Vol 9 A

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Final September 2008

VOLUME 9A
oI The Rules Governing Medicinal Products in the European Union

Guidelines on Pharmacovigilance Ior Medicinal Products Ior Human Use
GENERAL OUTLINE OF CONTENTS

INTRODUCTION
1. Legal Basis and Structure oI Volume 9A (Human Pharmacovigilance)
2. Legal Framework Ior Pharmacovigilance
3. The Roles oI the Various Parties
PART I Guidelines for Marketing Authorisation Holders
1. General Principles
2. Requirements Ior Pharmacovigilance Systems, Monitoring oI Compliance and
Pharmacovigilance Inspections
3. Requirements Ior Risk Management Systems
4. Requirements Ior Expedited Reporting oI Individual Case SaIety Reports
5. Requirements Ior Reporting in Special Situations
6. Requirements Ior Periodic SaIety Update Reports
7. Company-Sponsored Post-Authorisation SaIety Studies
8. Overall Pharmacovigilance Evaluation and SaIety-Related Regulatory Action
PART II Guidelines for Competent Authorities and the Agency
1. Undertaking oI Pharmacovigilance Activities by Competent Authorities in Member States
2.A Conduct oI Pharmacovigilance Ior Centrally Authorised Products
2.B Crisis Management Plan regarding Centrally Authorised Products
3. Conduct oI Pharmacovigilance Ior Medicinal Products Authorised through the Mutual
Recognition or Decentralised Procedure
4. Rapid Alert and Non-Urgent InIormation System in Pharmacovigilance
5. ReIerrals in Case oI SaIety Concerns Related to Products Authorised in the EU and Commission
Decisions Following Suspension, Revocation or Variation oI a Medicinal Product by a Member
State
6. Principles oI Collaboration with the World Health Organization in Matters oI International
Pharmacovigilance
PART III Guidelines for Marketing Authorisation Holders, Competent Authorities
and the Agency on Electronic Exchange of Pharmacovigilance Information
in the EU
PART IV Guidelines for Marketing Authorisation Holders and Competent Authorities
on Pharmacovigilance Communication
1. Introduction
2. Direct Healthcare ProIessional Communications

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ANNEXES
1. Glossary
2. Abbreviations
3. Other EU Guidelines and Relevant Terminology
4. ICH Guidelines
5. Templates
6. Distribution Requirements and Address Lists Ior Data Submission
DETAILED TABLE OF CONTENTS
INTRODUCTION _________________________________________________________ 14
1. Legal Basis and Structure of Volume 9A (Human Pharmacovigilance) __________ 14
2. Legal Framework for Pharmacovigilance___________________________________ 15
3. The Roles of the Various Parties __________________________________________ 16
3.1 The Marketing Authorisation Holder 16
3.2 The Competent Authorities 16
3.2.1 The Competent Authorities oI the Member States 16
3.2.2 The European Commission 16
3.3 The EU Pharmacovigilance System 16
3.3.1 The Role oI Competent Authorities oI the Member States Ior Products Authorised Through
National Procedures 16
3.3.2 The Role oI the Competent Authority oI the ReIerence Member State Ior Products
Authorised Through the Mutual Recognition or Decentralised Procedure 16
3.3.3 The Role oI the Rapporteur Ior Products Authorised Through the Centralised Procedure 17
3.3.4 The Role oI the Agency 17
3.3.5 The Role oI the CHMP Pharmacovigilance Working Party 17
PART I: GUIDELINES FOR MARKETING AUTHORISATION HOLDERS_____________ 18
1. General Principles ______________________________________________________ 19
1.1 Legal Basis oI the Marketing Authorisation Holder`s Obligations Ior Pharmacovigilance 19
1.2 Roles and Responsibilities oI the Marketing Authorisation Holder and the QualiIied Person
Responsible Ior Pharmacovigilance 19
1.2.1 The Role and Responsibilities oI the QualiIied Person Responsible Ior Pharmacovigilance
20
1.2.2 Responsibilities oI the Marketing Authorisation Holder in Relation to the QualiIied Person
Responsible Ior Pharmacovigilance 21
1.3 Contractual Arrangements 21
2. Requirements for Pharmacovigilance Systems, Monitoring of Compliance and
Pharmacovigilance Inspections ___________________________________________ 22
2.1 Introduction 22
2.1.1 Roles oI the Marketing Authorisation Holder 22
2.1.2 Roles oI the Agency 22
2.1.3 Roles oI the Competent Authorities in Member States 22
2.1.4 Pharmacovigilance Inspections 23
2.1.5 Detailed Description oI the Pharmacovigilance System to Be Included in the Marketing
Authorisation Application 23
2.1.6 ProoI oI the Services oI a QPPV and oI the Necessary Means to NotiIy Adverse Reactions,
to be Included in the Marketing Authorisation Application 23
2.2 Detailed Description oI the Pharmacovigilance System 23
2.2.1 Location in the Marketing Authorisation Application and Update oI the Detailed
Description 23
2.2.2 Statement oI the Marketing Authorisation Holder and the QPPV Regarding their
Availability and the Means Ior the NotiIication oI Adverse Reactions 23
2.2.3 Elements oI the Detailed Description oI the Pharmacovigilance System 24
2.2.3.a) QualiIied Person Responsible Ior Pharmacovigilance (QPPV) 24
2.2.3.b) Organisation 24
2.2.3.c) Documented Procedures 24
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2.2.3.d) Databases 26
2.2.3.e) Contractual Arrangements with Other Persons or Organisations Involved in the FulIilment
oI Pharmacovigilance Obligations 26
2.2.3.I) Training 26
2.2.3.g) Documentation 26
2.2.3.h) Quality Management System 26
2.2.3.i) Supporting Documentation 27
2.3 Monitoring oI Compliance by the Competent Authorities 27
2.3.1 QualiIied Person Responsible Ior Pharmacovigilance 27
2.3.2 Availability oI Pharmacovigilance Data 27
2.3.3 Change in the Evaluation oI the Risk-BeneIit Balance oI a Product 28
2.3.4 Expedited Adverse Reaction Reporting 28
2.3.5 Periodic SaIety Update Reports 28
2.3.6 InIormation Requested by Competent Authorities 29
