Présentation de l'éditeur : "Qui sont les personnes vulnérables, à quoi sont-elles vulnérables en matière d’essais cliniques et comment sont-elles protégées par le droit européen ? Au détriment d’une véritable définition, la vulnérabilité en droit est principalement appréhendée par la désignation de catégories vulnérables dont les caractéristiques communes soulèvent des interrogations. Pourquoi les personnes âgées ne font-elles pas partie des catégories vulnérables ? Pourquoi assimiler les femmes enceintes à des personnes inaptes à défendre leurs intérêts ? En quoi les patients atteints de maladie orpheline pourraient-ils être assimilés à une catégorie vulnérable en matière d’essais cliniques ? Comment qualifier les participants recrutés dans les pays en développement ? Les expérimentations abusives de l’histoire ont provoqué une réaction inverse consistant à exclure catégoriquement les personnes vulnérables des essais cliniques, dans un but initialement bienveillant. Cette bienveillance ne permet cependant plus de justifier l’impact néfaste de cette exclusion sur la qualité des soins de santé pour les personnes vulnérables. Afin de clarifier ces contradictions, permises par le caractère nécessairement relatif du concept de vulnérabilité, cette thèse propose de distinguer différents types de risques (pour l’autonomie d’une part, pour la santé d’autre part) et différentes perspectives (individuelle et collective), conduisant à la mise en valeur de deux prismes d’analyse : la vulnérabilité décisionnelle du participant vulnérable et la vulnérabilité de santé du patient vulnérable"

The European Union promotes the opening of public policy elaboration processes to civil participation. The EU Health Policy Platform constitutes a particularly original illustration thereof as it offers a privileged and permanent space for dialogue between citizens' representatives and the European Commission. This article testifies to the recent creation of a thematic network in the field of the European pharmaceutical legislation right during its revision.

Abstract Although several European law instruments specifically promote the development of orphan medicines, rare disease patients still suffer from an excessive lack of access to orphan drugs. In order to base a claim for equity of access to research benefits, health vulnerability is introduced as a human rights-based public health concept. It represents a potentially valuable and powerful means in European law for rare disease patients to claim for an improved public action to develop innovative orphan drugs, including through the use of novel data-driven technologies such as computer modelling and simulation, as they have the potential to palliate some of the obstacles in the current development process of orphan medicines. The human rights-based approach would be all the more valuable, as it would simultaneously draw attention on privacy aspects of vulnerability for orphan disease patients, especially regarding increased risks stemming from the processing of highly sensitive health data.

Au détriment d’une véritable définition, la vulnérabilité est majoritairement appréhendée par la désignation de catégories vulnérables dont les caractéristiques soulèvent interrogations et contradictions. Le traumatisme des expérimentations abusives de l’histoire a conduit à une exclusion quasi systématique des groupes vulnérables des essais, dans un but bienveillant mais avec comme conséquence une exclusion des bénéfices des progrès de la recherche en santé. Afin de clarifier ces contradictions, permises par le caractère nécessairement relatif du concept de vulnérabilité, cette thèse propose de distinguer différents types de risques (pour l’autonomie d’une part, pour la santé d’autre part) et différentes perspectives (individuelle et collective), conduisant à la mise en valeur de deux prismes d’analyse : la vulnérabilité décisionnelle du participant vulnérable et la vulnérabilité de santé du patient vulnérable.

Principales consommatrices de médicaments, les personnes âgées sont estimées représenter 30 % de la population européenne d’ici 2050. Paradoxalement, il existe un cruel manque d’information sur la prescription des médicaments à la population gériatrique compromettant la qualité des traitements et laissant aux médecins l’immense responsabilité de prescriptions improvisées potentiellement dangereuses ou au contraire potentiellement inefficaces. En effet, la population gériatrique est de facto soit exclue des essais cliniques, soit représentée par des personnes âgées en relativement bonne santé et peu représentatives des patients de la vie réelle. Malgré les démonstrations répétées dans la doctrine médicale du besoin d’inclusion de personnes âgées fragiles dans les essais cliniques, le droit européen n’offre que des réponses décevantes à ce besoin. Le déclin fréquent des facultés cognitives des personnes âgées rend la tâche doublement difficile (fragilité cognitive, début de démence comme l’Alzheimer ou maladies psychiatriques). Beaucoup de personnes âgées présentent une capacité de décision réduite sans encore bénéficier de protection juridique. Étonnamment, les lignes directrices éthiques ainsi que le droit européen sont peu sensibles aux stades qui précèdent l’incapacité juridique et ne font pas suite aux procédés intermédiaires proposés dans la doctrine éthique et médicale. Bien que ces questions relèvent des compétences nationales, la problématique est commune à l’Europe et les solutions devront nécessairement dépasser les frontières étatiques. L’implication du législateur européen est indispensable pour, si ce n’est imposer des règles communes, au moins donner une impulsion dans le sens d’une meilleure inclusion des personnes âgées fragiles dans les recherches biomédicales, et d’une meilleure promotion de leur autonomie.

