EUROPEAN COMMISSION Brussels, 14.7.2022 COM(2022) 338 final 2022/0216(COD) Proposal for a REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL on standards of quality and safety for substances of human origin intended for human application and repealing Directives 2002/98/EC and 2004/23/EC (Text with EEA relevance) {SEC(2022) 304 final} - {SWD(2022) 189 final} - {SWD(2022) 190 final} - {SWD(2022) 191 final}



EXPLANATORY MEMORANDUM 1.CONTEXT OF THE PROPOSAL •Reasons for and objectives of the proposal The Blood Directive - 2002/98/EC and the Tissues and Cells Directive - 2004/23/EC (the BTC legislation) have helped ensure the safety of millions of patients undergoing blood transfusion, transplantation and medically assisted reproduction. The legislation sets out quality and safety requirements for all activities from donation to human application (unless the donations are used to manufacture medicinal products or medical devices, in which case the legislation only applies to donation, collection and testing). Every year, EU patients are treated with 25 million blood transfusions (during surgery emergency, cancer or other care), a million cycles of medically assisted reproduction, over 35,000 transplants of stem cells (mainly for blood cancers) and hundred thousands of replacement tissues (e.g., for orthopaedic, skin, cardiac or eye problems). These therapies are only available thanks to the willingness of fellow citizens to make altruistic donations. In the European Union, the collection, processing and supply of each individual unit is typically organised on a local small-scale by public services, (academic) hospitals and non-profit actors. After almost 20 years in place, the legislation no longer addresses the scientific and technical state of the art and needs to be updated to take into account developments that have taken place in the sector. While an evaluation of the BTC legislation confirmed that it has brought very good levels of overall safety and quality in these sectors (less than one serious patient reaction for every 12,000 applications), shortcomings of the legislation were identified as follows: •Patients are not fully protected from avoidable risks due to out-of-date technical rules; •Blood, tissues and cells (BTC) donors and children born from donated eggs, sperm or embryos (offspring) are exposed to avoidable risks; •Member States have divergent approaches to oversight that hampers cross-border exchanges of BTC; •Full potential of BTC processed or used in new ways is not reached for patients; •Patients are vulnerable to interruptions in EU supply of BTC. The COVID-19 pandemic highlighted some of these shortcomings, in particular, those impacting on rules for preventing the risk of disease transmission by BTC and the lack of measures to ensure sufficiency of supply. The proposal aims to address these shortcomings, by revising the current legislation. The overall objective is to ensure a high level of health protection for EU citizens and ensure they have access to safe and effective BTC. As new technologies or risks will continue to emerge, it is desirable that the future framework is more effectively implemented, future proof, crisis resistant and agile enough to accommodate new risks and trends while continuing to provide appropriate safety and quality requirements. Being a REFIT initiative, areas for improving the efficiency of the legislation and simplifying its implementation by all stakeholders were also explored. •Consistency with existing provisions in the policy area The EU framework for safety and quality of substances of human origin (SoHOs) has currently three main Directives, respectively for Blood, Tissues and Cells, and Organs, together with implementing legislation. Each Directive sets safety and quality standards for all the steps from donation and collection from a donor body, over testing, processing, storage and distribution, to eventual application in the patients’ body. The current proposal covers blood, tissues and cells, and has links with the Organs Directive, in particular regarding closer collaboration between Member States’ competent authorities for blood, tissues and cells, and those for organs, and regarding vigilance requirements. Where BTC can be used in the manufacture of health products that are regulated by other Union legislation, or as the starting and raw material thereof, the SoHO framework applies on the first activities in the chain (donation, collection, testing) while these later activities (manufacturing, storage, distribution etc.) are regulated under these other appropriate legislative frameworks (e.g. medicinal products, including advanced therapy medicinal products, or medical devices). There are in place some mechanisms to ensure coherence between the BTC legislation and those adjacent frameworks. This proposal will reinforce the cooperation among those adjacent frameworks. As part of the Pharmaceutical Strategy for Europe , there is an ongoing evaluation and revision of the pharmaceutical legal framework. This proposal will feed into that work, in particular regarding the regulatory delineation between the BTC sector and the pharmaceutical sector. The delineating criteria are set by definitions in the pharmaceutical framework and are not altered by this proposal. •Consistency with other Union policies This initiative is part of the EU’s ambition to build a stronger European Health Union, so as to: (1) better protect the health of our citizens (including patients, donors and offspring); (2) equip the EU and its Member States to better prevent and address future pandemics (surveillance, data analysis, risk assessment, early warning and response) and (3) improve the resilience of EU health systems (sufficient supply of SoHOs).

The proposal further establishes links with the European Centre for Disease Prevention and Control (ECDC), for which the mandate has been proposed to be strengthened, also in this field of SoHOs. 2.LEGAL BASIS, SUBSIDIARITY AND PROPORTIONALITY •Legal basis The SoHO legislation is based on Article 168(4)(a) of the Treaty on the Functioning of the European Union (TFEU). As a shared competence with the Member States, and in line with the principle of subsidiarity, this Treaty Article gives the EU a mandate to set out measures establishing high standards of quality and safety for SoHOs while allowing Member States to maintain or introduce more stringent protective measures. Member States remain responsible for decisions of an ethical and organisational nature, such as allowing the donation of certain SoHOs or deciding allocation of certain SoHOs or who may access certain SoHO therapies (e.g., access to in vitro fertilisation therapies). While the EU Charter on Fundamental Rights requires non-commercialisation of the human body which translates into a principle of voluntary unpaid donation in the EU legislation, it is for the Member States to define the detailed implementation of this principle within the context of each country. When a Member State chooses to allow a particular new practice that can bring ethical questions (such as testing or storage of embryos), the safety and quality of this practice are then regulated by the EU SoHO legislation. •Subsidiarity (for non-exclusive competence) Ever-evolving disease threats, such as Zika, Human Immunodeficiency Virus (HIV) or viral hepatitis B, C and D, which can be transmitted through SoHOs, constitute cross-border threats to public health. In addition, the exchange of SoHOs between Member States and with third countries is necessary for ensuring optimal patient access and sufficiency of supply. This is in particular the case for SoHOs that are used as personalised therapies where it is essential that a recipient is specifically matched with a donor. Increasing cross-border exchanges of SoHOs necessitate ever-closer cooperation between a number of health professional groups and authorities to ensure that SoHOs remain traceable from the donor to the recipient and vice versa. Certain types of sector-specific expertise may also not be easily available in every Member State. By providing a framework for cross-border cooperation, based on a common set of rules, and connected to sector-specific expertise, EU-level measures are best placed to address such issues effectively. Establishing high standards of quality and safety for SoHOs at EU level facilitates equal access to safe therapies for all EU citizens, and encourages circulation of SoHO materials and products between Member States. Providing for a common framework that supports joint practices will promote simplification and efficiency. •Proportionality The overall initiative is limited to aspects that Member States cannot achieve satisfactorily on their own, and where there is clear EU added value. Many of the pursued objectives can only be met through highly technical rules and guidance that require specific expertise for their regular updating. From the three policy options considered (see the impact assessment staff working document, section 5.2), the preferred option requires that blood and tissue establishments meet safety and quality standards by following guidelines developed and updated by nominated expert bodies such as the ECDC and the European Directorate for the Quality of Medicines & HealthCare (EDQM, a Directorate of the Council of Europe). This option provides the highest effectiveness and efficiency, avoids the need for re-developing guidelines, and can ensure a high level of harmonisation as well as rapid updating of standards. The key added value of the EU approach in this proposal is to ensure, where appropriate, that common standards and guidelines make full use of the high level of latest scientific and technical expertise, as already available in expert bodies such as the ECDC and the EDQM, and therewith facilitate cross-border exchange of and access to safe SoHOs. In addition, the sharing of data through a common platform, and following common guidance, will enable policy making based on significantly more robust data. As stated in the impact assessment staff working document (section 7.5), the proposal does not interfere with the right for Member States to maintain and introduce more stringent measures when they consider them necessary (Article 168(4) of the TFEU) but does increase the level of safety and quality to be achieved in all Member States, thus reducing the need in most cases for more stringent measures that can create barriers to cross-border exchange and to patient access. In addition, the proposal will ensure the adoption of more stringent measures is made more visible so that exchanges can be more easily organised in full respect of those measures. Given that rules relating to ethical aspects of this field, or to healthcare organisation, are not included in the proposal, no special circumstances in individual Member States were identified that required a particular territorial variation in the measures to be applied. •Choice of the instrument The proposal takes the form of a new Regulation repealing two existing basic Acts, both Directives. A key element of the proposal is to establish more harmonised measures for Member States and organisations involved in collection, testing, processing, distribution, application of SoHOs, from donors to patients. Insufficient minimum harmonisation was identified as a key reason for reduced trust between Member States, resulting in reduced cross-border exchange and sub-optimal access for patients to SoHOs. A Regulation is considered the most suitable instrument since it does not require transposition and is directly applicable. 3.RESULTS OF EX-POST EVALUATIONS, STAKEHOLDER CONSULTATIONS AND IMPACT ASSESSMENTS •Ex-post evaluations/fitness checks of existing legislation The evaluation of the BTC legislation, published in 2019, identified the following gaps and shortcomings: 1.Patients are not fully protected from avoidable risks: the EU safety and quality requirements have not kept up to date with frequently changing scientific and epidemiological developments thus potentially exposing patients treated with BTC to avoidable risks. The ECDC provides up-to-date but non-binding guidance on safety measures, e.g. to address COVID-19 risks. The EDQM provides guidance on quality of BTC and many Member States put more stringent requirements in place. This situation can create legal confusion and unequal levels of safety and quality for patients. In addition, while new therapies have emerged since the BTC legislation was adopted, it is not always clear whether, and if so which, of the BTC Directives apply, leaving these substances unregulated or regulated in divergent ways (e.g., breast milk and faecal microbiota transplants). Some of these SoHOs do not meet the definitions of blood, tissues and cells included in the current legislation. 2.Divergent approaches to oversight cause unequal levels of safety and quality and barriers to the exchange of BTC across the EU: divergent national interpretations and implementations of the legislation lead to unequal protection and a lack of mutual trust between national authorities. This in turn creates barriers to cross-border exchange and to availability of BTC. These differences reflect the lack of common provisions for verification of effective implementation of inspection, authorisation and vigilance, and inconsistency in the levels of capacities, skills and independence required of inspectors supervising BTC establishments. 3.BTC donors and offspring (including children born from donated eggs, sperm or embryos) are exposed to avoidable risks: the current BTC legislation contains only very limited measures to protect and monitor BTC donors and offspring from donated sperm, eggs or embryos. In particular, the requirements to report donor adverse reactions are too limited and provisions for testing egg and sperm donors for genetic conditions are out of date with the technology available. Growing demand by commercial companies (e.g. egg banks for in vitro fertilisation, plasma collectors for medicinal product manufacture) increases the pressure to donate and consequently the need for robust donor protection measures.