2.3.7 Submission oI SaIety Variations 29
2.3.8 CHMP Commitments in Respect oI Centrally Authorised Products 29
2.3.9 Post-Authorisation SaIety Studies 30
2.3.10 Provision oI Additional Data on Studies 30
2.4 Pharmacovigilance Inspections 30
2.4.1 Conduct oI Inspections 30
2.4.2 Routine Inspections 31
2.4.3 Targeted Inspections 31
2.4.4 Pharmacovigilance System Inspections 32
2.4.5 Product-SpeciIic Inspections 32
2.4.6 Requesting and Reporting oI Inspections 32
2.4.7 Inspections oI Contractors and Licensing Partners 33
2.4.8 Inspections in European Economic Area 33
2.4.9 Inspections in Third Countries 33
2.4.10 Fees Ior Inspections Requested by the CHMP 33
2.4.11 Procedures Ior Coordination oI Pharmacovigilance Inspection Ior Centrally Authorised
Products 33
2.4.12 Procedures Ior Pharmacovigilance Inspections 33
2.4.13 Unannounced Inspections 34
2.4.14 Inspection Reports 34
2.4.15 Follow-up oI Inspection Findings 34
2.4.16 Sharing oI inspection inIormation 34
2.5 Regulatory Action 34
3. Requirements for Risk Management Systems _______________________________ 36
3.1 Introduction 36
3.2 Description oI the Risk Management System 38
3.3 EU Risk Management Plan (EU-RMP) 38
3.4 Situations Requiring an EU-RMP 39
3.4.1 Marketing Authorisations via the Centralised Procedure 39
3.4.2 Marketing Authorisations via the Mutual Recognition or Decentralised Procedures 40
3.5 Location in the Application 40
3.6 SaIety SpeciIication 40
3.6.1 Non-clinical Part oI the SaIety SpeciIication 41
3.6.2 Clinical Part oI the SaIety SpeciIication 41
3.6.2.a) Limitations oI the Human SaIety Database 41
3.6.2.b) Populations Not Studied in the Pre-Authorisation Phase 41
3.6.2.c) Adverse Events/Adverse Reactions 42
3.6.2.d) IdentiIied and Potential Interactions including Food-Drug and Drug-Drug Interactions 43
3.6.2.e) Epidemiology 43
3.6.2.I) Pharmacological Class EIIects 44
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3.6.2.g) Additional EU Requirements 44
3.6.3 Summary 45
3.7 Pharmacovigilance Plan 45
3.7.1 Routine Pharmacovigilance 45
3.7.2 Additional Pharmacovigilance Activities and Action Plans 45
3.7.3 Action Plan Ior SaIety Concerns 46
3.8 Evaluation oI the Need Ior Risk Minimisation Activities 46
3.8.1 Potential Ior Medication Errors 47
3.9 The Risk Minimisation Plan 47
3.10 Risk Minimisation Activities 48
3.10.1 Risk Communication 48
3.11 The Marketing Authorisation 48
3.12 Ensuring the EIIectiveness oI Risk Minimisation Activities 49
3.12.1 Assessment oI Risk Minimisation 49
3.13 Summary oI Activities in the EU-RMP 49
3.14 Submission oI Updated EU-RMP Documents 50
TABLE I.3.A: METHODS FOR RISK MINIMISATION 52
4. Requirements for Expedited Reporting of Individual Case Safety Reports _______ 56
4.1 Introduction 56
4.2 Reporting Time Frames 57
4.3 Requirements by Reporting Source 58
4.3.1 Spontaneous Reports Irom Healthcare ProIessionals 58
4.3.2 Reports Published in the Worldwide Literature 60
4.3.3 InIormation on Adverse Reactions Irom the Internet 61
4.3.4 Reports Irom Organised Data Collection Systems 61
4.3.5 Reports Irom Patients and Other Consumers 62
4.3.6 Reports Irom Other Non-Medical Sources 62
4.4 Data Elements Ior the Report 62
4.5 Method oI Reporting 63
5. Requirements for Reporting in Special Situations ____________________________ 64
5.1 Introduction 64
5.2 Reporting in the Period between the Submission oI the Marketing Authorisation
Application and the Granting oI the Marketing Authorisation 64
5.3 Reporting Following Suspension or Withdrawal oI the Marketing Authorisation Ior SaIety
or Commercial Reasons 64
5.4 Reporting oI Outcomes oI Use oI a Medicinal Product During Pregnancy 65
5.5 Reporting oI Adverse Reactions during BreastIeeding 66
5.6 Reporting oI Data on Use oI Medicinal Products in Children 66
5.7 Reporting Irom Compassionate/Named-Patient Use 66
5.8 Reporting oI Lack oI EIIicacy 66
5.9 Reporting oI Suspected Transmission oI InIectious Agents 67
5.10 Reporting in Relation to Overdose, Abuse and Misuse 68
5.11 Reporting oI Medication Errors 68
5.12 Reporting in the Event oI a Public Health Emergency 69
6. Requirements for Periodic Safety Update Reports ___________________________ 70
6.1 Introduction 70
6.2 General Principles 71
6.2.1 General Scope oI InIormation 71
6.2.2 One Periodic SaIety Update Report Ior Products Containing an Active Substance
Authorised to One Marketing Authorisation Holder 71
6.2.3 Products Authorised to More Than One Marketing Authorisation Holder 72
6.2.4 Frequency oI Review and Reporting 72
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6.2.4.a) Regular and Ad Hoc Submission oI Periodic SaIety Update Reports 72
6.2.4.b) Submission oI Periodic SaIety Update Reports Ior Renewal oI Marketing Authorisations 74
6.2.4.c) Circumstances Where the Periodicity May Be Amended 74
6.2.4.d) Preparation oI Periodic SaIety Update Report according to the International Birth Dates 76
6.2.5 ReIerence SaIety InIormation 76
6.2.6 Presentation oI Data on Individual Cases 78
6.2.6.a) Sources oI InIormation 78
6.2.6.b) Description oI the Adverse Reaction 78
6.2.6.c) Line listings and/or Summary Tabulations 79
6.3 Model Ior a Periodic SaIety Update Report (PSUR) 80
6.3.1 PSUR section 'Executive Summary 80
6.3.2 PSUR section 'Introduction 80
6.3.3 PSUR section 'Worldwide Marketing Authorisation Status 80
6.3.4 PSUR section 'Update oI Regulatory Authority or Marketing Authorisation Holder Actions
taken Ior SaIety Reasons 81
6.3.5 PSUR section 'Changes to ReIerence SaIety InIormation 81
6.3.6 PSUR section 'Patient Exposure 82
6.3.7 PSUR section 'Presentation oI Individual Case Histories 83
6.3.7.a) 'Cases Presented as Line-Listings 83
6.3.7.b) 'Cases Presented as Summary Tabulations 85
6.3.7.c) 'Marketing Authorisation Holder`s Analysis oI Individual Case Histories 85