On behalf of the Interest Group on Supranational Biolaw of the European Association of Health Law (EAHL IG Biolaw) and the I-BioLex research project (ANR-20-CE26-0007-01), Éloïse Gennet and Aurélie Mahalatchimy have been coordinating, since September 2021, the thematic network on the pharmaceutical strategy on the European Health Policy Platform (EUHPP) of the European Commission. The thematic network of the EAHL IG Biolaw, selected by the European Commission and by the users of the EUHPP platform, is entitled “Health as a fundamental value. Towards an inclusive and equitable pharmaceutical strategy for the European Union”. This network enables to link the EAHL IG Biolaw, exclusively constituted by researchers and academics in the field of health law in Europe, on the one hand with the European Commission and in particular DG Health, and on the other hand with socio-economic actors interested in EU law applicable to medicinal products and medical devices (patient representatives, representatives of health professionals or non-governmental organizations in the field of health). After several months of fruitful exchanges, the final joint statement which was very favorably received by DG Health and endorsed by several organizations (including the President of Aix-Marseille University and the CNRS) has been presented at the EU Health Policy Platform Annual Meeting 2022 at the European Commission and published on the EUHPP in May 2022.

Le projet ANR JCJC AAPG 2020 I-BioLex ‘Fragmentation et défragmentation du droit des innovations biomédicales’ est porté par Aurélie Mahalatchimy, chargé de recherche en droit au CNRS, au sein de l’UMR 7318 DICE CERIC, CNRS-Aix-Marseille Université-Université de Pau et des Pays de l’Adour-Université de Toulon et du Var. Ce projet de 4 ans (2021-2024) vise à étudier les processus de fragmentation et de défragmentation du droit européen applicable aux innovations biomédicales (principalement thérapie génique, médecine régénératrice et nanomédecine). Ce rapport a pour objectifs de montrer comment, tout au long du projet I-BioLex et après, les données issues de ce projet sont gérées : - Selon des bonnes pratiques concernant notamment la collecte, le stockage, la documentation, etc… - Dans le respect des exigences éthiques et juridiques relatives à la protection et la diffusion des données, aux conditions de partage et aux modalités de réutilisation, etc… - Dans le respect des principes FAIR (Facile à trouver, Accessible, Interopérable, Réutilisable) - Selon une approche visant à faciliter les échanges entre les collaborateurs du projet - Selon une approche d’anticipation des besoins afin de gagner du temps pour les publications et la valorisation des résultats.

Remaining liberties that GDPR provides to EU Member States as well as remaining ambiguities on GDPR interpretation keep feeding the debates in the ethical and legal literature. Projects like CINECA, seeking to facilitate health data exchanges between cohorts in Europe, Canada and Africa, offer valuable experience and input on essential ethical and legal gaps between countries and cohorts on questions such as the choice of the ethical lawful basis for international health data sharing and secondary processing for research purposes.

Remaining liberties that GDPR provides to EU Member States, as well as remaining ambiguities on GDPR interpretation, continue to feed debates in the ethical and legal literature. Projects like CINECA, which is seeking to facilitate health data exchanges between cohorts in Europe, Canada and Africa, offer valuable experience and input on essential ethical and legal gaps between countries and cohorts on questions such as the ethical lawful basis for international health data sharing and secondary processing for research purposes. The focus of this deliverable will be on answering, both from a legal and an ethical point of view, two priority questions: How to choose a legal basis for CINECA’s data processing? And how should CINECA apprehend broad consent to further data processing? The goal will be to study how the CINECA project could be efficiently conducted (especially data sharing) while being legally compliant with relevant laws and regulations across all member states, and most of all, being compliant with established ethical guidelines and practices across three continents. To answer these questions we have conducted research which has consisted in reviewing GDPR provisions and their institutional sources of interpretation; the corresponding legal and ethical literature; the National laws relevant for the cohorts involved in CINECA as well as cohorts’ internal governance frameworks and privacy policies when available. We present the arguments surrounding the use of GDPR legal exemptions for data processing for scientific research purposes, why researchers are wary to use it for ethical reasons related to the absence of consent, and the practicalities of the use of broad consent for secondary data processing. We recommend using the research exemption as a lawful basis for secondary data processing; Add broad consent as an appropriate safeguard for data subjects’ rights; Restrict the use of the research exemption to research conducted in the “public interest” as defined by National laws.

