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I m plem enting the pharm acovigilance legislation: focus on EU level activities 7 th Stakeholders forum on the implementation of the new Pharmacovigilance legislation Peter Arlett, Pharmacovigilance Department, EMA An agency of the European

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An agency of the European Union

I m plem enting the pharm acovigilance legislation: focus on EU level activities

7th Stakeholders forum on the implementation of the new Pharmacovigilance legislation Peter Arlett, Pharmacovigilance Department, EMA 27 September 2013

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In this presentation

1. Objectives, where we have come from: where we are going 2. What has been delivered in 2012 – 2013 and what are now routine activities 3. What remains to be done 4. Moving forward together

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2 2 0 0 3 2 0 0 4 2 0 0 5 2 0 0 6 2 0 0 7 2 0 0 8 2 0 0 9 2 0 1 0 2 0 1 1 2 0 1 2 2 0 1 3

2 0 0 3 : EC decision to undertake an assessment of the Community system

  • f pharmacovigilance

2 0 0 5 : I ndependent study completed to map the strengths and weaknesses of the EU system 2 0 0 7 : Commission strategy to strengthen and rationalise pharmacovigilance 2 0 0 6 -2 0 0 8 : Research, consultation, policy development Decem ber 2 0 0 8 : ‘Pharma package’ (Pharmacovigilance, I nformation to patients and falsified medicines) adopted by the European Commission and transmitted to Council and European Parliament to start the co-decision procedure for pharmacovigilance Decem ber 2 0 0 8 - 2 2 Septem ber 2 0 1 0 : Co-decision procedure until final favourable vote in the European Parliament 3 1 Decem ber 2 0 1 0 : Publication

  • f Regulation ( EC) 7 2 6 / 2 0 0 4 and

Directive 2 0 0 1 / 8 3 / EC ( entry into force in July 2 0 1 2 ) . 2 5 October 2 0 1 2 : Publication of Regulation ( EC) 1 0 2 7 / 2 0 1 2 and Directive 2 0 1 2 / 2 6 / EU ( entry into force in June and October 2 0 1 3 ) .

Where we have come from

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Where we are going: legislation objectives

Promote and protect public health by reducing burden of Adverse Drug Reactions and optimising the use of medicines:

  • Clear roles and responsibilities
  • Science based
  • Risk based/ proportionate
  • Increased proactivity/ planning
  • Reduced duplication/ redundancy
  • Integrate benefit and risk
  • Ensure robust and rapid EU decision-making
  • Strengthen the EU Network
  • Engage patients and healthcare professionals
  • Increase transparency and accountability
  • Provide better information on medicines

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Challenges

  • Major resource constraints
  • Size of change
  • Product lifecycle impacted
  • Number of stakeholders impacted

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Commission implementing regulation (EU) No 520/ 2012

  • Legally binding
  • 9 Chapters

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Com m ission I m plem enting Regulation ( EU) No 5 2 0 / 2 0 1 2 Chapter I Pharm acovigilance System Master File Chapter I I Minim um requirem ents for the quality system s for the perform ance of pharm acovigilance activities Chapter I I I Minim um requirem ents for the m onitoring of data in the Eudravigilance database Chapter I V Use of term inology, form ats and standards Chapter V Transm ission of reports of suspected adverse reactions Chapter VI Risk Managem ent Plans Chapter VI I Periodic Safety Update Reports Chapter VI I I Post-authorisation Safety Studies Chapter I X Final provisions

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Good pharmacoVigilance Practice (GVP)

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  • Self-standing guidance on

pharmacovigilance replacing Volume 9A

  • Addressed to EU Marketing Authorisation

Holders, Competent Authorities in Member States and Agency

  • Developed within EU network
  • 8 weeks public consultation
  • 2 types of ‘Chapters’:
  • Modules for major processes
  • Product or populations specific (P)
  • GVP structure:
  • A: Introduction
  • B: Structures and processes
  • C: Operation of the EU network

Good pharm acoVigilance Practice ( GVP) Module I Pharm acovigilance system s and their quality system s Module I I Pharm acovigilance system m aster file Module I I I Pharm acovigilance inspections Module I V Pharm acovigilance audits Module V Risk m anagem ent system s

Module VI Managem ent and reporting of ADRs Publication of Revision 1 as final Q4 2 0 1 3 Module VI I Periodic safety update reports Publication of Revision 1 as final Q4 2 0 1 3