6.3.8 PSUR section 'Studies 85
6.3.8.a) 'Newly Analysed Studies 85
6.3.8.b) 'Targeted New SaIety Studies 85
6.3.8.c) 'Published Studies 86
6.3.8.d) 'Other Studies 86
6.3.9 PSUR section 'Other inIormation 86
6.3.9.a) 'EIIicacy-related InIormation 86
6.3.9.b) 'Late-breaking InIormation 86
6.3.9.c) 'Risk Management Plan 86
6.3.9.d) 'Risk-BeneIit Analysis Report 86
6.3.10 PSUR section 'Overall SaIety Evaluation 87
6.3.11 PSUR section 'Conclusion 87
6.4 Contents oI the PSUR Summary Bridging Report 88
6.5 Contents oI the PSUR Addendum Report 88
7. Company-Sponsored Post-Authorisation Safety Studies_______________________ 90
7.1 Introduction 90
7.2 Objectives oI Post-Authorisation SaIety Studies 91
7.3 Responsibilities Ior the Conduct oI Post-Authorisation SaIety Studies 92
7.4 Liaison with Competent Authorities 92
7.4.1 Evaluation oI the Protocol 92
7.4.2 Reporting oI Adverse Reactions 93
7.4.3 Progress and Final Study Reports 94
7.5 Promotion oI Medicinal Products 94
7.6 Participation oI Healthcare ProIessionals 95
7.7 Ethical Issues 95
7.8 Procedure Ior Complaints 95
TABLE I.7.A: EPIDEMIOLOGICAL METHODS FOR POST-AUTHORISATION SAFETY STUDIES 96
TABLE I.7.B: ELEMENTS TO BE CONSIDERED IN THE PROTOCOL OF POST-AUTHORISATION SAFETY STUDIES AS APPROPRIATE 101
TABLE I.7.C: ELEMENTS TO BE CONSIDERED IN THE FINAL STUDY REPORT 104
8. Overall Pharmacovigilance Evaluation and Safety-Related Regulatory Action___ 106
8.1 Introduction 106
8.2 Signal Detection and Evaluation 106
8.3 Principles oI Risk-BeneIit Assessment 107
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8.3.1 Assessment oI BeneIits 107
8.3.2 Assessment oI Risks 107
8.3.3 Risk-BeneIit Assessment 108
8.4 Improving the Risk-BeneIit Balance 108
8.5 Withdrawal oI a Product Irom the Market on Risk-BeneIit Grounds 109
8.6 Communication 109
PART II: GUIDELINES FOR COMPETENT AUTHORITIES AND THE AGENCY ______ 110
1. Undertaking of Pharmacovigilance Activities by Competent Authorities in Member
States________________________________________________________________ 111
1.2 Establishment oI a Pharmacovigilance System 112
1.3 Management oI Spontaneous Reporting Programmes 113
1.3.1 General Principles 113
1.3.2 Receipt and Validation oI Individual Case SaIety Reports (ICSRs) 114
1.3.3 Processing Individual Case SaIety Reports 114
1.3.4 Reporting oI Individual Case SaIety Reports 115
1.3.5 Evaluation oI Individual Case SaIety Reports 116
1.3.6 Signal Detection 116
1.3.7 Provision oI InIormation to the World Health Organization and Other International Bodies
117
1.3.8 Feedback InIormation to Reporting Healthcare ProIessionals 117
1.3.9 Quality Management 117
1.3.10 ConIidentiality and Security 117
1.4 Company-Derived Pharmacovigilance Data 117
1.4.1 Risk Management Plans 118
1.4.2 Individual Case SaIety Reports 118
1.4.3 Periodic SaIety Update Reports 118
1.4.4 Data Irom Company-Sponsored Post-Authorisation SaIety Studies 119
1.4.5 Risk-BeneIit Reviews 120
1.4.6 Reports on Post-Authorisation Commitments 120
1.4.7 Other Data 121
1.5 Pharmacovigilance Data Irom Other Sources 121
1.5.1 Intensive Monitoring Schemes 121
1.5.2 Data on Medication Errors, Overdose, Misuse and Abuse 121
1.5.3 Other InIormation Sources Relevant to Pharmacovigilance 121
1.6 Procedures Ior Data Exchange 122
1.6.1 Technologies Ior Data Transmission 122
1.7 Overall Pharmacovigilance Evaluation and SaIety-Related Regulatory Action 122
1.8 Sanctions 124
1.9 Public Communication and Transparency 124
APPENDIX 1.A: MANDATE, OBJECTIVES AND RULES OF PROCEDURE OF THE PHVWP 125
2.A Conduct of Pharmacovigilance for Centrally Authorised Products_____________ 126
2.A.1 Introduction 126
2.A.2 Legal Framework 126
2.A.3 Principles 126
2.A.4 Functions and Procedures 128
2.A.4.1 Reporting oI Adverse Reactions and Other SaIety-Related InIormation 128
2.A.4.1.a) Pre-Authorisation Phase 128
2.A.4.1.b) Post-Authorisation Phase 128
2.A.4.2 Monitoring oI the SaIety ProIile 128
2.A.4.2.a) Signal IdentiIication 128
2.A.4.2.b) Signal Evaluation 129
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2.A.4.2.c) Evaluation oI Periodic SaIety Update Reports 129
2.A.4.2.d) Evaluation oI Post-Authorisation Studies, Worldwide Literature and Other InIormation 130
2.A.4.2.e) Evaluation oI Post-Authorisation Commitments 130
2.A.4.3 Handling oI SaIety Concerns 131
2.A.4.3.a) SaIety Concerns in the Pre-Authorisation Phase 131
2.A.4.3.b) SaIety Concerns in the Post-Authorisation Phase 131
2.A.4.4 InIormation to Healthcare ProIessionals and the Public 133
2.A.4.5 Advertising 133
TABLE II.2.A.A: ROLES AND THE RESPONSIBILITIES OF PARTNERS INVOLVED IN THE CONDUCT OF PHARMACOVIGILANCE FOR
CENTRALLY AUTHORISED PRODUCTS 134
2.B Crisis Management Plan regarding Centrally Authorised Products ____________ 136
2.B.1 Introduction 136
2.B.2 Principles oI the Crisis Management Plan 136
2.B.3 Crisis Management Structures 137
2.B.3.1. European Crisis Group 137
2.B.3.2 Agency Crisis Team 137
2.B.3.3 Advisory Network at the Level oI the Member States 139
2.B.4 Key Points oI the Procedure 139
2.B.5 Public Relations 139
3. Conduct of Pharmacovigilance for Medicinal Products Authorised through the
Mutual Recognition or Decentralised Procedure ____________________________ 140
3.2 Principles 140
3.3 Roles and Responsibilities 141
3.3.1 ReIerence Member State 141
3.3.2 Concerned Member States 141
3.3.3 CHMP Pharmacovigilance Working Party (PhVWP) 141
3.3.4 Coordination Group Ior Mutual Recognition and Decentralised Procedures 141
3.3.5 Agency and the Committee Ior Medicinal Products Ior Human Use 142
3.3.6 European Commission 142
3.3.7 Marketing Authorisation Holders 142
3.4 Functions and Procedures Ior the Conduct oI Pharmacovigilance 142
3.4.1 Pre-Authorisation Phase 142
3.4.1.a) Risk Management Plans 143