4.The BTC legislation lags behind innovation: new ways of processing donations in BTC establishments may bring significant benefits. However, these new therapies can also put patients at risk, as current authorisation procedures for new BTC processes do not require evidence that risk is justified by benefits. Moreover, this lack of adequate procedures does not inspire trust and prevent healthcare actors from developing and adopting innovative processes. Besides risks and benefits, safety and quality measures also need to take account of the typical economic (public/non-profit) settings where BTC are developed and prepared, and of the often incremental and open-access nature of these innovations. In addition, there are sometimes difficulties in defining the borderlines for novel BTC with other regulatory frameworks, in particular where medicinal products and medical devices are concerned. This creates administrative burdens and implicit disincentives for BTC establishments, healthcare professionals and academia to innovate. This legal uncertainty issue requires further evidence gathering to allow its extent and consequences to be fully assessed. 5.The EU is vulnerable to interruptions in supply of some BTC: for some essential BTC, the EU is highly dependent on imports to ensure sufficiency. In particular, the EU relies on the United States for an adequate supply of plasma used to manufacture plasma-derived medicines. In the current legislation, sufficiency of supply through voluntary unpaid donation is encouraged, though without concrete measures to protect or increase supply. This approach has not proven adequate to protect EU patients from the risk of shortages or sudden supply disruption. The lack of EU and national monitoring provisions for the supply of BTC makes it difficult to predict EU supply interruptions and to take action to mitigate the risks to patients. The proposal therefore provides measures to: 1.Ensure safety and quality for patients treated with SoHO therapies and fully protect them from avoidable risks linked to SoHOs. 2.Ensure safety and quality for SoHO donors and for children born from donated eggs, sperm or embryos. 3.Strengthen and allow for harmonisation of oversight practices among Member States. 4.Facilitate the development of safe and effective innovative SoHO therapies. 5.Improve the resilience of the sector, mitigating risk of shortages. Objectives 1 and 2 are closely linked, as they both involve setting technical requirements for safety and quality to better protect EU citizens. While the EU has no mandate to intervene directly in supply management, reliable monitoring and notification of shortages would help Member States detect sudden drops in supply of SoHOs, trends towards shortages or dependencies on other Member States or on third countries, and would help them to take appropriate mitigation actions. •Stakeholder consultations Stakeholder consultations were a key step in the impact assessment phase for the revision of the legislative framework on blood, tissues, and cells. Consultation activities aimed to assess stakeholders’ views and opinions on (i) the validity of the findings of the evaluation (2019), (ii) the three proposed policy options described in an Inception Impact Assessment (IIA) and (iii) the extent to which they would address the shortcomings identified in the evaluation, and their likely impacts. Stakeholders were consulted via (i) the IIA publication for feedback, (ii) online surveys and questionnaires, (iii) hearings and participatory workshops with national competent authorities and stakeholders, (iv) bilateral meetings with stakeholder organisations and (v) interviews with specific stakeholders. Overall, there is support among all stakeholders for the common measures proposed (revised legislation that allows for up-to-date technical guidance and fills existing legal gaps; strengthened oversight practices,; mechanism for legal advice whether and what SoHO requirements apply to a substance, if needed in coordination with other EU legal frameworks; tailored authorisation of SoHOs used or processed in new ways; and crisis preparedness and management). Stakeholders also expressed broad support for option 2 (technical rules set by expert bodies), which is seen as the most effective approach. Analysis of quantitative data from the public consultations confirmed that the degree of conflict among stakeholders was low, as this preference was widely agreed between all stakeholder categories. However, sector experts and national authorities also highlighted conditions that must be met for the option 2 approach to be a success, including the need for transparent drafting procedures that ensure that professionals as well as Member States can provide inputs, the need to allow for more stringent national requirements and the need to accommodate for geographic differences between the EU and the Council of Europe. In addition, the analysis of respondents to the consultations highlighted once again the strong links between the blood sector on the one hand and the tissue and cell sector on the other, thus supporting the decision to combine both Directives into a single legal act on SoHOs (Organs being excluded). Donors and patients as well as ethics bodies raised important points to be taken into consideration during the implementation phase of the new legal framework, regarding for example donor protection, voluntary unpaid donation principles or the use of new training opportunities for inspectors about fundamental rights (to further enable them to ensure that those are respected by establishments, and in particular non-discrimination of donors). Many stakeholders also underlined the lack of legal clarity on the delineation with other EU legal frameworks (in particular medicinal products, including advanced therapy medicinal products, and medical devices) and indicated many cases where they believe SoHO-based therapies are not appropriately regulated, including some cases with a negative impact on feasibility to supply and eventual patient access. Stakeholders considered that the eventual choice for the most appropriate legal framework should aim in first place to ensure safety and quality, but also take account of the setting of, the costs for and the feasibility of providing access to safe and effective therapies. There was broad support for a dedicated SoHO legal advisory mechanism and for efficient coordination with advisory mechanisms in other sectors. It was largely considered that this will allow to strengthen legal clarity as well as improve interplay where SoHOs become starting materials for therapies manufactured under these other legal frameworks. Also, while supportive, stakeholders pointed out that EU-level supply monitoring and crisis preparedness measures will demand significant efforts, without having any direct impact on the risk of shortages of critical SoHO. Finally, National Competent Authorities (NCAs) and blood and tissue establishments expressed concerns regarding some specific measures that would increase their costs or administrative burden. Consideration of EU level measures to provide support was taken into account when preparing the legal proposal. An overview of the activities carried out and the results is available in Annexes 2 and 18 of the impact assessment staff working document. •Collection and use of expertise The Commission used the findings from the evaluation of the BTC legislation (2019). The impact assessment has been based on research and analyses done by the Commission. The Commission also contracted two external, independent consultant teams, to perform:

–A study, carried out by ICF S.A. supporting the impact assessment of the policy options, which gathered information on impacts and costs for stakeholders of the proposed measures and options, and further documented borderline case studies. The study also organised participatory workshops bringing stakeholders together to discuss various topics. The study was guided by a steering group composed of three senior experts in the field of blood, tissues and cells, who supervised the process and validated the study findings. The external support study will be published alongside this proposal. –A feasibility study, carried out by Deloitte, focusing specifically on the costs, benefits and optimal approaches to the digitalisation of the sector. The preliminary report from that study is published as Annex 19 of the impact assessment staff working document. Many of the 448 references in the BTC legislation evaluation were articles published in scientific journals and included data and evidence that was still relevant for the impact assessment of the policy options. In addition, a number of further scientific articles were published more recently and were also used as evidence sources for the impact assessment. These represent high quality evidence, due to the peer review process used by the publishers. Evidence on costs is particularly difficult to gather in the SoHO sector, due to the predominant role of public sector organisations (public administrations, hospitals), where real costs related to SoHO activities are sometimes absorbed in overall hospital or institutional budgets. This explains the high variety of costs reported through the survey performed by the external study supporting the impact assessment, with NCAs and professionals. Sector experts, both from NCAs and from public establishments, were therefore brought together to identify and agree on reasonable average values and validate key assumptions that have been used to calculate costs. The identified impacts of the proposed policy measures were subjected to a multi-criteria decision analysis to compare the effectiveness and efficiency of the options. To that end, the impact assessment piloted the tool developed by the Joint Research Centre of the European Commission, SOCRATES (SOcial multi-CRiteria AssessmenT of European policieS), using it to compare the different options based on previously established criteria. •Impact assessments The impact assessment analysed three policy options for the setting of safety and quality standards: –Option 1 - Decentralised regulation: it provides blood and tissue establishments with the freedom to make reference to a variety of national and international guidance when conducting risk assessments of their own activities, with a view to setting their internal technical methods. –Option 2 - Joint regulation: it requires blood and tissue establishments to follow the technical guideline developed and updated by nominated expert bodies. –Option 3 - Central Regulation: it requires blood and tissue establishments to follow the safety and quality standards, all provided for in EU legislation. The preferred option is Option 2. Joint regulation brings the highest effectiveness and efficiency as it builds on established expertise in the field of SoHOs to ensure that up-to-date standards are applied across the EU. Option 1 would allow changes to standards to be implemented more quickly, but with a high level of variation across the EU and a high workload on small blood and tissue establishments. Option 3 would allow for the highest level of harmonisation, but would require more time to adapt standards and bring additional costs for EU institutions. This proposal therefore introduces high level standards in the legislative text for patient, donor and offspring protection and empowers the Commission to adopt implementing acts on the implementation of those standards if needed. Where there are no such implementing acts, professionals should, to meet these standards, apply safety and quality guidelines developed by the EDQM and the ECDC, in line with option 2. However, in line with option 1, it can also be acceptable to apply other, equivalent, guidelines accepted by national authorities and demonstrated as achieving equivalent standards of safety and quality. In the absence of a technical guideline from expert bodies, establishments can set their own technical method taking into account internationally recognised standards, scientific evidence and a documented risk assessment. This approach will facilitate an efficient and responsive implementation of safety and quality standards whenever risks and technologies change. It is proportionate in that it ensures EU legislation would be adopted for the implementation of a particular standard only when necessary and when it adds EU value (option 3). In addition, a series of common measures was assessed, in particular to fill some legal gaps in the BTC framework, strengthen oversight, facilitate innovation, through advice on when the SoHO legislation is applicable and a (risk-) proportionate authorisation pathway for new processes, and manage SoHOs supply (crisis). The implementation of some of these common measures will be supported by guidelines from expert bodies (option 2). Regarding the measure on establishing a SoHO advisory mechanism, this proposal does not propose any changes in the delineation of the borderline with the legal frameworks for pharmaceuticals or medical devices. The delineating criteria are defined in those other frameworks, in particular in Article 1 of Regulation (EU) 2017/745 (‘devices manufactured utilising derivatives of tissues or cells of human origin which are non-viable’), in Article 2 of Directive 2001/83/EC on medicinal products (‘intended to be placed on the market’ and ‘prepared industrially’), and consequently in Article 2 of Regulation (EC) No 1394/2007 on Advanced Therapy Medicinal Products (‘substantial manipulation’ and ‘not intended to be used for the same essential function’). This measure will rather facilitate coordination with established (or future) advisory mechanisms in those other frameworks. The preferred option would ensure that citizens are better protected when donating, or being treated with a substance of human origin, with more harmonised and up-to-date safety and quality rules across the EU. In addition, offspring from medically assisted reproduction will be better protected, as will patients treated with currently unregulated SoHOs (e.g. therapeutic use of donated breast milk or bedside preparations of SoHOs). The preferred option would bring a positive impact for professionals, in particular in blood and tissue establishments, when working with SoHO. Outdated, and sometimes costly, technical rules for safety and quality will be removed and replaced with standards based on the best scientific evidence and expertise available that will be updated in a timely manner (bringing efficiencies for establishments). The preferred option also allows for guidance to make common measures more efficient: a clear and (risk-) proportionate pathway will facilitate access to SoHOs prepared or used in new ways and supply-crisis management will be better aligned and coordinated. The common measures will also strengthen oversight by competent authorities, by bringing in principles and new or more-efficient practices (e.g., joint inspections). Authorities will also benefit from more proportionate measures (e.g., risk based inspections) and EU level support (e.g. a digital platform, EU auditing of oversight systems, EU training courses for authority personnel). These measures will increase mutual trust and facilitate the collaboration between Member States, which should ultimately facilitate the cross-border exchanges of SoHOs, hence patient access. Digitalisation will allow for further efficiencies in administrative processes, and the possibility for sharing of information will limit duplication of work across Member States. The main costs relate to monitoring measures (donor, offspring, supply), to registration of bedside preparations of SoHOs and to the risk-proportionate pathway to authorise SoHOs processed or used in new ways. Those costs mostly fall on professionals in blood and tissue establishments, hospitals and clinics and, to a lesser degree, on competent authorities. EU measures can be considered to offset these costs for professionals and authorities, in particular in the adjustment phase and in particular through supporting digitalisation. For EU institutions, the set-up of a common IT platform (the EU SoHO Platform) brings a significant cost, but will allow for a lightening of the (administrative) burden for national authorities and professionals. Further EU costs relate to coordination and co-funding of expert bodies.

•Regulatory fitness and simplification This initiative is part of the Commission Work Programme 2021 under Annex II (REFIT initiatives). The revision of the BTC legislation, with an approach proportionate to risks in different areas (authorisation or registration of establishments/entities, authorisation of new preparation processes, health monitoring of certain SoHO donors and offspring), brings opportunities for savings in the sector, and for carrying out some activities more efficiently with the same resources (e.g. risk-based inspections), though these opportunities have not always been fully quantified. The table below gives an overview of the main opportunities under the preferred option. REFIT Cost Savings – Preferred Option Description Amount Comments Graded oversight approach allows to oversee some establishments with lighter approach and less resources than today EUR 4 m 750 establishments eligible, mainly saving on inspection costs for authorities and for themselves Common IT-platform to share assessments of new SoHOs technologies reduces duplications >EUR 2 m Conservative estimate; Requests to authorise same new technologies are introduced and assessed in parallel across EU; Sensitive to unit cost of assessments and authorisations Risk-based schedule allows to inspect same activities/establishments more efficiently (targeting high-risk activities) Not quantified Model has rather assumed this to be a cost-neutral measure as the same number of resources (inspectors) allow for more oversight on most complex activities Recognition of authorisations of importing tissue establishments in other Member States, reduces need for ad-hoc import authorisations in different Member States EUR 0.5 m Applicable for almost 1 000 imports per year of blood stem cells (from bone marrow or peripheral blood) through a central registry (World Marrow Donor Association registry, subject to one joint authorisation) Removing obsolete tests and systematic screening measures from the legislation EUR 2 m (example – West Nile Virus NAT tests) Very high potential, given that every saving is multiplied by number of donations. Other examples could be the screening for tattoos/piercings or testing for syphilis. Digitalisation allows for more efficient administrative processes in authorities and establishments To be further quantified The EU SoHO Platform, financed by the Commission, will facilitate local administration including registration and reporting by professionals as well as authorisations and oversight by authorities. E.g. annual reporting costs are estimated to go down from current EUR 5 000-15 000 to EUR 200-2 000 with an automated reporting tool. Digital impacts are also expected, as data in the SoHO sector can become valuable digital assets in the areas of public health and innovation. A single IT system will bring important benefits as it can host flexible solutions, allowing Member States and establishments to maintain and connect with their own system or re-use existing components. It could become an important node in the EU digital ecosystem, and in particular in the future European Health Data Space (EHDS), which aims at opening opportunities and removing barriers to the use and reuse of health data, for the provision of healthcare, personalised medicine, research and innovation, policy making and regulatory activities. To benefit from the EHDS in the future, competent authorities in the field of SoHOs could consider the collaboration with competent bodies under the EHDS at national and EU level, including for aspects related to technical and semantic interoperability. •Fundamental rights The proposal would bring positive impacts on some fundamental rights of citizens (health protection, non-discrimination, privacy, informed consent), in particular by strengthening the provisions relating to donor protection and vigilance and the reporting of genetic conditions in children born from medically assisted reproduction with third party donation, and by ensuring that requirements for safety and quality are based on scientific evidence. However, for most of the ethical aspects, in particular the rights of children born from medically assisted reproduction, decisions are taken by Member States at national level. The proposal maintains the current principle of voluntary and unpaid donation (VUD) in line with Article 3 of the EU Charter of Fundamental Rights that prohibits the commercialisation of the human body. However, the proposal harmonises the differing versions in the blood and the tissue and cell Directives and adapts them to the principle of ‘financial neutrality’ recently recommended by the Council of Europe Committee on Bioethics. 4.BUDGETARY IMPLICATIONS The legislative financial statement attached to this proposal sets out the budgetary, human and administrative resource implications. Appropriations will be reallocated within the financial envelope of the EU4Health Programme in the Multiannual Financial Framework (MFF) 2021-2027. That Programme was established to respond to the need for further action at Union level to support cooperation and coordination among the Member States. That Programme should be a means to promote strengthened exchange of best practices between Member States, to support networks for the sharing of knowledge or for mutual learning, to address cross-border threats to health so as to reduce the risks of such threats and to mitigate their consequences, and to improve efficiency by avoiding the duplication of activities and optimising the use of financial resources. In that context, some activities organised jointly among Member States, such as inspections or SoHO preparations assessments, could be eligible for Union financial support. 5.OTHER ELEMENTS •Implementation plans and monitoring, evaluation and reporting arrangements The Commission will review the monitoring indicators periodically and evaluate the impacts of the legislative act after five years. The monitoring will be possible thanks to the data from reporting obligations on Member States and SoHO entities. The EU SoHO Platform will enable the collection of all elements of the continuous monitoring plan as it automates the extraction of relevant indicators without additional input from stakeholders. For the evaluation, additional data will be collected, in particular on the costs, the usability and the integration across systems. The data platform will be used to transparently publish aggregated indicators of general interest, such as serious adverse occurrences related to SoHOs, insufficiencies of supply or authorised SoHO preparations. •Detailed explanation of the specific provisions of the proposal The new Regulation, repealing the Blood Directive 2002/98/EC and the Tissues and Cells Directive 2004/23/EC, and their implementing legislation, is structured around obligations for the different stakeholders: the national competent authorities, the entities handling SoHOs, and the Commission. It includes specific requirements for all organisations that carry out activities that can affect the safety, quality or efficacy of SoHOs used for human application and describes obligations for designated authorities that will verify the proper implementation of the provisions. It will consist of the following main chapters: Chapter I: General provisions Chapter I contains general provisions of this Regulation. It defines the subject matter and the scope of application of the Regulation. In recognition of the importance of ensuring safety and quality of SoHOs that are not defined by the terms ‘blood’, ‘tissue’ or ‘cell’, such as breast milk and intestinal microbiota, and to future-proof the legislation in this regard, the scope is defined by the broader term SoHOs. Solid organs continue to be regulated by Directive 2010/53/EU and are excluded from the definition of this term. This chapter contains the definitions of the different elements of the Regulation and of the terminology used throughout the text. Furthermore, it introduces the description of SoHO activities and describes the possible more stringent measures set by Member States, in line with Article 168(4)(a) of the TFEU. Certain exclusions are described, along with the partial applicability of this Regulation when SoHOs are used to manufacture products regulated by other Union legislation, or as the starting and raw material thereof. Chapter II: Competent Authorities Chapter II contains the provisions regarding competent authorities for SoHOs, which are responsible for the SoHO supervisory activities. It covers the designation of competent authorities, the possibility to delegate certain SoHO supervisory activities, and general principles for their functioning (independence and impartiality, transparency). It also defines their general responsibilities and obligations. It covers the communication between competent authorities (within the SoHO sector) and consultation and cooperation with authorities of other regulated sectors. It lays down general obligations for authority personnel and provides for competent authorities obligations regarding Commission controls.