Module VI I I Post-authorisation safety studies Module I X Signal m anagem ent Module X Additional m onitoring Module XI Public participation Public consultation Q2 2 0 1 4 Module XI I Continuous pharm acovigilance Public consultation Q1 2 0 1 4 Module XI V I nternational cooperation Public consultation Q1 2 0 1 4 Module XV Safety com m unication Under developm ent Public consultation Published P I – Vaccines Publication as final Q4 2 0 1 3 Module XVI Risk m inim isation m easures Publication as final Q4 2 0 1 3

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Prioritised implementation agreed by EMA Management Board in December 2011 and 2012

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Not started On-going im plem entation I m plem ented

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What has been delivered and what is now routine

While date period for most of the slides relates to July 2012 to July 2013, a small number of slides use a different data period

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Prioritised implementation of the pharmacovigilance legislation

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Collection of key inform ation on m edicines

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RMP data

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RMP Data

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Prioritised implementation of the pharmacovigilance legislation

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PSURs: Outcomes at PRAC

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17 33 25 30 43 38 19 205 3 2 5 2 8 9 9 38 50 100 150 200 250 Dec-12 Jan-13 Feb-13 Mar-13 Apr-13 May-13 Jun-13 Total Maintenance CHMP Variation Suspension Revocation

  • 243 PSUR PRAC recommendations (single CAPs) from Dec

2012 till June 2013

  • 38 (16% ) PRAC recommendations to vary MA
  • No suspensions, no revocations
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PSURs: Observations

  • Procedure now better understood by all concerned parties – clear

improvements noted.

  • Increasing number of PSUR procedures leading directly to MA

variation – efficiency gains since no need for follow-up variation and health gains through rapid update of product information

  • Still room for further improvement in terms of better understanding

the new procedure:

– For regulators:

  • requests for additional information to be more clearly phrased
  • requests for labelling to be explicit and clearly justified

– For pharmaceutical industry: key success factor is the provision by companies of clear positions and proposals for regulatory action/ follow-up Further training to be provided

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Prioritised implementation of the pharmacovigilance legislation

Collection of key inform ation on m edicines

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135 studies registered: most since July 2012

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Prioritised implementation of the pharmacovigilance legislation

Collection of key inform ation on m edicines

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Article 57(2) data content

Reference Term inology:

  • R1: Pharmaceutical form
  • R2: Route of Administration
  • R3: ATC codes
  • R4: Units of Measurement
  • R5: Units of presentation
  • R6: Reference source

Substance I nform ation:

  • S1: Substance names
  • S2: Substance Translations
  • S3: Substance synonyms
  • S4: Substance class
  • S5: Reference source
  • S6: International Codes

Structured Medicinal Product I nform ation:

  • P1: MAH (Legal Entity)
  • P2: QPPV
  • P3: PhV Enquiries
  • P4: PSMF
  • P5: Authorisation country code
  • P6: Authorisation procedure
  • P7: Authorisation status
  • P8: Authorisation number
  • P9: Authorisation date
  • P10: MRP/ DCP/ EU number
  • P11: Date of withdrawal/ revocation/ suspension
  • P12: Package description
  • P13: Orphan drug designation
  • P14: Comments (e.g. paediatric use)
  • P15: Medicinal product name
  • P16: Medicinal product invented name
  • P17: Product generic name
  • P18: Product company name
  • P19: Product strength name
  • P20: Product form name
  • P21: Pharmaceutical Form
  • P22: Route of administration(s)
  • P23: Active ingredient(s), Adjuvant(s)
  • P24: Excipients
  • P25: Medical device(s)
  • P26: Strength of active ingredient(s)/ adjuvant(s)
  • P27: Therapeutic Indication(s)
  • P28: ATC code

Unstructured Medicinal Product I nform ation:

  • P29: Summary of Medicinal Product Characteristics

Organisation inform ation:

  • O1: MAH (Legal Entity)
  • O2: QPPV
  • O3: PhV Enquiries
  • O4: PhV System Master File

Business Service Product

P

Business Service Substance

S

Business Service Organisation Business Service Referential s

O R

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Article 57(2) data: business case

  • Better analysis and understanding of data/ information

– EudraVigilance data analysis, safety signal detection

  • Regulatory action to safeguard public health

– Support to referral procedures (e.g. interaction with MAHs) – Provision of other PRAC outputs to MAHs – Facilitation of PhV inspections – Longer term (ISO) – quality defects of medicines and counterfeits can be linked to the correct products

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Article 57(2) data: business case

  • Communication with stakeholders

– European medicines web portal (search for all human medicines authorised in the EU) – Publication of lists (work-sharing purposes, products under additional monitoring, PSUR list, list of withdrawn products) – Access to EudraVigilance data (proactive and reactive) – EU/ international data exchange

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Article 57(2) Implementation status

  • As of 23rd September, MAHs have submitted a total of

4 4 3 ,0 0 0 medicinal product entries to the Agency.