3.4.1.b) Concerns during the ongoing Mutual Recognition or Decentralised Procedure 143
3.4.2 Post-Authorisation Phase 143
3.4.2.a) Expedited Reporting oI Individual Case SaIety Reports 143
3.4.2.b) Periodic SaIety Update Reports and Other Relevant Post-Authorisation InIormation 143
3.4.2.c) Risk Management Plans 144
3.4.2.d) Signal Detection 144
3.4.2.e) Signal Evaluation 144
3.4.2.I) Proceedings in Case oI SaIety Concerns 145
3.4.2.g) Communication to Healthcare ProIessionals and the Public 146
4. Rapid Alert and Non-Urgent Information System in Pharmacovigilance________ 148
4.2 Criteria 149
4.2.1 Rapid Alert 149
4.2.2 Non-Urgent InIormation 150
4.3 Procedures 151
4.3.1 Sending a Rapid Alert or a Non-Urgent InIormation 151
4.3.2 Responses to a Rapid Alert or Non-Urgent InIormation 153
4.3.3 Assessment oI a Rapid Alert 153
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4.3.4 Assessment oI Non-Urgent InIormation 154
TABLE II.4.A: MINIMUM INFORMATION FOR TRANSMISSION OF A RAPID ALERT OR NON-URGENT INFORMATION ALWAYS TO BE
PROVIDED 155
5. Referrals in Case of Safety Concerns Related to Products Authorised in the EU and
Commission Decisions Following Suspension, Revocation or Variation of a Medicinal
Product by a Member State _____________________________________________ 156
6. Principles of Collaboration with the World Health Organization in Matters of
International Pharmacovigilance_________________________________________ 157
6.2 Provision oI Individual Case SaIety Reports 157
6.3 Review oI Signals Raised by the WHO Collaborating Centre 157
6.4 Provision oI InIormation on SaIety-Related Regulatory Action in the EU 158
6.5 Participation in the Annual Meetings oI the WHO Programme Ior International Drug
Monitoring 158
6.6 Other Collaboration 158
PART III: GUIDELINES FOR MARKETING AUTHORISATION HOLDERS, COMPETENT
AUTHORITIES AND THE AGENCY ON ELECTRONIC EXCHANGE OF
PHARMACOVIGILANCE INFORMATION IN THE EU ___________________________ 159
1. Introduction__________________________________________________________ 160
2. Applicable Electronic Reporting Guidelines________________________________ 161
3. Message Format and Message Processing__________________________________ 163
4. Electronic Reporting of Individual Case Safety Reports and Definition of
Exceptional Circumstances ____________________________________________ 163
5. Preparation of Individual Case Safety Reports and Data Privacy Laws _________ 164
5.1 How to Prepare Individual Case SaIety Reports 164
5.2 How to Prepare Individual Case SaIety Reports Related to Parent-Child/Foetus Cases 165
5.3 How to Report Follow-up InIormation 166
5.4 What to Take into Account Ior Data Privacy Laws 167
6. Nullification of Individual Cases _________________________________________ 167
TABLE III.6.A: EXAMPLES OF DIFFERENT SCENARIOS FOR WHICH CASE NULLIFICATIONS SHOULD AND SHOULD NOT BE
CARRIED OUT 168
7. Handling of Adverse Reaction Reports Published in the Worldwide Literature __ 171
TABLE III.7.A: EXAMPLE FOR THE REPORTING OF CASES ORIGINALLY REPORTED IN THE WORLDWIDE LITERATURE REFERRING
TO MORE THAN ONE PATIENT 173
8. Compliance with Required Reporting Timeframes __________________________ 174
9. Electronic Re-transmission of Cases between Multiple Senders and Receivers ___ 174
10. Electronic Reporting through Companys Headquarters _____________________ 174
11. Specific Provisions for the Electronic Reporting to EudraVigilance ____________ 175
11.1 EudraVigilance Database Modules 175
11.1.1 Adverse Reaction Data Collected in EudraVigilance Post-Authorisation Module 175
11.1.2 Adverse Reaction Data Collected in EudraVigilance Clinical Trial Module 176
11.2 Data Quality oI Individual Case SaIety Reports Transmitted Electronically 176
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11.3 Reporting oI all Serious Cases Irom outside the European Union 177
11.4 Retrospective Electronic Population oI EudraVigilance Post-Authorisation Module 177
11.4.1 Retrospective Electronic Population oI EudraVigilance Post-Authorisation Module:
Transmission Rules 178
11.5 Handling oI Languages 179
11.6 Population oI the EudraVigilance Medicinal Product Dictionary 180
11.7 Periodic Transmission oI Individual Case SaIety Reports not Transmitted on an Expedited
Basis in Electronic Format 181
11.7.1 Periodic Transmission oI Individual Case SaIety Reports in Electronic Format 182
PART IV: GUIDELINES FOR MARKETING AUTHORISATION HOLDERS AND
COMPETENT AUTHORITIES ON PHARMACOVIGILANCE COMMUNICATION______ 184
1. Introduction__________________________________________________________ 185
2. Direct Healthcare Professional Communications____________________________ 186
2.2 DeIinition oI Direct Healthcare ProIessional Communication 186
2.3 Key Principles Ior Public Communication on Medicinal Products 186
2.4 Situations Where a Direct Healthcare ProIessional Communication Should Be Considered
187
2.5 Key Principles Ior Preparation oI Texts Ior Direct Healthcare ProIessional
Communications 188
2.6 The Processing oI Direct Healthcare ProIessional Communications 189
2.6.1 The Roles and Responsibilities oI Marketing Authorisation Holders, the Competent
Authorities and the Agency 189
2.6.2 Phased Approach to Processing 191
2.6.3 Translations 194
ANNEXES _____________________________________________________________ 195
1. Glossary _____________________________________________________________ 196
1.1 General 196
1.2 Terms in Relation to Risk Management 202
1.3 Terms in Relation to Electronic Exchange oI Pharmacovigilance InIormation 204
2. Abbreviations_________________________________________________________ 208
3. Other EU Guidelines and Relevant Terminology____________________________ 209
3.1 Other EU Pharmacovigilance Guidelines 209
3.1.1 Note Ior Guidance on the Electronic Data Interchange (EDI) oI Individual Case SaIety
