The creation of an adaptable informed consent form for research purposes to overcome national and institutional bottlenecks in ethics review: experience from rare disease registries.

Background: The lack of harmonization of evaluation criteria by Ethics Committees in the European Union (EU) has led to inconsistent ethics reviews received by research sites participating in multicenter non-interventional studies. The European General Data Protection Regulation (GDPR) appears to be implemented at national level with a substantial degree of variance in interpretation. The European Reference Networks (ERNs) were struggling in setting an Informed Consent Form (ICF) for registries, allowing reuse of data for research purposes. The aim of this work is to develop an adaptable ICF for research purposes to be used in ERN registries. Methods: To work on this challenge, a team was established within the European Joint Programme on Rare Diseases (EJP RD) to develop a patients' registry ICF template allowing easy adaptation to ERNs, country, and site-level specificities. ERN and patients' representatives validated the choice of developing a GDPR-compliant template for research purposes. The feedback received from 34 Ethics Committees on the Clinical Patient Management System ICF, including the submission of patients' data to the ERN registries and the EU consent regulatory framework were analyzed along with existing ontologies for data access and reuse. An adaptable ICF was developed following iterative cycles of consultation and review by clinicians, research experts, ethics and regulatory advisors, and patients' representatives. The development of pediatric material for minor participants was also undertaken. Results and Conclusion: Research oriented ICF templates for adults and for parents/legal representatives of patients were released in 26 national languages. This adaptable ICF aims to foster, according to patients' preferences, the reuse of registries data for research purposes in compliance with the applicable laws and standards. Pediatric material is being finalized to collect minors' assent. ICF machine-readability is also progressing to enhance data discovery and facilitate its access and reuse conditions.

Introducing Key Elements Regarding Access to Personal Data for Scientific Research in the Perspective of Developing Innovative Medicines.

This article aims at opening discussions and promoting future research about key elements that should be taken into account when considering new ways to organise access to personal data for scientific research in the perspective of developing innovative medicines. It provides an overview of these key elements: the different ways of accessing data, the theory of the essential facilities, the Regulation on the Free Flow of Non-personal Data, the Directive on Open Data and the re-use of public sector information, and the General Data Protection Regulation (GDPR) rules on accessing personal data for scientific research. In the perspective of fostering research, promoting innovative medicines, and having all the raw data centralised in big databases localised in Europe, we suggest to further investigate the possibility to find acceptable and balanced solutions with complete respect of fundamental rights, as well as for private life and data protection.

Ethical, Legal and Regulatory Issues of Paediatric Translational Research. Call for an Adequate Model of Governance.

The lack of paediatric medicines, including innovative and advanced ones, is a long-lasting and well-known problem at European and international levels. Despite the existing legal frameworks and incentives, children remain deprived of many kinds of therapy because of challenges faced in appropriately study and tailoring medicinal and other products for them. In this context, the necessity to foster paediatric research addressing unsolved and uncovered issues within a 'translational approach' has appeared. This article, after having clarified the concept of translational research in the perspective of the establishment of a European paediatric research infrastructure (RI), will identify and point out ethical, legal and regulatory issues particularly relevant in a children's rights perspective. It concludes asking for the setting up of an adequate model of governance within a future RI, including adequate and independent ethical oversight and a pluridisciplinary common service dealing with ethical, legal and societal issues relevant for children.

Clinical Trial Application in Europe: What Will Change with the New Regulation?

The European framework surrounding clinical trials on medicinal products for human use is going to change as demonstrated by the large debate at European institutional level. One of the major challenges is to overcome the lack of harmonisation of clinical trial procedures among countries. This aspect is gaining more and more importance, considering the increasing number of multicentre and multinational studies. In this work, the actual European rules governing the Clinical Trial Application have been analysed throughout the different steps including the registration of the trial in the European database; the preparation of documents to be submitted and their contents; the preparation of documents related to the information and consent process; the submission to competent bodies. Specific issues related to paediatric research and trials involving non EU/EEA countries have been addressed as well. Results reveal that the European legislation offers a well defined set of European rules covering different aspects of a Clinical Trial Application. However, these are not suitable to meet the challenges from multicentre and multinational clinical studies. A stronger set of rules, such as is available in a composite European Regulation has been adopted and is expected to harmonise practices and enable sponsors to carry out well conducted trials. But will the new regulation overcome the existing criticisms of Directive 2001/20/EC?