  • New entries in the XEVMPD are received on a daily basis
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Strategy for achieving reliable Article 57(2) data

  • Two step approach is envisaged:

– Longer term: achieve QA (quality assurance) built into the overall process, alongside targeted ex-post controls – Short to medium term: built on current* QA activities complemented with QC (quality control)

* Note

  • Systematic semi-automatic monitoring via SAS routines of the new/ updated received data
  • Publication of detailed submission guidances
  • Free training to stakeholders
  • Dedicated helpdesk system
  • Comparisons with references sources (e.g. SmPC)
  • Monitoring/ evaluation of (limited) received feedback from stakeholders
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Article 57(2) Substance data Quality Control

Substance I nform ation:

  • S1: Substance names
  • S2: Substance Translations
  • S3: Substance synonyms
  • S4: Substance class
  • S5: Reference source
  • S6: International Codes

Business Service Substance

S This is one of the initial Quality Control activities started by the Agency to improve the quality of the Art57 submissions Two aspects need to be considered:

  • De-duplication of substance names
  • Completion of substance information content

Currently the EMA is focusing on the first aspect above: De- duplication of substance names

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Next Steps

The next steps in the Art57 implementation, including strategy and timelines for the kick-off of the maintenance phase, will be presented and discussed with the EU Pharmaceutical Industry Associations in the Art57 Implementation Working Group on 23 October 2013. Summary of the discussion will be published soon after the meeting. Supporting the wider EU data architecture strategy… ..

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Integrated Data Architecture

Extension of the Data Architecture Roadmap to cover other entities

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Industry & other stakeholders National Competent Authorities European Medicines Agency Business Processes Services

Substance Data Mgt Product Data Mgt Organisation Data Mgt Referentials Data Mgt Clinical Trials Marketing Authorisation Pharmacovigilance Manufacturing …

Data S P O R CT MA PhV Mfg …

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Prioritised implementation of the pharmacovigilance legislation

Collection of key inform ation on m edicines

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Spontaneous reporting by patients in EEA

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5000 10000 15000 20000 25000 Patient reporting Pre Leg* Patient reporting after Leg** 15407 24798

* Pre legislation data period - 02/ 07/ 2011 - 01/ 07/ 2012 * * Post legislation data period -02/ 07/ 2012 - 01/ 07/ 2013

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Reporting numbers: Pre and Post legislation

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Prioritised implementation of the pharmacovigilance legislation

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Prioritised implementation of the pharmacovigilance legislation

Better analysis/ understanding of data and inform ation

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Achievements of EV Data Quality management 07/ 2012 – 07/ 2013

  • Recoding of medicinal product terms reported in safety reports:

87,388 terms recoded

  • Duplicate detection & management of individual safety reports:

101,800 duplicate cases removed from the system

  • EudraVigilance Data Quality Assessments: 242 assessments

performed and senders (MAHs/ Sponsors/ NCAs) provided feedback

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Signals: Data and PRAC Outcomes

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7 9 5 3 4 3 2 4 10 4 2 1 2 4 2 5 3 3 5 5 1 1 2 1 2 4 6 8 10 12 14 16 Sep-12 Oct-12 Nov-12 Dec-12 Jan-13 Feb-13 Mar-13 Apr-13 May-13 Jun-13 PRAC Recommendation for a referral PRAC Request for Variation PRAC Request for cumulative review PRAC recommendation for a referral PRAC request for variation PRAC request for cumulative review

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Signal descriptions – first publication in coming days

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Prioritised implementation of the pharmacovigilance legislation

Better analysis of data and inform ation

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The current number of the additionally monitored drugs – 1 1 9 (published 9 August 2013)

95 100 105 110 115 120 Jun-13 Jul-13 Aug-13 106 111 119 Jun-13 Jul-13 Aug-13 Sep-13