The goal of CINECA is to enable the exchange of population scale health data across international borders to allow and promote the reuse of data for health research. The rationale for sharing and reusing data in public health research is deeply rooted in the promotion of a fair distribution of research risks and benefits, and it has become an essential and powerful tool for public health research. In pursuit of this goal, this deliverable aims to give an overview of all the different ethical, legal and societal issues that the CINECA project might be confronted with: public health ethics, personal data protection, ethics of data sharing, protection of consent and vulnerability as well as compliance issues between Canada, Africa and Europe. It has been elaborated in a bottom up approach, starting from the practical legal and ethical issues encountered notably through Work Package 9 (EC Ethics Requirements). As a basis for the lawful and ethical guarantees for data sharing and reuse within CINECA, all cohorts and consortiums have provided for the copies of their own ethics approvals (Deliverable 9.4), and they are all independently responsible for ensuring researchers accessing data have their own research ethics approval. This deliverable will serve as a starting point for the future deliverable 7.2 which will be aimed at identifying and discussing the gaps in the different legislative or regulatory frameworks and corresponding literature. As a consequence, this deliverable is divided into two main parts, the first one focusing on the collective perspectives of international data sharing in public health research, the second one examining the opposite perspective of the protection of individual data subjects when their personal data is used for secondary processing.

The question of comparability for Advanced Therapy Medicinal Products (ATMPs) is very often asked during Scientific Advice Meetings at the European Medicines Agency. Indeed, changes to ATMPs manufacturing processes, improvements/changes in equipment, raw materials and critical starting materials, or process scale are frequent in the early stages of development or even after marketing authorization. Quality comparability is the first step in the review of variations procedures of a medicinal product. Indeed, quality information is of major importance with analytical testing, risk-based approach and manufacturing evaluation as it will allow to conclude if non clinical and clinical data on comparability are also needed or not. The text of December 2019 of the Committee for Advanced Therapies (CAT), entitled “Questions and answers, Comparability considerations for Advanced Therapy Medicinal Products” contains the major questions companies can have when a comparison is needed between the pre- and post-change of the manufacturing process of ATMPs. The answers are based on analytical and statistical tools which are needed in frequent experimental changes situations. Generally, this text addresses the issues linked to the demonstration of comparability regarding the quality aspects of ATMPs. Another important text is the ICH Q5E guideline that addresses comparability of biological/biotechnological medicinal products which legally cover ATMPs. However, ATMPs are outside the scope of this guideline, except for the general principles that can be applied to ATMPs. Through of comparative textual analysis of these two texts, this poster will show the complementarity of the information provided, but also the very dynamic impact of the Q&A text targeted on ATMPs in comparison with the large recommendations of the ICH guideline on biotech products.

While Advanced Therapy Medicinal Products (ATMPs), a European legal classification of medicinal products based on genes, cells and tissues, raise specific quality issues, the latter are particularly acute in the context of clinical trials of ATMPs. In comparison to more traditional medicinal products, ATMPs have been subject to specific regulatory provisions in the European Union (EU) since 2007. In addition, many new guidelines have also been adopted to consider the issues raised by ATMPS. Most importantly for investigational ATMPs, the European Commission has adopted and published Guidelines on Good Clinical Practice specific to ATMPs in 2019. Not only are these guidelines targeting ATMPs, they also have a dedicated section on investigational ATMPs exploring the particular challenges raised when tissues and cells of human origin, are administered to a human trial subject, including when ATMPS incorporate medical devices, or delivered with the aim of reconstituting a given bodily tissue or organ. The aim of this poster is to highlight the specificity of quality requirements of investigational ATMPs by examining the dedicated subsections in the guidelines published by the European Commission and analysing them through the lens of the corresponding scientific literature. On the basis of the identification of the specific requirements regarding the quality of investigational ATMPs, the poster will reveal why they raise specific challenges and why these challenges deserve separate regulation in order to demonstrate quality in clinical trials.

