EUROPEAN COMMISSION Brussels, 21.4.2016 SWD(2016) 127 final COMMISSION STAFF WORKING DOCUMENT on the implementation of Directives 2004/23/EC, 2006/17/EC and 2006/86/EC on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells Accompanying the document REPORT FROM THE COMMISSION TO THE EUROPEAN PARLIAMENT, THE COUNCIL, THE EUROPEAN ECONOMIC AND SOCIAL COMMITTEE AND THE COMMITTEE OF THE REGIONS on the implementation of Directives 2004/23/EC, 2006/17/EC and 2006/86/EC setting standards of quality and safety for human tissues and cells

{COM(2016) 223 final}

{SWD(2016) 128 final}



Table of Contents 1. Introduction 2. Implementation of the EU tissues and cells legislation 2.1. Designation of Competent Authority or Authorities Responsible for the Implementation of Directive 2004/23/EC 2.2 Obligations of Member States Authorities 2.2.1 Supervision of human tissue and cell procurement 2.2.2. Accreditation/designation/authorisation/licensing of tissue establishments and tissue and cell preparation processes 2.2.3. Inspections and control measures 2.2.4 Traceability 2.2.5 Import/export of human tissues and cells 2.2.6. Register of tissue establishments and reporting obligations 2.2.7. Notification of serious adverse events and reactions 2.3 Donor selection and evaluation 2.3.1. Principles governing tissue and cell donation (Art. 12) 2.3.2. Consent, data protection and confidentiality 2.3.3. Donor selection and evaluation. Procurement of tissues and cells 2.3.4 Donor testing

2.4 Quality and safety of tissues and cells 2.4.1 Quality management, responsible person, personnel 2.4.2. Tissue and cell reception, processing, storage, labelling and packaging 2.4.3. Distribution of tissues and cells for human application (Intra-community exchange) 2.4.4 Relations between tissue establishments and third parties Annex 1: Individual country responses to the survey on the implementation of the EU Tissues and Cells Directives conducted in 2012 and based on 2011 information A.1.1. Survey response Austria A.1.2. Survey response Belgium A.1.3. Survey response Bulgaria A.1.4. Survey response Croatia A.1.5. Survey response Cyprus A.1.6. Survey response Czech Republic A.1.7. Survey response Denmark A.1.8. Survey response Estonia A.1.9. Survey response Finland A.1.10. Survey response France A.1.11. Survey response Germany A.1.12. Survey response Greece A.1.13. Survey response Hungary A.1.14. Survey response Ireland

A.1.15. Survey response Italy A.1.16. Survey response Latvia A.1.17. Survey response Liechtenstein A.1.18. Survey response Lithuania A.1.19. Survey response Luxembourg A.1.20. Survey response Malta A.1.21. Survey response Netherlands A.1.22. Survey response Norway A.1.23. Survey response Poland A.1.24. Survey response Portugal A.1.25. Survey response Romania A.1.26. Survey response Slovakia A.1.27. Survey response Slovenia A.1.28. Survey response Spain A.1.29. Survey response Sweden A.1.30. Survey response United Kingdom





ABBREVIATIONS ART = assisted reproductive technologies ATMP = advanced therapies medicinal products CMV = cytomegalovirus DBM = demineralised bone matrix EBV = Epstein–Barr virus EBMT = European Group for Blood and Marrow Transplantation EC = European Commission ECDC = European Centre for Disease Prevention and Control EEA = European Economic Area EU = European Union GMP = good manufacturing practices GTP = good tissue practices HBV = hepatitis B virus HCV = hepatitis C virus HSC = haematopoietic stem cells HIV = human immunodeficiency virus HFEA = Human Fertility and Embryology Authority HLA = human leukocyte antigen HTA = Human Tissue Authority

HTLV = human T-cell lymphotropic virus IgM = immunoglobulin M ISO = International Organization for Standardization JACIE = Joint Accreditation Committee-ISCT & EBMT NAT = nucleic acid amplification test PBSC = peripheral blood stem cells RATC = Rapid Alerts for Tissues and Cells SAE = serious adverse event SAR = serious adverse reaction SARE = serious adverse reactions and events SOP = standard operating procedures Member State and country codes: http://publications.europa.eu/code/en/en-370100.htm





1. Introduction This Staff Working Document accompanying the Report from the Commission to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions on the implementation of Directives 2004/23/EC, 2006/17/EC and 2006/86/EC setting standards of quality and safety for human tissues and cells summarises the results of a Commission survey on the implementation of the EU tissue and cell legislation conducted in 2013. The data reported was from 2011. The implementation survey was answered by all Member States except Greece, and also by two EEA countries, Liechtenstein and Norway. The individual country responses are included in Annex 1 to this document. Only Greece did not provide any information. Overall the cooperation with the Member States was satisfactory reflecting the very good interaction between the Commission services and the Member States in this area. This document addresses only the implementation of the EU tissues and cells legislation, whereas the outcome of the verification of completeness of transposition performed by the Commission is summarised in the overall Report on the implementation of the EU tissue and cell legislation. Information on the application of the principle of voluntary and unpaid donation (VUD) is presented in a separate Staff Working Document also accompanying the abovementioned Report. The implementation section of this document follows the structure of Directive 2004/23/EC, and includes three main chapters which address the obligations of Member States' authorities, donor selection and evaluation, and quality and safety of tissues and cells. 2. Implementation of the EU tissues and cells legislation The implementation survey covers a broad range of topics: 1. designation of competent authorities, 2. obligations of Member States’ authorities, 3. donor selection and evaluation, and 4. quality and safety of tissues and cells. Each sub-section ends with comments summarising the main findings. Overall, the implementation of the EU tissues and cells legislation by Member States is considered adequate. However, a number of Member States reported difficulties in the interpretation, implementation or enforcement of some of its requirements. As the EU legislation in the tissue and cell sector does not provide for full harmonisation, Member States had various approaches when implementing its provisions. These differences facilitate successful integration of the requirements into national legislation but in some cases they may limit the mutual acceptance of authorisations with consequences on the cross-border movement of tissues and cells. 2.1. Designation of Competent Authority or Authorities Responsible for the Implementation of Directive 2004/23/EC In the 2010 Communication on the application of Directive 2004/23/EC it was stated that all Member States had designated a competent authority in accordance with the provision laid down in Article 4(1), with 21 Member States having one competent authority responsible for all types of tissues and cells and five Member States (EL, FI, FR, PT, UK) with a specific competent authority for reproductive tissues and cells. The 2013 survey revealed some organisational changes in the Member States (Table I, Figure 1): In 15 Member States (AT, BE, BG, DE, DK, EE, FI, HR, HU, IE, LU, LV, MT, SI, SK) and Liechtenstein, there is only one competent authority; Four Member States (CZ, ES, RO, UK) reported that two competent authorities were designated in their countries. In the Czech Republic, while the main competent authority is responsible for tissue establishments’ authorisation and inspection, as well as vigilance, a second competent authority is in charge of granting import and export licences, European affairs and various aspects related to the national legislation. In the United Kingdom one competent authority is overseeing the traditional tissues and cells, and the other is responsible for the supervision in the Assisted Reproductive Technologies (ART) sector. In Romania one authority is mainly responsible for the accreditation of the tissue establishments, while a second one is in charge of inspections and vigilance. In Spain, the organisation is similar to the one in the United Kingdom, but the national ART competent authority has only a consultative role, whereas the authorisation, inspection and vigilance tasks were delegated to the regions; Six Member States (FR, LT, NL, PL, PT, SE) and Norway reported that three competent authorities were designated to oversee the tissues and cells field at national level; In France, Portugal and UK one of the competent authorities is responsible only for the oversight of the ART sector; Five Member States declared having regional competent authorities, namely DE, ES, FR, IT and SK. These authorities have been entrusted with tasks like accreditation/ authorisation/designation/licensing of tissue establishments, inspection and/or vigilance. In Italy regional authorities are responsible only for authorising the tissue establishments.

Fig. 1. Tissues and cells competent authorities in the reporting EU Member States and EEA countries In two Member States the designated competent authorities do not cover all the categories of tissues and cells as requested by the Directives. This is the case of Poland and Lithuania, where, due to an inappropriate transposition of the EU legislation in the ART sector, no competent authorities responsible for this particular field were reported. In addition to the oversight of the tissues and cells sector, in most of the Member States, the tissues and cells competent authorities are also supervising other sectors/activities (Figure 2). Table I. Tissues and cells national competent authorities Fig. 2. Other responsibilities of tissues and cells competent authorities Several Member States provided clarifications on the tasks and responsibilities of their national competent authorities. Germany and Ireland specified that they are also responsible for advanced therapy medicinal products and xenogenic medicinal products. Furthermore, some Member States reported that their competent authorities are also responsible for: cosmetic products, veterinary products (France, Ireland); tattoo inks, biocides, ancillary products, human breast milk (France); clinical trials approval, protection of animals (Ireland); data collection and traceability (Italy); licensing of import-export activities (Czech Republic, Poland); licensing organisations that remove, store, and use human tissue for purposes outside direct patient treatment (United Kingdom/HTA); public health regulation (Malta); policy development and implementation (Denmark, Ireland, United Kingdom); providing training programmes, international cooperation, relation with the media, research projects, transplant registries, promotion and education (Spain, Italy); enforcement (Ireland). Certainly the designation of the competent authority or authorities in the field of human tissues and cells for human application is a prerogative of the Member States and EEA countries. As demonstrated by the reported data, many national competent authorities are ministries or agencies or delegated bodies in the health sector. In some countries the nominated organisations also work on research, education or labour issues. Some countries with federal organisations have entrusted some important responsibilities (e.g. authorisation and inspection of tissue establishments) to the regional authorities. Whereas some Member States preferred to pool national capability in one large national competent authority usually responsible for several/all healthcare sectors, other countries chose to develop expertise by creating/maintaining distinct organisations dedicated to oversee the human tissues and cells sector or a specific area of this sector (e.g. ART). Irrespective of organisational structure, the bi-annual meetings of the tissues and cells competent authorities allow for sharing best practices, with specialised authorities giving significant input in their particular area of expertise and the others contributing with integrative standpoints within the broader context of the healthcare sector, especially when analysing borderline issues like those with the medical devices and medicinal products sectors. Comments All Member States have appointed competent authorities for tissues and cells, which can be considered satisfactory. In some Member States more than one authority is responsible for the oversight of the tissue and cell sector. In these cases the division of tasks is based on the tissue types concerned (e.g. separate authority for the ART sector), geographic competences (federal/regional/local) or instruments used (e.g. authorisation/inspection). In some Member States the authorities for tissues and cells are also responsible for the oversight of other sectors (e.g. organs, blood, medicinal products), which can be beneficial from an efficiency point of view. Ultimately it is for the Member States to decide on the organisational set-up of their competent authorities. However, Member States need to ensure adequate coordination and communication between all authorities involved, e.g. to discuss borderline issues or ensure adequate follow-up in case of shortcomings. Irrespective of the organisational set-up it is important that all authorities have adequate resources at their disposal and are independent from industry, from the professional sector and other influences. In this respect it could be problematic if one and the same person works for a national competent authority and – at the same time – for a national tissue establishment. 2.2 Obligations of Member States Authorities Directive 2004/23/EC contains a number of obligations for competent authorities. They relate to (1) the supervision of procurement, (2) the authorisation of tissue establishments, (3) inspections and control measures, (4) traceability, (5) imports and exports, (6) reporting obligations and (7) notification of serious adverse events and reactions. The implementation of these obligations is set out in this section. 2.2.1 Supervision of human tissue and cell procurement Under Article 5 of the Directive 2004/23/EC, the competent authority or authorities must ensure that tissue and cell procurement and testing are carried out in conditions accredited, designated, authorised or licensed for this purpose and that it complies with the requirements laid down in Directive 2006/17/EC. The survey showed that all reporting Member States authorise the conditions of procurement, as follows: Twelve Member States (BG, CY, CZ, DE, ES, FI, HR, HU, IE, LU, MT, SI) and Liechtenstein authorise the conditions of procurement by inspecting all procurement centres;

