The PROTECT project An Innovative PublicPrivate Partnership for

The PROTECT project An Innovative Public-Private Partnership for New Methodologies in Pharmacovigilance and Pharmacoepidemiology Progress Status: February 2011

PROTECT is receiving funding from the European Community's Seventh Framework Programme (FP 7/2007 -2013) for the Innovative Medicine Initiative (www. imi. europa. eu). 2

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. 3

Data collection from consumers – WP 4 Clinical trials Observational studies Benefits Electronic health records Spontaneous ADR reports Risks Signal detection WP 3 Benefit-risk integration and representation – WP 5 Signal evaluation WP 2 Validation studies WP 6 Training and education WP 7 4

Partners Public Private Regulators: EFPIA companies: EMA (Co-ordinator) GSK (Deputy Coordinator) DKMA (DK) AEMPS (ES) MHRA (UK) Sanofi- Aventis Roche Novartis Academic Institutions: University of Munich Pfizer FICF (Barcelona) Genzyme Amgen INSERM (Paris) Mario Negri Institute (Milan) Poznan University of Medical Sciences Others: WHO UMC GPRD University of Groningen IAPO University of Utrecht Imperial College London University of Newcastle Upon Tyne CEIFE Merck Serono Bayer Astra Zeneca Lundbeck Novo. Nordisk Takeda SMEs: Outcome Europe PGRx 5

WP 1: Project Management and Administration Objectives: To create and maintain the conditions needed to achieve the objectives and deliverables of the PROTECT project. Knowledge Scientific steer management towards the tools and overall project strategies objectives and strategy Quality Financial Administrative, Track of work control and organisational progress in line monitoring and assurance accountancy with the work and financial measures programme support 6

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

Art is made to disturb. Science reassures. Georges Braque Is it always true ? 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 Work plan • Three Working Groups (WG 1 -WG 3) – Databases – Confounding – Drug Utilisation 11

Work Package 2 – WG 1: Databases Work Plan 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 – British THIN databases – Dutch Mondriaan database – Spanish BIFAP project – British GPRD database – German Bavarian claims database 12

Work Package 2 – WG 1: Databases Progress status (1/3) 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 13

Work Package 2 – WG 1: Databases Progress status (2/3) 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 Beta 2 Agonists - Myocardial infarction Antiepileptics - Suicide Calcium Channel Blockers - Cancer 14

Work Package 2 – WG 1: Databases Progress status (3/3) Development of study protocols • Descriptive studies for the Drug AE pairs in all databases • 5 different study designs in selected databases – Cohort design – Case crossover – Nested case control design – Self controlled case series – Population based case control 6 Final protocols in Feb 2011 (separate protocols for antidepressants and benzodiazepines versus hip fracture) 15

Work Package 2 – WG 2: Confounding Work Plan • Objective – To evaluate and improve innovative methods to control confounding • Method – Creation of simulated cohorts – Use of methods to adjust for observed and unobserved confounding e. g. time-dependent exposure, propensity scores, instrumental variables, prior event rate ratio (PERR) adjustment, evaluation of measures of balance in real-life study 16

Work Package 2 – WG 2: Confounding Progress status • Finalisation of protocol to conduct simulation studies – Propensity score methods – Instrumental variable methods – Time-dependent confounding • First results on propensity scores (PS)/balance measures – Usefulness of measures for balance for reporting of the amount of balance reached in PS analysis and selecting the final PS model – Recommendation of methods to quantify balance of confounder distributions when applying PS methods: w standardised difference w Kolmogorov-Smirnov distance, or w overlapping coefficient 17

Work Package 2 - WG 3: 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 Euro. DURG agreed 18

Work Package 2 - WG 3: Drug Utilisation Progress Status Inventory on Drug Use data “Drug consumption databases in Europe” (last version January 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) 19

Work Package 3: Signal Detection Objective: To improve early and proactive signal detection from spontaneous reports, electronic health records, and clinical trials. 20

Work Package 3: Signal Detection Scope • Develop new methods for signal detection in Individual Case Safety Reports. • Develop Guidelines for signal detection and strengthening in Electronic Health Records. • Implement and evaluate concept-based Adverse Drug Reaction terminologies as a tool for improved signal detection and strengthening. • Evaluate different methods for signal detection from clinical trials. • Recommendations for good signal detection practices. 21

