum set of requirements for informed consent in clinical studies. Methods The template was based on a literature review including systematic reviews and guidelines searched on PubMed, Embase, Cochrane Library, NICE, SIGN, GIN, and Clearinghouse databases, and on comparison of templates gathered through an extensive search on the websites of research institutes, national and international agencies, and international initiatives. We discussed the draft versions step-by-step and then we referred to it as the "matrix" to underline its modular character and indicate that it allows adaptation to the context in which it will be used. The matrix was revised by representatives of two international patient groups. Results The matrix covers the process of ensuring that the appropriate information, context and setting are provided so that the participant can give truly informed consent. It addresses the key topics and proposes wording on how to clarify the meaning of placebo and of non-inferiority studies, the importance of individual participants' data sharing, and the impossibility of knowing in advance how the data might be used in future studies. Finally, it presents general suggestions on wording, format, and length of the information sheet. Conclusions The matrix underlines the importance of improving the process of communication, its proper conditions (space, time, setting), and addresses the participants' lack of knowledge on how clinical research is conducted. It can be easily applied to a specific setting and could be a useful tool to identify the appropriate informed consent format for any study. The matrix is mainly intended to support multicentre interventional randomized clinical studies, but several suggestions also apply to non-interventional research.

The early 21st century has seen a growing trend to perform large-scale clinical trials, in general, and across national borders, in particular.11 Atal, I., Trinquart, L., Porcher, R., Ravaud, P. (2015). Differential globalization of industry- and non-industry-sponsored clinical trials. PLoS One. 10(12), 1-17. https://doi.org/10.1371/journal.pone.0145122. ,22 Viergever, R.F., Li, K. (2015). Trends in global clinical trial registration: An analysis of numbers of registered clinical trials in different parts of the world from 2004 to 2013. BMJ Open. 5(9). https://doi.org/10.1136/bmjopen-2015-008932. Major reasons for this trend include the collective promotion of global health and the need to rapidly and effectively respond to threats to human health worldwide. The latest epidemic of Ebola Virus Disease (EVD) showed us that the systems put in place for the development of international clinical research were not ready to face the challenge of controlling that deadly disease.33 Keusch, G., McAdam, K., Cuff, P., Mancher, M., Busta, E.R. (2017). Integrating Clinical Research into Epidemic Response. Washington, D.C.: National Academies Press. https://doi.org/10.17226/24739. ,44 Keusch, G.T., McAdam, K.P.W.J. (2017). Clinical trials during epidemics. Lancet. 389(10088), 2455-2457. https://doi.org/10.1016/S0140-6736(17)31602-1. In addition to EVD, many diseases without new drugs and/or vaccines are listed in the reports published by the World Health Organization (WHO),55 World Health Organization. (2018). A research and development Blueprint for action to prevent epidemics. Retrieved January 20, 2018, from https://www.who.int/blueprint/en/. the Global Health Security Agenda (GHSA),66 Global Health Security Agenda. (2014). Action Packages. Retrieved April 26, 2019 from https://www.ghsagenda.org/packages. and the World Bank-sponsored International Vaccine Task Force.77 Academy of Medical Sciences. (2018). Money and Microbes : Strengthening Clinical Research Capacity to Prevent Epidemics (English). Washington, D.C.: Publisher. https://doi.org/10.1126/science.301.5637.1182b. The Clinical Research Initiative for Global Health (CRIGH)88 Clinical Research Initiative for Global Health. (2019). Overview. Retrieved July 24, 2019 from https://crigh.org/ was launched in 2017 corresponding to the Organization for Economic Cooperation and Development (OECD) recommendations99 OECD Global Science Forum. (2011). OECD Global Science Forum Facilitating International Cooperation in Non-Commercial Clinical Trials Facilitating International Cooperation in Non-Commercial Clinical Trials Organisation for Economic Co-Operation and Development. Global Science Forum. for better global governance of international non-commercial clinical research. CRIGH will encourage international cooperation to rapidly and efficiently respond to global health challenges which are mentioned above. One of the major challenges is the need for multiple ethics reviews by institutional review boards (IRB) or research ethics committees (REC).1010 Forjuoh, S.N. (2015). Challenges Associated with Multi-institutional Multi-site Clinical Trial Collaborations: Lessons from a Diabetes Self-Management Interventions Study in Primary Care. Journal of Clinical Trials. 05(03). https://doi.org/10.4172/2167-0870.1000219. International clinical trials are even more complex than single-country studies due to the diversity of legal and ethical frameworks. Researchers and sponsors who conduct an international and multi-site trial face two problems with ethics reviews: the differences between the countries and duplicate reviews within one country. Information on the current ethics review system in the EU1111 Druml, C., Wolzt, M., Pleiner, J., Singer, E.A. (2009). Research ethics committees in Europe: Trials and tribulations. Intensive Care Medicine. 