1. Who is Who and What is What in EU Pharmacovigilance
Vicki Edwards
QPPV and Head of Affiliate Vigilance Excellence
AbbVie

2. Overview European Commission European Medicines Agency (EMA) CHMP PRAC
Competent Authorities of Member States (CAs)
Marketing Authorisation Holder (MAH)
CIOMS
ICH
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3. European Commission
Pharmaceutical industry under the responsibility of DG SANCO (Directorate-General for Health and Consumer Affairs)
Competent Authority for Centrally Authorised Products
Drafts proposals for new European Laws
Presents to the European Parliament & Council
Implements the decisions of Parliament & Council
Enforcement of implementation of Decisions by Member States and MAHs
Manages the day to day business of the EU
Runs the programmes of the EU
Spends the EUs funds…..
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4. The EU Decision-Making Process
The EU’s decision-making process involves three main institutions
The European Parliament (EP), which represents the EU’s citizens and is directly elected by them.
The Council of the European Union, which represents the individual Member States.
The European Commission, which seeks to uphold the interests of the Union as a whole.
This ‘institutional triangle’ produces the policies and laws that apply throughout the EU. In principle, it is the Commission that proposes new laws, but it is the Parliament and Council that adopt them.
European Parliament (EP)
Council of the European Union
European Commission (EC)
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5. European Medicines Agency
Protection and promotion of public health through evaluation and supervision of medicines
Responsible for scientific evaluation of applications for MA for medicinal products (Centralised procedure)
Opinion presented to Commission for decision
Utilises scientific resources of 30 EU and EEA-EFTA countries
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6. Role of the EMA
Monitors the safety of medicines through the EU PV network
Takes appropriate action in the event of change to benefit : risk profile of a product
Provides scientific advice to academia and the Pharmaceutical Industry
Provides guidelines on quality, safety and efficacy
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7. Role of the EMA
Coordination of the supervision of products authorized in the EU
Monitor legal obligations of MAH
Transmission of Serious ADRs reports between Member States and to Rapporteur
Identify safety signals, in agreement with Rapporteur
Communication of Safety Issues (all parties)
Communication of Opinions to the European Commission
Communication with the MAH in consultation with Rapporteur
Development and maintenance of Eudravigilance database
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8. Committee for Medicinal Products for Human Use (CHMP)
Prepares EMA’s opinions on all questions concerning medicinal products
Centrally approved products
Assessment of MAAs and maintenance including modifications and extensions (variations)
MRP & decentralised products
Provides arbitration in event of Member State disagreement
Monitoring of safety of products through EU network of national medicines agencies
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9. Co-ordination Group for mutual recognition and decentralised procedures – Human (CMDh)
Examines any question related to marketing authorisations of a medicinal product in two or more member states
New applications
Variations
Renewals
PV activities
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10. New Pharmacovigilance Risk Assessment Committee PRAC
Regulation (EU) No 1235/2010 the Mandate shall cover:
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

11. PRAC Membership Appointed by each Member State 1 member + alternate
27 + EEA countries non-voting members
Appointed by the European Commission (public call for expressions of interest):
1 patient organisations rep + alternate 1 healthcare professionals rep + alternate 6 members to ensure relevant expertise available

12. Identified PRAC Activities (1/2)
Activity
Involvement
Agreement on RMPs + Monitoring their effectiveness
Risk Management Systems
List of harmonised submission frequencies and substances, assessment + recommendation
Periodic Safety Update Reports PSURs
Eudravigilance + Periodic Safety Update Reports repository
Functional specifications, any substantial changes
Medicines subject to additional monitoring
Addition to/removal from list extension of timeframe, symbol
Initial analysis + prioritisation assessment + recommendations
Signal detection