Reports (ICSRs) and Medicinal Product Reports (MPRs) in Pharmacovigilance During the
Pre- and Post-Authorisation Phase in the European Economic Area (EEA) 209
3.1.2 Technical Documentation EudraVigilance Human Version 7.0 Processing oI SaIety
Messages and Individual Case SaIety Reports (ICSRs) 209
3.1.3 Guideline on the Exposure to Medicinal Products During Pregnancy: Need Ior Post-
Authorisation Data 209
3.1.4 Guideline on the Conduct oI Pharmacovigilance Ior Medicines Used by the Paediatric
Population 209
3.1.5 Guideline on the Use oI Statistical Signal Detection Methods in the EudraVigilance Data
Analysis System 209
3.2 Relevant Terminology 209
3.2.1 Medical Terms 209
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3.2.2 Standard Terms on Pharmaceutical Dosage Forms, Routes oI Administration and
Containers 209
3.2.3 Controlled Vocabulary Ior Routes oI Administration 210
3.2.4 Controlled Vocabulary Ior Units and Measurements 210
3.3 Other Relevant Guidelines SpeciIic to Similar Biological Medicinal Products 210
3.3.1 Guideline on Similar Biological Medicinal Products 210
3.3.2 Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived
Products as Active Substance: Non-clinical and Clinical Issues 210
3.3.3 Annex to Guideline on Similar Biological Medicinal Products Containing Biotechnology-
derived Products as Active Substance: Non-clinical and Clinical Issues: Guidance on
Similar Medicinal Products Containing Recombinant Erythropoietins 210
Similar Medicinal Products Containing Recombinant Granulocyte-colony Stimulating
Factor 210
Similar Medicinal Products Containing Recombinant Human Soluble Insulin 210
Similar Medicinal Products Containing Somatropin 211
3.3.7 Guideline on Comparability oI Biotechnology-derived Medicinal Products aIter a Change
in the ManuIacturing Process: Non-clinical and Clinical Issues 211
3.4 Other Relevant Guidelines 211
3.4.1 Guideline on the Clinical Investigation oI Human Anti-D Immunoglobulin Ior Intravenous
and/or Intramuscular Use 211
3.4.2 Guideline on Immunogenicity Assessment oI Biotechnology-Derived Therapeutic Proteins
211
3.4.3 Guideline on the Clinical and Non-Clinical Evaluation During the Consultation Procedure
on Medicinal Substances Contained in Drug-Eluting (Medicinal Substance-Eluting)
Coronary Stents 211
4. ICH Guidelines _______________________________________________________ 212
4.1 ICH-E2B(R2) - Maintenance oI the Clinical SaIety Data Management Including: Data
Elements Ior Transmission oI Individual Case SaIety Reports 212
4.1.1 ICH-E2B Q&As (R5): Questions and Answers Data Elements Ior Transmission oI
Individual Case SaIety Reports 212
4.2 ICH-E2C(R1): Clinical SaIety Data Management - Periodic SaIety Update Reports Ior
Marketed Drugs including Addendum to ICH-E2C 212
4.3 ICH-E2D: Post-Approval SaIety Data Management - DeIinitions and Standards Ior
Expedited Reporting 212
4.4 ICH-E2E: Pharmacovigilance Planning 212
4.5 ICH-M1: Medical Terminology - Medical Dictionary Ior Regulatory Activities (MedDRA)
212
4.6 ICH-M2: Electronic Standards Ior Transmission oI Regulatory InIormation (ESTRI) -
Individual Case SaIety Report (ICSR) 212
4.7 ICH-M5: Data Elements and Standards Ior Drug Dictionaries 212
4.7.1 Routes oI Administration Controlled Vocabulary 212
4.7.2 Units and Measurements Controlled Vocabulary 213
5. Templates ____________________________________________________________ 214
5.1.1 Template Ior EU Risk Management Plan (EU RMP) 214
5.2.1 Template Ior Cover Page Ior PSUR Submission 215
5.2.2 Template Ior PSUR section "Worldwide Marketing Authorisation Status" 216
5.2.3 Template Ior PSUR section "Line-listings oI Individual Case Histories" 217
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5.2.4 Template Ior PSUR section "Summary Tabulations" 218
5.3.1 Template Ior Rapid Alert in Pharmacovigilance 219
5.3.2 Template Ior Non-Urgent InIormation in Pharmacovigilance 221
5.4.1 Template Ior Direct Healthcare ProIessional Communications 223
6. Distribution Requirements and Address Lists for Data Submission ____________ 225
6.1 Requirements Ior Expedited Reporting in Member States 225
6.1.1 SpeciIic Expedited (15-days) Reporting Requirements in Member States Ior ICSRs Irom
Spontaneous Reporting and Non-Interventional Studies Occurring in the Territory oI a
given Member State 226
Spontaneous Reporting and Non-Interventional Studies Occurring in the Territory oI
Another Member State 227
Spontaneous Reporting and Non-Interventional Studies Occurring Outside the EU 228
6.2 Distribution Requirements and Address Lists Ior Periodic SaIety Update Reports 229
INTRODUCTION
1. Legal Basis and Structure of Volume 9A (Human Pharmacovigilance)
Pharmacovigilance has been deIined by the World Health Organization as the science and activities
relating to the detection, assessment, understanding and prevention oI adverse eIIects or any other
medicine-related problem. Article 106 oI Directive 2001/83/EC speciIically requires the European
Commission in consultation with the European Medicines Agency (EMEA 'the Agency), Member
States and interested parties to draw up guidance on the collection, veriIication and presentation oI
adverse reaction reports in order to Iacilitate the exchange oI inIormation about human
pharmacovigilance within the Community. Similarly, Article 26 oI Regulation (EC) No 726/2004
includes a requirement Ior the Commission, in consultation with the Agency, Member States and
interested parties to draw up a guide.
This guidance is required to include technical requirements Ior the electronic exchange oI
pharmacovigilance inIormation in accordance with internationally agreed Iormats. In addition, the
European Commission is also required to publish a reIerence to an internationally agreed medical
terminology.
