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Olaf Klungel, PharmD, PhD

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1 Olaf Klungel, PharmD, PhD
The PROTECT project An Innovative Public-Private Partnership for New Methodologies in Pharmacovigilance and Pharmacoepidemiology Olaf Klungel, PharmD, PhD Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University

2 ACKNOWLEDGEMENTS The research leading to these results was conducted as part of the PROTECT consortium (Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium, which is a public-private partnership coordinated by the European Medicines Agency. The PROTECT project has received  support from the Innovative Medicine Initiative Joint Undertaking ( under Grant Agreement n° , resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/ ) and EFPIA companies’ in kind contribution. The views expressed are those of the authors only. PROTECT work in this presentation is work by WP2 colleagues.

3 Background PROTECT - Work package 2 (WP2) WP2 working groups (WG)
Contents Background PROTECT - Work package 2 (WP2) WP2 working groups (WG) Approach Preliminary results (WG1) Results (WG2 and WG3) Next steps Conclusion

4 These methods will be tested in real-life situations.
PROTECT Goal To strengthen the monitoring of benefit-risk of medicines in Europe by developing innovative methods to enhance early detection and assessment of adverse drug reactions from different data sources (clinical trials, spontaneous reporting and observational studies) to enable the integration and presentation of data on benefits and risks These methods will be tested in real-life situations.

5 Training and education WP7 Data collection from consumers – WP4
Validation studies WP6 Training and education WP7 Data collection from consumers – WP4 Clinical trials Observational studies Electronic health records Spontaneous ADR reports Benefits Risks Signal detection WP3 Signal evaluation WP2 Benefit-risk integration and representation – WP5

6 Partners Public Private EFPIA companies: Regulators:
EMA (Co-ordinator) DKMA (DK) AEMPS (ES) MHRA (UK) EFPIA companies: GSK (Deputy Co-ordinator) Sanofi- Aventis Roche Novartis Pfizer Amgen Genzyme Merck Serono Bayer Astra Zeneca Lundbeck NovoNordisk Takeda Academic Institutions: University of Munich FICF (Barcelona) INSERM (Paris) Mario Negri Institute (Milan) Poznan University of Medical Sciences University of Groningen University of Utrecht Imperial College London University of Newcastle Others: WHO UMC GPRD IAPO CEIFE SMEs: Outcome Europe PGRx

7 WP 2: Framework for pharmacoepidemiological studies
Objectives: To: develop test disseminate methodological standards for the: design conduct analysis of pharmacoepidemiological studies applicable to: different safety issues using different data sources 7 7

8 WP2 participants and their role
WP2 has 3 Working groups (WG) WG1 Databases WG2 Confounding WG3 Drug utilization Number of participants n=46 33 public, 13 private n=14 10 public, 4 private n=9 5 public, 4 private Public partners EMA, LMU-Muenchen, AEMPS, CEIFE, GPRD, DKMA and UU UU FIFC, LMU Private partners Amgen, AZ, Genzyme, GSK, La-Ser, Merck, Novartis, Roche and Pfizer Amgen, Novartis, Roche and Pfizer Amgen, Novartis and Roche WG Coordinators Raymond Schlienger 1 (Novartis) Mark de Groot2 (UU) Nicolle Gatto (Pfizer) Rolf Groenwold (UU) Joan Fortuny 3 (Novartis) Luisa Ibanez (FIFC) WP2 coleaders Olaf Klungel (UU) - Robert Reynolds (Pfizer) WP2 coleaders alternates Tjeerd van Staa (GPRD) - Jamie Robinson (Roche) WP2 Project Manager Ines Teixidor (UU) 1 from Oct 2010 replacing John Weil (GSK) 2 from 1 Feb replacing Frank de Vries (UU) 3 from 15 March 2012 replacing Hans Petri (Roche)

9 Work Package 2 – WG1: Databases
Conduct of adverse event - drug pair studies in different EU databases Selection of 5 key adverse event - drug pairs Development of study protocols for all pairs Compare results of studies Identify sources of discrepancies Databases Danish National registries (DKMA) Dutch Mondrian databases (MONDRIAAN) British GPRD databases (GPRD) British THIN databases (THIN) Spanish BIFAP project (BIFAP) German Bavarian claims database (BAVARIA) 9 9

10 Work Package 2 – WG1: Databases
Selection of key adverse events and drugs Selection criteria: Adverse events that caused regulatory decisions Public health impact (seriousness of the event, prevalence of drug exposure, etiologic fraction) Feasibility Range of relevant methodological issues 10 10

11 Work Package 2 – WG1: Databases
Selection of 5 key adverse events and drugs Initial list of 55 events and >55 drugs Finalisation based on literature review and consensus meeting Antidepressants (incl. Benzodiazepines) - Hip Fracture Antibiotics - Acute liver injury Beta2 Agonists - Myocardial infarction Antiepileptics - Suicide Calcium Channel Blockers - Cancer 11 11

12 Population nr’s 6 EU databases
Country Source Cum Population nr Active population nr (2008) GPRD UK GP 11 M 3.6 M Mondrian NL Multisource 1.4 M (GP) 1 M (GP), 13.5 (Pharmacy), 1.2 M (Claims) Bifap ES 3.2 M 1.6 M Danish registries DK 5.2 M (All DBs) THIN 7.8 M 3.1 M Bavarian Claims DE Claims 10.5 M 9.5 M