13. Identified PRAC Activities (2/2)
Activity
Involvement
Urgent Safety Procedures for the EU
Assessment, public hearings, recommendations
Consultations on requests (pre and post MA), assessment of protocols (incl. amendments + Recommendations, assessment of results + Recommendations
Post Authorisation Safety Studies
Consultation on list of active substances and medical literature subject to monitoring
Literature Adverse Drug Reactions monitoring
Safety announcements
Advice

14. PRAC Agenda Issues – All items
Proposed PRAC Statistics

15. PRAC outcomes/Signals with NAPs
Signal Overview
NAP (#19)
Signal
PhWP Follow-up
PRAC Recommendation
PRAC discussion
Roxithromycin
Rhabdomyolysis secondary to interaction with statins
Variation (3)
Sep 12/ Feb13
Hearing disorders                
Nicardipine
Thrombocytopenia
Dec 12 (Nov)
Codeine
Drug toxicity in CYP2D6 ultra-rapid metabolisers
Referral (5)
Oct 12
Short-acting beta agonists
Maternal cardiovascular events following use in tocolysis X
Hydroxyethyl starch (blood plasma substitutes)
Effect on renal function and mortality in septic patients
Domperidone
Cardiotoxicity
Feb 13
Thiocolchicoside
Genotoxic potential
Vitamin K antagonists
Interaction with Goji berries (Lycium barbarum)
Cumulative review (7)
Trazodone
Risk Minimisation for trazodone associated postural hypotension and somnolence
Mirtazapine
Pancreatitis
Tiotropium bromide
Anaphylactic reaction
Jan 13
Tiotropium bromide soft mist formulation (RESPIMAT)
Increased mortality from cardiovascular disease and all cause mortality
Tramadol
Hypoglycaemia
Zolpidem
Next-morning impaired mental alertness, including impaired driving ability
Anticholinergic drugs for inhaled use
Increased incidence of myocardial infarction and stroke in patients with chronic obstructive pulmonary disease (COPD)
No MAH action (4)
Fluoroquinolones
Retinal detachment
Human albumin solutions
Increased risk of death in patients with severe traumatic brain injury and in patients with burns
Influenza vaccine
Extensive limb swelling (ELS)
Oct 12/Nov 12
CAP&NAP (#3)
Somatropin
Convulsions SMQ Narrow
Cumulative review
Sep 12
Olmesartan
Increased risk of fatal cardiovascular events in patients with type 2 diabetes at increased cardiovascular risk
Variation
Hormonal contraceptives
Embolic and thrombotic events
Referral
Dec 12 (Nov)/Jan 13/Feb 13
PRAC outcomes/Signals with NAPs

16. Roles and Responsibilities of the Competent Authorities
Establish national pharmacovigilance systems
Responsible for PV for all products authorised nationally, including mutual recognition products
Responsible for monitoring centrally authorised products
Ensure data are shared between MS’s and EMA via EudraVigilance network
Inform the Commission, CHMP, EMA and MAH of any relevant actions
Provide serious ADR cases to EMA and MAH
Implement Commission Decision
Power to suspend a product in urgent circumstances
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17. PRAC and the other Groups/Committees
CHMP
Coordination Group CG
Recommendations
Member States
European Commission
Drug Information Association