Seven Member States (AT, DK, IT, PL, PT, SE, UK) reported inspecting some procurement centres; Nineteen Member States (AT, BE, BG, CY, DE, DK, EE, HR, HU, IT, LT, LU, LV, MT, NL, PL, PT, SE, UK) and Norway evaluate the documentation associated with the procurement made available by the tissue establishment working with procurement centres. Additionally, Member States reported other practices: Procurement sites have to be listed on the tissue establishment’s licence and inspected during routine inspections (Finland); Procurement activities are evaluated during the product evaluation, where documentation has to include a description of the procurement conditions (France); Procurement centres which operate through a third party agreement with a licensed establishment are not inspected by the national competent authority (United Kingdom). Estonia specified that only tissue establishments and healthcare professionals having contracts with tissue establishments are allowed to procure tissues. Ireland reported that when procurement occurs in Ireland, the activity is inspected and the site requires a tissue establishment authorisation; if the procurement occurs outside Ireland, the relevant documentation is inspected onsite at the Irish tissue establishment. Similar to Ireland, in Belgium procurement can be carried out only by authorised tissue establishments. Romania reported that one competent authority is responsible for evaluating the documentation of all the procurement centres, while the other authority is responsible for their inspection. Spain informed that the task of supervising human tissue and cell procurement was entrusted to the regional competent authorities. In 2011, 20 Member States and Liechtenstein and Norway, granted 640 authorisations for the conditions of procurement (Figure 3). Six Member States (FI, IE, LU, LV, PT, SE) did not grant any authorisation and in two Member States (Greece and Italy) such data were not available. Fig. 3. Number of authorisations for conditions of procurement granted in 2011 Most of the Member States provided the number of centres carrying out procurement activities in 2011. Of the 4825 procurement organisations carrying out procurement activities, most of them are dedicated to the collection of haematopoietic stem cells, followed by procurement of replacement tissues and reproductive cells (Figure 4). It has to be underlined that a number of 332 procurement organisations harvesting cells or tissues to be used for advanced therapy medicinal product (ATMP) manufacturing were also reported. A detailed analysis of the procurement organisations per Member State and type of tissues procured is presented in Figures 5 - 8. Fig. 4. Number of procurement organisations reported by the EU and EEA countries (2011 data) Fig. 5. Number of centres carrying out procurement of replacement tissues (e.g. musculoskeletal, cardiovascular, ocular tissue, skin) in 2011 Fig. 6. Number of centres carrying out procurement of HSC (e.g. bone marrow, peripheral blood stem cells, cord blood) in 2011

Fig. 7. Number of centres carrying out procurement of reproductive tissues and cells in 2011 Fig. 8. Number of centres carrying out procurement of tissues and/or cells for ATMP manufacturing in 2011 The survey revealed that all reporting Member States ensure that centres carrying out procurement of human tissues and cells centres comply with the requirements of Article 5 of Directive 2004/23/EC and its implementing Directive 2006/17/EC. Their approaches vary, with Member States only inspecting the site/centre, others only analysing the mandatory documentation (Belgium, Denmark), and most of them performing both inspections and analysis of the mandatory documentation (Fig 9). Fig. 9. Member States’ approaches for ensuring that centres carrying out procurement of human tissues and cells comply with the EU legal requirements Additional procedures were also reported. In Sweden tissue establishments perform audits of the procurement centre(s) and the audit reports are examined during the inspection of the tissue establishment. The competent authority in the United Kingdom (HTA) reported investigating allegations about non-compliance with procurement standards; moreover, to ensure continued compliance, correspondence is circulated to the sector (e.g. newsletter) and regular workshops are organised for updating the tissue establishments on the latest regulatory requirements. According to Article 5(1) of Directive 2004/23/EC Member States have to ensure that testing is carried out in conditions accredited, designated, authorised or licensed for this purpose. The survey showed that only in 10 Member States (CZ, DE, DK, HR, LU, MT, NL, RO, UK) and Liechtenstein and Norway, the tissues and cells competent authorities are also responsible for the accreditation/designation/authorisation or licensing of testing laboratories. In all the other Member States this is the competence of other authorities (Table II), as follows: Ministry of Health (Cyprus, Slovenia); Regional authorities (DE, ES, FI, HU, IT); National accreditation organisations.

Country Name of the national accreditation organisation BE Scientific Institute for Public Health BG Bulgarian Service for Accreditation EE Estonian Accreditation Centre FI National Institute for Health and Welfare FR Comité Français d'Accréditation IE Irish National Accreditation Board LV Latvian National Accreditation Bureau PL National Chamber of Diagnostic Laboratories PT Direcao-General de Saude SE The Swedish Board for Accreditation and Conformity Assessment SK Slovak National Accreditation Service UK Clinical Pathology Accreditation (private organisation, providing a voluntary national accreditation service) Table II. National accreditation organisation responsible for the accreditation/designation/ authorisation or licensing of testing laboratories Additionally, Malta, Romania and Liechtenstein reported that in their countries the tissues and cells competent authorities are responsible for the laboratories' accreditation, without being responsible for inspecting them. Austria reported having no national provisions on accreditation of testing laboratories. The Member States' approaches for ensuring that tests required for donors are carried out only by qualified laboratories accredited, designated, authorised or licensed in conformity with Article 5(2) of Directive 2004/23/EC are shown in Figure 10. Concerning the inspection of the testing laboratories, while in the Czech Republic, Denmark and the United Kingdom the tissues and cells competent authorities are also responsible for the laboratories' accreditation, in Hungary, Portugal and Spain this task is not in their remit. Eleven Member States also provided the number of qualified laboratories in their countries (2011 data) (Figure 11). Overall, the answers to this section of the questionnaire showed that Member States pay strict attention to the procurement of human tissues and cells. This is underlined by the fact that several countries allow procurement to be performed only by tissue establishments (BE, DE, EE, IT, SE) or authorise the conditions of procurement by inspecting all procurement centres (BG, CY, CZ, DE, ES, FI, HR, HU, IE, LU, MT, SI and LI). Additionally, in most of the responding countries, the documentation associated with the procurement is analysed during tissue establishments’ inspections. Fig. 10. Member States approaches for ensuring that donors’ testing is carried out in conformity with Article 5.2 of the Directive 2004/23/EC Fig. 11. Number of qualified testing laboratories/Member State (Total number = 421 – 2011 data) Comments The high number of procurement organisations shows that this activity is well developed across the Union, particularly in the larger Member States with tradition in this field (e.g. DE, FR, IT, UK). Furthermore, beside procurement of replacement tissues, haematopoietic stem cells and reproductive cells, some Member States also reported a significant number of centres carrying out procurement of tissue and cells for ATMP manufacturing. Concerning testing, the survey showed that in most of the reporting countries accreditation/designation/authorisation or licensing of testing laboratories is not under the competence of tissues and cells authorities. In most of the cases the national accreditation organisations are also responsible for the inspection of the testing laboratories. However, only the countries in which tissues and cells competent authorities are also responsible for the accreditation/designation/authorisation or licensing of testing laboratories provided data on the number of qualified laboratories on their territory. Wherever accreditation and inspections are undertaken by different authorities, a good communication and coordination between respective authorities needs to be ensured. 2.2.2. Accreditation/designation/authorisation/licensing of tissue establishments and tissue and cell preparation processes Under Article 6(1) of Directive 2004/23/EC, Member States must have in place an appropriate mechanism to ensure that all tissue establishments where activities of testing, processing, preservation, storage and distribution of human tissues and cells intended for human applications are undertaken have been accredited, designated, authorised or licensed by a competent authority for the purpose of those activities. All Member States reported that for replacement tissues and cells (e.g. musculoskeletal tissue, cardiovascular tissues, ocular tissues, skin, haematopoietic stem cells) an accreditation/designation/authorisation/licensing system of tissue establishments is in place. In the ART sector, 25 Member States reported having an accreditation, designation, authorisation, licensing system also for the ART tissue establishments, while two Member States (Lithuania, Poland) are still in the process of organising their national oversight system for this area.