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Additional monitoring

  • Mandatory for following products:

 Medicines containing a new active substance authorised after 1 January 2011  Any biological medicinal product authorised after 1 January 2011  Conditional or exceptional conditions of marketing  Obligation for post authorisation safety studies  Stricter reporting of adverse reactions

  • EMA publishes the list
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‘Black symbol’ for products under additional monitoring (1/ 2)

  • Black symbol:

– Selected by the European Commission following a recommendation of the PRAC (after involving stakeholders) on 7 March 2013 – Inverted equilateral black triangle

  • New text in Product Information

– SPC text: < { Black symbol} > This medicinal product is subject to additional monitoring. This is to allow any safety information to be identified rapidly. Healthcare professionals are encouraged to report any suspected adverse reactions. See section 4.8.> – PL text: < { Black symbol} This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

  • List of products under additional monitoring

– initial list published on 25th April 2013 and updated every month

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New communication material on additional monitoring (1/ 2)

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Factsheet + Video

  • Consultation: EC, HMA WGCP and

Project Team 3 involved in preparation

  • PRAC informed at September

meeting

  • All EU languages
  • Easily printable
  • Based on already published

information

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Prioritised implementation of the pharmacovigilance legislation

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Better analysis/ understanding of data and inform ation

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Prioritised implementation of the pharmacovigilance legislation

Regulatory action to safeguard public health

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PRAC volumes (July 2012 – July 2013)

1 2 4 2 7 5 8 1 1 3 2 2 2 1 13 15 13 10 8 10 7 13 17 13 7 3 10 34 50 57 64 50 60 45 61 20 35 30 33 51 53 31 33 1 4 2 3 6 6 5 13 16 3 4 2 2 1 2 1 3 4 8 5 6 5 6 11 15 11 20 40 60 80 100 120 140 160 180 Sep-12 Nov-12 Jan-13 Mar-13 May-13 Jul-13 Other safety issues - MS Other safety issues - CHMP PhVig Inspections PASS PSURs RMPs Signals Art.5(3) referrals

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Prioritised implementation of the pharmacovigilance legislation

Regulatory action to safeguard public health

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Referrals: Data

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  • Number of referrals (July 2012 – July 20131):

1 Also includes procedures started and finalised by PRAC in July 2013 2 In 6 procedures (29% ) an ad-hoc expert meeting has been organised 3 Finalised means final outcome obtained at either CHMP or CMDh

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Referral type Started Finalised

  • Art. 20

5 3

  • Art. 107i

5 3

  • Art. 31

11 3 Total 2 1 2 9 3

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Referrals: Outcomes

  • Overview of finalised referrals:
  • Time taken: 1 to 8 months

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Procedure name Article Finalised Committee Grounds Outcome EC Decision Duration ( calender days) Tredaptive 20 Jan-13 CHMP B-R Suspension Yes 1 month Trevaclyn 20 Jan-13 CHMP B-R Suspension Yes 1 month Pelzont 20 Jan-13 CHMP B-R Suspension Yes 1 month Tetrazepam 107i Apr-13 CMDh S Suspension Yes 3 months Cyproterone, ethinylestradiol - DIANE 35 & other medicines containing cyproterone acetate 2mg and ethinylestradiol 35 micrograms 107i May-13 CMDh S Variation Yes 3 months Almitrine 31PhV May-13 CMDh B-R Revocation No 7 months Codeine-containing medicinal products 31PhV Jun-13 CMDh B-R Variation No 8 months Diclofenac-containing medicinal products 31PhV Jun-13 CMDh B-R Variation Yes 8 months Flupirtine 107i Jun-13 CMDh S Variation Yes 6 months

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Referrals: Observations

  • Positive experience:

– High acceptance rate by CHMP/ CMDh of PRAC outcome – Compliance with legal deadlines – Shortening of scientific review process for Art 31 procedures – Excellent teamwork EMA Secretariat – PRAC Rapporteurs (in terms of procedural, content and data support aspects)

  • Issues requiring consideration:

– Optimal use of referrals tools for public health – Workload for Network high and remains unpredictable – Communication and planning: Need to continue to comply with existing communication platform (RAS-IRN involvement) to support the MSs Better workload planning to be encouraged, identified safety concerns and public health consequences permitting

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On-going procedures to date

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Prioritised implementation of the pharmacovigilance legislation