18. PRAC output with formal decision making phase – at least one CAP
Referrals
Art.107 & Art.31 & Art 20
PSUR Single Assessment
PASS Results
PRAC Recommendation & Assessment Report
Publication on EMA website (Art.26 Regulation)
CHMP No
In line with PRAC
Public justification
European Commission Decision-making phase
Publication on EMA website (Art.26 Regulation)
MAH MS
Commission decision
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19. PRAC output with formal decision making phase – NAPs only
Referrals
Art.107 & Art.31
PSUR Single Assessment
PASS Results
PRAC Recommendation & Assessment Report
Publication on EMA website (Art.26 Regulation)
CMDh
Yes No
Agreement by Consensus
Yes No No
Yes
In line with PRAC
In line with PRAC
CMDh consensus and timetable
PRAC AR ± scientific grounds for disagreement
CMDh consensus and timetable
PRAC AR ± scientific grounds for disagreement MS
Publication on EMA website (Art.26 Regulation)
MAH
Publication on EMA website (Art.26 Regulation)
MAH MS EC
Commission decision
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20. Roles and Responsibilities of the MAH
Ensure an appropriate system of pharmacovigilance and risk management
Provide description at application of MA (DDPS)
Assure responsibility and liability for marketed products
Ensure appropriate action can be taken, when necessary
Immediately notify the Competent Authorities of any change in the balance of risks and benefits of their products
Appoint a Qualified Person Responsible for Pharmacovigilance (QPPV)
Submit proof that the services of the QPPV are available at application of MA
MAH should adequately support the QPPV
Ensure mechanisms are to keep QPPV fully informed
Ensure that the QPPV has sufficient authority
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21. Council for International Organisations of Medical Sciences (CIOMS)
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22. What is CIOMS International, non-governmental, non-profit organisation
Established in 1949 by WHO and UNESCO
A forum to consider and prepare advice on contentious issues in research ethics and safety of pharmaceuticals for WHO, public health authorities, academia, pharmaceutical industry and others
Comprises various working groups
Modus operandi = Think Tank (practical solutions)
Think beyond local practices and regulations => optimise drug safety procedures internationally
Do not develop regulations but intended to inform and encourage those with rule-making responsibilities
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23. CIOMS Safety Working Groups I
CIOMS I (1990)
International Expedited Reporting
CIOMS IA (1992)
Report unpublished: Concept of Global Safety Database and comprehensive set of data fields and electronic specification
CIOMS II (1992)
CIOMS III (1995)
(First Edition)
International Reporting of Periodic Drug Safety Update Summaries (PSUR)
Guidelines for Preparing Core Clinical Safety Information on Drugs( Core Data Sheet)
CIOMS IV (1998)
Benefit – Risk Balance for Marketed Drugs: Evaluating Safety Signals
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24. CIOMS Safety Working Groups II
CIOMS III/V (1999)
Second Edition of CIOMS III : Including New Proposals for Investigator Brochures (DCSI)
CIOMS V (2001)
Current Challenges in Pharmacovigilance : Pragmatic Approaches
CIOMS VI (2005)
CIOMS VII ( 2007)
CIOMS VIII (2010)
CIOMS IX (in progress)
Management of Safety Information from CTs
The Development Safety Update Report (DSUR): Harmonizing the Format and Content for Periodic Safety Reporting During Clinical Trials
Points to Consider in the Application of Signal
Detection and Management in Pharmacovigilance
Practical Considerations for Development & Application of a Toolkit for Risk Management
CIOMS Safety Working Groups II
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25. International Conference on Harmonisation ICH – Basic Principles
Development of scientific consensus through discussions between regulatory & industry experts.
Regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration.
Wide consultation of the draft consensus document, through normal regulatory channels, before a harmonised text is adopted.
Commitment by regulatory parties to implement the ICH harmonised texts.
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26. ICH Process Technical discussions in GPS/development of consensus
Consensus achieved with release for consultation
Formal consultation outside ICH
ICH guideline finalized
Implementation in ICH regions
Step 1
Step 2
Step 3
Step 4
Step 5
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27. CIOMS, ICH and International Regulation
Basis for ICHE2A and international regulatory standards and definitions, including CIOMS I form
CIOMS IA
Basis for ICH E2B (Standards for electronic submission)
CIOMS II
Basis for ICH E2C, European, Japanese and US standards for PSURs
Recently updated
CIOMS III
Concept of CDS/CSI included in ICH E2C
CIOMS IV
Not formally incorporated into regulation but standard requested by EU authorities
CIOMS V
Basis for ICH E2D; incorporation into Volume 9a (EU)
CIOMS VII
Basis for ICH E2F (DSUR)
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28. Any Questions?
DipPharmMed – Module 9- April 2011
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