This Volume 9A has thereIore been prepared by the European Commission in close consultation with
the Agency, Member States and interested parties and is speciIically related to human
pharmacovigilance. It brings together general guidance on the requirements, procedures, roles and
activities in this Iield, Ior both Marketing Authorisation Holders and Competent Authorities oI
medicinal products Ior human use; it incorporates international agreements reached within the
Iramework oI the International ConIerence on Harmonisation (ICH).
Volume 9A is presented in Iour parts:
Part I deals with Guidelines Ior Marketing Authorisation Holders;
Part II deals with Guidelines Ior Competent Authorities and the Agency;
Part III provides the Guidelines Ior the electronic exchange oI pharmacovigilance in the EU; and
Part IV provides Guidelines on pharmacovigilance communication.
It should be noted, as with all guidance documents in rapidly evolving technical areas, that this
guidance is intended to be regularly reviewed and updated, with publication on the European
Commission`s website: http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/index.htm. This is
particularly true oI the detailed reporting requirements Ior individual member states and it should be
noted that Annex 6 'Distribution Requirements and Address Lists Ior Data Submission is currently
under review by the Member States and is thereIore likely to be updated in the near Iuture.

Introduction 14/229
2. Legal Framework for Pharmacovigilance
The legal Iramework Ior pharmacovigilance oI medicinal products Ior human use in the European
Union (EU) is given in Regulation (EC) No 726/2004
1
and Directive 2001/83/EC
2
on the Community
code relating to medicinal products Ior human use, as last amended by Directive 2004/24/EC
3
and by
Directive 2004/27/EC
4
(hereaIter reIerred to simply as Directive 2001/83/EC). It should be noted that
although Chapter 3 oI Regulation (EC) No 726/2004 and Title IX oI Directive 2001/83/EC contain the
majority oI pharmacovigilance provisions in the legislation, other measures directly relevant to the
conduct oI pharmacovigilance are Iound in other Chapters and Titles oI those legislative texts.
The requirements explained in these guidelines are based on the ICH guidelines, where these exist, but
may be Iurther speciIied or contain additional requests in line with the legislation oI the EU.
The pharmacovigilance obligations apply to all medicinal products authorised in the EU, including
those authorised beIore 1 January 1995 and whatever procedure was used Ior their authorisation. For
example, the obligations are the same Ior products authorised under Articles 10(1), 10(4), 10a, 13 to
16 and 16a to 16i oI Directive 2001/83/EC (generic`, similar biological medicinal product`, well-
established use`, homeopathic
5
` and herbal` products respectively) as Ior products authorised under
Article 6 oI the same Directive. However, it should be noted that, pursuant to Article 16(3) oI
Directive 2001/83/EC, the pharmacovigilance title oI that Directive does not apply to homeopathic
medicinal products which are the subject oI the simpliIied registration procedure (Article 14 (1) oI
Directive 2001/83/EC).
The legislation listed above describes the respective obligations oI the Marketing Authorisation Holder
and oI the Competent Authorities to set up a system Ior pharmacovigilance in order to collect, collate
and evaluate inIormation about suspected adverse reactions. All relevant inIormation should be shared
between the Competent Authorities and the Marketing Authorisation Holder, in order to allow all
parties involved in pharmacovigilance activities to assume their obligations and responsibilities. This
requires an intensive exchange oI inIormation between the Marketing Authorisation Holder, the
Competent Authorities oI Member States and the Agency as well as procedures to avoid duplication,
maintain conIidentiality and ensure the quality oI the systems and data.
Iceland, Liechtenstein and Norway have through the Agreement oI the European Economic Area
(EEA) adopted the complete Community acquis (i.e. the legislation at EU level, guidelines and
judgements) on medicinal products, and are consequently parties to the Community procedures.
Consequently, the Iollowing Guidelines do not only apply with regard to the Marketing Authorisation
Holder`s obligations towards Competent Authorities in Member States oI the EU but also to those
towards the States Iceland, Liechtenstein and Norway. Likewise they apply to the Competent
Authorities in these States themselves.
The obligations concerned with the monitoring oI adverse reactions occurring in clinical trials do not
Iall within the scope oI pharmacovigilance activities, as described in these Guidelines. The legal
Iramework Ior such obligations is Directive 2001/20/EC on the approximation oI the laws, regulations
and administrative provision oI the Member States relating to the implementation oI good clinical
practice in the conduct oI clinical trials on medicinal products Ior human use
6
. Part III oI Volume 9A
deals with technical aspects relating to adverse reaction/event reporting Ior pre- and post-authorisation
phases. Furthermore, the requirements Ior non-interventional studies are described in Chapter I.7, the

1
OJ L 136, 30.4.2004, p.1.
2
OJ L 331, 28.11.2001, p. 67.
3
OJ L 136, 30.4.2004, p. 85.
4
OJ L 136, 30.4.2004, p. 34.
5
With the exception oI those registered through the special, simpliIied registration procedure oI Article 14(1) oI
Directive 2001/83/EC.
6
OJ L 121 1.5.2001 p.34
Introduction 15/229
inclusion oI clinical trials data in Periodic SaIety Update Reports is described in Chapter I.6 and the
notiIication oI potential changes to the risk-beneIit balance in Chapter I.8.
3. The Roles of the Various Parties
3.1 The Marketing Authorisation Holder
The Marketing Authorisation Holder must ensure that it has an appropriate system oI
pharmacovigilance and risk management in place in order to assure responsibility and liability Ior its
products on the market and to ensure that appropriate action can be taken, when necessary (see Part I).
3.2 The Competent Authorities
3.2.1 The Competent Authorities of the Member States
The authorities oI the Member States are the Competent Authorities Ior medicinal products authorised
nationally through national procedures, including the mutual recognition and decentralised procedure.
The responsibilities Ior pharmacovigilance rest with the Competent Authorities oI all the Member
States in which the marketing authorisations are held. In addition the Member States are the
supervisory authorities Ior centrally authorised products (see Chapter II.1).
3.2.2 The European Commission
For medicinal products authorised through the centralised procedure the European Commission is the
Competent Authority. The European Commission is responsible Ior the adoption oI Decisions on the
basis oI Committee Ior Medicinal Products Ior Human Use (CHMP) Opinions relating to medicinal
products authorised through the centralised procedure and those products subject to the procedure oI
Articles 32, 33 and 34 oI Directive 2001/83/EC. The European Commission also has responsibilities
Ior the overall Community system oI pharmacovigilance and Ior the legal Iramework (see
Chapter II.1).
3.3 The EU Pharmacovigilance System
3.3.1 The Role of Competent Authorities of the Member States for Products
Authorised Through National Procedures
In accordance with the legislation, each Member State has established a pharmacovigilance system Ior
the collection and evaluation oI inIormation relevant to the risk-beneIit balance oI medicinal products.
