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: Areas of Responsibility 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: 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: Holistic Approach for 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

Sequence of the Evaluation of an Application Application for rapporteurship defining the evaluation team and its expertise

Forschungsbeauftragter Forschung beim Präsidenten Fachgebiet Pr2 Institutsleitung Präsident und Professor Hr. Prof. Dr. Löwer Vizepräsident und Professor Hr. Prof. Dr. Cichutek Forschungsbeauftragter Hr. Prof. Dr. Vieths Forschung beim Präsidenten Fachgebiet Pr2 Retroelemente Fr. Dr. Löwer Forschung beim Präsidenten Fachgebiet Pr1 Transmissible spongiforme Enzephalopathien Hr. Dr. Montrasio Referat L3 Presse, Öffentlichkeitsarbeit Fr. Dr. Stöcker Referat L2 Grundsatzfragen, Zentrale Steuerung Hr. Wiegelmann° Referat L5 Europäische Verfahren Fr. Dr. Schröder° Referat L4 Qualitäts- management Fr. Dr. v. Wangenheim Referat L1 Leitungsassistenz, Sprachendienst Fr. Plumbaum° Prüflabor für IVD PEI-IVD Fr. Dr. S. Nick Abteilung Z Verwaltung Hr. Dr. Frieser Referat S4 Rechtsangelegenheiten Fr. Ruoff° Abteilung S Sicherheit von Arzneimitteln und Medizinprodukten Fr. Dr. Keller-Stanislawski° Referat S1 Arzneimittelsicherheit Fr. Dr. Keller-Stanislawski Referat S2 In-vitro-Diagnostika Hr. Dr. Bornhak Referat S3 Sicherheit veterinärmedizinischer Mittel, Tierschutz Hr. Dr. Cußler° Abteilung 1 Bakteriologie Hr. Dr. Haase Fachgebiet 1/1 Bakteriologische Impfstoffe I Hr. Dr. Öppling Fachgebiet 1/2 Bakteriologische Impfstoffe II Hr. Dr. Schwanig Fachgebiet 1/3 Mikrobielle Sicherheit und Parasitologie Hr. Dr. Montag-Lessing Fachgebiet 1/4 Biostatistik Hr. Dr. Volkers Abteilung 2 Virologie Hr. PD Dr. Sutter Fachgebiet 2/1 Virusimpfstoffe Hr. Dr. Pfleiderer Fachgebiet 2/2 HIV-Impfstoffe, AIDS Hr. PD Dr. A. Werner Fachgebiet 2/3 Diagnostika Fr. Dr. Nick Fachgebiet 2/4 Molekulare Pathologie Hr. Dr. Nübling Fachgebiet 2/5 Virussicherheit Hr. Dr. Blümel* Abteilung 3 Immunologie Hr. Dr. Kalinke Abteilung 4 Veterinärmedizin Hr. Dr. Moos Fachgebiet 4/1 Bakterielle Impfstoffe und Immunsera Fr. Dr. E. Werner° Fachgebiet 4/2 Virusimpfstoffe I Fr. Dr. Jungbäck Fachgebiet 4/3 Virusimpfstoffe II Fr. Dr. Duchow Fachgebiet ZT Zentrale Tierhaltung Hr. Dr. Plesker Abteilung 5 Allergologie Hr. Prof. Dr. Vieths Abteilung 6 Medizinische Biotechnologie Hr. Prof. Dr. Cichutek Abteilung 7 Hämatologie / Transfusionsmedizin Hr. Prof. Dr. Seitz Referat Z1 Personal Hr. Posselt Fachgebiet 3/1 Immunchemie Hr. Dr. Giess Fachgebiet 3/2 Mono- und polyklonale Antikörper Fr. Dr. Schäffner Fachgebiet 3/3 Morphologie Hr. Dr. Boller Fachgebiet 5/1 Test-Allergene Hr. Dr. Höltz Fachgebiet 6/1 Gentransfer- Arzneimittel I Hr. PD Dr. Buchholz Fachgebiet 7/1 Gerinnungsfaktoren I Hr. PD Dr. Dodt* Referat Z2 Haushalt Hr. Robeck Fachgebiet 5/2 Therapie-Allergene Fr. Dr. May Fachgebiet 6/2 Gentransfer- Arzneimittel II Hr. PD Dr. Schweizer* Fachgebiet 7/2 Gerinnungsfaktoren II Hr. PD Dr. Dodt Referat Z3 Innerer Dienst Hr. Gunkel Fachgebiet 5/3 Klinische Allergologie und Toxikologie Fr. Dr. Lüderitz-Püchel Fachgebiet 6/3 Somatische Zelltherapeutika Hr. Dr. Flory° Fachgebiet 7/3 Chargenprüfung Blutprodukte, Albumin, Logistik Hr. Dr. Unkelbach Referat Z4 Technik Hr. Pieschner-v. Meltzer Fachgebiet 3/4 Tumorimpfstoffe, Zellbank, Medien Hr. Frieling Fachgebiet 5/4 Entwicklung und Standardisierung Hr. Dr. Scheurer* Fachgebiet 6/4 Xenogene Zelltherapeutika Hr. PD Dr. Tönjes Fachgebiet 7/4 Transfusionsmedizin Fr. Dr. Heiden Referat Z5 Organisation, Informationstechnik Hr. Dr. Frieser Fachgebiet 7/5 Inspektionen: Schulung, Koordination und Durchführung Hr. PD Dr. G. Werner External expert Referat Z6 Arbeitsschutz, Genehmigungen Fr. Dr. Pfitzner* Personalrat Vorsitzende Fr. Gravelius Gleichstellungs- beauftragte Fr. Dr. Krämer Schwerbehinderten- vertrauensfrau Fr. Grote Jugend- und Auszubildenden- vertretung Fr. Zitzmann *mit der Wahrnehmung der Geschäfte beauftragt ° für die Wahrnehmung der Geschäfte vorgesehen NG1 Neue Impfstoffstrategien N.N. NG2 Bioinformatik NG3 Zelldifferenzierung NG4 NG5 Wissenschaftliche Nachwuchsgruppen (NG) Sprecher: N.N. Dienst- und Fachaufsicht Dienstaufsicht