35(9), 1636-1640. https://doi.org/10.1007/s00134-009-1544-y ,1212 Veerus, P., Lexchin, J., Hemminki, E. (2014). Legislative regulation and ethical governance of medical research in different European Union countries. Journal of Medical Ethics. 40(6), 409-413. https://doi.org/10.1136/medethics-2012-101282. and USA1313 Grady, C. (2015). Institutional review boards purpose and challenges. Chest. 148(5), 1148-1155. https://doi.org/10.1378/chest.15-0706. are widely available, however, there is limited information on ethics review systems for countries in other areas. Therefore, the CRIGH Research Bioethics project, co-chaired by Council on Health Research for Development (COHRED), National Cancer Center Japan, and National Institutes of Health, conducted a cross-sectional survey to understand the differences of ethics review systems and how these could present obstacles for promoting international collaborative trials by non-profit, academic organizations, and to formulate recommendations to overcome these obstacles to facilitate ethical international collaborative health research and clinical trials. We developed the survey items referring to four international standards: the EU Clinical Trial Directive (Directive 2001/20/EC),1414 European Commission. (2019). Directive 2001/20/EC. Retrieved April 26, 2019 from https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2001_20/dir_2001_20_en.pdf the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) –Guideline for Good Clinical Practice (GCP),1515 ICH Harmonised Tripartite Guideline. (1996). Guideline For Good Clinical Practice. Retrieved April 26, 2019 from https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf. Standards and operational guidance for ethics review of health-related research with human participants published by WHO,1616 World Health Organization. (2011). Standards and Operational Guidance for Ethics Review of Health-Related Research with Human Participants.; 2011. Retrieved April 26, 2019 from https://www.ncbi.nlm.nih.gov/books/NBK310666/pdf/Bookshelf_NBK310666.pdf. and 45 CFR part 46.1717 45 CFR 46. Retrieved April 26, 2019 from https://www.govinfo.gov/content/pkg/CFR-2016-title45-vol1/pdf/CFR-2016-title45-vol1-part46.pdf. In addition, the information from COHRED’s routine assessment of RECs using RHInnO Ethics1818 RHInnO Ethics. Retrieved April 26, 2019 from www.rhinno.net. was used for the development of the questionnaire. The questionnaire contained 17 items regarding national ethics review system. We recruited experts of ethics review system in each country by snowball sampling in Latin America, Oceania, and South East Asia. In African countries, COHRED used its network of research ethics committees to recruit national experts. The experts included chairs of IRBs/RECs, committee members, and a clinical researcher. The survey questionnaire was sent via e-mail or Google Forms to the experts in 41 countries. Data collection periods were from November 2017 to June 2018. We had 31 responses (response rate = 75.7%): 17 in Africa, 9 in Asia, 4 in Latin America, and one from Australia. The legal basis of IRB/REC and the composition of committee members were similarly regulated; 81% (n=25/31) had a national requirement to establish IRB/RECs. Regarding the composition of committee members, 90% (n=28/31) required more than five members including at least one non-scientific member in a committee, and 97% (n=30/31) required Conflict Of Interest management of committee members. There was substantial variation in the number of IRB/RECs (Figure 1), in the use of a single opinion approach, national IRB/REC accreditation, availability of a review timeframe, transparency of IRB/REC’s decisions, and training for committee members (Table 1). Figure 1 shows the number of IRB/RECs in the countries whose experts responded to our survey. The number varied from one to 1700. Our survey showed the differences in characteristics of ethics review systems, some being potential hurdles for conducting international and multi-site trials: multiple ethics approvals for multi-site trials within a country, lack of trained committee members to properly review the study, or different timeframes for the review. We can make four recommendations for accelerating and improving ethics review of international, multi-site trials based on our survey results. First, countries should strive to adopt “single opinion” for multi-site clinical trials. A “single opinion” approach to multi-site trial review within a country will reduce duplicate reviews and delays caused by the need to re-review. Duplicate reviews within a country are a huge hurdle to promote an international and multi-site trial. The EU has already mandated “single opinion” for multisite clinical trials carried out in more than one member state since 2001 based on its Clinical Trials Directive.1818 European Commission, op. cit. note 14. The USA has also planned to mandate single IRB review for multi-site trial within the U.S. National Institutes of Health (NIH) system.1919 Gordon, V., Culp, M., Wolinetz, C. (2017). Final NIH Policy on the Use of a Single Institutional Review Board for Multisite Research. Clinical and Translational Science. 