As reported by the Member States, inspections play a key role in the accreditation/ designation/authorisation/licensing process which varies from prior compulsory on-site inspections to desk-based review of documentation and routine inspections (Figure 12). In five Member States (ES-ART sector, FR, SE, SK, UK) and Norway inspection is not a prerequisite for the designation, authorisation, accreditation, or licensing of tissue establishments. Fig. 12. National requirements for accrediting/designating/authorising/licensing of tissue establishments Under Article 6(2), the competent authority or authorities must authorise the tissue and cell preparation processes which the tissue establishment is entitled to carry out. Compared with the 2008 data when only three Member States were conducting inspections solely for the purpose of authorising preparation processes, this second survey reveals that 14 Member States are now organising such inspections (Figure 13). In the other Member States, in the absence of specific authorisation systems, tissue and cell preparation processes are either authorised by reviewing applications of the submitted documentation or during a general inspection for the purpose of authorising a tissue establishment. Fig. 13. National systems for authorising tissue and cell preparation processes Two Member States, Croatia and the Netherlands, reported that a certification of the tissue establishment to a quality system standard provided by an external entity is also required. In other Member States (Cyprus, France and Spain), the certification by an external entity is optional, but recommended. In Italy there are different approaches depending on the type of tissues/cells: whereas haematopoietic stem cells centres are inspected in collaboration with JACIE and cord blood banks require ISO certification, for the other types of tissues and cells, no certification is required by law. Compared to 2008 when 1716 tissue establishments were accredited/designated/ authorised/licensed, the current survey showed that at 31/12/2011 a total of 2047 tissue establishments were accredited, designated, authorised or licensed in the EU (Figures 14 and 15). Fig. 14. Number of accredited/designated/authorised/licensed tissue establishments per type of human tissues and cells (2011 data) Fig. 15. Number of accredited/designated/authorised/licensed tissue establishments per type of human tissues and cells (comparative data) The numbers of accredited/designated/authorised/licensed tissue establishments per country are presented in Figure 16. Only one Member State, namely Malta, reported having no authorised tissue establishments on their territory. Norway provided no information on the number of tissue establishments. Fig. 16. The number of accredited/designated/authorised/licensed tissue establishments/country (2011 data) Additionally in 2011, 1674 tissue establishments were authorised/re-authorised by competent authorities in 26 Member States (AT, BE, BG, CY, CZ, DE, DK, EE, FI, FR, HR, HU, IE, IT, LT, LU, LV, MT, NL, PL, PT, RO, SE, SI, SK, UK ) and Liechtenstein. Eighteen Member States (AT, BE, BG, CY, CZ, DE, FR, HR, HU, IE, IT, LV, MT, PL, RO, SI, SK, UK) and Liechtenstein indicated that 528 tissue establishments were pending approval of authorisation/re-authorisation at 31/12/2011. Information on the status of the tissue establishments (public vs. private) was provided by 25 Member States and Liechtenstein. The situation is summarised in Figures 17 and 18. Two other countries, Spain and Norway, indicated that such data are not available. Fig. 17.Tissue establishments’ status (public vs. private)/country (2011 data)

Fig. 18.Tissue establishments’ status (public vs. private)/type of tissue (2011 data) Overall, 916 public and 828 private accredited/designated/authorised/licensed tissue establishments were reported. As shown in Figure 18, only in the ART field and the cord blood sector the number of private tissue establishments exceeds the number of the public ones (69% and 59% respectively). Some interesting mixed models have emerged such as the tissue sector in Italy, where the private sector role is limited to that of a third party for processing or storage, with all donation, promotion and distribution activities remaining in public hands. Under Article 6(5), competent authorities may agree to the direct distribution of tissues and cells for immediate transplantation to a recipient. Six Member States (CY, DE, DK, LT, FR, PT) indicated that in 2011 tissues and/or cells were distributed under the direct agreement of an competent authorities. In most of the cases, these were HSC (bone marrow, PBSC, cord blood, donor lymphocyte infusion), but also ocular tissues (Denmark, Portugal), heart valves (Portugal), musculoskeletal tissue (Lithuania, Portugal) and amniotic membrane (Portugal). Comments The importance of the tissue and cell sector was demonstrated by its development in the last three years, with an almost 20% increase in the number of authorised tissue establishments compared with the previous survey. In two areas (musculoskeletal tissues and reproductive cells) a significant rise in the tissue establishments’ number was noted, whereas for other types of tissues and cells the number of authorised tissue establishments slightly decreased. Additionally, if for most types of tissues and cells the public sector prevails, in the field of ART approximately 60% of the ART establishments belong to the private sector. The development of the private sector is more significant in some Member States (e.g. the Netherlands), while in others (e.g. BG, CZ, DE, RO) is due to the expansion of private ART establishments and cord blood banks. Summing up, the answers concerning the accreditation/designation/authorisation/licensing of tissue establishments and tissue and cell preparation processes showed that this core responsibility is well implemented across the Union. However, when the survey was launched, two Member States were still in the process of transposing into national legislation the requirements for safety and quality in the ART field, and one Member State had no operational competent authority and submitted no replies to the implementation questionnaire. The survey showed that the authorisation process is quite heterogeneous, which may hinder the process of mutual acceptance of authorisations between EU Member States. Even though half of the responding Member States require a prior on-site inspection, most of the countries grant a tissue establishment authorisation/accreditation/licence based on a desk-based review of the documentation. Additionally, depending on the Member State's approach, tissue establishments’ authorisations/accreditations/licences are granted for a limited or unlimited time interval. A combination of approaches was also reported for authorising tissue and cell preparation processes. Numerous recent technological developments which generated new processing methodologies, unheard of a decade ago (e.g. pre-cutting of corneas with the transplant of only the anterior or posterior segment to one patient, decellularisation of skin and heart valves, new pathogen inactivation or sterilisation techniques) have increased the importance of robust preparation process authorisation. As suggested by some Member States, a more harmonised procedure and/or establishing an EU authorisation template for preparation process authorisation may contribute to reaching mutual acceptance between Member States. While it is for Member States to decide which terminology to use for the initial permission to operate as a tissue establishment, it should be transparent and mutually clear for competent authorities that the requirements of the EU legislation have been met in every Member State. The differences in terminology used might create some confusion, in particular as some of these terms (e.g., accreditation) are also used to describe reviews by private, non-governmental entities. Overall, the survey shows that it is important that all Member States continue improving their practices on authorisation, accreditation, licensing and designation according to the EU legislation. 2.2.3. Inspections and control measures Under Article 7(1) of Directive 2004/23/EC, Member States must ensure that the competent authority or authorities organise inspections and that the tissue establishments carry out appropriate control measures. As reported in the first implementation survey, most of the countries have comprehensive inspection systems place. Twenty-four Member States (AT, BE, BG, CY, DE, DK, EE, ES, FI, FR, HR, HU, IE, IT, LU, LV, MT, NL, PL, PT, RO, SE, SI, UK) and Liechtenstein and Norway confirmed the existence of such systems (Table III).

AT Austrian Agency for Health and Food Safety (AGES) BE Directorate General Inspection of FAMHP BG National Transplant Agency - Department "Registers, information, control and development of transplant" CY Ministry of Health CZ Clinical Practice and Surveillance over Biological Material Processing (part of Inspection Division) DE Regional competent authorities in the German Länder supported by the Paul-Ehrlich-Institute. DK Danish Medicines and Medicines Authority EE State Agency of Medicines, Department of Biologicals within the structure of the agency. ES Regional competent authorities. FI Fimea’s Inspectorate unit within the "Supervision and licenses Department" FR ANSM (INSBIO Department) - for non-reproductive tissues and cells. Regional agencies - for ART establishments HR Ministry of Health - Service for Blood, Tissues and Cells Inspection HU Officers of the National Public Health and Medical Officer Service - Office of the Chief Medical Officer, Department of Health Administration IE Irish Medicines Board - Compliance department IT CNT - Tissue and Cell section. For HPC and cord blood banks inspections are carried out in collaboration with CNS. LI Arzneimittelkontrolle, for coordination and the Swissmedic inspectorate by agreement. LT Legal and Supervisory Division of the National Transplant Bureau under the Ministry of Health of Lithuania LU Ministère de la santé - Division de la médecine curative. LV State Agency of Medicines - Pharmaceutical activities compliance evaluation department MT Superintendence of Public Health NL Health Care Inspectorate NO Norwegian Board of Health Supervision PL National Centre for Tissue and Cell Banking PT DGS - Departamento da Qualidade na Saúde, for non-reproductive tissues. Ministry of Health' administrative body for Health Inspections (IGAS) in collaboration with CNPMA, for ART establishments. RO Ministry of Health - State Sanitary Inspectorate SE The Health and Social Care Inspectorate SI Agency for Medicinal Products and Medical Devices SK In preparation UK HTA - Regulation directorate for tissue establishments handling non-reproductive tissues and cells and reproductive tissues. HFEA - Directorate of Compliance - for ART establishments Table III. Competent authorities responsible for inspections (2011 data) One Member State, Slovakia, is currently developing/revising the inspection system at national level. Most Member States reported that tissue establishment inspection schemes overlap or interact with inspections performed in other sectors (mostly blood, organs, medicinal products/advanced therapies (Figure 19). Only seven Member States (CY, HU, LT, LU, PL, PT, SK) and Liechtenstein indicated having in place national inspection schemes dedicated only to tissue establishments. 19. Overlaps of the tissue establishment inspection schemes Twenty-five Member States provided data on the staffing of inspection departments within the national competent authorities (Figure 20) and the number of inspections performed in 2011 (Figures 21a and 22a), as well as their outcome (Figures 21b and 22b). Fig. 20. Number of inspectors/Member State (numbers provided by FR, HU, RO and SE include also the inspectors in the regional authorities) For Spain, where inspection was entrusted to the competent authorities in the autonomous regions, no data on either staffing or the number of inspections performed in 2011 were provided. Germany indicated that inspections are carried out by the regional competent authorities of the German Länder, supported by the national competent authority and provided data only on the number of inspections performed in 2011. Additionally, France specified that for the ART sector the regional agencies were given the task of inspecting the ART establishments, but the national authority is responsible for ensuring the appropriate training of the ART inspectors and for publishing an annual report on these inspections. Several Member States pointed out that inspections are carried out by inspectors of the national competent authority together with inspectors from the regional competent authorities (e.g. HU, IT, RO). Sweden reported that inspections are performed by the national competent authority together with inspectors from the regional offices. No information was received from Slovakia. Two Member States, France and the United Kingdom, provided data on the number of specialised inspectors for the ART establishments. Regarding staffing, 13 Member States (BE, DK, EE, HR, IE, LU, LV, MT, PL, PT, RO, SE, SI) and Liechtenstein specified that inspectors responsible for the inspection of tissue establishments are also in charge of performing inspections in other sectors (e.g. blood, organs, medicinal products, sanitary inspections). Regarding the number of inspections carried out in 2011, a number of 542 inspections of tissue establishments for non-reproductive tissues and cells was reported, as follows: 506 routine inspections; Four inspections following the communication of a serious adverse reaction (SAR) or event (SAE), and; 32 other inspections (enforcement inspections; inspections for new preparation processes; suspicion of illegal activities; verification of traceability and new activities; verification of corrective actions following a previous inspection; inspections due to a whistle-blower; inspection following moving to new premises). Regarding the outcome of these inspections, in 48 cases (9%) no shortcomings were noted, minor or major shortcomings were identified in 331 (61%) cases and 150 cases (28%) respectively, whereas in five cases inspections were followed by either suspension (four cases) or revocation of authorisation and closure of the tissue establishment (one case) (Figure 21b).