Regulatory action to safeguard public health

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Prioritised implementation of the pharmacovigilance legislation by the EMA

Com m unication w ith stakeholders

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  • Agenda is published on Day 1 of PRAC by mid-day
  • Meeting highlights are published on Friday of PRAC week
  • Safety referrals are published on Friday of PRAC week
  • Minutes are published on the following month after adoption

Transparency of activities for Pharmacovigilance Risk Assessment Committee

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Prioritised implementation of the pharmacovigilance legislation by the EMA

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Com m unication w ith stakeholders

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Prioritised implementation of the pharmacovigilance legislation by the EMA

Com m unication w ith stakeholders

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Prioritised implementation of the pharmacovigilance legislation by the EMA

Com m unication w ith stakeholders

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Publication of RMP summaries

Pilot phase to be initiated in October 2013.

  • Summary (Part VI.2 of RMP) to be published at the time of the

EPAR publication.

  • Summary to be updated in case of important changes to RMP.
  • Summary is aligned with other information (EPAR summary,

product information).

  • For all newly - authorised CAPs;
  • For other (not newly authorised) CAPs, RMP summary to be

published when RMP is updated.

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Prioritised implementation of the pharmacovigilance legislation by the EMA

Com m unication w ith stakeholders

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Legal notice: EMA w ebsite serves as the EU Medicines W eb-portal

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Beyond 2013… what still needs to be done

Topics Activities

Literature monitoring EMA service to industry for population of EudraVigilance with case reports of old substances. EudraVigilance Delivery of enhanced functionalities and IT system audit results in centralised reporting for industry Article 57(2) data submission and handling Updates (variations) to the data can be submitted by industry and data fully used to support regulation, safety and stakeholder needs. Periodic Safety Update Reports Delivery of PSUR repository and single PSUR assessment process for NAPs allowing centralised reporting for industry and faster warnings for NAPs Risk Management System Implement risk-based system for measuring the effectiveness of risk minimisation Transparency and communication Delivery of EU Medicines web-portal and public hearings.

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Beyond 2013… what still needs to be done W e w ill get there…..w orking together

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Project Coordination Group EMA/ MSs Project Team 1

Collection of key inform ation on m edicines

Revised Project governance model

Training Content Group Pharmacovigilance Audit Facilitation Group

  • EV
  • ‘e-submission’

activities

  • Patient reporting

EMA/ MSs Project Team 2

Better analysis and understanding of data and inform ation

  • Signal
  • RMP/ PSUR
  • PASS/ PAES
  • Additional

monitoring

EMA/ MSs Project Team 3

Com m ittees and Com m unication w ith stakeholders

  • Online publishing
  • f information
  • Coordination of

safety messages

  • Public hearings
  • Referrals -

Transparency/ Prod uct information Pharmacovigilance Inspectors Working Group

  • 3. PSUR
  • 5. RMP/ PASS/ PAES

1. EV/ ADR reporting

EMA Subproject Team s EMA/ MSs Project Team s

  • 4. Additional monitoring
  • 6. Committees
  • 7. Referrals
  • 2. ‘Product info’ (Art 57

/ 123(4)/ Lists

Signal Management Review Team (SMART WG)

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Project Oversight Com m ittee ( ERMS-FG) Heads of Medicines Agencies

BEMA SG Project Manager WG QM Direct reporting Liaison EMA membership MSs membership EMA/ MSs membership

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What have we achieved

A huge change has been delivered for better public health improvement:

  • Better public participation
  • increase of patient reports by 10,000
  • Patients and HCPs voting on PRAC
  • Better planning – risk management plans now routine
  • Better evidence – routine identification of data needs for referrals
  • Faster decision-making
  • Referrals finalised in 1 to 8 months
  • PSURs directly lead to label changes
  • Greater transparency – agendas, minutes, signals
  • Better information – black triangle, ADR reporting, warnings

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But there is still more to do

Deliver on the simplifications:

  • Further improve on the processes already implemented
  • Centralised ADR reporting
  • Centralised PSUR reporting
  • Literature monitoring by EMA for industry

Full delivery on better information:

  • EU medicines webportal

Together w e can

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Conclusions

Major change has been delivered:

  • Collaboration
  • Consultation
  • Concentration

Public health has been improved:

  • Better evidence
  • Faster decisions and labelling
  • Greater transparency
  • Greater participation and empowerment

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