10(3), 130-132. https://doi.org/10.1111/cts.12447. However, only 13 countries mandate a “single opinion” for a multi-site trial within their national borders. One challenge is that a single IRB cannot review the local context of each institution included as a research site. Another challenge could be “IRB shopping,” because researchers can choose IRBs for the review, and they can submit protocols to multiple IRBs until one is found that will approve the protocol. Despite these challenges, “single opinion” would be still beneficial for promoting international and multi-site trials. Countries should at least provide an option for researchers to choose a “single opinion” approach for a multi-site trial within one country. Second, national requirements should include training and continuing education in research ethics for IRB/RECs members. The training of IRB/REC members could improve the protocol review, ensuring response in an adequate time and standardizing its quality. However, not all surveyed countries required training for IRB/REC members. A potential reason may be insufficient availability of educational tools and in multiple languages. Even if a country requires training for IRB/REC members, they cannot have effective education without resources. E-learning approaches could be effective in countries with a large number of IRB/RECs and adequate internet infrastructure, and on-site education could be implemented in countries with a small number of committees or low internet access. We need further discussion on the development of universal training tools in several languages and their availability through online platforms. Among its future activities, our group aims to assess the landscape of available tools. In addition to learning core competencies, IRB/REC members need to be up-to-date with changes in local regulation and their impact on ethics review (e.g. the General Data Protection Regulation in the EU). Moreover, we should consider streamlining the number of committees within a country to effectively and swiftly implement standardized education since countries with hundreds of IRB/REC represent a challenge to successful training. Third, national requirements should include an adequate timeframe for the ethics review process. It is essential to establish a reasonable timeframe for the trial review, because ethics review in a country which has no timeframe requirement would cause a bottleneck for promoting an international multi-site trial. Although the timeframe may depend on the type of review,2020 World Health Organization. (2018). Ethics Review Committee: review process. Retrieved December 25, 2018 from https://www.who.int/ethics/review-committee/review_process/en/ the IRB/REC human resources and their experience, and the internal processes within each country, setting a 60-day maximum provides an estimate for investigators, who could than plan and prepare accordingly before the international trial starts. We need to set minimal timeframe of ethics review to harmonize the starting point of international trials. Fourth, technological innovations such as web-based ethics review management and expert decision support platforms including RHInnO Ethics2121 RHInnO Ethics, op. cit. note 18. also can provide solutions for the issues above, especially in the countries with under-resourced IRBs/RECs and research systems. Many countries in Africa have implemented the RHInnO Ethics platform with support from the European and Developing Countries Clinical Trial Partnership (EDCTP), research funders, and international non-profits. By providing real-time access to a virtual REC Administrator qualified to manage complex clinical research at the level required by, for example, the US Department of Health and Human Services, the RHInnO Ethics platform can provide the ability to conduct high level efficient review in time to virtually any REC Administrator2222 Kasule, M., Wassenaar, D.R., IJsselmuiden, C., Mokgatla, B. (2016). Silent Voices: Current and Future Roles of African Research Ethics Committee Administrators. IRB Ethics and Human Research. 38(1), 13-19. in Africa that has access to internet, and speed up clinical research substantially.2323 Mokgatla, B., Bahati, P., IJsselmuiden, C.I. (2017). Enhancing the Efficiency and Quality of African Research Ethics Review Processes – Through an Automated Review Platform. Journal of AIDS Clinical Research. 8(2), 2. https://doi.org/10.4172/2155-6113.1000658. While we realize that working globally entails working with and respecting national autonomy, especially in the ethics of research, we also want to emphasize that it is time to harmonize ethics review processes for international multi-site trials as an effective and low-cost manner to achieve global health. We appreciate the contribution of experts in each country who responded to our survey. We would like to thank Dr. Joe Millum at National Institute of Health, Dr. Sergio Litewka at the University of Miami, and Mr. Douglas Puricelli Perin at National Cancer Institute-Center for Global Health for their useful comments on survey items and the manuscript. This project is funded by CRIGH project.2424 Clinical Research Initiative for Global Health, op. cit. note 8.

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.