Work Package 3: Sub-projects 1. Merits of disproportionality analysis 2. Structured database of known ADRs 3. Concordance with risk estimates 4. Signal detection recommendations 5. Better use of existing ADR terminologies 6. Novel tools for grouping ADRs 7. Other information to enhance signal detection 8. Signal detection based on SUSARs 9. Subgroups and risk factors 10. Signal detection in Electronic Health Records 11. Drug-drug interaction detection 12. Duplicate detection 22

Work Package 3 – Structured database of SPC 4. 8 • Objective: Making available, in a structured format, already known ADRs to allow for – Triaging out known ADRs – Automatic reduction of masking effects • Approach: – Manual identification – Pooling of existing structured information (? ) – Free text extraction! • Progress to date: – All 375 SPCs of CAPs (substances). Addition of non-CAPs under discussion. 23

Work Package 3 – Structured database of SPC 4. 8 • Proof-of-concept analysis of free text extraction algorithm – Initial match rate increased from 72% to 98% Drug SPC Term Aclasta FLU-LIKE SYMPTOMS Verbatim match Fuzzy matching algorithm Flu symptoms Advagraf OTHER ELECTROLYTE ABNORMALITIES - Electrolyte abnormality Advagraf PAIN AND DISCOMFORT - Pain and discomfort NEC Advagraf PRIMARY GRAFT DYSFUNCTION - Primary graft dysfunction* Advagraf PRURITUS Pruritus* Advagraf PSYCHOTIC DISORDER Psychotic disorder* Advagraf PULSE INVESTIGATIONS ABNORMAL - Investigation abnormal Advagraf RASH Rash* Advagraf RED BLOOD CELL ANALYSES ABNORMAL - Red blood cell analyses* Advagraf RENAL FAILURE Renal failure* Advagraf RENAL FAILURE ACUTE Acute renal failure, Renal failure acute* Advagraf RENAL IMPAIRMENT Renal impairment* Advagraf RENAL TUBULAR NECROSIS Renal tubular necrosis* Advagraf RESPIRATORY FAILURES - Respiratory failure, Failure respiratory Advagraf RESPIRATORY TRACT DISORDERS - Respiratory tract disorders NEC Advagraf SEIZURES - Seizure, Seizures* Advagraf SHOCK Shock* Better option: Red blood cell abnormal 24

Work Package 3 – Database survey • Scope – Eudra. Vigilance, Vigi. Base – National data sets: AEMPS, BFARM, DKMA, MHRA – Company data sets: AZ, Bayer, Genzyme, GSK • Focus – # reports, # drugs and # ADR terms – Types of reports (AEs or ADRs, Vaccines, Seriousness, . . . ) – Additional information (presence of data elements available for stratification and sub-setting, e. g. demographics) – Supporting systems (analytical methods, medical triages) • Current status – Survey deployed and completed by most organisations 25

Work Package 3 - Better use of existing terminologies • Proof of concept – Temozolomide – Not illustrating timeliness – Vigi. Base as of Feb 2009 Term Level of terminology # Reports IC Erythema Multiforme PT 13 +0. 30 Stevens-Johnson Syndrome PT 19 +0. 68 Toxic Epidermal Necrolysis PT 6 +0. 51 Bullous Conditions HLT 42 -0. 01 Severe Cutaneous Adverse Reactions SMQ 47 -0. 04 WHO-ART HLT 35 +0. 46 Erythema Multiforme 26

Work Package 3 – Novel tools to group ADRs • Approach – Automatic generation of groups of Med. DRA terms based on semantic information – Based on a mapping of Med. DRA to SNOMED CT – Groups Med. DRA terms based on semantic distance • Progress – Evaluation study completed – Comparison with standard Med. DRA SMQs as gold standard • Next steps: – Refinement of methods – Use in signal detection! 27

Work Package 3 - Signal detection from clinical trials • Overall scope – Inform best practices on which data should be used and which methods are optimal – Explore novel uses of existing clinical data in ongoing and completed clinical trials for safety signal detection • Progress Draft protocol – Conduct benchmark survey of available methods and processes – Create a library of publications on this topic – Identify compounds and relevant data sets for retrospective analysis. – Conduct analyses and document results. – Create recommendations for best practices 28