Fig. 21a. Number of authorised tissue establishments for non-reproductive tissues and cells and the number of inspections carried out in 2011 Fig. 21b. Outcome of the 2011 inspections of authorised tissue establishments for non-reproductive tissues and cells For the ART sector, 338 inspections were carried out in 2011 in 23 Member States as well as in Liechtenstein and Norway (Figure 22a). These included: - 305 routine inspections; - 8 inspections following the communication of a serious adverse reaction (SAR) or event (SAE) and; - 25 other inspections (e.g. following major organisational changes). The outcome of these inspections was as follows: in 63 cases no shortcomings were noted, minor or major shortcomings were identified in 243 cases and 131 cases respectively, whereas in six cases inspections were followed by either suspension (three cases) or revocation of authorisation and closure of the tissue establishments (three cases) (Figure 22b). Fig. 22a. Number of authorised ART establishments and the number of inspections carried out in 2011 Fig. 22b. Outcome of the 2011 inspections of authorised ART establishments Besides the abovementioned inspections, in 2011 inspections of procurement organisations outside the tissue establishments took place in 13 Member States (AT, BE, BG, CZ, DE, DK, FI, LU, MT, PL, PT, RO, SI) and Liechtenstein. Additionally, inspections of third parties were performed by 12 Member States (BE, BG, CZ, DE, FR, HR, IT, MT, NL, PL, RO, SI). Most of the Member States indicated a variety of reasons for which third party inspections were not performed (e.g. no legal obligation, lack of inspection capacity, few or no third party agreements, third parties are limited to testing laboratories which are licensed and inspected by other authorities, tissue establishments have to audit the third parties and the audit report is reviewed during routine inspections). Concerning the implementation of Article 7(2), 23 Member States confirmed respecting the required time interval between two inspections (two years). Moreover, Hungary informed that tissue establishments are inspected every year. Sweden indicated that all tissue establishments were authorised in 2010, and inspected for the first time in 2010 and 2011; thereafter the time interval between inspections has not exceeded two years. Four Member States (DK, HR, IT (only for the HPC and ART establishments) and NL) reported difficulties to fulfil this requirement mainly due to staffing problems within the national inspectorates. In response to the requirement of Article 7(5) of Directive 2004/23/EC, in August 2010, the Commission published the Operational manual for competent authorities on inspection of tissue and cell procurement and tissue establishments – Guidelines for inspection (Commission Decision 2010/453/EU). The Manual was translated in all the official languages. Even though the Manual is not legally binding, 22 Member States (AT, BE, BG, CY, CZ, DK, EE, ES, FI, HR, HU, IE, IT, LU, LV, MT, NL, PL, PT, RO, SI, SK), and Liechtenstein and Norway reported using this Manual at national level. DE reported that according to the national legislation, the manual is not mandatory, but it is recommended as a guideline. Four Member States (DE, LT, SE, UK) reported that national guidelines were developed and are currently used at national level. Twenty-five Member States (AT, BE, BG, CY, CZ, DE, DK, EE, ES, FI, FR, HR, HU, IE, IT, LT, LV, MT, NL, PL, PT, RO, SI SK, UK), and Liechtenstein and Norway, sent their inspectors to the training courses organised by the EU-funded projects EUSTITE and SOHO V&S and rated their usefulness and efficacy from good (three countries), to very good (ten countries) and essential (14 countries). Regarding inspections of procurement sites in third countries from where tissue and cell preparations were imported into the EU, only Germany and France indicated organising such inspections. Germany reported that the inspection in the third country was a requirement pursuant to section 72b of the German Medicinal Products Act, whereas France specified that, in some cases, the national competent authority was asked to verify the accuracy of the data provided by the exporting procurement centre to the French tissue establishments.

As laid down in Article 7(6) and in agreement with the national competent authorities in three Member States (Bulgaria, Czech Republic, and Spain), joint inspections with other Member States' competent authorities were organised. Bulgaria reported that a joint inspection was performed with the French competent authorities. Spain reported that the inspectors of the HTA inspected the Transplant Service Foundation (Spain) in relation to distribution of skin to the United Kingdom. Additionally, the United Kingdom reported a case where a Regulation Manager observed an inspection in Germany in 2012 following allegations made against a German tissue establishment about procurement without consent. In line with the provisions in Article 7(7) of Directive 2004/23/EC, four Member States (CZ, FR, NL, UK) requested or organised inspections of a tissue establishment located in another EU country, in collaboration with the competent authority(ies) from that Member State. The Czech Republic indicated that the purpose of the inspection was to exchange information and regulatory approaches, whereas for France's and Netherlands' competent authorities the objective was to substantiate the data provided by the tissue supplier in that Member State. Most of the Member States and Norway indicated an interest in developing joint inspections. Lack of resources and personnel are seen as the main obstacles for the five countries (CY, DK, FI, LU and LI) who declared having no interest in organising such inspections. Comments The analysis of the replies concerning inspections of tissue establishments indicates a good implementation of the Directives’ requirements. If in most cases minor or major shortcomings were recorded, only a few suspensions and revocations of authorisations were reported, showing that tissue establishments are striving to comply with the EU quality and safety requirements. Besides suggesting a high degree of compliance, which would be welcomed, the small number of suspensions/revocations may also indicate under-enforcement (e.g. in countries which have never reported any shortcomings). No data on the number of tissue establishments that voluntarily ceased operations or were forced to cease operations for other reasons (e.g. economic) were provided. Concerning the time interval between inspections, several Member States underlined the difficulty of performing inspections every two years. It was also suggested that instead of a fixed time interval, a risk-based approach may be equally valuable. The development of a risk assessment tool to prioritise inspections based on factors like the size of establishment, range of activity, experience of designated individuals responsible for oversight of the licence and compliance history was reported by some Member States. The heterogeneous practices reported (desk-based vs. on-site inspections, routine vs. non-routine inspections), the discrepancies in the number of inspectors and their training/expertise, or the impossibility to provide the number of staff in charge of inspections in the regional competent authorities may explain why an agreement on the mutual acceptance of inspections was not yet reached. Even though most of the Member States reported using the non-binding “Operational manual for competent authorities on inspection of tissue and cell procurement and tissue establishments” published by the Commission in 2010, it was suggested that the current practices in the Member States should be further analysed and addressed, so that shortcomings identified during inspections in different Member States (e.g. classification of minor, major and critical deficiencies) result in similar consequences for the inspected establishment (e.g. indications for a revocation or suspension for similar deficiencies). Concerning joint inspections, their outcome was in general satisfying and in particular allowed bringing expertise where this might be missing within their own Member State. 2.2.4 Traceability Member States must ensure that all tissue and cells procured, processed, stored or distributed on their territory can be traced from the donor to the recipient and vice versa. Additionally, Member States are required to implement a donor identification system which assigns a unique code to each donation and to each of the products associated with it (Article 8 of Directive 2004/23/EC and Article 9 and 10 of Directive 2006/86/EC). Twenty-three Member States (BE, BG, CY, CZ, DE, DK, FI, FR, HR, HU, IE, IT, LT, LU, LV, MT, NL, PL, PT, RO, SI, SK, UK) reported that a donor identification system was implemented in their countries. In most Member States, the unique code for each donation is assigned by the tissue establishment (BE, BG, CY, CZ, DK, EE, FI, FR, HR, HU, IE, LT, LU, LV, PL, PT), while in others by the procurement centre (DE, MT, SI, UK). Other approaches were also notified: Portugal reported that the donation identification system in the ART sector underwent changes since the last reporting exercise. Since the 1st of January 2013, the unique code for each donation has been allocated centrally by the ART competent authority (Conselho Nacional de Procriação Medicamente Assistida); Slovenia and Portugal (for the ART sector) specified that a national database was put in place, providing for an automatic allocation of donation numbers; Norway indicated that the donor identification is based on the national unique personal number identification system. Two Member States, Austria and Spain, as well as Liechtenstein, indicated having difficulties in implementing the provisions related to the donor identification system. Romania notified that the unique national donor identification system is under construction. Austria reported that the Federal Ministry of Health deferred the implementation of ISBT128 due to difficulties encountered during implementation, whereas in Spain and Liechtenstein, the requirements of Article 8 have been partially implemented (Art. 8.1), awaiting final guidance from the Commission regarding the implementation of the Single European Code. Article 8 also requires tissue establishments to keep the data ensuring full traceability for a minimum of 30 years. This requirement is fulfilled by all the Member States which reported to the Commission. In 25 Member States (AT, BE, BG, CY, CZ, DE, DK, EE, ES, FI, FR, HR, HU, IE, IT, LT, LU, MT, NL, PL, PT, RO, SE, SK, UK-HTA) and Norway it is mandatory to retain both paper and electronic records. For the ART sector, the UK (HFEA) indicated that records can be electronic or paper records. In Latvia, Slovenia and Liechtenstein this requirement is fulfilled only by keeping paper records. Member States have different approaches for ensuring the implementation of the provisions in Article 9 of Directive 86/2006/EC (e.g. data storage for 30 years). Most of the Member States (AT, BE, BG, CY, DE, DK, EE, FI, FR, IE, IT, LU, LV, MT, NL, PL, PT, SE, UK) and Liechtenstein and Norway reported verifying this requirement during routine inspections. In the United Kingdom, this requirement is also checked at the initial licence application stage. Austria, Croatia and the Czech Republic ask the tissue establishments to include appropriate procedures in their SOP. Spain specified that this requirement was not implemented in the ART sector. Comments