Background : Good Manufacturing Practice (GMP) guidelines established by the European Commission are essential to ensure quality, safety and efficacy of medicinal products. Guidelines are designed to address specific risks of medicinal products and as such, are continuously being adapted. Advanced Therapy Medicinal Products (ATMPs) are medicinal products that have been regulated in the European Union from 2007 to cover the emerging field of genes, tissues or cell-based therapies. Dedicated GMP guidelines for ATMPs are enforceable since 2017. Consequently, GMP guidelines covering manufacture of biological active substances and medicinal products for human use including biological active substances (hereafter “Biologicals”) have been revised in June 2018 with the objective to prevent overlapping scope. Research question and methods: Our hypothesis is that the biological nature that commonly characterize ATMPs and biologicals may sustain a large body of similarities in the manufacturing aspects as addressed by the respective guidelines. We aim to comparatively analyze the two following texts : Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products, and Manufacture of Biological active substances and Medicinal Products for human use including biological active substances. Focus has been given on manufacturing, i.e. production recommendations including personnel, premises, equipment, documentation, starting and raw materials, seed lot and cell bank systems. In a systematic approach we highlighted similarities and specificities in the text outlines (paragraph and section titles). Then content has been comparatively investigated based on chosen relevant key words found in both texts (production, operation principles, production area, facilities, cross contamination in production, environmental monitoring and specifications, starting and raw materials).

Quality control and batch release raise specific challenges for ensuring quality and complying with regulatory requirements in order to obtain manufacturing and marketing authorizations for Advanced Therapy Medicinal Products (ATMPs). ATMPs are medicinal products based on genes, cells and tissues that have been specifically regulated in the European Union (EU) from 2007. In the guidelines on Good Manufacturing Practices (GMP) specific to ATMPs from the European Commission, specific requirements cover quality control and batch release. They are distinct from the ones than can be found in other guidelines on GMP applicable to other kinds of biological medicinal products. Through a comparative textual analysis of the GMP guidelines for biological medicinal products and ATMPs, this poster will highlight the key areas of similarities and differences. Our analysis mainly focuses on qualification and validation procedures, batch release process, quality defects and product recalls, and automated production of ATMPs. This analysis reveals why we have two different texts and whether they are based on substantial differences regarding quality control and batch release between ATMPs and other types of biological medicinal products.

The European Medicines Agency has recently revised its guidelines on quality, non-clinical and clinical aspects of Gene Therapy Medicinal Products (GTMPs text) and of medicinal products containing genetically modified cells (GMCMPs text), respectively in 2018 for the former and in 2020 for the latter. The latest revision has been particularly justified by the new developments in genome editing techniques, especially the wide use of the CRISPR-Cas technique, and with T-cells. Gene therapy medicinal product (GTMP) is a legal sub-category of medicines among Advanced Therapy Medicinal Products (ATMPs). However, medicinal product containing genetically modified cells (GMCMP) is not explicitly mentioned as a legal subcategory under EU regulation n°1394/2007 on ATMPs. Nevertheless, both GTMPs and GMCMPs should be considered as ATMPs under European Union Law. On the one hand, quality issues have been raised for all ATMPs regarding the reproducibility of the manufacturing process given the variable character of the starting materials. On the other hand, there is an overlap in the scope of the aforementioned guidelines when medicinal products containing genetically modified cells are to be considered gene therapy medicinal products. What are the similarities and differences between the quality of gene therapy medicinal products and the quality of medicinal products containing genetically modified cells while both are ATMPs? This poster is based on a comparative analysis of the quality sections of the two above-mentioned texts. In a first systematic approach, we identified the similarities and the specificities of texts outline (sub-section titles). Then, we analysed contents through the establishment of 3 types of comparative tables using color codes: common titles, different titles with similar contents, different titles with different contents in order to highlight similarities and specificities regarding the quality requirements between these two kinds of medicinal products when they are intended for use in humans and presented for marketing authorization applications.

In the European Union, gene and cell therapy medicinal products are mainly regulated by the specific legal framework applicable to Advanced Therapy Medicinal Products (ATMPs): regulation (EC) n°1394/2007. Yet most ATMPs that have been authorised for marketing in the European Union are also classified as orphan medicinal products. The latter are regulated by a different but also specific legal instrument : Regulation (EC) n°141/2000, which aims to promote the development of innovative medicines for orphan diseases thanks to a set of incentives for investigators. However, after twenty years of implementation, results are still unsatisfactory for several reasons. One of these reasons is that the market of orphan medicinal products had “started to look more similar to ‘standard’ medicines” than innovative medicines like ATMPs. Moreover, it has also been observed that even when marketed, orphan medicinal products fail in being equally accessible to patients in the different Member States. The European Commission has started a long and thorough revision process of the pharmaceutical legislation in order to give a new impulse to the development of, and access to, truly innovative orphan medicinal products, which may have a positive impact for patients as well as for investigators working on gene and cell therapies. In this poster, we will discuss what aspects of the revision of the regulation on orphan medicinal products may have an impact on the development of gene and cell therapy in the European Union.

