Transcript Name of the meeting

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 (FP7/2007-2013)
for the Innovative Medicine Initiative
(www.imi.europa.eu).
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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.
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Data collection from consumers – WP4
Clinical trials
Observational
studies
Benefits
Electronic
health records
Spontaneous
ADR reports
Risks
Signal detection
WP3
Benefit-risk integration and
representation – WP5
Signal evaluation
WP2
Validation
studies
WP6
Training and
education
WP7
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Partners
Public
Private
Regulators:
EMA (Co-ordinator)
DKMA (DK)
EFPIA companies:
AEMPS (ES)
MHRA (UK)
Sanofi- Aventis
GSK (Deputy Coordinator)
Roche
Novartis
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 Upon
Tyne
Pfizer
Amgen
Genzyme
Others:
WHO UMC
GPRD
IAPO
CEIFE
Merck Serono
Bayer
Astra Zeneca
Lundbeck
NovoNordisk
Takeda
SMEs:
Outcome Europe
PGRx
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WP 1: Project Management and
Administration
Objectives:
To create and maintain the conditions needed to
achieve the objectives and deliverables of the
PROTECT project.
Scientific steer
towards the
overall project
objectives and
strategy
Quality
control and
assurance
measures
Knowledge
management
tools and
strategies
Administrative, Track of work
organisational progress in line
with the work
and financial
programme
support
Financial
monitoring and
accountancy
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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
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Art is made to disturb. Science reassures.
Georges Braque
Is it always true ?
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Two studies on the use of statins and the risk of fracture done
in GPRD around the same period by two different groups.
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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
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Work Package 2
Work plan
• Three Working Groups (WG1-WG3)
– Databases
– Confounding
– Drug Utilisation
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Work Package 2 – WG1: 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
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Work Package 2 – WG1: 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
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Work Package 2 – WG1: 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
Beta2 Agonists - Myocardial infarction
Antiepileptics - Suicide
Calcium Channel Blockers - Cancer
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Work Package 2 – WG1: 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)
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Work Package 2 – WG2: 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
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Work Package 2 – WG2: 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:
 standardised difference
 Kolmogorov-Smirnov distance, or
 overlapping coefficient
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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 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)
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Work Package 3: Signal Detection
Objective:
To improve early and proactive signal detection from
spontaneous reports, electronic health records, and
clinical trials.
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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.
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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
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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.
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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
Pruritus*
Advagraf
PSYCHOTIC DISORDER
PSYCHOTIC DISORDER
Psychotic disorder*
Advagraf
PULSE INVESTIGATIONS ABNORMAL
-
Investigation abnormal
Advagraf
RASH
RASH
Rash*
Advagraf
RED BLOOD CELL ANALYSES ABNORMAL
-
Red blood cell analyses*
Advagraf
RENAL FAILURE
RENAL FAILURE
Renal failure*
Advagraf
RENAL FAILURE ACUTE
RENAL FAILURE ACUTE
Acute renal failure, Renal failure acute*
Advagraf
RENAL IMPAIRMENT
RENAL IMPAIRMENT
Renal impairment*
Advagraf
RENAL TUBULAR NECROSIS
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
Shock*
Better option:
Red blood cell
abnormal
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Work Package 3 – Database survey
• Scope
– EudraVigilance, VigiBase
– 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
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Work Package 3 - Better use of existing
terminologies
• Proof of concept
– Temozolomide
– Not illustrating timeliness – VigiBase as of Feb 2009
Term
Level of
terminology
# Reports
IC
Erythema Multiforme
PT
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+0.30
Stevens-Johnson Syndrome
PT
19
+0.68
Toxic Epidermal Necrolysis
PT
6
+0.51
Bullous Conditions
HLT
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-0.01
Severe Cutaneous Adverse
Reactions
SMQ
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-0.04
WHO-ART HLT
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+0.46
Erythema Multiforme
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Work Package 3 – Novel tools to group
ADRs
• Approach
– Automatic generation of groups of MedDRA terms based on
semantic information
– Based on a mapping of MedDRA to SNOMED CT
– Groups MedDRA terms based on semantic distance
• Progress
– Evaluation study completed
– Comparison with standard MedDRA SMQs as gold standard
• Next steps:
– Refinement of methods
– Use in signal detection!
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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
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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)
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Work Package 3 - Other
• Subpackage 11: Drug-drug interaction detection
 reference set under construction
• Subpackage 12: Duplicate detection
 completed in VigiBase
• Study protocols agreed for
– Subpackage 1: Merits of disproportionality analysis
– Subpackage 2: Concordance with risk estimates
– Subpackage 5: Better use of existing terminologies
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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
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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
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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
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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
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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
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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.
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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
 Perspectives of patients, healthcare prescribers, regulatory
agencies and drug manufacturers
 From pre-approval through lifecycle of products
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Work Package 5: Workstreams
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
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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.
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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
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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).
• PrOACT-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.
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Work Package 5: Workstream B
Collabor
ators
Literature
search
Other
initiative
s
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
Present case-studies results emphasising on
communication of, and use of graphical
representations for, understanding benefits
and risks
• 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
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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)
 Uncertainty about what the main benefits and risks are.
 Uncertainty about the population who has the disease.
 Different time for Benefit and for Risk (long term risks).
 Individual benefit-risk, or subgroups of benefit risk.
 New drugs vs. long marketed drugs.
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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.
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Work Package 5: Workstream D
• Scope
– Data Collection dependent from Framework used:
 Using PrOACT-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
 Additional data collection from existing data sets (PSURs, formal B-R
reviews)
 Creation of new data (e.g. questionnaires for patient preferences
elicitation)
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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
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Work Package 5: Workstream F
• Scope
– Workstream (WS) F is:




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
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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
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Work Package 6 - Inventory of data
sources
• Creating a comprehensive list of data sources
(ongoing)
– Review of European databases (electronic healthcare
records, cohorts, registries)
– ENCePP
– 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)
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Work Package 7: Training & communication
Objective:
To identify training opportunities and support training
programmes to disseminate the results achieved in
PROTECT.
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Work Package 7: Scope
• Development of a platform of training opportunities.
• Regular interaction with EU2P Consortium.
• Communication Plan: draft list of conferences and
other international forums suitable for the
presentation of the results of PROTECT.
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Work Package 7: Training Platform
https://w3.icf.uab.es/trainingopp
(under development)
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More information?
Website: www.imi-protect.eu
Email: [email protected]
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