Chapter III: SoHO Supervisory Activities Chapter III covers all activities competent authorities undertake vis-à-vis SoHO entities or processes, with the obligation to maintain a register of SoHO entities and a procedure for their registration; the obligation to have a system for the authorisation of SoHO preparations, and a procedure for these authorisations, with provisions for conducting the assessment of SoHO preparations, possibly in a joint process with one or more competent authorities, and further specific obligations for SoHO preparation assessors. This Chapter also covers the obligation to have an authorisation system for SoHO establishments (specific in case of importing SoHO entities) and a procedure for their authorisation (SoHO establishments/importing SoHO entities). It stipulates the obligations for inspections of SoHO establishments and other SoHO entities, possibly via joint inspections, and the specific obligations for inspectors. It provides for the obligations for competent authorities regarding data publication, traceability, vigilance and, SoHO Rapid Alerts. Chapter IV: General Obligations on SoHO Entities Chapter IV outlines all the general obligations on SoHO entities, namely their registration, the nomination of a Responsible Person if they release SoHOs for clinical use, the obligations regarding export of SoHOs. It also lays down the obligation for authorisation of SoHO preparations, and the procedure for application for such authorisation. It also covers the obligations for importing SoHO entities regarding their authorisation, and the application for such authorisation. It provides for the obligations for SoHO entities regarding activity data collection and reporting, traceability and coding, the obligation to apply 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 Chapter V lays down the general obligations on SoHO establishments, a sub-set of SoHO entities that process and store SoHOs. It provides for their authorisation and the application procedure for such authorisation, the obligation to have a Quality Management system in place, and the obligation to designate a physician responsible for specific tasks. Chapter VI: SoHO Donor Protection Chapter VI contains the provisions related to the protection of SoHO donors, with standards, and how to implement these standards concerning donor protection. Chapter VII: Recipient and Offspring Protection Chapter VII contains the provisions related to the protection of patients treated with SoHO (recipients) and offspring from medically assisted reproduction, with standards, and how to implement these standards concerning recipient and offspring protection. It also stipulates conditions for the release of SoHOs for human application, and conditions for exceptional release. Chapter VIII: Supply Continuity Chapter VIII lays down provisions to ensure the continuity of supply of SoHOs. It covers the obligation for Member States to have national SoHO emergency plans (for SoHOs that are critically important for patients) and the responsibilities of competent authorities and entities regarding supply alerts for critical SoHOs. It also stipulates the conditions for derogation from the obligations to authorise SoHO preparations in emergencies, provides for additional emergency measures taken by Member States and finally lays down the obligation for SoHO entities carrying out activities with critical SoHOs to have an emergency plan in place. Chapter IX: SoHO Coordination Board Chapter IX establishes the SoHO Coordination Board (SCB) to support Member States in the coordination of implementation of this Regulation and the delegated and implementing acts adopted pursuant to it. This chapter also provides for the composition of the Board and how its functioning is organised. Chapter X: Union Activities Chapter X outlines the activities organised at Union level, regarding training and exchange of competent authorities’ personnel, the Commission controls in Member States, and the support provided by the Commission to support the implementation of the Regulation. It also refers to the cooperation with the EDQM, which should address procedures for the development and revision of technical guidelines, including evidence gathering, guideline drafting and public consultation. Chapter XI: EU SoHO Platform Chapter XI describes the EU SoHO Platform that will support information sharing between authorities and with SoHO entities, and outlines its general functionalities. Chapter XII: Procedural Provisions Chapter XII contains the procedural provisions of the Regulation with regard to confidentiality and data protection obligations. It furthermore contains provisions regarding the exercise of delegation, the urgency procedure and the committee procedure. Finally, it lays down the penalties applicable to infringements of the provisions of this Regulation to be set by Member States.

As regards delegated acts, following the adoption of the proposal, the Commission intends to create an expert group in line with decision C (2016) 3301 in order to advise and assist it in the preparation of delegated acts, as well as on issues related to implementation of the Regulation as regards: (a)preparing opinions at the request of the Commission on the regulatory status of a substance, product or activity (and consulting equivalent advisory bodies established in other relevant Union legislation); (b)providing expertise relevant for the development of technical guidelines, other guidelines and technical methods to the Commission; (c)reviewing reports on activity data and on vigilance data prior to publication by the Commission; (d)contributing to the continuous monitoring of technical progress and assessment of whether the safety and quality requirements set out in this Regulation are adequate to ensure safety and quality of SoHOs and SoHO preparations and the safety of SoHO donors; (e)supporting the Commission to exchange views with Union or international level professional associations working in the field of SoHOs on issues of general interest in relation to the applicability of the provisions of this Regulation; (f)providing expertise to the Commission for the development of guidelines, standards or similar on an international level for SoHOs and their quality and safety, when appropriate; (g)advising the Commission on the appropriate content and format of Union training programmes for competent authority personnel and supporting the performance of training activities; (h)providing advice and expertise on the preparation of delegated acts. The expert group should also provide technical advice to the Commission when it considers that the EDQM guidelines are not sufficient to meet a standard for donor protection or a standard for recipient and offspring protection as provided for in this Regulation. Chapter XIII: Transitional Provisions This Chapter sets the transitional provisions applicable to establishments and SoHO preparations authorised under the former BTC legislation. It stipulates the status of SoHO stored before the application of this Regulation. Finally, it contains the transitional measures related to the date of adoption of certain delegated and implementing acts. Chapter XIV: Final Provisions The final chapter stipulates the repeal of Directives 2002/98/EC and 2004/23/EC. It also sets the provision for the evaluation of the Regulation, and its dates of entry into force and application. 2022/0216 (COD) Proposal for a REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL on standards of quality and safety for substances of human origin intended for human application and repealing Directives 2002/98/EC and 2004/23/EC (Text with EEA relevance) THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION,

Having regard to the Treaty on the Functioning of the European Union, and in particular Article 168(4), point (a), thereof, Having regard to the proposal from the European Commission, After transmission of the draft legislative act to the national parliaments, Having regard to the opinion of the European Economic and Social Committee, Having regard to the opinion of the Committee of the Regions, Acting in accordance with the ordinary legislative procedure, Whereas: (1)In accordance with Article 168(1), first subparagraph, of the Treaty on the Functioning of the European Union (TFEU) and Article 35 of the Charter of Fundamental Rights of the European Union, a high level of human health protection is to be ensured in the definition and implementation of all Union policies and activities. (2)Article 168(4), point (a), TFEU provides that the European Parliament and the Council should adopt measures setting high standards of quality and safety for organs and substances of human origin (SoHOs), blood and blood derivatives. At the same time, Member States cannot be prevented from maintaining or introducing more stringent protective measures. Pursuant to Article 193 TFEU, Member States are to notify the Commission of any such measures. According to Article 168(7) TFEU, the measures adopted pursuant to Article 168(4), point (a) should not affect national provisions on the donation or medical use of organs and blood. (3)As regards Article 168(4), point (a), TFEU, standards for the safety and quality of organs and SoHOs, blood and blood derivatives should ensure a high level of human health protection. Therefore, this Regulation aims at setting high standards by ensuring, amongst others, the protection of SoHO donors, taking into consideration their fundamental role in the provision of SoHOs and for recipients, as well as measures to monitor and support the sufficiency of the supply of SoHOs that are critical for the health of patients. (4)Directives 2002/98/EC and 2004/23/EC of the European Parliament and of the Council constitute the Union’s regulatory framework for blood and for tissues and cells, respectively. Although these Directives have harmonised to a certain degree the rules of Member States in the area of safety and quality of blood, tissues and cells, they include a significant number of options and possibilities for Member States to implement the rules they laid down. This results in divergences between national rules, which can create obstacles to cross-border sharing of these substances. A fundamental revision of those Directives is needed for a robust, transparent, up-to-date and sustainable regulatory framework for these substances, which achieves safety and quality for all parties involved, enhances legal certainty and supports continuous supply, whilst facilitating innovation for the benefit of public health. In order to achieve a coherent application of the legal framework, it is appropriate to repeal Directives 2002/98/EC and 2004/23/EC and to replace them by a Regulation. (5)Directives 2002/98/EC and 2004/23/EC are highly interconnected and contain very similar provisions for oversight and equivalent principles for safety and quality in the two sectors they regulate. In addition, many authorities and operators work across these sectors. As this Regulation aims to define high level principles that will be common to both the blood and of tissues and cells sectors, it would be appropriate that it replaces these Directives and merges the revised provisions into one legal act. (6)This Regulation should apply to blood and blood components, as regulated by Directive 2002/98/EC, as well as to tissues and cells, including