The survey showed that a donor identification system was implemented by most Member States, with the unique code for each donation being assigned predominantly by the tissue establishments. It has to be underlined that countries which reported difficulties in implementing the donation identification system were either developing a central allocation system or were waiting for the adoption of the implementing legislation introducing a Single European Code for tissues and cells. Moreover, most of the Member States reported that detailed coding requirements and a harmonised implementation of the Single European Code for tissues and cells is desirable and actively supported the development by the Commission of the new coding requirements, adopted in 2015. Regarding data storage, almost all Member States and EEA countries comply with the 30 years rule, by requesting both paper and electronic records and by verifying this requirement during routine inspections. 2.2.5 Import/export of human tissues and cells Under Article 9(1) of Directive 2004/23/EC, Member States must take all necessary measures to ensure that all imports of tissues and cells from third countries are undertaken by tissue establishments accredited, designated, authorised, licensed for the purpose of those activities and that imported tissues and cells can be traced from the donor to the recipient and vice versa. In 2008, only 11 Member States reported having clearly identified tissue establishments authorised to import tissues and cells. The current survey revealed that 16 Member States (AT, BE, BG, CY, CZ, DE, DK, EE, FI, FR, HR, PT, RO, SE, SI, UK), as well as Norway, have a register of tissue establishments that are explicitly authorised to perform import/export of tissues and cells from third countries and provided data on their number. According to the data provided by these countries for 2011, 297 tissue establishments were authorised to import and 306 were authorised to export tissues and cells from/to third countries. Compared to the previous report (2008 data) when 16 Members States reported importing tissues and/or cells, the current survey shows that more countries (22) were importing tissues and/or cells in 2011 (Figure 23). Fig. 23. Countries importing human tissues and cells for human application (2011 data) Twenty-two countries indicated that imports from third countries were carried out in 2011, but only 15 provided data on the type and volume of the imported tissues and cells (Figures 24 and 25). Only nine Member States also collect data on the source of imports (BE, CZ, EE, ES, FI, HR, IT, SI, UK/HFEA). According to the reported data, most of the imports were from USA, Australia, Canada, Israel, and Switzerland. Other countries mentioned were China/Hong Kong, Taiwan, Russia, Uruguay and Bosnia Herzegovina. Six Member States acknowledged importing tissues and cells, but could not provide data on the amount and type of tissues or cells imported, and one Member State (Germany) is collecting data without distinguishing between tissues and cells imported from third countries and those distributed from other EU Member States. Seven Member States (BG, CY, HU, LU, LV, RO, SK) and Liechtenstein reported that no imports of tissues and cells were carried out in 2011. Fig. 24. Type of tissues and cells imported (data reported for 2011 by 15 countries) Additionally, Germany reported that according to section 8d of the German Transplantation Act (TPG), all tissues entering Germany (both from third countries and EU Member States) must be notified to the Paul Ehrlich Institute, irrespective of their source (e.g. an EU Member State or a third country). In 2011, 45,073 units of tissues and cells entered Germany: 550 ocular tissue (cornea), 2,550 cardiovascular tissues (heart valves, vessels, and pericardium), 41, 648 musculoskeletal tissues (bone, cartilage, soft tissues), 325 reproductive cells (sperm), as well as 3,436,004 cm2 of skin. Fig. 25. Volume of tissues and cells imported (units of tissues or cells; 2011 data) Due to the heterogeneous approach in recording data for the import of human tissues and cells it is still difficult to quantify the amount of imports into the Union. Under Article 9(2), Member States must also take all necessary measures to ensure that all exports of tissues and cells to third countries are undertaken by tissue establishments accredited, designated, authorised or licensed for that purpose. Eighteen Member States (AT, BE, DE, DK, EE, ES, FI, FR, HR, IE, IT, MT, NL, PL, PT, SE, SI, UK) and Norway have a register of tissue establishments authorised to export tissues and cells to third countries. Fourteen Member States (AT, BG, CZ, EE, FI, HR, HU, LT, LU, LV, MT, RO, SI, SK) and Liechtenstein and Norway reported that no exports of tissues and cells occurred in 2011 (Figure 26).

Fig. 26. Tissue and cell exporting countries (2011 data) Overall 12,152 units of tissues and cells were reported as exported to third countries. Of the 11 countries exporting human tissue and/or cells in 2011, four specified that information on the country of destination is not collected by the national competent authority (CY, IE, SE, UK/HTA). The exporting countries, as well as the type and volume (in units) of tissues and cells exported, are shown in Figures 27 and 28. Fig. 27. Exporting countries - type of tissues and cells (data reported for 2011 by 11 countries) Fig. 28. Volume of tissues and cells exported (units of tissues or cells; 2011 data) Similarly to the data reported for imports, Germany specified that according to section 8d of the German Transplantation Act (TPG) there is no distinction between export to third countries and distribution to EU Member States, therefore all tissues and cells leaving Germany are reported to the Paul Ehrlich Institute on an annual basis. In 2011, 148,285 units were reported as sent to healthcare facilities outside Germany, as following: 188 ocular tissue (cornea, limbal cells), 2,131 cardiovascular tissues (pericardium), 144,373 musculoskeletal tissues (bone, cartilage, soft tissues), 130 other (amniotic membrane), 1,463 reproductive cells (sperm). Additionally, 2,825,092 cm2 of skin was also sent outside Germany. The competent authority or authorities may also authorise the import or export of tissues and cells in case of an emergency (Art 9.3b). Nine Member States (CY, DE, DK, HR, MT, NL, RO, SI, UK) and Norway, indicated that direct distribution of tissues and cells to a specific recipient was authorised in 2011 for haematopoietic stem cells and ocular tissues. Concerning the relation with self-sufficiency, the Member States approaches are different for import and export activities: For exporting tissues and/or cells: oBG, DK, ES, HR, IT, PL, PT, RO, SK reported that export of tissues and cells is authorised only after checking if local and/or national needs are fulfilled; oBulgaria and Latvia indicated that exportation is authorised based on estimations performed on an annual basis; oBE, CZ, DK, EE, HU, IT, PL, SE, SI, UK indicated that exportation of tissues and/or cells is authorised irrespective of national needs. For importing tissues and/or cells: oBG, DK, ES, HR, IE, IT, RO, and Norway reported that imports are authorised only after checking that local/national needs are not fulfilled; oBG, IE, PL, PT, SE and Norway specified that imports of tissues/cells are authorised based on estimations showing that there is chronic deficiency of those tissues/cells. Some Member States (Italy, Poland) acknowledged having a strict approach regarding tissues and cells coming from other EU Member States, which are treated like those imported from third countries. The United Kingdom informed that the Human Tissue Authority (HTA) provides specific online guidance for tissue establishments on import and export. Comments These data show that it would be useful for competent authorities to collect more comprehensive data on imports and exports of human tissues and cells through the tissue establishments' compulsory annual reports in accordance with Article 10(1), however, at this stage the reporting format is not harmonised.

