The PROTECT project
Olaf Klungel, PharmD, PhD
Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University
An Innovative Public-Private Partnership for New Methodologies in Pharmacovigilance and Pharmacoepidemiology
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.
Contents
• Background PROTECT - Work package 2 (WP2)
• WP2 working groups (WG)
– Approach
– Preliminary results (WG1)
– Results (WG2 and WG3)
– Next steps
• Conclusion
3
PROTECT Goal
4
These methods will be tested in real-life situations.
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
5
Clinical trials Observational studies
Electronic health records
Spontaneous ADR reports
Risks
Benefit-risk integration and representation – WP5
Signal detectionWP3
Benefits
Validation studies
WP6
Training and education
WP7
Signal evaluationWP2
Data collection from consumers – WP4
Partners
6
Public PrivateRegulators:
EMA (Co-ordinator)
DKMA (DK)
AEMPS (ES)
MHRA (UK)
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
EFPIA companies:
GSK (Deputy Co-ordinator)
Sanofi- Aventis
Roche
Novartis
Pfizer
Amgen
Genzyme
Merck Serono
Bayer
Astra Zeneca
Lundbeck
NovoNordisk
Takeda
SMEs:
Outcome Europe
PGRx
Others:
WHO UMC
GPRD
IAPO
CEIFE
WP 2: Framework for pharmacoepidemiological studies
7
To:• develop
• test
• disseminate
of pharmacoepidemiological studies applicable to:
• different safety issues
• using different data sources
methodological standards for the:• design
• conduct
• analysis
Objectives:
8
WP2 participants and their role
• WP2 has 3 Working groups (WG)
WG1Databases
WG2Confounding
WG3Drug utilization
Number of participants
n=4633 public, 13 private
n=1410 public, 4 private
n=95 public, 4 private
Public partnersEMA, LMU-Muenchen, AEMPS, CEIFE,
GPRD, DKMA and UUUU FIFC, LMU
Private partnersAmgen, 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. 2011 replacing Frank de Vries (UU)3 from 15 March 2012 replacing Hans Petri (Roche)
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
9
• British THIN databases (THIN)
• Spanish BIFAP project (BIFAP)
• German Bavarian claims database (BAVARIA)
• Danish National registries (DKMA)
• Dutch Mondrian databases (MONDRIAAN)
• British GPRD databases (GPRD)
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
Work Package 2 – WG1: Databases
Antidepressants (incl. Benzodiazepines) - Hip Fracture
Antibiotics - Acute liver injury
Beta2 Agonists - Myocardial infarction
Antiepileptics - Suicide
Calcium Channel Blockers - Cancer
11
Selection of 5 key adverse events and drugs– Initial list of 55 events and >55 drugs
– Finalisation based on literature review and consensus meeting
Population nr’s 6 EU databases
12
Database 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 GP 3.2 M 1.6 M
Danish registries DK Multisource 5.2 M (All DBs) 5.2 M (All DBs)
THIN UK GP 7.8 M 3.1 M
Bavarian Claims DE Claims 10.5 M 9.5 M
Characteristics of 6 EU DBs
13
Database Coding diagnoses
Coding drugs
Start year Nation wide
GPRD Read BNF 2001 7% UK
Mondrian ICPCICD
ATC 1991 90% NL (pharmacy)0.6% NL (GP)
Bifap ICPC ATC 2001 7% ES
Danish registries ICD ATC 1994 (med prod)1977 (pat register)
100% DK
THIN READ BNF 2003 5.7% UK
Bavarian Claims ICD ATC 2001 84% (Bavaria)
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
14
WG1 Preliminary results:Antibiotic use by age in 6 EU databases
15
DRAFT PRELIMINARY RESULTS
WG1 Preliminary results: Antidepressant use by year in 6 EU databases
16
DRAFT PRELIMINARY RESULTS
17
WG1 Preliminary results: BZD use by age in 6 EU databases
Mondriaan-ZGA: results correspond to 2008
DRAFT PRELIMINARY RESULTS
18
WG1 Preliminary results: Incidence of hip/femur fracture by age in 2009 in 4 EU databases
DRAFT PRELIMINARY RESULTS
19
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
Work Package 2 – WG2: Confounding
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
Simulation study propensity scores
21
Application of propensity scores
22
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)
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
25
Work Package 2 – WG3: Drug Utilisation
Progress Status Inventory on Drug Use data “Drug consumption
databases in Europe” (last version August 2011: http://www.imi-protect.eu/results.html)
– 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)
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
27
28
• 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
Finally
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).