The Competent Authority continually monitors the saIety proIile oI the products available on its
territory and takes appropriate action where necessary and monitors the compliance oI Marketing
Authorisation Holders with their obligations with respect to pharmacovigilance. The Competent
Authority should ensure that Marketing Authorisation Holders implement, when appropriate, Risk
Management Plans to eIIectively monitor and manage risks associated with the saIety oI their
products. Furthermore the Competent Authority should ensure that pharmacovigilance data are shared
between Member States and the Agency via the data-processing network EudraVigilance (see Part II).
3.3.2 The Role of the Competent Authority of the Reference Member State for
Products Authorised Through the Mutual Recognition or Decentralised
Procedure
The responsibilities oI pharmacovigilance rest with the Competent Authorities oI all the Member
States in which the marketing authorisations are held. For practical reasons, the Member States agree
that the ReIerence Member State will normally take the lead Ior medicinal products authorised through
the mutual recognition or decentralised procedures and responsibility Ior evaluating and producing
Assessment Reports on saIety concerns, in accordance with an agreed timetable. The ReIerence
Introduction 16/229
Introduction 17/229
Member State takes responsibility Ior the coordination oI communication with the Marketing
Authorisation Holder on such matters (see Chapter II.3) and Ior the monitoring oI the compliance oI
the Marketing Authorisation Holder with his obligations with respect to pharmacovigilance. These
arrangements do not replace the legal responsibilities oI the Marketing Authorisation Holder with
respect to individual Competent Authorities.
3.3.3 The Role of the Rapporteur for Products Authorised Through the
Centralised Procedure
The Competent Authorities oI the Member States are responsible Ior monitoring centrally authorised
medicinal products in their respective territories. However, the pre-authorisation Rapporteur takes the
lead in pharmacovigilance, unless otherwise decided by the CHMP. The Rapporteur is responsible Ior
evaluating and producing Assessment Reports on saIety concerns related to a centrally authorised
product, in accordance with an agreed timetable (see Chapters II.2.A and II.2.B) and Ior the
monitoring oI the compliance oI the Marketing Authorisation Holder with its obligations with respect
to pharmacovigilance.
3.3.4 The Role of the Agency
The role oI the secretariat oI the European Medicines Agency (EMEA 'the Agency) is one oI
coordination oI the supervision, under practical conditions oI use, oI medicinal products which have
been authorised within the EU and the provision oI advice on the measures necessary to ensure their
saIe and eIIective use, in particular by evaluation, coordination oI the implementation oI
pharmacovigilance obligations and the monitoring oI such implementation.
The Agency`s scientiIic committee, the CHMP, aided by its Pharmacovigilance Working Party
(PhVWP), is responsible Ior evaluating evidence and Iormulating Opinions on emerging saIety
concerns with centrally authorised products, based on the Rapporteur`s Assessment Report. The
Agency secretariat is responsible Ior communicating with the Marketing Authorisation Holders oI
centrally authorised products on such concerns (see Chapter II.2) and Ior the co-ordination oI issues
relating to the monitoring oI the compliance oI the Marketing Authorisation Holder with its
pharmacovigilance obligations (see Chapter I.2).
The role oI the Agency secretariat is one oI co-ordination in the case oI reIerrals made to the CHMP
Ior application oI the procedures laid down in Articles 32, 33 and 34 oI Directive 2001/83/EC. The
CHMP, aided by the PhVWP, is responsible Ior evaluating evidence and Iormulating Opinions on
matters reIerred to it (see Chapter II.5).
3.3.5 The Role of the CHMP Pharmacovigilance Working Party
The Mandate (see Appendix II.1.A) oI the CHMP Pharmacovigilance Working Party (PhVWP) is to
provide advice on the saIety oI medicinal products and the investigation oI adverse reactions, in order
to enable eIIective risk identiIication, assessment and management, in the pre- and post-authorisation
phase (see Chapter I.3), leading to recommendations on harmonised and synchronised action at the
request oI the Competent Authorities and Ior centrally authorised products, and Ior products reIerred
under Article 32, 33 and 34 oI Directive 2001/83/EC at the request oI the CHMP.

PART I:
Guidelines Ior Marketing Authorisation Holders
18/229
1. General Principles
1.1 Legal Basis of the Marketing Authorisation Holders Obligations for
Pharmacovigilance
The legal basis Ior the Marketing Authorisation Holder`s obligations Ior pharmacovigilance oI
medicinal products Ior human use in the EU is given in Regulation (EC) No 726/2004 and Directive
2001/83/EC.
1.2 Roles and Responsibilities of the Marketing Authorisation Holder and the
Qualified Person Responsible for Pharmacovigilance
The Marketing Authorisation Holder should ensure that he has an appropriate system oI
pharmacovigilance in place in order to assume responsibility and liability Ior his products on the
market and to ensure that appropriate action may be taken when necessary. The Marketing
Authorisation Holder should thereIore ensure that all inIormation relevant to the risk-beneIit balance
oI a medicinal product is reported to the Competent Authorities and the Agency Iully and promptly in
accordance with the legislation.
When submitting an application Ior a marketing authorisation, the Applicant, in preparation Ior the
role and responsibilities as Marketing Authorisation Holder, should submit a description oI the
pharmacovigilance system (Article 8(3)(ia) oI Directive 2001/83/EC) and submit prooI that the
services oI a QualiIied Person Responsible Ior Pharmacovigilance, hereaIter reIerred to as the QPPV,
are in place (Article 8(3)(n) oI Directive 2001/83/EC) (see Chapter I.2).
The Marketing Authorisation Holder should have permanently and continuously at his disposal a
QPPV, residing in the EU
7
.
The role oI the QPPV is very important, and this Chapter thereIore describes the role and
responsibilities oI the QPPV and also provides guidance Ior the Marketing Authorisation Holder on
how to adequately support the QPPV.
Each company (i.e. Applicant/Marketing Authorisation Holder or group oI Marketing Authorisation
Holders using a common pharmacovigilance system) should appoint one QPPV responsible Ior overall
pharmacovigilance Ior all medicinal products Ior which the company holds marketing authorisations
within the EU (see also Chapter I.2).
National regulations in some Member States require a nominated individual in that country who has
speciIic legal obligations in respect oI pharmacovigilance at a national level. One such individual may
also act as the QPPV Ior the whole EU. Alternatively, the QPPV Ior the EU may be a separate person,
additional to requirements under the relevant national regulations.