haematopoietic peripheral blood, umbilical-cord blood and bone-marrow stem cells, reproductive cells and tissues, foetal tissues and cells and adult and embryonic stem cells, as regulated by Directive 2004/23/EC. Since donation and human application of SoHOs other than blood, tissues and cells are increasingly common, it is necessary to extend the scope of this Regulation to any SoHO, regardless of whether it meets the definition of ‘blood’, ‘tissue’ or ‘cell’, to avoid that certain groups of donors or recipients are not protected by an appropriate Union level quality and safety framework. This will, for example, ensure the protection of donors and recipients of human breast milk, intestinal microbiota, blood preparations that are not used for transfusion, and any other SoHO that may be applied to humans in the future. (7)Solid organs are excluded from the definition of SoHOs for the purposes of this Regulation and, thus, from its scope. Their donation and transplantation are significantly different and are regulated in a dedicated legal framework, set out in Directive 2010/53/EU of the European Parliament and of the Council. Shortcomings have not been raised regarding the existing quality and safety provisions for organs. Nonetheless, when organs are removed from a donor for the purposes of separating tissues or cells for human application, for example heart valves from a heart or pancreatic islets from a pancreas, this Regulation should apply. (8)Ensuring the quality and safety of SoHOs is crucial, especially where such substances interact with the body of the recipient. Hence, this Regulation should not cover the placing of a substance on the body when it does not have any biological or physiological interaction with that body, such as in the case of wigs made from human hair. (9)All SoHOs that are intended to be applied to humans fall within the scope of this Regulation. SoHOs can be prepared and stored in a variety of ways, becoming SoHO preparations, which can be applied to recipients. In these circumstances, this Regulation should apply to all activities from donor recruitment to human application and outcome monitoring. SoHOs or SoHO preparations can also be used to manufacture products regulated by other Union legislation, or as the starting and raw material thereof, in particular on medical devices, regulated by Regulation (EU) 2017/745 of the European Parliament and of the Council, on medicinal products, regulated by Directive 2001/83/EC of the European Parliament and of the Council and by Regulation (EC) No 726/2004 of the European Parliament and of the Council, including on advanced therapy medicinal products, regulated by Regulation (EC) No 1394/2007 of the European Parliament and of the Council, or on food, regulated by Regulation (EC) No 1925/2006 of the European Parliament and of the Council. The criteria that define when SoHOs or SOHO preparations become products regulated under other Union legislation are not defined in this Regulation but are defined in those other acts. In addition, this Regulation should apply without prejudice to Union legislation on genetically modified organisms. (10)When SoHOs are used in the autologous setting without any manipulation, processing or storage, the application of this Regulation would not be proportionate to the limited quality and safety risks arising in such a setting. When autologous SoHOs are collected and processed before being re-used in the same person, risks appear that should be mitigated. Thus, there needs to be an assessment and authorisation of the processes applied to ensure that they are demonstrated to be safe and effective for the recipient. When autologous SoHOs are collected to be processed and also stored, risks of cross-contamination, loss of traceability or damage to the biological properties inherent to the substance, and necessary for efficacy in the recipient, also appear. Thus, the requirements for SoHO establishment authorisation should apply. (11)When SoHOs are used to manufacture products regulated by other Union legislation, or as the starting and raw material thereof, in order to ensure a high level of protection and contribute to legal clarity and certainty, this Regulation should apply to the extent that the activities to which they are subjected are not regulated by the other Union legislative framework. Without prejudice to other Union legislation, and in particular to Directive 2001/83/EC, Regulations (EC) No 726/2004, (EC) No 1925/2006, (EC) No 1394/2007 and (EU) 2017/745, this Regulation should at least apply to the recruitment and selection of donors, donation, collection and donor testing as well as to release, distribution, import and export when those activities concern SoHOs up to the point of their transfer to operators regulated by other Union legislation. This means that close interaction between this regulatory framework and other related frameworks is essential to ensure interplay and coherence between relevant legal frameworks, without gaps or overlaps. (12)SoHOs can also be combined with other regulated products before human application. In these circumstances, close interaction between this regulatory framework and other related frameworks is also necessary to ensure a high level of human health protection for all cases where these substances are used. (13)Given the special nature of SoHOs, resulting from their human origin, and the increasing demands for these substances for human application or for the manufacture of products regulated by other Union legislation, or as the starting and raw material thereof, it is necessary to ensure a high level of health protection for donors as well as for recipients. SoHOs should be obtained from individuals whose health status is such that no detrimental effects will ensue as a result of the donation. This Regulation should therefore include principles and technical rules to monitor and protect donors. As different types of donation imply different risks for donors, with varying levels of significance, the monitoring of donor health should be proportionate to those levels of risk. This is particularly important when donation involves some risk to the donor’s health due to a need for pre-treatment with medicinal products, a medical intervention to collect the substance or a need for donors to donate repeatedly. Donations of oocytes, bone marrow, peripheral blood stem cells and plasma should be considered to imply a significant risk.

(14)When a harmful genetic condition is detected in the offspring resulting from medically assisted reproduction with third party donation, the transmission of that information enables the prevention of further use of donations affected by that genetic risk. It is thus important that relevant information in such cases is effectively communicated between SoHO entities and acted upon appropriately. (15)This Regulation does not prevent Member States from maintaining or introducing more stringent protective measures that are compatible with Union law. Member States should notify the Commission of any such measures. More stringent protective measures put in place by Member States should be evidence-based and proportionate to the risk to human health, for example based on overall safety concerns and corresponding risks in a Member State or specific local risks. They should not discriminate against persons on grounds of sex, racial or ethnic origin, religion or belief, disability, age or sexual orientation, unless that measure or its application is objectively justified by a legitimate aim, and the means of achieving that aim are appropriate and necessary. (16)This Regulation should not interfere with national legislation in the health area with objectives other than quality and safety of SoHOs that is compatible with Union law, in particular legislation concerning ethical aspects. Such aspects arise due to the human origin of the substances, which touches upon various sensitive and ethical concerns for Member States and citizens, such as access to particular services that use SoHOs. This Regulation should also not interfere with decisions of an ethical nature made by Member States. Such ethical decisions might concern the use, or limitation of the use, of specific types of SoHOs or specific uses of SoHOs, including reproductive cells and embryonic stem cells. When a Member State allows the use of such cells, this Regulation should apply in full with a view to ensuring safety and quality and to protecting human health. (17)This Regulation is not meant to cover research using SoHOs when that research does not involve application to the human body, for example in vitro research or research in animals. However, human substances used in research involving studies where they are applied to the human body should comply with the rules laid down in this Regulation. (18)As a matter of principle, programmes promoting the donation of SoHOs should be founded on the principle of voluntary and unpaid donation, altruism of the donor and solidarity between donor and recipient. Voluntary and unpaid SoHO donation is also a factor which can contribute to high safety standards for SoHOs and therefore to the protection of human health. It is also recognised, including by the Council of Europe Committee on Bioethics, that while financial gain should be avoided, it may also be necessary to ensure that donors are not financially disadvantaged by their donation. Thus, compensation to remove any such risk is acceptable but should never constitute an incentive that would cause a donor to be dishonest when giving their medical or behavioural history or to donate more frequently than is allowed, posing risks to their own health and to that of prospective recipients. Such compensation should, therefore, be set by national authorities, at a level appropriate in their Member State to reach such objectives. (19)In order to maintain public trust in SoHO donation and use programmes, information that is given to prospective donors, recipients or physicians regarding the likely use and benefits of particular SoHOs or SoHO preparations when applied to recipients should accurately reflect reliable scientific evidence. This should ensure that donors, or their families, are not coerced to donate by exaggerated descriptions of benefits and prospective patients are not given false hopes when making decisions on their options for treatment. The verification of compliance with this Regulation through supervisory activities is of fundamental importance to ensure that, across the Union, the objectives of the Regulation are effectively achieved. The responsibility to enforce this Regulation lies with the Member States, whose competent authorities should monitor and verify, through the organisation of supervisory activities, that relevant Union requirements are effectively complied with and enforced. (20)Competent authorities should be designated by the Member States for all the areas that fall within the scope of this Regulation. While Member States are best placed to identify the competent authority or authorities for each area, for example by geography, topic or substance, they should also be required to designate a single national authority that ensures appropriately coordinated communication with other Member States’ competent authorities and with the Commission. The SoHO National Authority should be considered the same as the designated competent authority