Work Package 3 - Signal detection in Electronic Healthcare Records (EHRs) • Overall scope – EHRs versus ICSRs for early signal detection – Confirmatory vs exploratory data analysis • Focus so far has been on the adaptation of an existing analytical platform to THIN • Detailed protocols under development (completion by Aug 2011) 29

Work Package 3 - Other • Subpackage 11: Drug-drug interaction detection reference set under construction • Subpackage 12: Duplicate detection completed in Vigi. Base • Study protocols agreed for – Subpackage 1: Merits of disproportionality analysis – Subpackage 2: Concordance with risk estimates – Subpackage 5: Better use of existing terminologies 30

Work Package 4: Data collection from consumers Objectives: To assess the feasibility, efficiency and usefulness of modern methods of data collection including using web-based data collection and computerised, interactive voice responsive systems (IVRS) by telephone 31

Work Package 4 - Project Definition • Prospective, non interventional study which recruits pregnant women directly without intervention of health care professional • Collect data from them throughout pregnancy using either web based or interactive voice response systems (IVRS): – medication usage, lifestyle and risk factors for congenital malformation • Compare data with that from other sources and explore differences • Assess strengths and weaknesses of data collection and transferability to other populations 32

Work Package 4 - Issues with current methods Using health care professionals to capture data • Expensive and data capture relatively infrequent • Will miss drug exposure before comes to attention of HCP • Patients may not tell truth about “sensitive” issues 33

Work Package 4 - Issues with current methods Using EHR records • non prescription medicines, homeopathic and herbal medicines not captured – ? Women switch to “perceived safer” medicines • Medicines prescribed/dispensed may not be medicines consumed – problem with p. r. n. medicines (i. e. dosage as needed) • EHR may miss lifestyle and “sensitive” information 34

Work package 4 - Study population • 4 countries: Denmark United-Kingdom The Netherlands Poland • 1400 pregnant women per country – Self identified as pregnant – Volunteers may not be “typical” of pregnant population – can characterise 35

Work Package 4: Patient workflow overview Study subject picks up a leaflet in a pharmacy or browses specific web sites to find out about the study in one of 4 countries. Study subject enrolls for the web or phone (IVRS) method of data collection. IVRS Web n = 1200 per country Study subject completes the surveys online. n = 200 per country Study subject completes the surveys via an outbound reminder or by inbound call she initiates. Final outcome survey is completed at the end of pregnancy. 36

Work Package 5: Benefit-Risk Integration and Representation Objectives: • To assess and test methodologies for the benefit-risk assessment of medicines • To develop tools for the visualisation of benefits and risks of medicinal products è Perspectives of patients, healthcare prescribers, regulatory agencies and drug manufacturers è From pre-approval through lifecycle of products 37

Work Package 5: Workstreams A Develop framework for benefit-risk analysis B Review of methodologies used, elicitation of preferences and integrating effects and preferences C Criteria for case study selection & case study selection D Determine data to be gathered from case studies and format required E Develop software to support application of methodology and graphical representation F Application of methodology and graphical methodology to case studies wave 1 38

Work Package 5: Work Plan 1. Review of methodologies used to model effects of medicines, elucidation of patients’ preferences and integrating effects and preferences. Review of methodologies for graphical representation and visualisation techniques. 2. Selection of case studies (waves 1 and 2) 3. Data selection/requirements for case studies 4. Identification/development of software for B/R. 5. Application of methodology, recommendations, finalisation of tools, protocols for validation studies. 39

Work Package 5: Workstream A - completed • Framework for B-R analysis: achieved through a Charter (SC approved) – Large scope covering principally post-approval setting, individual and population-based decision making, various perspectives (patients, prescriber, regulators, industry) – Address possible interdependencies with other PROTECT WPs – Review of B-R methodologies and graphical representation tools – Selection of candidate methodologies based on specified criteria – Process for selection of case studies, according to selection criteria – Implementation of case studies using relevant methodologies and including preferences of various stakeholders – Test available representation technologies applied to above mentionned case studies and B-R methodologies – Publication and presentation of case studies in various settings 40

