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Haematopoietic stem cells:
implications of the EU directive
for practice in Ireland
Paul Browne,
Blood and Marrow Transplant Programme,
St. James’s Hospital

The stem cell hierarchy
Embryonic stem cell
Pluripotent somatic
stem cell
Neural Muscle Hepatic Blood Endothelium

Stem cells live in
bone marrow niches
Stem cell
Marrow
stroma
Adhesion
molecule
Matrix protein

G-CSF mobilises stem cells
Circulation
G-CSF
BM stroma

What do stem cells look like

Red cell colony CFU-E

White cell colony CFU-GM

BMT: Stem cell source
• Bone marrow from donor
• Peripheral blood from donor
• Umbilical cord blood
• Autologous blood or marrow

Stem cell transplants
in Europe
HSCT rate in Europe 1990
HSCT rate in Europe 2000

Transplant rate /10 X 10 6 inhabitants
600
500
400
Economic factors in HSCT:
Transplant rate and GNP
CZ
300
SK
200
EST HR
100 PL
BY TR
0 BG
RUS
LTMK
E
P
GR
SLO
IRL
I
FB
S
SF D
UK
where is Ireland
NL A
GNP = gross national product; HCE = health care expenditure per capita
DK
N
CH
0 10 20 30 40
GNP per capita
Social insurance based health care system
Tax funded health care system
Centralised health care system
Transplant rate /10 X 10 6 inhabitants
600
500
400
300
200
100
0
PL
TR
RUS
Transplant rate and HCE
H
CZ
GR P
SLO
I
E B F
SF S D
A NL
UK
DK
IRL
N
CH
0 1,000 2,000 3,000
Healthcare expenditure per capita

HSCT in Europe 1990-2000
Main indications: allogeneic
5,000
Number of HSCT
4,000
3,000
2,000
1,000
0
1990
1991
1992
1993
1994
1995
Year
1996
1997
1998
1999
2000
Leukaemia
Lymphoma
Non malignant
disorders

HSCT in Europe 1990–2000
Main indications: autologous
6,000
Number of HSCT
5,000
4,000
3,000
2,000
1,000
Leukaemia
Lymphoma
Myeloma
Breast
Cancer
Other
Solid
Tumours
0
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000
Year

Adult BMT Programme: St James’s Hospital
Total Transplant Program 1984-2003
120
100
80
60
40
20
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
0
Year
AUTO BMT
ALLO BMT
TOTAL
No.of Transplants

BMT for haematological disorders
• Acute myeloid leukaemia
• Acute lymphoblastic leukaemia
• Hodgkin’s disease
• Non-Hodgkin’s lymphoma
• Multiple myeloma
• Chronic myeloid leukaemia
• Aplastic anaemia

Survival of patients with acute myeloid
leukemia after bone marrow transplant
100
PROBABILITY, %
80
60
40
20
N = 59
0
0 1 2 3 4 5
YEARS
Fe03_5.ppt

Autografts by disease indication
M yeloma
34%
ALL
3%
Germ Cell Ca
5%
Myelofibrosis
1%
CLL
5%
CML (STI)
7%
Lymphoma
24%
HD
8%
AML
7%
CML (new)
6%
Lymphoma n=21
HD n=7
AML n=6
CML (new)n=5
CML (STI) n= 6
CLL n=4
Germ Cell Ca n=4
ALL n=3
Myeloma n= 31
Myelofibrosis n=1

Autologous stem cell harvests/cryopreservation:
Shared care model
Tullamore
5%
Cork
7%
Waterford
9%
Mater
1% St James n=29
St James
32%
Beaumont n=14
Limerick n=12
AMiNCH n=9
Letterkenny /Sligo
6%
AMiNCH
10%
Limerick
14%
Beaumont
16%
Letterkenny /Sligo n=5
Cork n=6
Tullamore n=4
Waterford n=8
Mater n=1

The EU Directive
• Competent authority:
Irish Medicines Board
• Tissue establishment:
“The cryo/stem cell lab”
• Responsible person:
Medical Director

The Responsible Person
The person designated under paragraph 1 shall be responsible for:
(a) ensuring that human tissues and cells intended for human
applications in the establishment for which that person is
responsible are procured, tested, processed, stored and
distributed in accordance with this Directive and with the laws
in force in the Member State;
(b) providing information to the competent authority or authorities
as required in Article 6;
(c) implementing the requirements of Articles 7, 10, 11, 15, 16 and
18 to 24 within the tissue establishment.

The EU Directive:
Quality Management System
• Standard operating procedures
• Training and reference manuals
• Donor records
• Traceability
• Accurate documentation
• Audit of outcome

Serious adverse events/reactions
1. Member States shall 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, as well as any serious adverse reaction
observed during or after clinical application which may be linked to the
quality and safety of tissues and cells.
2. All persons or establishments using human tissues and cells regulated by this
Directive shall report any relevant information to establishments engaged in
the donation, procurement, testing, processing, storage and distribution of
human tissues and cells in order to facilitate traceability and ensure quality
and safety control.
3. The responsible person referred to in Article 17 shall ensure that the
competent authority or authorities is or are notified of any serious adverse
events and reactions referred to in paragraph 1 and is or are provided with a
report analysing the cause and the ensuing outcome.

Import/export of stem cells
Member States shall take all necessary measures to ensure that
all imports of tissues and cells from third countries are
undertaken by tissue establishments accredited, designated,
authorised or 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 accordance with the
procedures referred to in Article 8.
Member States and tissue establishments that receive such
imports from third countries shall ensure that they meet
standards of quality and safety equivalent to the ones laid down
in this Directive.

Core principle:
Progenitor cell products are unique
and irreplaceable

SJH Cryobiology Lab activity
Cryobiology Lab Total Procedures: 1998-2003.
600
500
400
300
200
100
0
1998 1999 2000 2001 2002 2003

Laboratory personnel
Minimum staffing for any functional
cryobiology laboratory includes:
• Chief Medical Scientist, serving as
Laboratory Director
• Senior Medical Scientist (2 posts)
• Basic Grade Medical Scientist (2 posts)
• Quality Manager

Laboratory facility
How clean is a clean room
Controlled environment
Gowning
cGMP facility
What level
Microbiological control

JACIE standards and programme

HSC laboratories in Ireland
•Cork
•Galway
• Dublin: St. James
St. Vincents
Mater
OLHSC

Irish Haematology Society:
Summary of recommendations
• Develop JACIE/cGMP standard cryobiology laboratories at IBTS
Dublin, Cork
• Transfer of existing hospital-based processing at St. James’s to
IBTS facility.
• Enhancement of existing facilities at St. Vincent’s Hospital, Mater
and Galway to cGMP standard
• Discussions with Crumlin OLHSC re optimal development of
paediatric stem cell laboratory
• Each laboratory to provide support for products collected and/reinfused
at one or multiple approved clinical transplant sites/units.
• Provision of consultant sessional commitment for each designated
facility, as outlined

Implementation in Ireland
• DOHC Steering group
• Health Service Executive
• Resource implication