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An agency of the European Union
Three years of the Pharmacovigilance Risk Assessment Committee –
Where are we now?
June M Raine Chair, PRAC
MEB College Day Workshop 3rd June 2015
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The Pharmacovigilance Risk Assessment Committee is the committee at the European medicines Agency that is responsible for assessing and monitoring safety issues for human medicines
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Outline of presentation
• Why is there the need for a pharmacovigilance committee in EU?
• What has PRAC delivered via the new legislative public health tools in its first three years?
• Where next? What is still to be done to fully realise the potential of the new legislation to achieve excellence in public health protection?
Brussels, 19 July 2012
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Why need for pharmacovigilance?
Duijnhoven et al PLoS March 2013
Patients studied prior to approval of new medicine For 200 new “standard” medicines between 2000 and 2010, median total no patients= 1708, for orphan drugs = 438 patients studied For 84 medicines for chronic use 79.8% met guidelines for 12 months (at least 100 participants)
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Pharmacovigilance cycle
Better
characterised
risks of
medicine
Risk minimisation,
communication,
maintain favourable
benefit risk
Ongoing
evaluation of
benefit risk
Monitor risk
minimisation
effectiveness
Signal
detection in
real world use
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New EU legislation in 2012
Clear legal framework for drug safety monitoring
Patient reporting of adverse drug reactions
Timely review of new safety issues
Risk management plans for all new medicines
Post-authorisation studies - regulatory oversight
Greater transparency
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PRAC’s mandate
All aspects of the risk management of the use of medicinal products including the detection, assessment, minimisation and communication
relating to the risk of adverse reactions, having due regard to the therapeutic effect of
the medicinal product, the design and evaluation of post-authorisation safety studies
and pharmacovigilance audit
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PRAC’s main goals
• Proactively investigating drug safety - continuous signal detection, filling knowledge gaps via post-authorisation studies
• Responding to safety and benefit risk issues – risk-proportionate decisions to rigorous timescales, effectiveness of risk minimisation
• Driving forward the new era in transparency - real time access to information on PRAC activities
• Increasing involvement of stakeholders - health professionals, patients and public
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Pharmacoepidemiology
Marieke de Bruin
Stephen Evans
Pharmacovigilance
Hervé Le Louët
Signal detection
Lennart Waldenlind
Biologicals and vaccines
Brigitte Keller Stanislawski
Risk Communication
Jane Ahlqvist Rastad
European Commission experts
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HCP and patient representatives
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32 meetings
Over 150 protocol reviews
Over 1000 PSURs
33 safety referrals
Over 300
signals
Over 600 risk management
plans
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PRAC monthly activities
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Patient ADR reporting
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Strengthened ADR reporting
* Number of ICSRs received in EudraVigilance before de-duplication
0
50.000
100.000
150.000
200.000
250.000
300.000
Pre Legislation02/07/11 - 01/07/12 After Legislation
02/07/12 - 01/07/13 After Legislation02/07/13 - 01/07/14
234.275
281.357 295.043
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Additional monitoring list
Monthly review by PRAC of proposed additions to the list of new medicines for additional monitoring
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Strengthened ADR reporting
EudraVigilance database provides common signal detection tools for all member states
>54% serious safety issues detected earlier if EV used in addition to other resources
Drug Safety 33(6) 475-487
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Signal of medication error
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Signal management review
PRAC’s Signal Management Review Team meets monthly under Dr Sabine Straus’ leadership to work on:
- Tools and processes
- Methodological guidance
- Signal detection methods
Implementing Regulation requires that “the Pharmacovigilance Risk Assessment Committee shall regularly review the methodology(ies) used and publish recommendations, as appropriate”
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Pacurariu et al Drug Safety 15 Nov 2014
Signals & drug lifecycle
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19
PRAC safety referrals
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Referrals started and finalised
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0
1
2
3
4
5
6
5 5 5
3 3 3
2 2
1 1 1 1 1
4
6
4 4
1 1
6
1
4
3
1
2
1
3
1 1 1 1
(Co) Rapporteurship per Member State
*3 procedures have multiple co-rapporteurs (SABA-HU, BE, CS, IT; RAS - UK, IT, SV, DE, NL, PT, SK, IE,
ES, Ambroxol/Bromhexine – PT, AT, BE)
Rapp
Co-Rapp
Rapporteurs for referrals
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Review of all available data on known risk of VTE associated with combined hormonal contraceptives
Full information on risk of VTE to support decisions by women and their healthcare professionals
HCPs and women reminded to be watchful for symptoms and signs
Combined hormonal contraceptives VTE
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Valproate & developmental disorders
Teratogenicity known since time of market authorisation
Assessment of latest evidence on risk of developmental disorder in infants following pregnancy exposure of mother
Strengthened warnings in product information to support decisions by women
Patient representatives involved in advising on risk minimisation measures
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Ivabradine & cardiovascular risk
Small but significant increase of cardiovascular
death, MI and heart failure in SIGNIFY study in
ivabradine arm
Risk Minimisation Measures to include initiation heart
rate, dose, monitoring for atrial fibrillation &
stopping within 3 months if no benefit
Drug utilisation study to monitor RMM effectiveness
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Proactive pharmacovigilance
Shift from reactive vigilance to proactive investigation of drug safety
To fill in gaps in knowledge, Risk Management Plans and PASS protocols are PRAC’s major priority
PRAC experts in pharmacoepidemiology provide specialist contributions on design and methodology
Better evidence on which to base regulatory decisions
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Types of PASS reviewed by PRAC
Registries (prospective cohorts)
- Eg assess safety profile, health outcomes in clinical use, consider existing infrastructure consider comparator
Database studies
- Eg risk characterisation, investigation of targeted AEs
Drug utilisation studies
Eg to assess effectiveness of risk minimisation measures or help plan PAS
Special populations
- Pregnancy registries, paediatrics, elderly
Medication errors
- Human factors studies
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Strontium ranelate
PASS imposed after PSUR raised concerns about cardiovascular safety and further in-depth evaluation of benefit risks under Article 20 referral MAH`s proposal: descriptive study using retrospective healthcare databases Main methodological issues related to ability of proposed algorithms to extract reliable information on variables and endpoints from proposed data sources
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Isotretinoin pregnancy prevention
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Driving forward transparency
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Information
technology
Innovative
science
Innovative
methodologies
Involvement
of patients
Impact
evaluation
PRAC’s work moving forward
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Innovative science
Using pharmacogenomics to define populations at risk of ADRs
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Innovative methodologies
Incorporating new methodologies in signal detection, benefit risk evaluation and risk communication based on research and best evidence
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Impact evaluation
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Information technology
Innovative Medicines Initiative WEB-RADR project
Development of a mobile app for
–ADR reporting
–Provision of information to users
Evaluation of using social media data to identify ADRs
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Involving patients & public
Interaction with patient and health professional organisations so far during formal reviews
Input to setting goals for RMMs, reviewing thresholds and decisions on effectiveness of RMMs
Opportunity of public hearings to be introduced later in 2015
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Reflections on 3 years of PRAC
Real-time signal detection and signal prioritisation every month at PRAC
Rapid action to manage risk with binding outcomes
Benefit risk monitoring throughout a medicine’s life cycle in clinical use
New era of transparency and openness in place
Current initiatives based on best evidence, effectiveness evaluation, and stakeholder engagement
PRAC’s goal is measurable impact of what we do: demonstrable excellence in public health protection
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Hartelijk dank!