Paola Di Ciaccio Vanja Nikolac

Paola Di Ciaccio Vanja Nikolac

ITALYintheHSCfield:HOWISTHISRULED? Directive 2004/23/EC of the European Parliament and of the Council of 31March2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells Directive 2006/17/EC implementing Directive 2004/23/EC of the European Parliament and of the Council as regards certain technical requirements for the donation, procurement and testing of human tissues and cells Directive 2006/86/EC of 24 October 2006 implementing Directive 2004/23/EC of the European Parliament and of the Council as regards traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells LAW DECREE November 6 2007, n.191 Transposition of Directive2004/23/EC on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells LAW DECREE January 25 2010, n.16 Transposition of Directives 2006/17/EC and 2006/86/EC of the European Parliament and of the Council as regards certain technical requirements for the donation, procurement and testing of human tissues and cells, as well as regards traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells

IDENTIFICATION OF RESPONSIBILITIES STANDARD REQUIREMENTS FOR TISSUE ESTABLISHMENTS (RESPONSIBILITY OF CENTRES) RESPONSIBILITIES OF COMPETENT AUTHORITIES IN SINGLE MEMBER STATES FOR CHECK ON APPLICATION OF TE STANDARDS

BLOOD CELLS CompetentAuthoritiesin DONATO Italy: HealthMinisterand RE Regions act through technical bodies, CNT and CNS ORGANS TISSUES

ITALIAN NATIONAL TRANSPLANT CENTRE ITALIAN NATIONAL BLOOD CENTRE Law n. 91, Aprile 1, 1999 Art.7 Law n.219. October 21, 2005 They are technical and organizational structures that coordinate the national transplant network (for organs, tissues and cells) and the national blood donation network, respectively They are both located in Rome at the ITALIAN NATIONAL INSTITUTE OF HEALTH A ROLE INBETWEEN HEALTH MINISTRY AND REGIONAL AUTHORITIES

DIRECTIVE 23/2004/EC Article 4 implementation of requirements foreseen by Directives Article 6 authorization and accreditation of tissue establishments Article 7 adoption by CAs of adequate control measures and inspection system (every two years) to ensure adherence to Directive requirements Article 8 guarantee traceability Article 9 vigilance on import/export Article 10 data and activity registry and compulsory annual public report Article 11 notification and investigations of serious adverse events and reactions

ACTIVITIES IN HSC FIELD Data collectionand processing National coordinatingand supportingbody Training of professionalsand inspectors Issuing of protocols and guidelines Inspections Vigilance and surveillance(saers)

HSC Donor identification issues and registries need for high degree of compatibility; about one third of patients requiring HSCT finds a compatible donor within his/her family; patients without a family compatible donor rely then on unrelated donors from international registry. Pat Don

International bone marrow registry(i) 23,853,648 (23,246,742 donors and 606,906 CBU's) Bone Marrow Donors Worldwide (BMDW) is the continuing effort to collect the HLA phenotypes and other relevant data of volunteer stem cell donors and cord blood units, and is responsible for the co-ordination of their worldwide distribution. Participants are 73 stem cell donor registries from 52 countries, and 47 cord blood banks from 32 countries. BMDW started as an initiative of the Immunobiology Working Party of the European Group of Blood and Marrow Transplantation (EBMT) in 1988. In February 1989 the first edition was distributed, which contained the donor files of eight registries with a total of 155,000 volunteer stem cell donors.

International bone marrow registry(ii) Unrelated Cord Blood Units Adults Unrelated Donors - Bone Marrow - Peripheral Blood Stem Cells Cord Blood Banks Registries HLA typing Laboratories (Biological identity profile) Patients Transplant Centre

MATCHED UNRELATED DONORS in the world 20000 18000 16000 14000 12000 10000 Top five countries in 2012: Germany 6,247 41% USA 3,374 22% Japan 1,332 9% China 639 4% UK-ANT 405 3% 19.265 18.302 16.876 4.150 15.399 13.305 12.227 10.493 10.989 8000 6000 4000 4.126 2000 0 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Bone marrow Peripheral blood Cord blood

WHYTHISISSUEINARTHIQS(I) Increased transplant activity; increase the clinical indications; improvement of supportive care; increasing age of the patients; increasing age of donors.

WHYTHISISSUEINARTHIQS(II) Risks related to HSC donation are generally considered as non-existent. However, over the years various reports from individual transplantation centers and donor registries have shown that the collection procedure can be related to the onset of a number of symptoms, with changes in vital signs and/or examinations, in the majority of cases of moderate and transient entity. Some serious adverse events/reactions (including death) have been reported. HSC donor follow-up is widely recognized to be insufficient, especially regarding related donors.