The data provided, even though incomplete and sometimes ill-defined, confirm that more and more human tissues and cells - such as skin, bones, ocular tissues, heart valves, and haematopoietic stem cells - are imported from third countries or are exported for the benefit of patients outside the European Union. It has to be noted that it is difficult to draw conclusions regarding the volume of imports and exports of human tissues and cells due the absence of a harmonised framework for data collection in the Member States. It should be underlined that some level of harmonisation exists for such data due to the Eurocet project. However the fact that some countries do not distinguish between distribution within the European Union and import/export from/to third countries may be considered an important hurdle against data collection and analysis. In some countries the differences between the legal framework under which the tissue and cell legislation was transposed (e.g. transplantation vs. medicinal products legislation) may also contribute to the different datasets collected at national level. Furthermore, mostly due to their more stringent quality and safety requirements, some countries treat tissues and cells distributed by EU Member States and those imported from third countries in the same way. It is expected that the recently adopted legal requirements regarding the procedures for verifying the equivalent standards of quality and safety of imported tissues and cells will streamline the tissue and cells imports, and the collection of related data, guaranteeing the appropriate level of safety and quality across the Union. 2.2.6. Register of tissue establishments and reporting obligations Under Article 10(1) of Directive 2004/23/EC, tissue establishments must keep a record of their activities and submit an annual report to the competent authority or authorities, which should be publicly available. Twenty Member States (AT, BE, BG, DE, EE, ES, FI, HR, HU, IE, IT, LT, MT, PL, PT, RO, SE, SI, SK, UK) and Liechtenstein and Norway, have created an annual report model on the activities of tissue establishments that makes the reporting of the yearly activities by tissue establishments easier. All the reporting Member States receive annual reports from their tissue establishments corresponding to activities in the previous year(s). An overview of the number of tissue establishments providing data to the national competent authorities is presented in Figure 29. Fig. 29. Annual reporting by the tissue establishments (2011 data) It should be emphasised that the annual reports submitted by the tissue establishments are essential in providing a suitable indication of the activities carried out in the field as well as reference data for assessing the needs and risks in the tissue and cell transplantation field. Only nine Member States (BE, BG, CZ, ES, IT, MT, PL, RO, SE) and Norway, had made the tissue establishments' reports publicly available in 2012. For the Member States which did not make the tissue establishments’ reports available, the main reasons were that at the moment of submitting their replies to the implementation survey, legal provisions in their national legislation were absent (inappropriate transposition of Art. 10(1)) or there was an insufficient capacity at competent authority level. Under Article 10(2) of Directive 2004/23/EC, the competent authorities are responsible for maintaining a publicly accessible register of tissue establishments specifying the activities for which they have been accredited/designated/authorised/licensed. Twenty-five Member States and Norway indicated that they have a public register available (AT, BE, BG, CY, CZ, DE, DK, EE, ES, FI, FR, HR, HU, IE, IT, LT, LV, MT, NL, PL, PT, RO, SE, SI, UK). In most cases the annual reports and the register are accessible through the competent authorities' web pages (Table IV). Liechtenstein reported that there are no legal requirements in their national legislation concerning the publicly accessible register of tissue establishments. Luxembourg informed that the information is given on demand. In Slovakia, this register is under preparation. Table IV. Publicly accessible national registers of tissue establishments (2011 data) Under Article 10(3) of Directive 2004/23/EC, Member States and the Commission should establish a network linking the national tissue establishment registers. Until now this network was ensured through Eurocet7, which is a registry of national tissue establishments and activity reports managed by the Italian Competent Authority. Twenty-three Member States acknowledged that they also report data to Eurocet on a voluntary basis (AT, BE, BG, CY, CZ, DE, ES, FI, FR, HR, HU, IT, LT, LU, LV, MT, PL, PT, RO, SE, SI, SK UK). Three Member States (Denmark, Ireland, and Netherlands) and EEA countries do not usually report their data to Eurocet. In this respect, the Danish competent authority specified that data request for clinical information on tissues/cells is not part of their activities. Ireland informed that their competent authority (the Irish Medicines Board at the time) is not legally required to submit data regarding tissues and cells activity to the Eurocet registry and Netherlands declared that no raw data is readily accessible to the competent authority. Comments Overall, the Member States and the EEA countries comply with the requirements in Article 10 of Directive 2004/23/EC. National registers of tissues establishments are made available through the competent authorities' web pages and also via the Eurocet page. However, the tissue establishments’ reports are not publicly available in all the reporting countries, mainly due to an insufficient transposition of this provision into the national legislation which resulted in several pre-infringement procedures through the EU Pilot platform. If the issue of making the annual reports provided by the tissue establishments public can be dealt with only at national level, the new legal provisions for the application of the Single European Code shall also satisfy the requirement in Art 10(3), by establishing the EU Tissue Establishment Compendium including all the tissues establishments with their contact details and the status of their accreditation/designation/authorised or licence. By updating the data in this Compendium, the tissues and cells competent authorities demonstrate full transparency and provide support to healthcare professionals searching for a tissue or cell provider within the Union. Moreover, the inclusion in the EU Tissue Establishment Compendium will reinforce the credentials of the EU tissue establishments in front of their partners and customers around the world.

2.2.7. Notification of serious adverse events and reactions Under Article 11(1) of Directive 2004/23/EC, Member States must ensure that there is a system in place to report, investigate, register and transmit information about serious adverse events and reactions which may influence the quality and safety of tissues and cells and which may be attributed to the procurement, testing, processing, storage and distribution of tissues and cells. Serious adverse reactions observed during or after clinical application which may be linked to the quality and safety of tissues and cells should be also reported. The procedures for notifying serious adverse events and reactions were adopted in Commission Directive 2006/86/EC. AT Austrian Medicines and Medical Devices Agency (AGES) BE Federal Agency for Medicines and Health Products (FAMHP) BG Executive Agency for Transplantation (IAT) CY Ministry of Health CZ State Institute for Drug Control (Pharmacovigilance Department) DE Paul Ehrlich Institute (PEI) DK Danish Health and Medicines Authority EE State Agency of Medicines ES National Transplant Organisation (ONT), the competent authorities of the autonomous regions and the National Group of Biovigilance. FI Finnish Medicines Agency (Fimea) FR Agence de la Biomedicine (ABM) HR Ministry of Health HU National Public Health and Medical Officer Service - Office of the Chief Medical Officer (NPHMOS-OCMO) IE Irish Medicines Board (IMB) - Tissue & Cell Vigilance IT National Transplant Centre (CNT) LI Amt für Gesundheit LT National Transplant Bureau under the Ministry of Health LU Direction de la Santé LV State Agency of Medicines - Senior expert of Pharmaceutical Activities Compliance Evaluation Department MT The Directorate for Health Care Standards of the Superintendence of Public Health NL Health Care Inspectorate (IGZ) NO Norwegian Directorate of Health PL National Centre for Tissue and Cell Banking (for tissue establishments), Poltransplant and National Centre for Tissue and Cell Banking (for procurement and transplantation). PT Instituto Português do Sangue e da Transplantação (for non-reproductive tissues and cells) and Conselho Nacional de Procriação Medicamente Assistida (CNPMA - for the ART sector) RO Ministry of Health – the State Sanitary Inspectorate SE Health and Social Care Inspectorate SI Agency of Medicinal Products and Medical Devices of the Republic of Slovenia UK HTA (for non-reproductive tissues and cells) and HFEA (for the ART sector) Table V. Organisations responsible for tissue and cell vigilance (2011 data) All reporting Member States except for Slovakia have a national vigilance system in place. In most Member States vigilance falls under the responsibility of the main national competent authority, but in several Member States this is either delegated to the regional competent authorities (DE, ES) or specific bodies (NL - Health Care Inspectorate). An overview of the organisations responsible for tissue and cell vigilance in the reporting EU and EEA countries is included in Table V. Only in 15 Member States (AT, BE, CZ, DE, DK, ES, FI, FR, HU, IE, LT, MT, NL, PT, SI) and Liechtenstein and Norway, were dedicated vigilance officers appointed. In the other countries, this role is assigned to the tissues and cells inspectors. Additionally in the United Kingdom, for the ART sector the HFEA appointed a dedicated vigilance officer, whereas HTA reported having a dedicated team of Regulation Managers in place who assess SAREs from establishments. A Regulation Officer acts as the administrator and data manager for the team and the reporting system is monitored by the team on a 24-hour basis, and any reports received are responded to within 24 hours. Regarding the compliance of tissue establishments in reporting SAR and SAE to the national competent authorities, the percentage of the tissue establishments complying with this requirement (expressed as % from the total number of authorised tissue establishments at national level) is shown in Figure 30. The relatively large group of establishments that do not report SARE data is a point that requires further attention. Fig. 30. SAR/SAE reporting to the national competent authorities (2011 data) In addition, Italy informed that tissue establishments are required to report SAR/SAE as they occur and the competent authority compiles the annual report. However the tissue establishments must provide detailed information to transplant centres on how and when to report SAR/SAE and this is reviewed during routine inspection. A similar approach was reported by the United Kingdom competent authorities (HTA and HFEA), where tissue establishments have to report SAR/SAEs within 24 hours of their discovery, and not via an annual report. Most of the Member States (AT, BE, BG, CY, CZ, DE, DK, ES, FR, HR, HU, IE, LT, LV, MT, PL, PT, RO, SE, SI, UK-ART sector) and Liechtenstein and Norway confirmed having in place a mandatory procedure for SAR/SAE reporting by the transplantation centres to the distributing tissue establishments, this also being a requirement in their national legislation. Members States not having such a procedure in place have different approaches: In Estonia and Slovakia, reporting of SAR/SAE by the transplantation centres is obligatory by law; In Finland, Italy and Netherlands, when distributing tissues and/or cells, the tissue establishments are responsible for providing full instructions for reporting to the transplantation centres; In the United Kingdom, for non-reproductive tissues and cells and reproductive tissues, the SAREs reporting requirement is outlined in HTA standards. Establishments licensed by the HTA are required to have end-user agreements in place with transplantation centres, which include the requirement to report SAREs, and incident reporting is promoted and also monitored on inspection. Regarding recalls, all countries require their tissue establishments to have a recall procedure. Only four Member States (DK, EE, FR and UK) reported that recalls were issued by tissue establishments in their country for 2011. In accordance with Article 7(1) of Directive 2006/86/EC, Member States must submit to the Commission an annual report on the serious adverse reactions and events notified to the competent authority. Most of the Member States acknowledged using at national level the template (based on the Annexes of Directive 2006/86/EC). In seven Member States (BE, DE, FR, NL, PT, SI, UK) and Norway, a template and guidelines developed at national level are used. Twenty-two Member States (AT, BE, BG, EE, ES, FI, FR, HR, HU, IE, IT, LT, LU, MT, NL, PL, PT, RO, SE, SI, SK, UK) and Norway confirmed giving feedback to the tissue establishments regarding SAR/SAE recorded at national level. Nineteen Member States (BE, BG, EE, ES, FI, FR, HR, HU, IE, LT, LU, MT, PL, PT, RO, SE, SI, SK, UK) and Norway reported giving feedback to the tissue establishments regarding SAR/SAE recorded at EU level.

