the protect project
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
![Page 1: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/1.jpg)
The PROTECT project
Olaf Klungel, PharmD, PhDDivision of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute
for Pharmaceutical Sciences, Utrecht University
An Innovative Public-Private Partnership for New Methodologies in Pharmacovigilance and Pharmacoepidemiology
![Page 2: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/2.jpg)
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.
![Page 3: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/3.jpg)
3
Contents
• Background PROTECT - Work package 2 (WP2) • WP2 working groups (WG)
– Approach– Preliminary results (WG1)– Results (WG2 and WG3)– Next steps
• Conclusion
![Page 4: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/4.jpg)
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
![Page 5: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/5.jpg)
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
![Page 6: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/6.jpg)
Partners
6
Public PrivateRegulators:EMA (Co-ordinator)DKMA (DK)AEMPS (ES)MHRA (UK)
Academic Institutions:University of MunichFICF (Barcelona)INSERM (Paris)Mario Negri Institute (Milan)Poznan University of Medical Sciences University of GroningenUniversity of UtrechtImperial College LondonUniversity of Newcastle
EFPIA companies:GSK (Deputy Co-ordinator)Sanofi- AventisRocheNovartisPfizerAmgen GenzymeMerck SeronoBayerAstra ZenecaLundbeckNovoNordiskTakeda
SMEs:Outcome EuropePGRx
Others:WHO UMCGPRDIAPOCEIFE
![Page 7: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/7.jpg)
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:
![Page 8: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/8.jpg)
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 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. 2011 replacing Frank de Vries (UU)3 from 15 March 2012 replacing Hans Petri (Roche)
![Page 9: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/9.jpg)
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)
![Page 10: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/10.jpg)
Work Package 2 – WG1: DatabasesSelection 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
![Page 11: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/11.jpg)
Work Package 2 – WG1: Databases
Antidepressants (incl. Benzodiazepines) - Hip FractureAntibiotics - Acute liver injury
Beta2 Agonists - Myocardial infarctionAntiepileptics - 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
![Page 12: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/12.jpg)
12
Population nr’s 6 EU databases
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
![Page 13: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/13.jpg)
13
Characteristics of 6 EU DBs
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% ESDanish registries ICD ATC 1994 (med prod)
1977 (pat register)100% DK
THIN READ BNF 2003 5.7% UKBavarian Claims ICD ATC 2001 84% (Bavaria)
![Page 14: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/14.jpg)
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
![Page 15: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/15.jpg)
WG1 Preliminary results:Antibiotic use by age in 6 EU databases
15
DRAFT PRELIMINARY RESULTS
![Page 16: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/16.jpg)
WG1 Preliminary results: Antidepressant use by year in 6 EU databases
16
DRAFT PRELIMINARY RESULTS
![Page 17: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/17.jpg)
17
WG1 Preliminary results: BZD use by age in 6 EU databases
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90+0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
BIFAPDENMARKGPRDMONDRIAAN-LINHMONDRIAAN-ZGATHIN
AGE GROUP
Prev
alen
ce p
er 1
0.00
0 p-
y
Mondriaan-ZGA: results correspond to 2008
DRAFT PRELIMINARY RESULTS
![Page 18: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/18.jpg)
18
WG1 Preliminary results: Incidence of hip/femur fracture by age in 2009 in 4 EU databases DRAFT PRELIMINARY RESULTS
![Page 19: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/19.jpg)
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
![Page 20: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/20.jpg)
20
Work Package 2 – WG2: ConfoundingProgress 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
![Page 21: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/21.jpg)
21
Simulation study propensity scores
![Page 22: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/22.jpg)
22
Application of propensity scores
![Page 23: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/23.jpg)
23
Work Package 2 – WG2: ConfoundingNext 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)
![Page 24: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/24.jpg)
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
![Page 25: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/25.jpg)
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)
![Page 26: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/26.jpg)
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
![Page 27: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/27.jpg)
27
![Page 28: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/28.jpg)
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
![Page 29: The PROTECT project](https://reader035.vdocuments.net/reader035/viewer/2022081603/56815d0b550346895dcb0e16/html5/thumbnails/29.jpg)
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).