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

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”

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

European Procedures for Products in PEI‘s Remit (until 31 December 2005) Distribution of (Co-)rapporteurships [Hum]

European Procedures for Products in PEI‘s Remit (until 31 December 2005) Distribution of RMSs with Germany involved [Hum]

Scientific Advice [Hum] for Biological Products Co-ordination by PEI (in Percent)

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

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

Research Grants

Widening the Basis for Decision Experimental investigations Potency of anti-D immunoglobulins Potency of recombinant Factor VIII Dose calculation for first-in-man-studies

Potency of Anti-D Immunoglobulin Correlation between PEI’s and Manufacturer’s Results 1800 A A A 1500 A A A A A A Measurement A 1200 C C C 900 B B C C C C C 600 600 900 1200 1500 1800 Manufacturer

Comparison of potency of a rec Comparison of potency of a rec. FVIII obtained with different Chromogenic Assays The company assayed potency using a Chromogenic Assay (CA) system (CA-1) with some modifications. PEI uses a different system (CA-2) for OMCL batch release of plasma FVIII (PD-FVIII); all batches BDD-FVIII were far below stated potency; also NIBSC found low values. PEI comparison with all three commercial chromogenic tests CA-2, CA-1 (without modification), and CA-3 found values well below the company´s

In vitro titration of TGN1412 binding to CD28 µg/ml 20 In vitro titration of TGN1412 binding to CD28 expressed by human T cells 6.67 120 TGN 1412 Rituximab 2.22 100 80 % specific binding 60 0.73 40 20 0.24 100 10 1 0.1 0.01 0.001 µg/ml specific binding 0.081 0.027 0.009 unstained TGN 1412-Alexa 488

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 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!

Change of the Manufacturing Process: Fever after a TBE- Vaccine, Germany 1994-2000 Removal of Albumin Example of implications of changes of the manufacturing process Removal of Thiomersal

Background PEI 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

PEI Dr. Bärbel-Maria Kurth

Is there a common pathological mechanism? Study 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

Study Protocol Structure Epidemiological approach Pathological approach Qualitative research Standardised 1. case ascertainment 2. 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

Paul Ehrlich: 14.03.1854 - 20.08.1915 Zwischen 1900 und 1915 ist nur in den Jahren 1903 und 1914 der 26. Februar ein Donnerstag