As regards communication of rapid alerts, 22 Member States (AT, BE, CY, DE, EE, ES, FI, FR, HR, HU, IE, LT, LU, LV, MT, NL, PL, PT, SE, SI, SK, UK) and Liechtenstein and Norway reported that a system/procedure is in place at national level for notifying tissue establishments and procurement sites in case of a national rapid alert or of a rapid alert issued via the EU RATC platform. Five Member States reported not having such a system/formal procedure: Bulgaria informed that the system is under construction and communication is done by email; The Czech Republic reported using the already established system for pharmaceuticals or medical devices; Denmark reported that the national system is effective in notifying the tissue establishments which thereafter are responsible for contacting the POs; Italy declared that no written procedure was formalised and rapid alerts are communicated by email on a case-by-case basis; Romania informed that a national procedure was under development, but the Ministry of Health is responsible for communicating the alerts issued via the EU RATC platform to the National Transplant Agency and the sanitary inspectors. Moreover, 21 Member States (AT, BE, CY, CZ, DE, DK, ES, FI, FR, HR, HU, IE, LT, MT, NL, PL, PT, RO, SE, SI, UK) circulate the alerts received via the tissues and cells national vigilance system, when relevant, to other national vigilance/alert systems (haemovigilance, pharmacovigilance, medical devices). Concerning training courses for the personnel in charge of vigilance at national/local level, 22 Member States (AT, BG, CY, DE, DK, EE, ES, FI, FR, HR, HU, IE, IT, LT, LV, MT, NL, PL, PT, RO, SI, UK) and Norway welcomed the organisation of specific courses at EU level. The training course organised by the SoHO V&S project was ranked as good (one Member State), very good (11 Member States) and excellent (ten Member States). Only five Member States (BE, CZ, LU, SE, SK) and Liechtenstein did not send their staff to these courses, mostly because of lack of time or turnover of personnel. Comments The importance of SARE reporting is confirmed by the interest of the Member States in collaborating with the Commission to improve the current reporting system (e.g. refine the SARE reporting templates for improving collection of data in the ART sector) and to expand communication with other countries and other sectors (e.g. foster cooperation with relevant third countries with regard to SAR/SAE reporting, establishment of an interface for SARE reporting to other product areas, such as medical devices used throughout the donation-clinical application chain. Nevertheless, the aim of the annual reporting to the Commission is to identify the most frequent causes of SAR/SAE allowing for the development of appropriate corrective measures, which will ultimately make the medical application of human tissues and cells safer. In this context, because many errors are not always reported voluntarily or are discovered at a later stage and not reported in a timely manner, the corrective measures may not be made in a timely manner. Additionally, the “root causes” of these SARE/SAE should be correctly identified, analysed and reported with enough level of detail in order to allow for a complete description of the practices/factors which may lead to systematic errors. Moreover, underreporting and accurate data collection remain two objectives which need to be addressed at all levels, from clinical practitioners and tissue establishment staff to competent authorities. Something that has to be emphasised is the support of the Member States' authorities in the development of the Rapid Alerts for Tissues and Cells (RATC) launched by the Commission in February 2013, which allows national health authorities to exchange, in a timely manner, urgent information in case of alerts (including SAR/SAE) relating to human tissues or cells transferred between Member States. The first annual summary report of the RATC platform published in August 2014 showed an increase in the number of the alerts initiated by the national vigilance contact points, the platform providing wider possibilities of communication and information dissemination with the choice of contacting single or groups of national competent authorities. 2.3 Donor selection and evaluation Directives 2004/23/EC and 2006/17/EC contain a number of requirements regarding donor selection and evaluation. They relate to (1) principles governing tissue and cell donation, (2) consent, data protection and confidentiality the authorisation of tissue establishments, (3) donor selection and evaluation and procurement of tissues/cells, (4) testing of tissue and cell donors. 2.3.1. Principles governing tissue and cell donation (Art. 12) Under Article 12(1) of Directive 2004/23/EC, Member States must endeavour to ensure voluntary unpaid donations of tissues and cells. Donors may receive compensation strictly limited to making good the related inconveniences. In such cases, Member States must define the conditions under which compensation may be granted. Member States must regularly submit reports on these measures to the Commission. On the basis of these reports the Commission will inform the European Parliament and the Council of any necessary measures it intends to take. The results of the 2014 survey performed by the Commission on the implementation of the principle of VUD for tissues and cells in the Union are included in the Commission Staff Working Document on the implementation of the principle of voluntary and unpaid donation for human tissues and cells, accompanying the Report from the Commission to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions on the implementation of Directives 2004/23/EC, 2006/17/EC and 2006/86/EC setting standards of quality and safety for human tissues and cells. In a nutshell, the latest survey shows that, overall, Member States comply with Article 12, with most responding countries reporting that the principle of VUD is mandatory at national level. However, its concrete application varies across the Union, with considerable heterogeneity as regards practices vis-à-vis tissue and cell donors. 2.3.2. Consent, data protection and confidentiality Under Article 13(1) of Directive 2004/23/EC, the procurement of human tissues and cells shall be authorised only after all mandatory national consent or authorisation requirements have been met.

Regarding the consent system for living donation of tissues and cells, with the exception of Liechtenstein, all the other reporting countries have an opt-in system (explicit consent) (Figure 31). Concerning the consent system for deceased donation of tissues and cells, an overview of the replies is shown in Figure 32. Fig. 31. The consent systems for living donation of tissues and cells Fig. 32. The consent systems for deceased donation of tissues and cells Whereas, the consent system for living and deceased donation is different in 17 countries (AT, BE, BG, CZ, FI, FR, HR, HU, IT, LV, PL, PT, SE, SI, SK, UK and Norway), only three Member States (Denmark, Luxembourg and Spain) have different consent systems for deceased tissue and organ donation. Irrespective of the consent system, in case of deceased donations, there are various options for who is allowed to authorise tissue donation (Figure 33). Fig. 33. Persons allowed authorising deceased donation of tissues and cells Several Member States provided additional clarifications. In Netherlands, in case of a donor child aged 12 or below the consent is given by the legal guardian. The United Kingdom specified that in England, Wales and Northern Ireland a person in life or a person's "nominated representative" can give consent, but there is no mention of "nominated representatives" under the Human Tissue Act in Scotland. In all reporting Member States and EEA countries, the consent is verified during inspections by various means, from analysis of documentation and interviews with personnel to interviews with living donors or relatives of deceased donors (Figure 34). Fig. 34. Verification of donors consent during inspections (2011 data) Article 13(2) of Directive 2004/23/EC requests the Member States take all the necessary measures to ensure that donors and their relatives, as well as any persons granting authorisation on behalf of the donors are provided with the appropriate information. All reporting countries, except Ireland and Slovakia, stated that only trained personnel are allowed to provide such information. In Ireland, the requirement of Art 13(2), the information provided to donors and their families is also verified during inspections together with the donor files. Additionally, in some Member States (BG, DE, ES, LT, PL, SE, SK, UK), the information for donors is standardised at national or regional level. Germany specified that general information for donors is available due to national public awareness activities and is also provided by medical associations. For ART donors, in Spain the information is controlled at regional level and in the United Kingdom it is assessed during the initial application for tissue establishment licence. Concerning national measures taken to ensure that both donors and recipients remain unidentifiable as required by Art.14(1) of Directive 2004/23/EC, several approaches were reported. Many Member States (CZ, DE, EE, ES, FI, FR, HR, HU, IE, LT, LV, RO) and Norway stated that anonymity is ensured by the application of the data protection national legislation. In addition, anonymity is ensured by implementing the unique donor identification number (coding system) for both donor and recipient (AT, BE, BG, CY, IT, LU, MT, PL, SE, SI, UK-HTA and LI). Additional methods were: control measures decided by tissue establishments (Denmark); verification by the competent authority of the access to information and of the procedures put in place by the tissue establishment to ensure the confidentiality (Portugal); providing third parties only with the tissue code (Slovakia). Member States and EEA countries also reported on the measures taken to ensure that the identity of the recipient is not disclosed to the donor and vice versa required under Article 14(3) of Directive 2004/23/EC. Besides applying the national requirements on data protection (CY, DE, EE, ES, FR, HU, IE, LT, LV, NL, RO, SI), introducing the unique donor identification number (AT, FI, HR, IT, LU, MT, PL, SE, SK and LI, NO) is another method widely used for ensuring data confidentiality. Other approaches were reported: restricted access to the donor data (Bulgaria); requirements included in the tissue establishments' SOP and inspected by the competent authority before granting a licence (Czech Republic); appropriate procedures put in place by both tissue establishments and organisations responsible for human application (Denmark); validation by the competent authority of the procedures; validation by the competent authority of the procedures established at tissue establishment level (Portugal); with the exception of directed donations, information regarding the donor identity is not included in the recipient file and vice-versa (United Kingdom). With regard to disclosure of donor data in case of gamete donation, the approaches taken by the reporting Member States and EEA countries are summarised in Figure 35. The special circumstances in which some countries (generally prohibiting the disclosure of gamete donor data) would allow disclosure include: Children reaching 14 years old (Austria); When the egg donor is a relative of the woman who wishes to undergo artificial insemination (Estonia);

In case of a child born with a congenital disease (Spain); Children conceived through IVF procedures (Norway); When donors express consent to disclose his/her data and only when the children born following ART procedures with donated gametes turn 18; other cases following a court decision (Portugal); At the request of authorities (e.g. police, coroner office)(Romania); Only to the child at adult age, but not to his/her parents)(Sweden); To the medical staff only for medical reasons (Slovenia). Fig. 35. Disclosure of gamete donor data (2011 data) Comments Overall, the survey showed that regardless of the consent system, all responding countries put measures in place for verifying donors’ consent. On the other hand, only in a few Member States is this checked by interviewing the living donors or the relatives of the deceased donors. In addition only trained personnel are allowed to provide appropriate information to donors, but only in a few countries has this information been standardised at national level. Concerning donor anonymity, most countries rely on the EU and national data protection legislation, but also on coding. In this context, the new requirements on the application of the Single European Code for tissues and cells may be considered an additional tool for ensuring that donor data are not disclosed to the recipient. 2.3.3. Donor selection and evaluation. Procurement of tissues and cells Under Article 15 of Directive 2004/23/EC, donor evaluation and selection by the tissue establishments should be carried out in accordance with the provisions laid down in Annex I (donors of non-reproductive tissues and cells) and III (donors of reproductive tissues and cells) of Directive 2006/17/EC. Compliance with these requirements is verified by inspections of tissue establishments, procurement sites, and ART establishments by audit documentation, standardised questionnaires at national levels and/or regular evaluation of medical personnel (Figure 36 and 37). Furthermore, three Member States (Belgium, Germany, Italy) reported having more stringent criteria for donor selection: Belgium reported having one additional selection criterion - “persons that have undergone documented or undocumented neurosurgery''; Germany informed that the exclusion criteria are adapted to the donor of a specific tissue; Italy reported that additional tests are required - NAT testing for HIV, HBV and HCV of HSC donors; toxoplasma IgM for amniotic membrane donors is mandatory; CMV IgM for heart valve, vessels and amniotic membrane; CMV for skin; CMV, toxoplasma and EBV testing for HPC unrelated donors; serum archive for all donors.