HOWWEAREGOINGTOTACKLETHIS Revision of existing standards and their harmonization with EU directives, in close collaboration with international registry and professionals scientific societies; Definition of European guidelines to assure high leveldonorssafetyinallms.

CROATIA- Competent Authority Population 2011 census 4,284,889 Area 56,594 km2 Capital Zagreb Competent Authority Ministry of Health

Croatian Ministry of Health- organisational chart

Croatian Ministry of Health Competent authority for blood tissues and cells organs assisted reproductive technologies Institute for transplantation and biomedicine Data collection Authorisation Regulatory issues Organisational and financial issues Service for Inspection of Blood, Tissues and Cells Inspection Supervision of the implementation of acts and other regulations Vigilance (adverse reaction and event reporting system)

CROATIAN LEGISLATION IN THE FIELD OF HSC 2nd, improved set of legislation transposing EUTCDs Directive 2004/23/EC of the European Parliament and of the Council of 31March2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells ACTON THE APPLICATION OF HUMAN TISSUES AND CELLS December 14 2012

CROATIAN LEGISLATION IN THE FIELD OF HSC Directive 2006/17/EC implementing Directive 2004/23/EC of the European Parliament and of the Council as regards certain technical requirements for the donation, procurement and testing of human tissues and cells Directive 2006/86/EC of 24 October 2006 implementing Directive 2004/23/EC of the European Parliament and of the Council as regards traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells Commission Decision 2010/453/EU of 3 August 2010establishing guidelines concerning the conditions of inspections and control measures, and on the training and qualification of officials, in the field of human tissues and cells provided for in Directive 2004/23/EC of the European Parliament and of the Council Ordinance On the conditions in terms of premises, personnel, medical and technical equipment and quality system for the performance of the activities of collection, procurement, testing, processing, preservation, storage and distribution of human tissues and cells June 17 2013 Ordinance On the method of monitoring serious adverse events and serious adverse reactions in the field of application of human tissues and cells, the method of keeping records, the notification time limits and the content and format of the annual report April 17 2013 Ordinance On the requirements concerning professional qualifications and professional training and on the method of conducting supervision in the field of application of human tissues and cells April 30 2013

CBB: deserves special attention Umbilical Cord Blood First transplantation in 1988., in Paris, in a patient with Fanconi anemia First unrelated cord blood transplant in adult in 1996. In1997. International NetCordFoundation,a non-profit association of umbilical cord blood banks was established- today aprox. 35 banks and registries are members Intheglobal network of CBB thereare aprox. 600 000 UCB units (ElianeGluckman, AnnalisaRuggeri, FernandaVolt, Renato Cunha, KarimBoudjedirandVandersonRocha: Milestones in umbilical cord blood transplantation, 2011 Blackwell Publishing Ltd, British Journal of Haematology, 154, 441 447) More than 20 000 units have been distributed (Ibid.)

CBB deserves special attention Umbilical Cord Blood mobility source

CBB deserves special attention Umbilical Cord Blood Long term leukaemia-free survival in children (Wagner et al, 1996; Locatelli et al, 1999) and adults (Cairo& Wagner, 1997; Rubinstein et al, 1998; Laughlin et al, 2001; Sanz et al, 2001) is similar for cord blood transplant recipients and matched unrelated bone marrow transplant recipients Improvedresults, mostly in adults, with the use of double cord blood transplants (Barker et al, 2005; Brunstein et al, 2007; Rocha et al, 2010) Notch-mediated expansionresultingin rapidengraftment (ColleenDelaney, ShellyHeimfeld, Carolyn Brashem-Stein, Howard Voorhies, Ronald L. Manger, and Irwin D. Bernstein1; Notch-mediated expansion of Human Cord Blood Progenitor Cells Capable of Rapid Myeloid Reconstitution, Nat Med. 2010 February; 16(2): 232. doi:10.1038/nm.2080) Shows that storing of high quality units is not only worth but essential

CBB deserves special attention Umbilical Cord Blood- advantages Simple collection procedure Has to berisk for donor-a mother or a newborn No donor attrition Low risk of viral transmitting Immediate availability in emergency Easy delivery Grater proportion of rare haplotypes present in UCB banks then in BMT registries (Anfisa Stanevsky a, Gal Goldstein b, Arnon Nagler: Umbilical cord blood transplantation: Pros, cons and beyond)

Targets Developing guidelines for CB banking establishing common goodpracticeforthefieldinms Setting guide for CBB inspection leading to harmonisation in inspection practice (including inspectors education and skills, inspection documentation, performance) and mutual recognition of EU inspection bodies