Human body elements for human applications

One of the main challenges here is to know whether the human body elements used for therapeutic applications in human are transplants or whether they have been transformed into medicinal products based on blood or blood components or into Advanced Therapy Medicinal Products.

If they are transplants, they will be regulated by the European Directives on tissues and cells or on blood and blood components for their entire development pathway from the donation, procurement, testing, processing, preservation, storage and distribution and by national laws transposing these Directives and sometimes providing specific and more stringent national rules than the European ones. 

If they are medicinal products based on blood or blood components or Advanced Therapy Medicinal Products, the human body elements used for therapeutic applications in human will have to comply successively with two different set of legislations along their development pathway: first, the European Directives on tissues and cells or on blood and blood components for their donation, collection/procurement and testing, second the European pharmaceutical legislation for their following steps of development into medicinal products.

Moreover, some Member States apply the blood directives (blood establishment authorization) while other apply the tissues and cells directives (tissues and cells establishment authorization) for blood cells when used as a starting material for the manufacture of ATMPs. Nevertheless, both donors and patients remain similarly protected as long as the two sets of legislations (tissues and cells, and blood and blood components) provide for equivalent standards of quality and safety. On this topic, see for instance in the UK, the agreement between the Human Tissue Authority (in charge of the implementation of the tissues and cells rules) and the National Medicines Agency (MHRA in charge of the implementation of the blood rules) allowing the collection of blood as a starting material for an ATMP to be performed under either a Tissues and Cells or Blood Establishment Licence.

Finally, an evaluation of the Blood and the Tissues and Cells EU legislations conducted in 2017 has identified several shortcomings although it has confirmed “the very good levels of overall safety and quality in these sectors (less than one serious patient reaction for every 12,000 applications)”. These shortcomings of the current Blood and Tissues and cells EU legislations are: the current rules are no longer up to date with the dynamic blood, tissues and cells sectors; key oversight principles are not sufficiently robust; some citizen groups, such as donors and offspring are not adequately protected; the legislation does not keep pace with innovation; requirements are insufficient to support sufficiency and a sustainable supply for all blood, tissues and cells.

On the legal classification as transplants/transfusions or medicinal products (blood based medicinal products or advanced therapy medicinal products), national competent authorities for tissues and cells, and for blood and blood components have offices and procedures to support and guide gene and cell therapy developers. See also: the entry on Early interactions with regulators (in progress). 

Moreover, a European Commission’s proposal for a new Regulation on substances of human origin (SoHO) published in July 2022 has constituted the starting point of the revision process to address the current shortcomings of EU legislations on blood and tissues and cells.

Of note, the proposal moves the legislation from two main and distinct directives (on human blood and blood components, and on human tissues and cells) to one regulation on substances of human origin. This will allow to reduce the current diverging implementations of the directives as long as the regulation will be directly applicable without requirement of national transpositions. The global approach proposed on substances of human origin will also allow to cover substances of human origin currently unregulated or regulated in divergent ways: breast milk, faecal or intestinal microbiota transplants, bedside preparations of substances of human origin.

More specifically, the proposal for a new regulation on SoHO includes XIV chapters as follows:

• Chapter I “General provisions” defines the subject matter and the scope of application of the Regulation; introduces the description of SoHO activities and describes the possibility for Member States to set more stringent measures; describes certain exclusions (such as solid organs) and partial applicability when SoHOs are used to manufacture products regulated by other Union legislation, or as the starting and raw material thereof (such as medicinal products based on blood and advanced therapy medicinal products)
• Chapter II “Competent Authorities” covers the designation of competent authorities which are responsible for the SoHO supervisory activities (and the possibility to delegate certain of these activities), the general principles for their functioning (independence and impartiality, transparency), their responsibilities and obligations, and their communication together (within the SoHO sector) and with authorities of other regulated sectors (mainly medical devices and medicinal products including advanced therapy medicinal products in particular). 
• Chapter III “SoHO Supervisory Activities” covers all activities competent authorities undertake vis-à-vis SoHO entities or processes, including several obligations such as to maintain a register of SoHO entities, to have a system and a procedure for the authorisations of SoHO preparations and SoHO establishments, to conduct inspections (with possible joint inspections) of SoHO establishments, as well as obligations related to data publication, traceability, vigilance and, SoHO Rapid Alerts.
• Chapter IV “General Obligations on SoHO Entities” notably covers regarding registration, authorization, export, import, activity data collection and reporting, traceability and coding, application of the Single European Code to SoHOs distributed for human application (except for some specific SoHOs), and vigilance notifications.
• Chapter V “General Obligations on SoHO Establishments” (a sub-set of SoHO entities that process and store SoHOs) covers the obligations to have a system and a procedure for their authorisations, a Quality Management system, and to designate a physician responsible for specific tasks.
• Chapter VI “SoHO Donor Protection” includes provisions and standards and how to implement them to ensure donor protection.
• Chapter VII “Recipient and Offspring Protection” includes provisions and standards and how to implement them to ensure the protection of patients treated with SoHO (recipients) and offspring from medically assisted reproduction.
• Chapter VIII “Supply Continuity” notably covers the obligation for Member States to have national SoHO emergency plans and the responsibilities of competent authorities and entities regarding supply alerts for critical SoHOs (obligation to have an emergency plan in place), as well as the conditions for derogation from certain obligations and to provide national additional measures in case of emergencies.
• Chapter IX “SoHO Coordination Board” establishes a new coordination board (with composition and functioning) to support Member States in the implementation of this new legislation.
• Chapter X “Union Activities” covers the activities organized at the European Union level: training and exchange of competent authorities’ personnel, Commission controls in Member States, support provided by the Commission for the implementation of the Regulation, and cooperation with the European Directorate for the Quality of Medicines & Healthcare at the Council of Europe. 
• Chapter XI “EU SoHO Platform” describes the general functionalities of this platform supporting information sharing between authorities and with SoHO entities
• Chapter XII “Procedural Provisions” regarding confidentiality and data protection obligations, the exercise of delegation, the urgency procedure, the committee procedure, establishment by Member States of penalties applicable to infringements.
• Chapter XIII “Transitional Provisions” regarding the current Blood and Tissues and Cells EU legislations, and the adoption of certain delegated and implementing acts.
• Chapter XIV “Final Provisions” relates to the repeal of the current Blood and Tissues and Cells EU legislations, evaluation, dates of entry into force and application of the new Regulation.

The full legislative process of revision of this EU legislation can be followed here and the full history of the revision process is detailed on a dedicated European Commission webpage here. 

Published: 17/07/2023

Author:

Aurélie Mahalatchimy, EuroGCT’s WP4 Convenor, UMR 7318 DICE CERIC, Aix-Marseille University, CNRS, Aix-en-Provence- France

Reviewed by:

Under internal review by EuroGCT Commercialisation Working Group.