Fig. 36. Verifying the compliance of tissue establishments and procurement sites with the requirements of Annexes I and III of the Directive 2006/17/EC (2011 data) Fig. 37. Verifying the compliance of ART establishments with the requirements of Annex II of the Directive 2006/17/EC (2011 data) A general concern that is expressed regularly by the competent authorities is the absence of regulation focused on the protection of the living donor. In most Member States, the evaluation of deceased donors of tissues and cells relies on the medical records of the donor, the interview with the donor's family or a person who knew the donor well and the autopsy report. In approximately half of the reporting countries an interview with the treating physician or with the general practitioner is also required (Figure 38). One country (Liechtenstein) reported having only living donors. Moreover, other practices were also reported: Belgium reported that a physical examination of the body is also required; In Germany, a post mortem physical examination as well as the results of the laboratory tests required according to Annex II of Directive 2004/23/EC; Liechtenstein reported that there are only living donors, for cord blood cells; Slovakia informed that other examinations might be done in case they are needed; The United Kingdom reported that there are no mandatory sources and tissue establishments may use several sources to evaluate a donor. Fig. 38 Evaluation of deceased donors of human tissues and cells (2011 data) Concerning the selection of donors of reproductive cells, four Member States indicated having more stringent criteria than those listed in Annex III to Directive 2006/17/EC: Belgium - Testing for Treponema pallidum; Czech Republic - HIV p 24 laboratory testing (NAT testing is not acceptable); Portugal - age of the donor (maximum age for oocyte donors is 35 and for sperm is 45. For ovocyte donation only three ovocyte pick-ups cycles per donor are allowed. For sperm donation, a donor can be used for the birth of eight living children);

United Kingdom – age of donors. HFEA also specified that posthumous use of gametes or embryos created using gametes from a donor who has since deceased may only be used if the gamete provider has been screened in accordance with the requirements set out in the EU Directives. No Member State declared having more stringent criteria for autologous donation than those listed in Annex I to Directive 2006/17/EC. Furthermore, no Member States request more information on the donation of tissues/cells than the mandatory one as laid down in the Annex to Directive 2004/23/EC. In most of the Member States compliance with the requirements for tissues and cells procurement, packaging and transport is verified by the competent authorities when performing inspections. Auditing of tissue establishments and centres of human application, as well as inspections of the centres of human application have been reported by several countries as additional measures for verifying compliance with the EU procurement, packaging and transport requirements (Figure 39). Other Member States also reported requesting written SOPs and approval licence (Czech Republic), authorisation of procurement establishments pursuant to sec. 20b of the German Medicinal Products Act (Germany), more requirements for specific tissues and cells (Italy), related information in the Tissue Establishment Dossier that is requested prior to inspections (Malta), correct procedures in place at the initial application assessment stage, and follow up during two-yearly inspections (United Kingdom). Fig. 39. Verification of compliance with the EU requirements for procurement, packaging in Directive 2006/17/EC (2011 data) Comments In summary, the survey showed that inspections are the most important verification method used by the Member States' competent authorities when verifying the compliance of tissue establishments with the EU donor evaluation and selection requirements. Nevertheless it has to be underlined that a few countries rely only on the medical records of the donor and/or the autopsy report without interviewing the donor’s family or his/her treating physician/general practitioner, which may raise concerns. In relation to the selection of gamete donors, only two Member States (Portugal, United Kingdom) reported that the donor’s age was included among the selection criteria for oocyte donors. The use of selection criteria should be transparent and subject to continuous evaluation in order to minimise safety risks. Several Member States have called for an enhanced harmonisation of the criteria for donor selection and evaluation, stressing the importance of using a standardised donor evaluation procedure (e.g. consultation of all relevant sources for the medical and behavioural history of deceased donors). 2.3.4 Donor testing Under Article 4 of Directive 2006/17/EC, the national competent authorities must ensure that donors of tissues and cells, except donors of reproductive cells, undergo the biological tests set out in point 1 of Annex II. Also, Article 4(2) of Directive 2006/17/EC requires the competent authorities to ensure that donors of reproductive cells undergo the biological tests set out in points 1, 2 and 3 of Annex III. An overview of the donor testing in all the reporting countries is shown in Figure 40 (for donors of non-reproductive tissues and cells) and Figure 41 (for donors of reproductive tissues and cells). Fig. 40. Testing of donors non-reproductive tissues and cells (2011 data) Fig. 41. Testing of donors of reproductive tissues and cells (2011 data) The survey confirms that all reporting countries comply with the mandatory testing requirements laid down in Annex I to Directive 2006/17/EC. The other testing requirements such as testing of HTLV-1 antibody for donors living in or originating in high-prevalence areas or with sexual partners origination from those areas, as well as additional testing depending on the donors’ travel and exposure history and the characteristics of the tissue and cell donated (e.g. CMV, EBV, Toxoplasma gondii, malaria, West Nile virus, Dengue fever, Chikungunya, Trypanosoma cruzi) are also performed. One practical concern for the implementation of such requirements is however the lack of a common view on high-prevalence areas for these diseases. The Commission has therefore asked ECDC to elaborate assessments and maps for use by the Member States' competent authorities and tissue establishments across the Union. Compared to the 2008 data, many countries introduced more stringent testing requirements of donors of non-reproductive tissues and cells (Fig 38), as following: NAT HIV: AT, BE, DK, ES, FI, FR, HR, PT;

NAT HBV: AT, BE, ES, FI, FR, HR, LT; NAT HCV: AT, BE, DK, ES, FI, FR, HR, LT, PT. Regarding testing donors of reproductive cells, most of the reporting countries comply with the requirements in Annex III to Directive 2006/17/EC, with some exceptions. Two Member States (Lithuania, Poland) did not comply entirely because of inappropriate transposition of the Directives for the ART sector. Additionally, nine Member States (HU, IE, IT, LU, MT, RO, SE, SI, SK) and Liechtenstein do not perform NAT for Chlamydia as requested in Annex III to Directive 2006/17/EC. Three Member States (Austria, Belgium and Finland) declared that more stringent requirements were introduced for donors of reproductive cells (e.g. mandatory NAT testing for HIV, HBV and HCV). Concerning NAT testing, several countries specified that this type of testing is mandatory only in specific circumstances: Austria: only for deceased donations and living autologous donations; Croatia: only for non-reproductive tissues and cells; Denmark: for deceased donors; Estonia: for donors of reproductive and non-reproductive tissues and cells NAT HIV 1 and NAT HCV tests are required only if Anti-HIV 1 and Anti HCV-Ab are not performed; Finland: for donors of non-reproductive tissues and cells; France: for non-reproductive tissues and cells, and only NAT HIV for egg donation (immediately before the collection of the eggs as a second determination of the viral status of the donor) ; Germany: for deceased donors (exceptions for cornea and skin), in addition to serological testing; Lithuania: only for HBV and HCV; Portugal: only for non-reproductive tissues and cells. Countries in which NAT testing is not obligatory by law, have different approaches toward introducing this type of testing: Denmark intends to make NAT testing for HIV, HBV and HCV mandatory for egg donors; Estonia, Ireland and Romania encourage the use of NAT testing, but the cost-benefit has to be taken into account; In Hungary the NAT technique is performed, but it is not compulsory by law; In Latvia NAT is performed routinely for HIV, HBV and HCV, but is not mandatory by law; In Cyprus the technique is performed for donors of reproductive cells, if cells are issued without retesting of donors after 180 days;

In Poland NAT testing is used only for verification of questionable serological results; Four Member States (IE, MT, NL, SE) and Norway declared having no plans to make NAT testing mandatory (mainly because epidemiological data and the cost-benefit analysis do not motivate such a decision); Slovenia reported that no discussion/decision was taken at national level regarding this issue; In the United Kingdom the Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO) has recommended NAT testing, in particular product testing rather than donor serum testing. Mandatory NAT testing is supported by HTA particularly in case of a treatment involving donation from multiple donors and where the donations are not stored and therefore cannot be retested at 180 days. Seven Member States (AT, DE, FI, HR, IE, IT, SI) and Norway expressed concerns regarding the accuracy of tests for cadaveric donors, mainly because of the limited number of manufacturers and the absence of validated CE-marked kits. Therefore, in some countries (e.g. Germany) the competent authorities recommend validating the assay systems before use on cadaveric samples. Nine Member States (CY, ES, HR, HU, IE, IT, LV, PT, SE) reported requesting international accreditation for testing laboratories (e.g. ISO, EFI). In Romania the accreditation is not mandatory, but nevertheless it is frequently used. Comments The data reported show that most of the EU and EEA countries comply with the testing requirements stipulated in Directives 2004/23/EC and 2006/17/EC. Several countries have introduced more stringent testing requirements such as NAT testing for HBV, HCV and HIV for either or both donors of non-reproductive and reproductive tissue and cells, whereas in most Member States and EEA countries the use of this type of testing is not motivated by the cost-benefit analysis and/or the epidemiological context. Additional tests required by Member States are usually justified for local reasons, like e.g. the increased prevalence of a certain infectious disease. These criteria may however also create barriers for exchanging tissues and cells between Member States. Members States should therefore have at least mutual transparent view on the tests implemented in each of the Member States. Several of the testing requirements have been subject to discussion in the bi-annual competent authorities meetings and their relevance/value and use/feasibility should be continuously assessed in order to keep the tests aligned with the changes in the underlying risks that they need to help address. An agreement at EU level on the compulsory use of NAT screening in certain circumstances based on new scientific data on its efficacy and cost-effectiveness may decrease even further the viral transmission risk. It should also be kept in mind that the application of (some) tests can have a major impact on the local availability of tissues and cells. It was noted in the discussions of the competent authority meetings that while the theoretical value of testing can be high, the effective value depends largely on the implementation and validation of these tests. Testing can therefore not be considered as the single pillar for safety of tissues and cells but is to be combined with deferral criteria and, where applicable, inactivation techniques. It is only the combined implementation of all pillars t