Ethical standards for clinical trials conducted in third countries: the new strategy of the European Medicines Agency.

Clinical trials increasingly occur on a global scale as industry and government sponsors in wealthy countries move trials to low- and middle-income countries. The globalization of clinical research raises important questions about the economical and ethical aspects of clinical research and the translation of trial results to clinical practice: which ethical standards are applied? Are trials results accurate and valid, and can they be extrapolated to other settings? This article provides an overview of the strategy approved by the European Medicines Agency (EMA) to clarify ethical standards for clinical research conducted outside the European Economic Area (EEA) and included in Marketing Authorization Applications. Reference to the EMA Reflection paper is made.

Ethical key issues and fundamental rights in paediatric research.

PURPOSE: This article is aimed at describing the methodology of "ethical reasoning" that finally led TEDDYNoE (Task-force in Europe for Drug Development for the Young) to propose the integration of international human rights law to develop coherent and exhaustive ethical recommendations on paediatric research at a European level. METHODS: A large number of ethical guidelines and texts of varying legal force existing in the field of clinical research and in particular related to paediatrics are analysed. Differences and non-coordinated implementation are pointed out. RESULTS: Differences, tensions or outright contradictions among the provisions of these texts can generate confusion leading to the adoption of different ethical standards across Europe. In this context, the real challenge is to ensure that each child involved in a clinical trial in the EU territory may rely directly on the same principles and rights. Taking international human rights law as the main starting point to develop a coherent framework for paediatric research that incorporates all the relevant ethical considerations and existing guidelines is a way of achieving this objective. CONCLUSIONS: The implementation, at national and local level, of the "European Ethical Recommendations" (Eudralex 2008 vol. 10), based on international human rights law, seems to be the next step in facilitating a coordinated approach to the application of the Directive 2001/20/EC, as well as developing quality and ethically sound paediatric research.

Clinical research with children: the European legal framework and its implementation in French and Italian law.

According to the International Convention of the Rights of the Child, an improvement of the protection of the rights of children in Europe should be accomplished by inserting the principle of best interests and evolving capacities in the legal framework related to paediatric clinical research. In this article, an overview is given of the European legal framework governing clinical research on minors in a comparative approach. The lack of coordination between different International and European ethical/ legal statements and its impact on national legislations is evaluated by analyzing provisions that have been foreseen in Italy and in France as a result of the ratification/implementation process. A presentation of the perspectives of paediatric research in Europe is provided.

European survey on ethical and legal framework of clinical trials in paediatrics: results and perspectives.

This article constitutes a synthesis and analysis of the results of the "Survey on the ethical and legal frameworks existing in Europe for paediatric clinical trials" carried out by the European network TEDDY. TEDDY is a "Network of Excellence" funded by the Sixth EU Framework Programme (FP6). It began its activities in June 2005 and it is scheduled to run until 2010. It involves 19 partners in 11 countries. The overall goal of TEDDY is to promote the availability of safe and effective medicines to children in Europe by integrating existing expertise and the good practices. In the domain of ethics, the main aim of TEDDY is raise the awareness of the public and researchers concerning issues linked to biomedical research in paediatrics, by contributing to developing the debate on the ethical and legal stakes, as well as the potential deviations, in order to ensure the best possible protection of children participating in clinical trials. This study, with twenty-seven participating countries (23 EU Member States and 4 countries associated to the Fifth and Sixth EU Framework Programme), proposes to highlight the existing differences in the legislation of European countries concerning the procedure of consent, as well as the guarantee of the paediatric expertise within the Ethics Committees which are in charge of evaluating research protocols. The study shows that, even though the Directive 2001/20/EC has been transposed, the value attributed to the consent of minors who participate in clinical trials is different depending on the European state. Despite the general rule of having the written consent of the legal representative of the minor, over a certain age (different in relation to each state) and under certain conditions, to give the consent alone to participate in biomedical research. Furthermore, there is an Ethics Committee for minors in only four countries. In addition, we illustrate the lack of information and in-depth debate in Europe concerning the ethical stakes of clinical trials in paediatrics. An overview of possible legal deviations is also presented.