in Member States where only one competent authority is designated. (21)For the performance of supervisory activities aimed at verifying the correct application of SoHO legislation, Member States should designate competent authorities that act independently and impartially. It is therefore important that their function of oversight is separate and independent from the performance of SoHO activities. In particular, competent authorities should be free from undue political influence and from industry interference that might affect their operational impartiality. (22)For the performance of supervisory activities aimed at verifying the correct application of SoHO legislation, Member States should designate competent authorities that act in the public interest, are appropriately resourced and equipped, and offer guarantees of impartiality, professionalism and transparency. When infringements relate to direct health risks, and the publication of information regarding those infringements can contribute to risk mitigation and the protection of donors, recipients or offspring from medically assisted reproduction, competent authorities should, where necessary, be able to prioritise transparency of their enforcement activities over the protection of confidentiality of the party that has infringed the Regulation. (23)The correct application and enforcement of the rules falling within the scope of this Regulation require an appropriate knowledge of those rules. It is therefore important that the staff performing supervisory activities have an appropriate professional background and are regularly trained, in accordance with their area of competence, on the obligations resulting from this Regulation. (24)When there is doubt about the regulatory status of a particular substance, product or activity under this Regulation, competent authorities should consult with the relevant authorities responsible for other relevant regulatory frameworks, namely medicinal products, medical devices, organs or food, with the aim of ensuring coherent procedures for the application of this Regulation. Competent authorities should inform the SoHO Coordination Board of the outcome of their consultations. When SoHOs or SoHO preparations are used to manufacture products regulated under other Union legislation, or as the starting and raw material thereof, competent authorities should cooperate with the relevant authorities on their territory. This cooperation should aim to reach an agreed approach for any subsequent communications between the authorities responsible for SoHO and for the other relevant sectors, as needed, regarding authorisation and monitoring of the SoHOs or the product manufactured from SoHOs. It should in principle be the responsibility of the Member States to decide on a case-by-case basis on the regulatory status of a substance, product or activity. However, in order to ensure consistent decisions across all Member States with regard to borderline cases, the Commission should be empowered to, on its own initiative or at the duly substantiated request of a Member State, decide on the regulatory status of a particular substance, product or activity under this Regulation. (25)Competent authorities should perform supervisory activities regularly, on the basis of a risk assessment and with appropriate frequency, on entities and activities governed by this Regulation. The frequency of supervisory activities and the mode, whether on-site or by remote document review, should be established by the competent authorities, having regard to the need to adjust the control effort to the risk and to the level of compliance expected in the different situations, including the possible violations of this Regulation perpetrated through fraudulent or other illegal practices and previous compliance history. Accordingly, the likelihood of non-compliance with all the areas of this Regulation should be taken into account when scheduling supervisory activities. (26)Commission experts should be able to perform controls, including audits, in Member States to verify the effective application of the relevant requirements of competent authorities and of the supervisory activity systems. Commission controls should also serve to investigate and collect information on enforcement practices or problems, emergencies and new developments in Member States. Official controls should be performed by personnel who are independent, free from any conflict of interest and in particular who are not in a situation which, directly or indirectly, could affect their ability to carry out their professional duties in an impartial manner. (27)Since SoHO preparations are subjected to a series of SoHO activities prior to their release and distribution, competent authorities should assess and authorise SoHO preparations to verify that a high level of safety, quality and efficacy is achieved consistently by the application of that specific series of activities, performed in that specific manner. When SoHOs are prepared with newly developed and validated collection, testing or processing methods, consideration should be given to the demonstration of safety and efficacy in recipients by means of requirements for clinical outcome data collection and review. The extent of such required clinical outcome data should correlate with the level of risk associated with the activities performed for that SoHO preparation and use. Where a new or modified SoHO preparation poses negligible risks for recipients (or offspring in the case of medically assisted reproduction), the vigilance reporting requirements provided for in this Regulation should be adequate to demonstrate safety and quality. This should apply for well-established SoHO preparations that are introduced in a new SoHO entity but have been robustly demonstrated as safe and effective by their use in other entities. (28)With regard to SoHO preparations that pose a certain level of risk (low, moderate or high), the applicant should propose a plan for clinical outcome monitoring that should fulfil different requirements appropriate to the risk indicated. The most up-to-date guidance of the European Directorate for the Quality of Medicines & HealthCare (EDQM, a Directorate of the Council of Europe) should be considered relevant in the design of clinical follow-up studies proportionate in extent and complexity to the identified level of risk of the SoHO preparation. In the case of low risk, in addition to the mandatory continuous vigilance reporting, the applicant should organise proactive clinical follow-up for a defined number of patients. For moderate and high risk, in addition to the mandatory vigilance reporting and the clinical follow-up, the applicant should propose clinical investigation studies with monitoring of pre-defined clinical end-points. In case of high risk, these should include a comparison with standard treatments, ideally in a study with subjects allocated to test and control groups in a randomised manner. The competent authority should approve the plans before they are implemented and should assess the outcome data as part of a SoHO preparation authorisation. (29)In the interests of efficiency, it should be permitted to conduct clinical outcome studies using the established framework in the pharmaceutical sector for clinical trials, as set out in Regulation (EU) No 536/2014 of the European Parliament and of the Council, when operators wish to do so. Whilst applicants can choose to record the clinical data generated during the clinical outcome monitoring themselves, they should also be permitted to use existing clinical data registries as a means of such recording when those registries have been verified by the competent authority, or are certified by an external institution, in terms of the reliability of their data management procedures. (30)In order to facilitate innovation and reduce administrative burden, competent authorities should share with each other information on the authorisation of new SoHO preparations and the evidence used for such authorisations, including for the validation of certified medical devices used for SoHO collection, processing, storage or application to patients. Such sharing could allow authorities to accept previous authorisations granted to other entities, including in other Member States and to thus significantly reduce the requirements to generate evidence. (31)A broad range of public and private organisations influence the safety, quality and efficacy of SoHOs, even if they do not maintain banks of those SoHOs. Many organisations carry out a single SoHO activity, such as collection or donor testing on behalf of one or many organisations that maintain banks of SoHOs. The SoHO entity concept includes this broad range of organisations, from donor registries to physicians that apply SoHOs to recipients or use SoHO processing devices at the recipient’s bedside. The registration of all such SoHO entities should ensure that competent authorities have a clear overview of the field and its scale and can take enforcement action when deemed necessary. A SoHO entity registration should refer to the legal entity, regardless of the number of physical sites associated with the entity. (32)Competent authorities should review the SoHO entities registered in their territory and ensure that those entities that carry out both processing and storage of SoHOs are inspected and authorised as SoHO establishments before starting those activities. A SoHO establishment authorisation should refer to the legal entity, even when one SoHO establishment has many physical sites. Competent authorities should consider the impact on safety, quality and efficacy of the SoHO activities carried out at SoHO entities that do not meet the definition of a SoHO establishment and decide whether particular entities should be subject to establishment authorisations due to the risk or scale associated with their activities. Similarly, SoHO entities that have a poor record in terms of compliance with reporting or other obligations might be suitable candidates for authorisation as SoHO establishments. (33)With regards to standards concerning donor, recipient and offspring protection, this Regulation should provide for a hierarchy of rules for their implementation. As risks and technologies change, this hierarchy of rules should facilitate an efficient and responsive uptake of the most up-to-date guidelines for implementing the standards set out in this Regulation. As part of that hierarchy, in the absence of Union legislation describing particular procedures to be applied and followed to meet the standards set out in this Regulation, following the guidelines of the European Centre for Disease Prevention and Control (ECDC) and the EDQM should be considered as a means to demonstrate compliance with the standards laid down in this Regulation to ensure high level of quality, safety and efficacy. SoHO entities should be permitted to follow other guidelines, provided that it has been demonstrated that those other guidelines achieve the same level of quality, safety and efficacy. In cases of detailed technical issues for which neither Union legislation nor the ECDC and the EDQM have defined a technical guideline or rule, operators should apply a locally defined rule that is in line with relevant internationally recognised guidelines and scientific evidence and is appropriate to mitigate any risk identified.

