AIFA European Conference
on Clinical Research for Decision Making
The German experience
Johannes Löwer
Paul-Ehrlich-Institut
Rome, 30 March 2007
www.pei.de
PEI
PEI: Areas of Responsibility
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•
Vaccines (human, veterinary)
Sera, immunoglobulins, monoclonal antibodies
Allergens (diagnostic, therapeutic)
Blood products (plasma derived, recombinant)
Blood components for transfusion
Gene transfer products
Cell therapy products (somatic, xenogeneic)
Tissues
(Engineered tissues)
PEI
PEI: Duties
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Authorisation of medicinal products
Official batch release
Scientific advice
Pharmakovigilance
Expert support for inspections
Permission of clinical studies
Experimental research
Advice to government
PEI
PEI: Holistic Approach
for each Group of Medicinal Products
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•
•
•
•
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Authorisation of medicinal products
Official batch release
Scientific advice
Pharmakovigilance
Expert support for inspections
Permission of clinical studies
Experimental research
Advice to government
PEI
Sequence of the Evaluation of an Application
• Application for rapporteurship defining the
evaluation team and its expertise
PEI
Paul-Ehrlich-Institut
Bundesamt für Sera und Impfstoffe
Institutsleitung
Forschungsbeauftragter
Forschung beim
Präsidenten
Fachgebiet Pr2
Retroelemente
Forschung beim Präsidenten
Fachgebiet Pr1
Transmissible spongiforme
Enzephalopathien
Präsident und Professor
Hr. Prof. Dr. Löwer
Referat L1
Leitungsassistenz,
Sprachendienst
Hr. Prof. Dr. Vieths
Fr. Dr. Löwer
Hr. Dr. Montrasio
Vizepräsident und Professor
Hr. Prof. Dr. Cichutek
Fr. Plumbaum°
Referat L2
Referat L3
Grundsatzfragen,
Presse,
Zentrale Steuerung Öffentlichkeitsarbeit
Hr. Wiegelmann°
Fr. Dr. Stöcker
Referat L4
Qualitätsmanagement
Referat L5
Europäische
Verfahren
Fr. Dr. v. Wangenheim
Fr. Dr. Schröder°
Prüflabor für IVD
PEI-IVD
Fr. Dr. S. Nick
Abteilung 1
Bakteriologie
Abteilung 2
Virologie
Abteilung 3
Immunologie
Abteilung 4
Veterinärmedizin
Abteilung 5
Allergologie
Abteilung 6
Medizinische
Biotechnologie
Abteilung 7
Hämatologie /
Transfusionsmedizin
Hr. Dr. Frieser
Abteilung S
Sicherheit von
Arzneimitteln und
Medizinprodukten
Fr. Dr. Keller-Stanislawski°
Hr. Dr. Haase
Hr. PD Dr. Sutter
Hr. Dr. Kalinke
Hr. Dr. Moos
Hr. Prof. Dr. Vieths
Hr. Prof. Dr. Cichutek
Hr. Prof. Dr. Seitz
Referat Z1
Personal
Referat S1
Arzneimittelsicherheit
Fachgebiet 1/1
Bakteriologische
Impfstoffe I
Fachgebiet 2/1
Virusimpfstoffe
Fachgebiet 3/1
Immunchemie
Fachgebiet 4/1
Bakterielle Impfstoffe
und Immunsera
Fachgebiet 5/1
Test-Allergene
Fachgebiet 6/1
GentransferArzneimittel I
Fachgebiet 7/1
Gerinnungsfaktoren I
Hr. Posselt
Fr. Dr. Keller-Stanislawski
Hr. Dr. Öppling
Hr. Dr. Pfleiderer
Hr. Dr. Giess
Fr. Dr. E. Werner°
Hr. Dr. Höltz
Hr. PD Dr. Buchholz
Hr. PD Dr. Dodt*
Referat Z2
Haushalt
Referat S2
Sicherheit von
In-vitro-Diagnostika
Fachgebiet 1/2
Bakteriologische
Impfstoffe II
Fachgebiet 2/2
HIV-Impfstoffe,
AIDS
Fachgebiet 3/2
Mono- und polyklonale
Antikörper
Fachgebiet 4/2
Virusimpfstoffe I
Fachgebiet 5/2
Therapie-Allergene
Fachgebiet 6/2
GentransferArzneimittel II
Fachgebiet 7/2
Gerinnungsfaktoren II
Hr. Robeck
Hr. Dr. Bornhak
Hr. Dr. Schwanig
Hr. PD Dr. A. Werner
Fr. Dr. Schäffner
Fr. Dr. Jungbäck
Fr. Dr. May
Hr. PD Dr. Schweizer*
Hr. PD Dr. Dodt
Referat Z3
Innerer Dienst
Referat S3
Sicherheit
veterinärmedizinischer
Mittel, Tierschutz
Fachgebiet 1/3
Mikrobielle Sicherheit
und Parasitologie
Fachgebiet 2/3
Diagnostika
Fachgebiet 3/3
Morphologie
Fachgebiet 4/3
Virusimpfstoffe II
Fachgebiet 5/3
Klinische Allergologie