13 Characteristics of 6 EU DBs
Database Coding diagnoses Coding drugs Start year Nation wide GPRD Read BNF 2001 7% UK Mondrian ICPC ICD ATC 1991 90% NL (pharmacy) 0.6% NL (GP) Bifap 7% ES Danish registries 1994 (med prod) 1977 (pat register) 100% DK THIN READ 2003 5.7% UK Bavarian Claims 84% (Bavaria)

14 Approach Common protocol for each drug-ae pair
Descriptive studies for drug-ae pairs in all databases 5 different study designs in selected databases Extensive sensitivity analyses on main methodological issues Common standards, templates, procedures Detailed data specification including definitions of exposures, outcomes, and confounders for each database. Blinding of results of individual DB analyses Submission of protocols to ENCePP registry of studies

15 WG1 Preliminary results: Antibiotic use by age in 6 EU databases

16 WG1 Preliminary results: Antidepressant use by year in 6 EU databases

WG1 Preliminary results: BZD use by age in 6 EU databases DRAFT PRELIMINARY RESULTS Mondriaan-ZGA: results correspond to 2008

WG1 Preliminary results: Incidence of hip/femur fracture by age in 2009 in 4 EU databases DRAFT PRELIMINARY RESULTS

19 Work Package 2 – WG2: Confounding
Work Plan Objective To evaluate and improve innovative methods to control confounding Method Simulation studies to test methods Application of methods to real-life data sets 19 19

20 Work Package 2 – WG2: Confounding
Progress status Guideline for conduct of simulation studies Propensity score methods Instrumental variable methods First results Usefulness of measures for balance for reporting of the amount of balance reached in PS analysis and selecting the final PS model Comparison of methods to control for time-dependent confounding Evaluation of IV in case-control and cohort studies 20 20

21 Simulation study propensity scores

22 Application of propensity scores

23 Work Package 2 – WG2: Confounding
Next steps Analysis of instrumental variables (IV) in Drug AE pairs Evaluate the potential for IV analysis on the selected Drug AE pairs in the databases that are available within PROTECT Feb 2012: Identify potential IV for each of the 5 Drug AE pair and in each WG1 database Aug 2013: Results of IV studies in databases (if an appropriate IV can be identified & measured) 23 23

24 Work Package 2 – WG3: Drug Utilisation
Work Plan Use of national drug utilisation data (incl IMS) Inventory of data sources on drug utilisation data for several European countries Evaluation and dissemination of methodologies for drug utilisation studies in order to estimate the potential public health impact of adverse drug reactions Collaboration with EuroDURG agreed 24 24

25 Work Package 2 – WG3: Drug Utilisation
Progress Status Inventory on Drug Use data “Drug consumption databases in Europe” (last version August 2011: 11 research working groups across Europe identified Databases heterogeneous, administrative focus and influenced by the national health system structure Collecting DU data (in/out hospital) from public databases (for 6 selected drugs) from IMS (Antibiotics, Antidepressants and Benzodiazepines. Explored for other drugs) 25 25

26 Work Package 2 – WG3: Drug Utilisation
Next steps Literature Search on Randomized Controlled Trials (RCT) Search for existing meta-analyses or syntheses available in the literature (avoid duplication of work already done). Dec 2011: Development of specific protocols for literature search Jan 2012: Start of literature search starts. Dec 2012: Results of the literature search on RCTs expected. Public health impact of selected Drug AE pairs Evaluate validity of drug use data Estimate the exposed population to drugs and calculate population attributable risk 26 26


28 Finally Reduce variation due to methodological choice of individual researchers Explain variation due to characteristics of country/database Disseminate methodological guidance for PE studies More consistency in drug-ae studies to improve B/R assessment of medicines

29 Members of PROTECT WP2 J. Slattery, Y. Alvarez, G. Candore, J. Durand (European Medicines Agency); J. Hasford, M. Rottenkolber (Ludwig-Maximilians-Universität-München); S. Schmiedl (Witten University); F. de Abajo Iglesias, A. Afonso, M. Gil, C. Huerta Alvarez, B. Oliva, G. Requena (Agencia Espanola de Medicamentos y Productos Sanitarios); R. Brauer, G. Downey, M. Feudjo-Tepie, M. Schoonen (Amgen NV); S. Johansson (AstraZeneca); J. Robinson, M. Schuerch, I. Tatt (Roche); L.A. Garcia, A. Ruigomez (Fundación Centro Español de Investigación Farmacoepidemiológica); J. Campbell, A. Gallagher, E. Ng, T. Van Staa (General Practice Research Database); O. Demol (Genzyme); J. Logie, J. Pimenta, K. Davis (GlaxoSmithKline Research and Development LTD); L. Bensouda-Grimaldi (L.A. Sante Epidemiologie Evaluation Recherche); U. Hesse, P. F. Rønn (Lægemiddelstyrelsen (Danish Medicines Agency) ); M. Miret (Merck KGaA ); P. Primatesta, R. Schlienger, E. Rivero, J. Fortuny (Novartis); A. Bate, N. Gatto, R. Reynolds (Pfizer); E. Ballarin, L. Ibañez, J.R. Laporte, M. Sabaté, P. Ferrer (Fundació Institut Català de Farmacologia); V. Abbing-Karahagopian, D. de Bakker, M.L. de Bruin, F. de Vries, A.C.G. Egberts, B. Leufkens, P. Souverein, L. van Dijk, E. Voogd, M. De Groot, H. Gardarsdottir, F. Rutten, R. Van den Ham, O. Klungel, S. Belitser, A. De Boer, R. Groenwold, A. Hoes, W. Pestman, K. Roes, S. Ali, J. Uddin (Universiteit Utrecht).

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