Advanced Therapy Medicinal Products (ATMPs), a European legal classification of medicinal products based on genes, cells and tissues, raise specific issues in the context of clinical trials. In comparison to more traditional medicinal products, ATMPs have been subject to specific regulatory provisions in the European Union (EU) since Regulation (EC) n°1394/2007. Yet for the clinical trials with ATMPs, the general regime laid out in Regulation 536/2014 on clinical trials (which came into effect on 31 January 2022) applies, together with the ICH E6 Guidelines on Good Clinical Practice (GCP). For clinical trials conducted in the EU, compliance with GCP is mandatory. The European Commission has also adopted and published 2019 Guidelines on GCP specific to ATMPs, as required by Article 4 of Regulation (EC) n°1394/2007 on ATMPs. These guidelines both adapt the ICH guidelines to ATMPs’ characteristics and provide additional measures that have been considered necessary. However, they are not exhaustive as they explain only some specificities of ATMPs and they remain complementary to the general rules. After having analysed these documents, we will highlight the specificity of requirements for investigational ATMPs in order to reveal the specific challenges they are addressing and why these challenges warrant separate regulation in order to obtain clinical trials’ authorisation for investigational ATMPs.

Advanced Therapy Medicinal Products (ATMPs) is a European classification of medicinal products based on genes, cells and tissues that have been specifically regulated in the European Union (EU) from 2007. Their manufacturing (i.e. their production) raises specific challenges for ensuring quality and complying with regulatory requirements in order to obtain manufacturing and marketing authorizations. For this reason, detailed guidelines on Good Manufacturing Practices specific to ATMPs have been adopted by the European Commission, and have been enforceable since 2017. They are distinct from other guidelines on GMP applicable to other kinds of biological medicinal products. Separate GMP guidelines, covering manufacture of biological active substances and medicinal products for human use including biological active substances were revised in June 2018 with the objective of preventing overlaps in scope with the ATMP GMP guidelines. Our hypothesis is that the biological nature that commonly characterizes ATMPs and biologicals may give rise to significant similarities in the manufacturing aspects as addressed by the respective guidelines. Through a comparative textual analysis of the GMP guidelines for biological medicinal products and ATMPs, this poster will highlight the key areas of similarities and differences. This analysis reveals why we have two different texts and whether they are based on substantial differences regarding production between ATMPs and other types of biological medicinal products.

Universités internationales d'été du Mercantour organisées par le CERIC, UMR DICE, Université d'Aix-Marseille sous la direction d'Estelle Brosset, Professeure à l'Université d'Aix-Marseille

Colloque annuel 2024 Chaire EUBioethics organisé par l'IRENEE, Université de Lorraine avec l’UPEC, le laboratoire MIL et la Chaire Jean Monnet IJSEE sous la direction scientifique de Maria Fartunova-Michel, MCF HDR, Université de Lorraine/IRENEE et Béligh Nabli, Professeur de droit public, Université Paris Est-Créteil/MIL

Colloque organisé par le CERIC/ILF-GERJC (UMR DICE), Faculté de droit et de science politique, Aix-Marseille Université sous la direction scientifique de Laura Canali, Valentine Delcroix et Saïdou Diop.

Workshop organisé par le CERIC sous la responsabilité scientifique d'Éloïse Gennet, Chaire de Professeur Junior, Aix-Marseille Université et d'Habib Badjinri Touré, Post-doctorant, Aix-Marseille Université, le CERIC

Organisée par le Centre d'études et de recherches internationales et communautaires (UMR 7318 DICE CERIC) et le Centre de Droit de la Santé (UMR 7268 ADES) sous la direction de Aurélie Mahalatchimy et Sophie Gambardella, chargées de recherche CNRS au CERIC (UMR DICE) et Guylène Nicolas, MCF au Centre de droit de la santé - Faculté de droit et de science politique, Université d'Aix-Marseille

Organisé par le CERIC, à l’initiative de l’Association Internationale Droit Ethique et Science, avec le soutien de la Commission nationale française pour l’UNESCO et du Centre de Droit de la Santé (UMR7268 ADES)

Journée Louis Dubouis organisée dans le cadre de la chaire DESAPS sous la direction scientifique de Nathalie de Grove-Valdeyron, Chaire Jean Monnet et Emmanuelle Rial-Sebbag, Chaire UNESCO, Ethique, Science et Société

7th EAHL Conference under the auspices of the Secretary General of the Council of Europe, Mr Thorbjorn Jagland