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Olaf Klungel, PharmD, PhD

Explaining differences in drug-adverse event associations across and within EU databases The PROTECT project. An Innovative Public-Private Partnership for New Methodologies in Pharmacovigilance and Pharmacoepidemiology. Olaf Klungel, PharmD, PhD

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Olaf Klungel, PharmD, PhD

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  1. Explaining differences in drug-adverse event associations across and within EU databasesThe 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, www.imi-protect.eu) 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 (www.imi.europa.eu) under Grant Agreement n° 115004, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) 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. Contents • Background PROTECT (WP2) • Selection of 6 drug-ae pairs • Analysis in 6 EU databases • Preliminary descriptive results • Population impact across EU countries • Conclusion

  4. These methods will be tested in real-life situations. PROTECT Goal • To strengthen the monitoring of benefit-risk of medicines in Europeby 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

  5. Partners Public Private 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

  6. WP2 participants and their role 1from Oct 2010 replacing John Weil (GSK) 2 from 1 Feb. 2011 replacing Frank de Vries (UU) 3 from 15 March 2012 replacing Hans Petri (Roche) • WP2 has 3 Working groups (WG)

  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

  8. Two studies on the use of statins and the risk of fracture done in GPRD around the same period by two different groups.

  9. Why such a difference ? • Different patients (source population, study period, exclusion criteria) • Study design (e.g. matching criteria for age) • Definition of current statin use (last 6 months vs. last 30 days) • Possibly different outcomes (mapping) • Possibly uncontrolled/residual confounding

  10. 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 • Dutch Mondrian databases • British GPRD databases • British THIN databases • Spanish BIFAP project • German Bavarian claims database

  11. 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

  12. 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

  13. Population nr’s 6 EU databases

  14. Characteristics of 6 EU DBs

  15. Approach • Common protocol for each drug-ae pair • Extensive sensitivity analyses on main methodological issues • Leader(s) for each protocol • Leader(s) for each database • Detailed data specification including definitions of exposures, outcomes, and confounders for each database. • Blinding of results of individual DB analyses

  16. Preliminary results: Antibiotic use by year in 6 EU databases DRAFT PRELIMINARY RESULTS

  17. Preliminary results: Antibiotic use by age in 6 EU databases DRAFT PRELIMINARY RESULTS

  18. Preliminary results: Antibiotic use in 4 EU databases DRAFT PRELIMINARY RESULTS • Point prevalence of Antibiotic Exposure by season from 2004-2009

  19. Preliminary results: Antidepressant use by year in 6 EU databases DRAFT PRELIMINARY RESULTS

  20. Preliminary results: BZD use per year for 6 EU databases DRAFT PRELIMINARY RESULTS

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

  22. Preliminary results: Incidence of hip/femur fracture in 6 EU databases DRAFT PRELIMINARY RESULTS

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

  24. Calculation of Population Attributable Risk

  25. Next steps • Conduct of association studies 6 drug-ae pairs: • Cohort studies (end 2012 complete) • Nestedcase-control studies • Population-based control studies • Case-cross over studies • Self-controlled case series

  26. Finally • Reducevariationduetomethodologicalchoice of individualresearchers • Explainvariation due to characteristics of country/database • More consistency in drug-ae studies to improve B/R assessment of medicines

  27. 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 ProductosSanitarios); 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 InvestigaciónFarmacoepidemiológica); 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. SanteEpidemiologie 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 (FundacióInstitutCatalà 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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