und Toxikologie
Fachgebiet 6/3
Somatische
Zelltherapeutika
Fachgebiet 7/3
Chargenprüfung
Blutprodukte,
Albumin, Logistik
Abteilung Z
Verwaltung
Hr. Gunkel
Referat Z4
Technik
Hr. Dr. Cußler°
Referat S4
Rechtsangelegenheiten
Hr. Pieschner-v. Meltzer
Fr. Ruoff°
Hr. Dr. Montag-Lessing
Fr. Dr. Nick
Hr. Dr. Boller
Fr. Dr. Duchow
Fr. Dr. Lüderitz-Püchel
Hr. Dr. Flory°
Fachgebiet 1/4
Biostatistik
Fachgebiet 2/4
Molekulare Pathologie
Fachgebiet 3/4
Tumorimpfstoffe,
Zellbank, Medien
Fachgebiet ZT
Zentrale Tierhaltung
Fachgebiet 5/4
Entwicklung und
Standardisierung
Fachgebiet 6/4
Xenogene
Zelltherapeutika
Hr. Dr. Nübling
Hr. Frieling
Hr. Dr. Plesker
Hr. Dr. Scheurer*
Hr. PD Dr. Tönjes
Hr. Dr. Volkers
Referat Z5
Organisation,
Informationstechnik
Fachgebiet 2/5
Virussicherheit
Hr. Dr. Frieser
Hr. Dr. Blümel*
Hr. Dr. Unkelbach
Fachgebiet 7/4
Transfusionsmedizin
Fr. Dr. Heiden
Fachgebiet 7/5
Inspektionen:
Schulung, Koordination
und Durchführung
External
expert
Referat Z6
Arbeitsschutz,
Genehmigungen
Hr. PD Dr. G. Werner
Fr. Dr. Pfitzner*
Personalrat
Vorsitzende
Gleichstellungsbeauftragte
Schwerbehindertenvertrauensfrau
Jugend- und
Auszubildendenvertretung
Fr. Gravelius
Fr. Dr. Krämer
Fr. Grote
Fr. Zitzmann
*mit der Wahrnehmung der Geschäfte
beauftragt
° für die Wahrnehmung der Geschäfte
vorgesehen
Dienst- und Fachaufsicht
Dienstaufsicht
Wissenschaftliche Nachwuchsgruppen
(NG) Sprecher: N.N.
NG1
Neue
Impfstoffstrategien
NG2
Bioinformatik
NG3
Zelldifferenzierung
NG4
N.N.
N.N.
N.N.
N.N.
NG5
N.N.
PEI
Sequence of the Evaluation of an Application
• Application for rapporteurship defining the
evaluation team and its expertise
• Appointment of the rapporteur by the CHMP
• Evaluation
• Review by the PEI Peer Review Group
PEI
Good Regulatory Practice (GRP) in the PEI
Peer Review Group
Members:
• Experienced scientists not involved in the evaluation
of the product in question
Aim:
• To widen the scientific basis of the decisions made by
the assessors
• To assist in the decision on critical issues
• To provide access to the “regulatory memory”
Involvement:
• Obligatory in centralised and decentralised
procedures and in the co-ordination of “Scientific
Advice”
PEI
Sequence of the Evaluation of an Application
• Application for rapporteurship defining the
evaluation team and its expertise
• Appointment of the rapporteur by the CHMP
• Evaluation
• Review by the PEI Peer Review Group
• Finalization of the assessment report
• Support to the CHMP member
PEI
European Procedures for Products in PEI‘s Remit
(until 31 December 2005)
Distribution of (Co-)rapporteurships [Hum]
45
40
Co-Rapporteur
Rapporteur
35
24
30
25
20
15
10
2
20
9
4
D
E
I)
E
(P
B
E
D
K
1
5
2
3
1
0
12
7
7
6
11
5
13
ES
FI
1
5
FR
1
4
IE
11
5
IT
N
L
2
N
O
2
SE
U
K
H
U
PEI
European Procedures for Products in PEI‘s Remit
(until 31 December 2005)
Distribution of RMSs with Germany involved [Hum]
Allergene
Ig
40
35
1
MAK
Blutprodukte
30
9
Komb. Impfstoff
Viraler Impfstoff
25
2
Bakt. Impfstoff
20
7
15
4
1
1
T
K
U
SE
D
E
B
2
2
1
1
1
4
D
E
(P
EI
)
K
1
0
5
4
L
2
3
4
1
2
IT
5
1
2
1
4
A
1
4
N
9
FR
10
PEI
Percent
Scientific Advice [Hum] for Biological Products
Co-ordination by PEI (in Percent)
100
90
80
70
60
50
40
30
20
10
0
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
PEI
PEI: Duties
•
•
•
•
•
•
•
•
Authorisation of medicinal products
Official batch release
Scientific advice
Pharmakovigilance
Expert support for inspections
Permission of clinical studies
Experimental research
Advice to government
PEI
Major Research Areas
• Safety of Biological and Biotechnology
Medicines
• New Test Methods
• Pathogenesis of Prion Diseases and Viral
Infections
• Viral Gene Transfer and Cell Therapy
