Paola Di Ciaccio

Vanja Nikolac

Directive 2004/23/ECof the European Parliament and of the Council of

31 March 2004 on setting standards of quality and

safety for the donation, procurement, testing,

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

Directive 2006/17/ECimplementing 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

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

Directive 2006/86/ECof 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

ITALY in the HSC field: HOW IS THIS RULED?

STANDARD REQUIREMENTS FOR TISSUE ESTABLISHMENTS(RESPONSIBILITY OF CENTRES)

RESPONSIBILITIES OF COMPETENT AUTHORITIES

IN SINGLE MEMBER STATES

FOR CHECK ON APPLICATION OF TE STANDARDS

IDENTIFICATION OF RESPONSIBILITIES

BLOOD CELLS

ORGANS TISSUES

DONATORE

Competent Authorities in Italy: Health Minister and

Regions act through technical bodies, CNT and CNS

They are technical and organizational structures thatcoordinate the national transplant network (for organs,

tissues and cells) and the national blood donationnetwork, respectively

They are both located in Romeat the ITALIAN NATIONAL INSTITUTE OF HEALTH

A ROLE INBETWEEN HEALTH MINISTRY AND REGIONAL AUTHORITIES

Law n. 91, Aprile 1, 1999Art.7

ITALIAN NATIONAL TRANSPLANT CENTRE

ITALIAN NATIONAL BLOOD CENTRE

Law n.219. October 21, 2005

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

DIRECTIVE 23/2004/EC

ACTIVITIES IN HSC FIELD

� Data collection and processing

� National coordinating and

supporting body

� Training of professionals and

inspectors

� Issuing of protocols and guidelines

� Inspections

� Vigilance and surveillance (SAERs)

HSC Donor identification issues and registries

Pat Don

• need for high degree ofcompatibility;

• about one third of patientsrequiring HSCT finds acompatible donor withinhis/her family;

• patients without a familycompatible donor rely thenon unrelated donors frominternational registry .

International bone marrow registry (I)

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.

23,853,648(23,246,742 donors

and 606,906 CBU's)

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)

Adults Unrelated Donors

- Bone Marrow

- Peripheral Blood Stem Cells

Unrelated

Cord Blood Units

Registries

HLA typing Laboratories

(Biological identity profile)

Cord Blood

Banks

Patients

Transplant Centre

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

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

Cord bloodPeripheral bloodBone marrow

10.493

12.227

13.305

15.399

16.876

18.302

19.265Top five countries in 2012:

Germany 6,247 41%

USA 3,374 22%

Japan 1,332 9%

China 639 4%

UK-ANT 405 3%

4.126

10.989

4.150

MATCHED UNRELATED DONORS in the world

WHY THIS ISSUE IN ARTHIQS (I)

• Increased transplant activity;• increase the clinical indications;• improvement of supportive care;• increasing age of the patients;• increasing age of donors.

• Risks related to HSC donation are generally considered as non-existent.

• However, over the years various reports from individualtransplantation centers and donor registries have shown thatthe collection procedure can be related to theonset of anumber of symptoms, with changes in vital signs and/orexaminations, in the majority of cases of moderate andtransient entity.

• Some serious adverse events/reactions(including death) havebeen reported.

• HSC donor follow-up is widely recognized to beinsufficient,especially regardingrelated donors.

WHY THIS ISSUE IN ARTHIQS (II)

HOW WE ARE GOING TO TACKLE THIS …

⇒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

level donors safety in all MS.

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

Competent authority forblood

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 Ministry of Health

CROATIAN

LEGISLATION IN THE FIELD OF HSC

Directive 2004/23/EC

of the European Parliament and of the

Council of 31 March 2004 on setting

standards of quality and safety for the

donation, procurement, testing,

processing, preservation, storage and

distribution of human tissues and cells

ACT ON THE APPLICATION OF HUMAN

TISSUES AND CELLS

December 14 2012

2nd, improved set of legislation transposing EUTCDs

CROATIAN

LEGISLATION IN THE FIELD OF HSC

Directive 2006/17/ECimplementing 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

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

Directive 2006/86/ECof 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

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

Commission Decision 2010/453/EU

of 3 August 2010 establishing 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 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.

• In 1997. International NetCord Foundation, a non-profit association of umbilical cord blood banks was established - today aprox. 35 banks and

registries are members

• In the global network of CBB there are aprox. 600 000 UCB units (Eliane Gluckman, Annalisa Ruggeri, Fernanda Volt, Renato Cunha, Karim Boudjedir and Vanderson Rocha: 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

• Improved results, 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 expansion resulting in rapid engraftment (Colleen Delaney, Shelly Heimfeld, 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 be risk 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 commongood practice for the field in MS

• Setting guide for CBB inspection leading to harmonisation ininspection practice (including inspectors’ education and

skills, inspection documentation, performance) and mutual

recognition of EU inspection bodies