(34)Where evidence demonstrates that specific processing steps reduce or eliminate the risk of transmission of specific infectious or non-infectious disease agents, the quality and safety standards for the verification of donor eligibility by means of donor health evaluations, including testing, and the related guidelines for their implementation, should take this evidence into account. Thus, in the case of, for example, plasma for fractionation, that in a subsequent step in the manufacturing process of medicinal products undergoes sterilisation steps, certain donor eligibility criteria used for donation of plasma for transfusion might not be necessary nor appropriate. (35)The EDQM is a structural part of the Council of Europe working under the European Pharmacopoeia Partial Agreement. The text of the Convention on the elaboration of a European Pharmacopoeia (ETS No. 050), accepted by Council Decision 94/358/EC, is considered to be the text of the European Pharmacopoeia Partial Agreement. Member States of the Council of Europe that have signed and ratified the European Pharmacopoeia Convention are the member States of the European Pharmacopoeia Partial Agreement and are therefore the members of the intergovernmental bodies functioning within the framework of this partial agreement, including among others: the European Pharmacopoeia Commission, the European Committee on Organ Transplantation (CD-P-TO), the European Committee on Blood Transfusion (CD-P-TS) and the European Committee on Pharmaceuticals and Pharmaceutical Care (CD-P-PH). The European Pharmacopoeia Convention has been signed and ratified by the European Union and all its Member States, all of whom are represented in their intergovernmental bodies. In this context, the work of the EDQM on developing and updating guidelines on safety and quality of blood, tissues and cells, should be considered an important contribution to the field of SoHOs in the Union and should be reflected in this Regulation. The guidelines address issues of quality and safety beyond the risks of communicable disease transmission, such as donor eligibility criteria for the prevention of the transmission of cancer and other non-communicable diseases and the assurance of safety and quality during collection, processing, storage and distribution. It should therefore be possible to use those guidelines as one of the means to implement the technical standards provided for in this Regulation. (36)The ECDC, established by Regulation (EC) No 851/2004 of the European Parliament and of the Council, is a Union agency with the mission of strengthening Europe's defences against communicable diseases. The work of the ECDC on developing and updating guidelines on safety and quality of SoHOs from a communicable disease threat perspective, should be considered an important contribution in the field of SoHOs in the Union and should be reflected in this Regulation. In addition, the ECDC established an expert network for the Microbial Safety of SoHOs, which ensures the implementation of the requirements on the ECDC’s relations with the Union Member States and EEA Member States stated in Regulation (EC) No 851/2004, regarding strategic and operational collaboration on technical and scientific issues, surveillance, responses to health threats, scientific opinions, scientific and technical assistance, collection of data, identification of emerging health threats, and public information campaigns related to the safety of SoHOs. This SoHO expert network should provide information or advice in relation to relevant outbreaks of communicable diseases, in particular regarding the eligibility and testing of donors and the investigation of serious adverse occurrences involving suspected transmission of a communicable disease. (37)It is necessary to promote information and awareness campaigns at national and Union level on the importance of SoHOs. The aim of these campaigns should be to help European citizens to decide whether to become donors during their lifetime and let their families or legal representatives know their wishes regarding donation after death. As there is a need to ensure the availability of SoHOs for medical treatments, Member States should promote the donation of SoHOs, including plasma, of high quality and safety, thereby also increasing self-sufficiency in the Union. Member States are also urged to take steps to encourage a strong public and non-profit sector involvement in the provision of SoHO services, in particular for critical SoHOs and the related research and development. (38)In order to promote a coordinated application of this Regulation, a SoHO Coordination Board (SCB) should be set up. The Commission should participate in its activities and chair it. The SCB should contribute to a coordinating the application of this Regulation throughout the Union, including by helping Member States to conduct SoHO supervisory activities. The SCB should be composed of persons designated by the Member States based on their role and expertise in their competent authorities, and should also involve experts that are not working for competent authorities, for specific tasks where access to necessary in-depth technical expertise in the field of SoHOs is required. In the latter case, appropriate consideration should be given to the possibility of involving European expert bodies such as the ECDC and the EDQM and existing professional, scientific and donor and patient representative groups at Union level in the field of SoHOs. (39)Some substances, products or activities have been subject to different legal frameworks with different requirements in the Member States. This causes confusion among operators in the field, and the consequent legal uncertainty is a disincentive to professionals to develop new ways to prepare and use SoHOs. The SCB should receive relevant information on national decisions made on cases where questions were raised on the regulatory status of SoHOs. The SCB should keep a compendium of the opinions issued by the SCB or the competent authorities and of decisions made at Member State level, so that competent authorities considering the regulatory status under this Regulation of a particular substance, product or activity may inform their decision-making process by referring to that compendium. The SCB should also document agreed best practices to support a common Union approach. It should also cooperate with similar Union level bodies established in other Union legislation with a view to facilitating coordinated and coherent application of this Regulation between Member States and across bordering legislative frameworks. These measures should promote a coherent cross-sectoral approach and facilitate SoHO innovation. (40)The concept of a plasma master file (PMF) was established in Commission Directive 2003/63/EC. Since that Directive provided for a specific regulatory role for the European Medicines Agency (EMA) in relation to authorisation of plasma for fractionation, the SCB should also collaborate with the relevant EMA expert working groups to exchange experience and good practices so that criteria for the eligibility of donors of plasma for fractionation and of donors of blood for transfusion are implemented by Member States in a consistent and coherent way. (41)In order to limit administrative burden on competent authorities and the Commission, the latter should establish an online platform (the ‘EU SoHO Platform’) to facilitate timely submission of data and reports as well as improved transparency of national reporting and supervisory activities. (42)The processing of personal data under this Regulation should be subject to strict guarantees of confidentiality and should comply with the rules on the protection of personal data laid down in Regulation (EU) 2016/679 of the European Parliament and of the Council and in Regulation (EU) 2018/1725 of the European Parliament and of the Council . (43)As the EU SoHO Platform requires the processing of personal data, it will be designed respecting the principles of data protection. Any processing of personal data should be limited to achieving the objectives and obligations of this Regulation. Access to the EU SoHO Platform should be limited to the extent necessary to carry out supervisory activities provided for in this Regulation. (44)This Regulation respects the fundamental rights and observes the principles recognised in particular by the Charter of Fundamental Rights of the European Union and in particular human dignity, the integrity of the person, the protection of personal data, the freedom of art and science and to conduct business, non-discrimination, the right to health protection and access to health care, and the rights of the child. To achieve these aims, all supervisory and SoHO activities should always be carried out in a manner that fully respects those rights and principles. The right for dignity and integrity of donors, recipients and of offspring born from medically assisted reproduction should always be taken into account, amongst others, by ensuring that consent for donation is freely given and donors or their representatives are informed with regards to the intended use of the donated material, that donor eligibility criteria are based on scientific evidence, that the use of SoHOs in humans is not promoted for commercial purposes or with false or misleading information regarding efficacy so that the donors and recipients can make well-informed and deliberate choices, that activities are conducted in a transparent manner that prioritises the safety of donors and recipients, and that allocation and equitable access to SoHOs are defined in a transparent manner, on the basis of an objective evaluation of medical needs. This Regulation should therefore be applied accordingly. (45)SoHOs, by definition, relate to persons, and there are circumstances where the processing of personal data relating to donors and recipients may be necessary to achieve the objectives and requirements of this Regulation, especially provisions relating to vigilance and communication between competent authorities. This Regulation should provide a legal basis under Article 6 and, where relevant, fulfil the conditions under Article 9(2), point (i), of Regulation (EU) 2016/679 for processing of such personal data. With respect to personal data processed by the Commission, this Regulation should provide a legal basis under Article 5 and, where relevant, fulfil the conditions under Article 10(2), point (i), of Regulation (EU) 2018/1725. Data on safety and efficacy of new SoHO preparations in recipients should also be shared, with appropriate protective measures, to allow aggregation at Union level for more robust evidence gathering on the clinical efficacy of SoHO preparations. For all data processing, such processing should be necessary and appropriate with a view to ensuring compliance with this Regulation in order to protect human health. Data on donors, recipients and offspring should hence be limited to the minimum necessary and pseudonymised. donors, recipients and offspring should be informed of the processing of their personal data in line with the requirements of Regulations (EU) 2016/679 and (EU) 2018/1725, and in particular as provided for under this Regulation, including the possibility of exceptional cases where circumstances require such processing. (46)In order to enable better access to health data in the interests of public health, Member States should entrust competent authorities as data controllers within the meaning of Regulation (EU) 2016/679 with powers to take decisions on the access to and re-use of such data. (47)The exchange of SoHOs between Member States is necessary for ensuring optimal patient access and sufficiency of supply, particularly in the case of local crises or shortages. For certain SoHOs that need to be matched between the donor and the recipient, such exchanges are essential to allow patients to receive the treatment they need. In this context, the objective of this Regulation, namely to ensure quality and safety of SoHOs and a high level of protection of donors, needs to be achieved at Union level, by establishing high standards of quality and safety for SoHOs, based on a common set of requirements that are implemented in a consistent manner across the Union. Thus, the Union may adopt measures, in accordance with the principle of subsidiarity as set out in Article 5 of the Treaty on European Union. In accordance with the principle of proportionality, as set out in that Article, this Regulation does not go beyond what is necessary in order to achieve