Work Package 5: Overview • Wave 1: has 4 case studies: Raptiva, Tysabri, Ketek, and Acomplia. • Drugs which have data readily available from EPARs. • Not revisiting EMA decisions, but use to demonstrate and test methodologies. • Review of existing methods not inventing new methods. • Emphasis on graphical representation. • Methods estimating(1) magnitude / incidence of events and (2) value elicitation of benefits and risks, from a patient and regulator perspective and how combine them into a single measure. WS C Case studies WS D Framework / Data WS F Application WS B Methods • Not developing software, but explore suitable existing software (possibly with adaptation). • Pr. OACT-URL framework for performing benefit-risk analysis. • Oversee working parties for extracting objective measures of magnitude / incidence of benefits and risks. WS E Software / graphics • Apply the methodology to the case studies using the data • May also elicit the subjective value data for the benefits and risks. 41

Work Package 5: Workstream B Collabor ators Literature search Other initiatives Methodological review Elicitation of suitable methods Literature search Other External initiative meeting s s Visual representations review Elicitation of suitable graphics Integration of methodologies and visual representations Develop visual representations add-ons and software Application to case studies • Protocol for evidence synthesis endorsed by all members • 34 items to review have been identified through literature search • List of evaluation criteria has been generated • Focus on their potential for graphical representation Present case-studies results emphasising on communication of, and use of graphical representations for, understanding benefits and risks 42

Work Package 5: Workstream C • Progress – Criteria for wave 1 case studies and drugs for case studies (Acomplia ®, Raptiva ®, Tysabri ®, Ketek ®) – Draft criteria for wave 2 and library of possible candidates (more challenging) w Uncertainty about what the main benefits and risks are. w Uncertainty about the population who has the disease. w Different time for Benefit and for Risk (long term risks). w Individual benefit-risk, or subgroups of benefit risk. w New drugs vs. long marketed drugs. 43

Work Package 5: Workstream C • Next steps – Discussion with other workstreams for appropriate data identification and extraction (WS D), applicability of case studies for WS F to run. – Identify potential presentations and publications. 44

Work Package 5: Workstream D • Scope – Data Collection dependent from Framework used: w Using Pr. OACT-URL (generic framework for decision making), identification of data sources to be used depend on detailed description of each of the steps of the framework (see back up slide) – Lead to a draft “Guidelines for preparing a Case Study Report” – Based on Acomplia® experience, most data/information necessary for B-R assessement at time of market authorisation and of market withdrawal were included into EPAR (Regulators perspective) – In addition to EPAR, additional data sources for other drugs or for other perspectives will require w Additional data collection from existing data sets (PSURs, formal B-R reviews) w Creation of new data (e. g. questionnaires for patient preferences elicitation) 45

Work Package 5: Workstream D • Next steps – Prepare identification of data sources to be used/created for other Wave 1 case studies (Raptiva ®, Tysabri®, Ketec®) – Actual supply of data 46

Work Package 5: Workstream F • Scope – Workstream (WS) F is: w w applying the methodology from WS B to the case studies selected from WS C using the data collected in WS D with the software and graphical methods selected by WS E – Done by four interdisciplinary teams in four locations – More than one method will be applied to each case study, and several methods explored overall – The aim of the first wave is to test the application of the methods and framework on relatively simple case studies – This then feeds back into the second wave to refine the tools 47

Work Package 6: Validation Objectives: • To validate and test the transferability and feasibility of methods developed in PROTECT to other data sources and population groups • To determine the added value of using other data sources as a supplement or alternative to those generally used for drug safety studies, in order to investigate specific aspects or issues. Started in September 2010 48

Work Package 6 - Inventory of data sources • Creating a comprehensive list of data sources (ongoing) – Review of European databases (electronic healthcare records, cohorts, registries) – ENCe. PP – EFPIA • Outcomes of other Work Packages (2 -5) will be evaluated in light of the inventory of data sources (e. g. type of data, covariate information, mode of collection, type of prescription data, etc) 49

Work Package 7: Training & communication Objective: To identify training opportunities and support training programmes to disseminate the results achieved in PROTECT. 50

Work Package 7: Scope • Development of a platform of training opportunities. • Regular interaction with EU 2 P Consortium. • Communication Plan: draft list of conferences and other international forums suitable for the presentation of the results of PROTECT. 51

Work Package 7: Training Platform https: //w 3. icf. uab. es/trainingopp (under development) 52

More information? Website: www. imi-protect. eu Email: Protect_Support@ema. europa. eu 53