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

Who is Who and What is What in EU Pharmacovigilance

Vicki Edwards

QPPV and Head of Affiliate Vigilance Excellence

AbbVie

Overview

• European Commission• European Medicines

Agency (EMA)• CHMP• PRAC• Competent Authorities of

Member States (CAs)• Marketing Authorisation

Holder (MAH)• CIOMS• ICH

DipPharmMed – Module 9- April 2011 2Who’sWho

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• 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…..

European Commission

Who’sWhoDipPharmMed – Module 9- April 2011

DipPharmMed – Module 9- April 2011

Who’sWho

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 Commission (EC)

Council of the European Union

European Parliament (EP)

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Who’sWho

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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Who’sWho

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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• 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

Role of the EMA



Who’sWho

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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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


Who’sWho 9

New Pharmacovigilance Risk Assessment Committee PRAC

Regulation (EU) No 1235/2010 the Mandate shall cover:

All aspects of the risk management of the useof 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

PRAC Membership

Appointed by each MemberState

1 member + alternate

27 + EEA countries non-votingmembers

Appointed by the European Commission (public call for expressions of interest):

1 patient organisations rep +alternate1 healthcare professionals rep +alternate6 members to ensure relevant expertise available

Identified PRAC Activities (1/2)

Activity Involvement

Risk Management SystemsAgreement on RMPs + Monitoring their effectiveness

Periodic Safety Update ReportsPSURs

List of harmonised submission frequencies and substances,

assessment + recommendation

Eudravigilance + Periodic SafetyUpdate Reports repository

Functional specifications, any substantial changes

Medicines subject to additional monitoring

Addition to/removal from list extension of timeframe, symbol

Signal detection Initial analysis + prioritisationassessment + recommendations

Identified PRAC Activities (2/2)

Activity Involvement

Urgent Safety Proceduresfor the EU

Assessment, public hearings, recommendations

Post Authorisation SafetyStudies

Consultations on requests (pre and post MA), assessment of protocols (incl. amendments +Recommendations, assessment of

results + Recommendations

Literature Adverse DrugReactions monitoring

Consultation on list of activesubstances and medical literature subject to monitoring

Safety announcements Advice

PRAC Agenda Issues – All items

Proposed PRAC Statistics 14

Signal Overview

PRAC outcomes/Signals with NAPs 15

NAP (#19) SignalPhWP

Follow-upPRAC

Recommendation PRAC discussion

Roxithromycin Rhabdomyolysis secondary to interaction with statins Variation (3) Sep 12/ Feb13

Roxithromycin Hearing disorders Sep 12/ Feb13

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 Oct 12

Hydroxyethyl starch (blood plasma substitutes) Effect on renal function and mortality in septic patients X Oct 12

Domperidone Cardiotoxicity X Feb 13

Thiocolchicoside Genotoxic potential Feb 13

Vitamin K antagonists Interaction with Goji berries (Lycium barbarum) Cumulative review (7)

Oct 12

TrazodoneRisk Minimisation for trazodone associated postural hypotension and somnolence Oct 12

Mirtazapine Pancreatitis Oct 12

Tiotropium bromide Anaphylactic reaction Jan 13

Tiotropium bromide soft mist formulation (RESPIMAT)

Increased mortality from cardiovascular disease and all cause mortality Jan 13

Tramadol Hypoglycaemia Feb 13

ZolpidemNext-morning impaired mental alertness, including impaired driving ability Feb 13

Anticholinergic drugs for inhaled use

Increased incidence of myocardial infarction and stroke in patients with chronic obstructive pulmonary disease (COPD) X

No MAH action (4) Oct 12

Fluoroquinolones Retinal detachment X Oct 12

Human albumin solutions Increased risk of death in patients with severe traumatic brain injury and in patients with burns X Oct 12

Influenza vaccine Extensive limb swelling (ELS) Oct 12/Nov 12

CAP&NAP (#3)

Somatropin Convulsions SMQ Narrow Cumulative

review Sep 12

OlmesartanIncreased risk of fatal cardiovascular events in patients with type 2 diabetes at increased cardiovascular risk X Variation Oct 12

Hormonal contraceptives Embolic and thrombotic events ReferralDec 12 (Nov)/Jan

13/Feb 13

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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


PRAC and the other Groups/Committees

Drug Information Association

www.diahome.org 17

Coordination

Group CG

Member States European Commission

PRAC

Recommendations

CHMP

PRAC output with formal decision making phase – at least one CAP


Who’sWho 18

Publication on EMA website

(Art.26 Regulation)

CHMP

In line with PRACNo Public

justification

European Commission Decision-making phase

Commission decision

PRAC output with formal decision making phase – NAPs only


Who’sWho 19

Publication on EMA website

(Art.26 Regulation)

CMDh

Agreement by Consensus

Yes No

In line with

PRAC

In line with

PRAC

Yes No No Yes

CMDh consensus and timetable

PRAC AR ± scientific grounds for disagreement

CMDh consensus and timetable

PRAC AR ± scientific grounds for disagreement

Commission decision

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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


Council for International Organisations of Medical

Sciences (CIOMS)


Who’sWho 21

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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


Who’sWho

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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


Who’sWho

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CIOMS Safety Working Groups IICIOMS III/V (1999) Second Edition of CIOMS III : Including

New Proposals for Investigator Brochures (DCSI) CIOMS V (2001) Current Challenges in Pharmacovigilance :

Pragmatic ApproachesCIOMS 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


Who’sWho


Who’sWho

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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Who’sWho 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 2

Step 3

Step 4

Step 5

Step 1

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CIOMS, ICH and International Regulation

CIOMS I 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)DipPhaMed – Module 9- April 2011

Who’sWho


Who’sWho

Any Questions?

Documents

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