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

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PROTECT Goal

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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

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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

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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

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To:• develop

• test

• disseminate

of pharmacoepidemiological studies applicable to:

• different safety issues

• using different data sources

methodological standards for the:• design

• conduct

• analysis

Objectives:

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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

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• 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

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Work Package 2 – WG1: Databases

Antidepressants (incl. Benzodiazepines) - Hip Fracture

Antibiotics - Acute liver injury

Beta2 Agonists - Myocardial infarction

Antiepileptics - Suicide

Calcium Channel Blockers - Cancer

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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

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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

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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

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

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DRAFT PRELIMINARY RESULTS

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

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DRAFT PRELIMINARY RESULTS

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WG1 Preliminary results: BZD use by age in 6 EU databases

Mondriaan-ZGA: results correspond to 2008

DRAFT PRELIMINARY RESULTS

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

DRAFT PRELIMINARY RESULTS

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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

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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

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Application of propensity scores

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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)

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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

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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)

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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

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• 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

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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).