PEI

AIFA European Conferenceon Clinical Research for Decision Making

www.pei.de

Rome, 30 March 2007

The German experience

Johannes LöwerPaul-Ehrlich-Institut

PEI

• 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: Areas of Responsibility

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

PEI: Holistic Approachfor each Group of Medicinal Products

• 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

Prüflabor für IVDPEI-IVD

Fr. Dr. S. Nick

Dienst- und Fachaufsicht

Dienstaufsicht

*mit der Wahrnehmung der Geschäfte beauftragt° für die Wahrnehmung der Geschäfte vorgesehen

Institutsleitung

Präsident und ProfessorHr. Prof. Dr. Löwer

Vizepräsident und ProfessorHr. Prof. Dr. Cichutek

Forschungsbeauftragter

Hr. Prof. Dr. Vieths

Forschung beim Präsidenten Fachgebiet Pr1

Transmissible spongiformeEnzephalopathien

Hr. Dr. Montrasio

Forschung beimPräsidenten

Fachgebiet Pr2Retroelemente

Fr. Dr. Löwer

PersonalratVorsitzende

Fr. Gravelius

Gleichstellungs-beauftragte

Fr. Dr. Krämer

Schwerbehinderten-vertrauensfrau

Fr. Grote

Jugend- und Auszubildenden-

vertretung

Fr. ZitzmannNG1Neue

Impfstoffstrategien

N.N.

NG2Bioinformatik

N.N.

NG3Zelldifferenzierung

N.N.

NG4

N.N.

NG5

N.N.

Wissenschaftliche Nachwuchsgruppen (NG) Sprecher: N.N.

Abteilung 4Veterinärmedizin

Hr. Dr. Moos

Fachgebiet 4/1Bakterielle Impfstoffe

und Immunsera

Fr. Dr. E. Werner°

Fachgebiet 4/2Virusimpfstoffe I

Fr. Dr. Jungbäck

Fachgebiet 4/3Virusimpfstoffe II

Fr. Dr. Duchow

Fachgebiet ZTZentrale Tierhaltung

Hr. Dr. Plesker

Fachgebiet 6/4Xenogene

Zelltherapeutika

Hr. PD Dr. Tönjes

Abteilung 6Medizinische

Biotechnologie

Hr. Prof. Dr. Cichutek

Fachgebiet 6/1Gentransfer-Arzneimittel I

Hr. PD Dr. Buchholz

Fachgebiet 6/2Gentransfer-

Arzneimittel II

Hr. PD Dr. Schweizer*

Fachgebiet 6/3Somatische

Zelltherapeutika

Hr. Dr. Flory°

Abteilung 5Allergologie

Hr. Prof. Dr. Vieths

Fachgebiet 5/1Test-Allergene

Hr. Dr. Höltz

Fachgebiet 5/2Therapie-Allergene

Fr. Dr. May

Fachgebiet 5/3Klinische Allergologie

und Toxikologie

Fr. Dr. Lüderitz-Püchel

Fachgebiet 5/4Entwicklung undStandardisierung

Hr. Dr. Scheurer*

Fachgebiet 7/1Gerinnungsfaktoren I

Hr. PD Dr. Dodt*

Fachgebiet 7/2Gerinnungsfaktoren II

Hr. PD Dr. Dodt

Fachgebiet 7/3Chargenprüfung Blutprodukte,

Albumin, Logistik

Hr. Dr. Unkelbach

Fachgebiet 7/4Transfusionsmedizin

Fr. Dr. Heiden

Fachgebiet 7/5Inspektionen:

Schulung, Koordinationund Durchführung

Hr. PD Dr. G. Werner

Abteilung 7Hämatologie /

Transfusionsmedizin

Hr. Prof. Dr. Seitz

Abteilung 1Bakteriologie

Hr. Dr. Haase

Fachgebiet 1/1Bakteriologische

Impfstoffe I

Hr. Dr. Öppling

Fachgebiet 1/2Bakteriologische

Impfstoffe II

Hr. Dr. Schwanig

Fachgebiet 1/3Mikrobielle Sicherheit

und Parasitologie

Hr. Dr. Montag-Lessing

Fachgebiet 1/4Biostatistik

Hr. Dr. Volkers

Referat S4Rechtsangelegenheiten

Fr. Ruoff°

Abteilung SSicherheit von

Arzneimitteln undMedizinprodukten

Fr. Dr. Keller-Stanislawski°

Referat S1Arzneimittelsicherheit

Fr. Dr. Keller-Stanislawski

Referat S2Sicherheit von

In-vitro-Diagnostika

Hr. Dr. Bornhak

Referat S3Sicherheit

veterinärmedizinischerMittel, Tierschutz

Hr. Dr. Cußler°

Abteilung 3Immunologie

Hr. Dr. Kalinke

Fachgebiet 3/1Immunchemie

Hr. Dr. Giess

Fachgebiet 3/2Mono- und polyklonale

Antikörper

Fr. Dr. Schäffner

Fachgebiet 3/3Morphologie

Hr. Dr. Boller

Fachgebiet 3/4Tumorimpfstoffe,Zellbank, Medien

Hr. Frieling

Referat Z6Arbeitsschutz,

Genehmigungen

Fr. Dr. Pfitzner*

Abteilung ZVerwaltung

Hr. Dr. Frieser

Referat Z1Personal

Hr. Posselt

Referat Z2Haushalt

Hr. Robeck

Referat Z3Innerer Dienst

Hr. Gunkel

Referat Z4Technik

Hr. Pieschner-v. Meltzer

Referat Z5Organisation,

Informationstechnik

Hr. Dr. Frieser

Abteilung 2Virologie

Hr. PD Dr. Sutter

Fachgebiet 2/1Virusimpfstoffe

Hr. Dr. Pfleiderer

Fachgebiet 2/2HIV-Impfstoffe,

AIDS

Hr. PD Dr. A. Werner

Fachgebiet 2/3Diagnostika

Fr. Dr. Nick

Fachgebiet 2/4Molekulare Pathologie

Hr. Dr. Nübling

Fachgebiet 2/5Virussicherheit

Hr. Dr. Blümel*

Referat L3Presse,

Öffentlichkeitsarbeit

Fr. Dr. Stöcker

Referat L2Grundsatzfragen,

Zentrale Steuerung

Hr. Wiegelmann°

Referat L5Europäische

Verfahren

Fr. Dr. Schröder°

Referat L4Qualitäts-

management

Fr. Dr. v. Wangenheim

Referat L1Leitungsassistenz,

Sprachendienst

Fr. Plumbaum°

Paul-Ehrlich-InstitutBundesamt für Sera und Impfstoffe

Externalexpert

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

Members:• Experienced scientists not involved in the evaluation

of the product in questionAim:• 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”

Good Regulatory Practice (GRP) in the PEI Peer Review Group

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

20

24

4

9

1

11

32

51

51

41 11

2

5

6

27

13

7

12

20

5

10

15

20

25

30

35

40

45

Co-Rapporteur Rapporteur

European Procedures for Products in PEI‘s Remit(until 31 December 2005)

Distribution of (Co-)rapporteurships [Hum]

PEI

4

9

4

7

2

9

1

13

24

4

1

5 4

21

111

22

4

121

11

0

5

10

15

20

25

30

35

40

DE (PEI)

BEDK FR IT NL SE

UK AT

Allergene

Ig

MAK

Blutprodukte

Komb. Impfstoff

Viraler Impfstoff

Bakt. Impfstoff

European Procedures for Products in PEI‘s Remit(until 31 December 2005)

Distribution of RMSs with Germany involved [Hum]

PEI

010

203040

50607080

90100

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Per

cen

tScientific Advice [Hum] for Biological Products

Co-ordination by PEI (in Percent)

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

0 €

1.000.000 €

2.000.000 €

3.000.000 €

4.000.000 €

5.000.000 €

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

Manufacturer

Measurement

600 900 1200 1500 1800

600

900

1200

1500

1800

A A

A

A A

A

AAA

A

BB

C

CC

CC CC C

Potency of Anti-D ImmunoglobulinCorrelation between PEI’s and Manufacturer’s Results

PEI

Comparison of potency of a rec. FVIII obtained with different Chromogenic Assays

1000

260

658

182

704

203

809

214

0

200

400

600

800

1000

1200

BDD-FVIII 1000 BDD-FVIII 250

IU/v

ial

CA-1 mod.

PEI, CA-2

PEI, CA-1

PEI, CA-3

PEI

PEI

In vitro titration of TGN1412 binding to CD28expressed by human T cells

20

6.67

2.22

0.73

0.24

0.081

0.027

0.009

µg/ml

unstainedTGN 1412-Alexa 488

0

20

40

60

80

100

120

0.0010.010.1110100

µg/ml specific binding

% s

pec

ific

bin

din

g

TGN 1412Rituximab

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 meningo-encephalitis, 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

1 5 8 5 13 1838 72 39 27174

193

428

2940

0

500

1000

1500

2000

2500

3000

1994 1995 1996 1997 1998 1999 2000

serious

All fever reports

Removal of Thiomersal

Removal of Albumin

Schlaud 2005Background

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 KurthPEI

Schlaud 2005Study questions

• 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

Schlaud 2005

Study ProtocolStructure

Pathological Pathological approachapproach

Epidemiological Epidemiological approach approach

Qualitative research• Standardised

1. case ascertainment2. autopsies children aged 9-23 mo

• Additional in depths investigations

Quantitative research• All cases of death in children

aged 1-23 mo • Self Controlled Case Series• Case Control Study PEI

PEI