• Immunobiology of Allergens
PEI
Research Grants
5.000.000 €
4.000.000 €
3.000.000 €
2.000.000 €
1.000.000 €
0€
2003
2004
2005
2006
PEI
Widening the Basis for Decision
• Experimental investigations
– Potency of anti-D immunoglobulins
– Potency of recombinant Factor VIII
– Dose calculation for first-in-man-studies
PEI
Potency of Anti-D Immunoglobulin
1200
1500
A
A A
A
A
A
A
AA A
900
C
C
C
B
B
C
CC C
600
Measurement
1800
Correlation between PEI’s and Manufacturer’s Results
600
900
C
1200
Manufacturer
1500
1800
PEI
Comparison of potency of a rec. FVIII
obtained with different Chromogenic Assays
1200
CA-1 mod.
1000
PEI, CA-2
1000
PEI, CA-1
809
PEI, CA-3
800
704
IU/vial
658
600
400
260
182
200
203
214
0
BDD-FVIII 1000
BDD-FVIII 250
PEI
PEI
20
In vitro titration of TGN1412 binding to CD28
expressed by human T cells
6.67
120
TGN 1412Rituximab
% specific binding
µg/ml
2.22
0.73
100
80
60
40
20
0
100
0.24
10
1
0.1
0.01
0.001
µg/ml specific binding
0.081
0.027
0.009
unstained
TGN 1412-Alexa 488
PEI
Widening the Basis for Decision
• Experimental investigations
• Epidemiological investigations
– Tick-born encephalitis in children
– Sudden unexpected death in the second
year of life after vaccination
PEI
PEI Study: Severe TBE in Children
TBE in children (Germany)
A survey for the years 1997 and 1998
Collection of clinically relevant cases and evaluation
of the natural course of the disease in children up to
16 years of age
Questionnaires were sent to 478 pediatric and
neurological hospitals.
Response rate: 81 % (n= 387)
n=17 cases (n=14 meningitis, n=2 meningoencephalitis, n=1 meningitis + cerebellitis)
Age: median 8 yrs (min. 3 til max. 14 yrs)
On average 9 days stay in hospital
No permanent damages!
PEI
Change of the Manufacturing Process: Fever after a
TBE- Vaccine, Germany 1994-2000
2940
3000
Removal of Albumin
2500
serious
2000
All fever reports
1500
1000
428
Removal of Thiomersal
500
193
174
1
38
5
72
8
39
5
27
13
18
0
1994
1995
1996
1997
1998
1999
2000
PEI
Background
Schlaud 2005
Problem:
• Spontaneous notifications of > 20 cases of death in close
temporal association (< 3 days) to hexavalent vaccination
– All died suddenly and unexpectedly
– Four of them died in their second year of life
– Statistical analyses estimating the observed versus
expected cases revealed a standardised mortality ratio
(SMR) of 23.5 (95% CI 4.8–68.6) within 2 days after
vaccination for one of the two licensed hexavalent vaccines
Limitations of current assessment:
• based on a low absolute number of cases
• high probability of incomplete case-ascertainment
• case detection may be biased
• data on exposure may be incomplete
• data on ‘background incidence’ may be incomplete
standardised study was deemed necessary
PEI
Dr. Bärbel-Maria Kurth
PEI
Study questions
Schlaud 2005
• Is there a temporal association between
vaccination and risk of sudden death in the first
two years of life?
• For what length of time after vaccination is the
risk of death potentially increased?
• Is this potential association qualitatively and
quantitatively the same at different stages of life?
• Is this potential association the same across
different –hexavalent- vaccines?
• Is there a common pathological mechanism?
• Is the risk of sudden death associated with
vaccination?
The complete number of answers cannot be
obtained by a single study approach
PEI
Study Protocol
Structure
Pathological
approach
Qualitative research
• Standardised
1. case ascertainment
2. autopsies children aged 9-23 mo
• Additional in depths investigations
Schlaud 2005
Epidemiological
approach
Quantitative research
• All cases of death in children
aged 1-23 mo
• Self Controlled Case Series
• Case Control Study
PEI
PEI

PEI