that objective. (48)In order to be able to supplement this Regulation where necessary with additional standards concerning the protection of donors, recipients and offspring from medically assisted reproduction to take into account technical and scientific developments in the field of SoHOs, and with additional rules on the authorisation of importing SoHO entities, on obligations and procedures for importing SoHO entities, on the organisation of Union training and exchange programmes, on technical specifications concerning the EU SoHO Platform, and on data protection, the power to adopt acts in accordance with Article 290 TFEU should be delegated to the Commission. It is of particular importance that the Commission carries out appropriate consultations during its preparatory work, including at expert level, and that those consultations be conducted in accordance with the principles laid down in the Interinstitutional Agreement of 13 April 2016 on Better Law-Making. In particular, to ensure equal participation in the preparation of delegated acts, the European Parliament and the Council receive all documents at the same time as Member States' experts, and their experts systematically have access to meetings of Commission expert groups dealing with the preparation of delegated acts. (49)In order to ensure uniform conditions for the implementation of this Regulation regarding the authorisation system for importing SoHO entities, the application for importing SoHO entity authorisations, the activity data collection and reporting by SoHO entities, the European coding system, the establishment, management and functioning of the SCB, and the general functionalities of the EU SoHO Platform, implementing powers should be conferred on the Commission. (50)In order to ensure uniform conditions for the implementation of this Regulation, including the determination of the regulatory status of a substance, product or activity, rules and practical arrangements in respect of the consultation and cooperation with competent authorities of other regulatory sectors, the national registers of SoHO entities, the registration process of SoHO entities, the SoHO preparation authorisation system and the authorisation of SoHO preparations, the SoHO establishment authorisation system, the inspections of SoHO establishments, the consultation and coordination related to vigilance, the quality management system for SoHO establishments, the implementation of the standards concerning the protection of donors, recipients and offspring from medically assisted reproduction, the national SoHO emergency plans, the tasks of the SoHO Coordination Board, and the transitional provisions concerning SoHO preparations, implementing powers should be conferred on the Commission. Those powers should be exercised in accordance with Regulation (EU) No 182/2011 of the European Parliament and of the Council. (51)Transitional provisions should be laid down in order to ensure a smooth transition from the former regimes for tissues and cells and for blood and blood components to this new Regulation, in particular in order to adapt practices to the new requirements, the changes in SoHO entities, SoHO establishments and SoHO preparations, and to avoid that donated SoHOs are discarded unnecessarily. A transitional regime for establishments already designated, authorised, accredited or licensed before the date of application of this Regulation should be introduced to ensure legal certainty and clarity. In particular, there should be clarity for the establishments concerned as regards their registration and authorisation status as well as their tasks and responsibilities under this Regulation, whilst allowing competent authorities additional time to transfer the relevant information to the systems introduced by this Regulation. To allow for a smooth transition, it is also appropriate that those preparation processes already authorised and lawfully used under the former regimes are still valid, and that SoHOs already collected and stored before the date of application of this Regulation may be used for a certain period of time. The European Data Protection Supervisor was consulted in accordance with Article 42(1) of Regulation (EU) 2018/1725 and delivered an opinion on … [date of the opinion], HAVE ADOPTED THIS REGULATION: CHAPTER I

GENERAL PROVISIONS Article 1 Subject matter This Regulation establishes measures setting high standards of quality and safety for all substances of human origin (‘SoHOs’) intended for human application and for activities related to those substances in order to ensure a high level of human health protection, in particular for SoHO donors, SoHO recipients and offspring from medically assisted reproduction. This Regulation is without prejudice to national legislation which establishes rules relating to aspects of SoHOs other than their quality and safety and the safety of SoHO donors. Article 2 Scope 1.This Regulation shall apply to SoHOs intended for human application, to SoHO preparations, to products manufactured from SoHOs and intended for human application, to SoHO donors and recipients, and to the following SoHO activities: (a)SoHO donor recruitment; (b)SoHO donor history review and eligibility assessment; (c)SoHO testing of donors for eligibility or matching purposes; (d)collection of SoHOs from donors or patients; (e)processing of SoHOs; (f)quality control testing of SoHOs; (g)storage of SoHOs; (h)SoHO release; (i)distribution of SoHOs; (j)import of SoHOs; (k)export of SoHOs; (l)human application of SoHOs; (m)SoHO clinical outcome monitoring.

2.In cases of autologous use of SoHOs where: (a)SoHOs are processed and stored before application, this Regulation shall apply in full; (b)SoHOs are processed and not stored before application, only the provisions on vigilance referred to in Article 35, on SoHO rapid alerts referred to in Article 36, on SoHO entity registration referred to in Article 37, on SoHO preparation authorisation referred to in Article 40, and on activity data collection and reporting referred to in Article 44 shall apply; (c)SoHOs are not processed and not stored before application, this Regulation shall not apply. 3.For SoHOs that are used to manufacture products in accordance with Union legislation on medical devices, regulated by Regulation (EU) 2017/745, on medicinal products, regulated by Regulation (EC) No 726/2004 and Directive 2001/83/EC, including on advanced therapy medicinal products, regulated by Regulation (EC) No 1394/2007, or on food, regulated by Regulation (EC) No 1925/2006, or as the starting and raw material thereof, the provisions of this Regulation applicable to the activities of SoHO donor recruitment, donor history review and eligibility assessment, testing of donors for eligibility or matching purposes, and collection of SoHOs from donors or patients shall apply. Insofar as the activities of SoHO release, distribution, import and export relate to SoHOs prior to their distribution to an operator regulated by the other Union legislation referred to in this subparagraph, the provisions of this Regulation shall also apply. By way of derogation from the first subparagraph, in cases where SoHOs, SoHO preparations, or products manufactured from SoHO, as referred to in that subparagraph, are exclusively for autologous use, only those provisions of this Regulation that concern the collection of SoHOs from patients shall apply. 4.Where non-viable SoHOs or their derivatives, as defined in Article 2, point (17), of Regulation (EU) 2017/745, incorporate, as an integral part, a medical device, and where the action of the non-viable SoHOs or their derivatives is principal and not ancillary to that of the device, the non-viable SoHOs or their derivatives shall be governed by this Regulation. If the action of the non-viable SoHOs or their derivatives is ancillary to that of the device and not principal, the provisions of this Regulation, insofar as they concern donor recruitment, donor history review and eligibility assessment, testing of donors for eligibility or matching purposes, collection of SoHOs from donors or patients, shall apply. Article 3 Definitions For the purpose of this Regulation the following definitions shall apply: (1)‘blood’ means the liquid that circulates in arteries and veins carrying oxygen to and carbon dioxide from the tissues of the body; (2)‘blood component’ means a constituent of blood such as red cells, white cells, platelets and plasma, that can be separated from it; (3)‘cell’ means a mass of cytoplasm with or without a nucleus, that is bound externally by a cell membrane. Usually microscopic in size, cells are the smallest structural and functional unit of an organism; (4)‘tissue’ means a group of cells that function together as a unit; (5)‘substance of human origin’ (SoHO) means any substance collected from the human body in whatever manner, whether it contains cells or not and whether those cells are living or not. For the purposes of this Regulation, SoHO does not include organs in the sense of Article 3, point (h), of Directive 2010/53/EU; (6)‘human application’ means inserted, implanted, injected, infused, transfused, transplanted, ingested, transferred (as in transfer to the uterus or fallopian tube of a woman), inseminated or otherwise added to the human body in order to create a biological, mechanical or physiological interaction with that body; (7)‘SoHO activity’ means an action, or series of actions, that has a direct impact on the safety, quality or efficacy of SoHOs, as listed in Article 2(1); (8)‘SoHO donor’ means any person who has presented themselves to a SoHO entity with a view to making a donation of SoHOs, whether that donation is successful or not; (9)‘SoHO recipient’ means the person to whom SoHOs are applied; (10)‘medically assisted reproduction’ means the facilitation of conception by intra-uterine insemination of sperm, in vitro fertilisation or any other laboratory or medical intervention that promotes conception;

(11)‘offspring from medically assisted reproduction’ means fetuses and children that are born following medically assisted reproduction; (12)‘SoHO preparation’ means a particular type of SoHO that: (a)has been subjected to one or more SoHO activities, including processing, in accordance with defined quality and safety parameters; (b)meets a pre-defined specification; and (c)is intended for application to a recipient for a specific clinical indication or is intended for distribution for manufacture of a product regulated by other Union legislation, or as the starting and raw material thereof; (13)‘donor recruitment’ means any activity aimed at encouraging persons to become SoHO donors; (14)‘collection’ means a process by which SoHOs are removed, procured, excreted, secreted or obtained by any other manner, including any preparatory steps, such as hormone treatment, needed to facilitate the process; (15)‘processing’ means any operation involved in the handling of SoHOs, including washing, shaping, separation, fertilisation, decontamination, sterilisation, preservation and packaging; (16)‘quality control’ means several tests or checks to confirm that a SoHO activity or SoHO preparation meets pre-defined quality criteria; (17)‘storage’ means the maintenance of SoHOs under appropriate controlled conditions until distribution; (18)‘release’ means a process through which it is verified that a SoHO or a SoHO preparation meets defined safety and quality criteria and the conditions of any applicable authorisation before distribution; (19)‘distribution’ means transportation and delivery, within the Union, of released SoHOs or SoHO preparations intended for human application or for the manufacture of products regulated under other Union legislation, or as the starting and raw material thereof, including within the same organisation when SoHOs are delivered from a SoHO entity to a unit responsible for human application; (20)‘import’ means activities carried out to bring SoHOs or SoHO preparations into the Union from a third country, including the organisation of such activities and physical verification of coherence with associated documentation, the appropriateness of transport conditions, the integrity of packaging and the adequacy of labelling before release; (21)‘export’ means distribution of SoHOs or SoHO preparations to third countries; (22)‘clinical outcome monitoring’ means evaluation of the health of a SoHO recipient for the purpose of monitoring the results of a SoHO preparation application, maintaining care and demonstrating safety and efficacy; (23)‘autologous use’ means collection of SoHO