The QPPV should be appropriately qualiIied, with documented experience in all aspects oI
pharmacovigilance in order to IulIil the responsibilities and tasks oI the post. II the QPPV is not
medically qualiIied, access to a medically qualiIied person should be available.
The name and 24-hour contact details oI the QPPV and back-up procedures to ensure business
continuity and continued IulIilment oI pharmacovigilance obligations should be notiIied to the
Competent Authorities oI the Member States in which marketing authorisations are held or, Ior
centrally authorised products, to the Competent Authorities oI all Member States and to the Agency.

7
As explained in the Introduction, the EFTA States having signed EEA Agreement adopted the complete
Community acquis on medicinal products, and thereIore the QPPV may also reside in the EFTA States having
signed the EEA Agreement.
PART I 19/229
1.2.1 The Role and Responsibilities of the Qualified Person Responsible for
Pharmacovigilance
The QPPV is responsible Ior
establishing and maintaining/managing the Marketing Authorisation Holder`s
pharmacovigilance system;
having an overview oI the saIety proIiles and any emerging saIety concerns (see Glossary in
Annex 1.2 Ior deIinition oI saIety concern) in relation to the medicinal products Ior which the
Marketing Authorisation Holder holds authorisations;
acting as a single contact point Ior the Competent Authorities on a 24-hour basis.
It is recognised that this important role oI the QPPV may impose extensive tasks on the QPPV,
depending on the size and nature oI the pharmacovigilance system and the number and type oI
medicinal products Ior which the company holds authorisations. The QPPV may thereIore delegate
speciIic tasks, under supervision, to appropriately qualiIied and trained individuals, e.g. acting as
saIety experts Ior certain products, provided that the QPPV maintains system oversight and overview
oI the saIety proIiles oI all products. Such delegation should be documented.
In case oI absence, the QPPV should ensure that all responsibilities are undertaken by an adequately
qualiIied person. This person should also reside in the EU (see Footnote 7).
The QPPV should have oversight oI the pharmacovigilance system in terms oI structure and
perIormance and be in a position to ensure in particular the Iollowing system components and
processes, either directly or through supervision:
the establishment and maintenance oI a system which ensures that inIormation about all
suspected adverse reactions which are reported to the personnel oI the Marketing
Authorisation Holder, and to medical representatives, is collected and collated in order to be
accessible at least at one point within the EU;
the preparation Ior Competent Authorities oI the Member States, where the medicinal product
is authorised, oI the reports reIerred to in Article 104 oI Directive 2001/83/EC and in case oI
centrally authorised products the preparation Ior the Agency and Competent Authorities oI the
Member States oI the reports reIerred to in Article 24 oI Regulation (EC) No 726/2004.
Detailed guidance Ior the preparation oI these reports are included in:
Chapter I.4 on Individual Case SaIety Reports (ICSRs),
Chapter I.6 on Periodic SaIety Update Reports (PSURs), and
Chapter I.7 on reports on company-sponsored post-authorisation saIety studies;
the conduct oI continuous overall pharmacovigilance evaluation during the post-authorisation
period (see Chapter I.8);
the ensuring that any request Irom the Competent Authorities Ior the provision oI additional
inIormation necessary Ior the evaluation oI the beneIits and the risks aIIorded by a medicinal
product is answered Iully and promptly, including the provision oI inIormation about the
volume oI sales or prescriptions oI the medicinal product concerned; and
the provision to the Competent Authorities oI any other inIormation relevant to the evaluation
oI the beneIits and risks aIIorded by a medicinal product, including appropriate inIormation on
post-authorisation studies and data Irom sources described in Chapter I.5.
The oversight reIerred to above should cover the Iunctioning oI the Marketing Authorisation Holder`s
pharmacovigilance system in all relevant aspects, including quality control and assurance procedures,
standard operating procedures, database operations, contractual arrangements, compliance data (e.g. in
relation to the quality, completeness and timeliness Ior expedited reporting and submission oI Periodic
SaIety Update Reports), audit reports and training oI personnel in relation to pharmacovigilance.
PART I 20/229
PART I 21/229
The QPPV should also act as the Marketing Authorisation Holder`s contact point Ior
pharmacovigilance inspections or should be made aware by the Marketing Authorisation Holder oI
any inspection, in order to be available as necessary.
1.2.2 Responsibilities of the Marketing Authorisation Holder in Relation to the
Qualified Person Responsible for Pharmacovigilance
The Marketing Authorisation Holder should adequately support the QPPV and ensure that there are
appropriate processes, resources, communication mechanisms and access to all sources oI relevant
inIormation in place Ior the IulIilment oI the QPPV`s responsibilities and tasks.
The Marketing Authorisation Holder should ensure that there is Iull documentation covering all
procedures and activities oI the QPPV and that mechanisms are in place to ensure that the QPPV may
receive or seek all relevant inIormation. The Marketing Authorisation Holder should also implement
mechanisms Ior the QPPV to be kept inIormed oI emerging saIety concerns and any other inIormation
relating to the evaluation oI the risk-beneIit balance. This should include inIormation Irom ongoing or
completed clinical trials and other studies the Marketing Authorisation Holder is aware oI and which
may be relevant to the saIety oI the medicinal product, as well as inIormation Irom sources other than
the speciIic Marketing Authorisation Holder, e.g. Irom those with whom the Marketing Authorisation
Holder has contractual arrangements.
The Marketing Authorisation Holder should ensure that the QPPV has suIIicient authority
to implement changes to the Marketing Authorisation Holder`s pharmacovigilance system in
order to promote, maintain and improve compliance; and
to provide input into Risk Management Plans (see Chapter I.3) and into the preparation oI
regulatory action in response to emerging saIety concerns (e.g. variations, urgent saIety
restrictions, and, as appropriate, communication to Patients and Healthcare ProIessionals).
The Marketing Authorisation Holder should assess risks with potential impact on the
pharmacovigilance system and plan Ior business contingency, including back-up procedures (e.g. in
case oI non-availability oI personnel, adverse reaction database Iailure, Iailure oI other hardware or
soItware with impact on electronic reporting and data analysis).
1.3 Contractual Arrangements
A Marketing Authorisation Holder may transIer any or all oI the pharmacovigilance tasks and
Iunctions, including the role oI the QPPV, to another person(s) or organisation, but the ultimate
responsibility Ior the IulIilment oI all pharmacovigilance obligations and the quality and integrity oI
this always resides with the Marketing Authorisation Holder. In such cases, it is the responsibility oI
the Marketing Authorisation Holder to ensure that detailed and clear documented contractual
arrangements Ior meeting pharmacovigilance obligations are in place between Marketing
Authorisation Holder(s) and persons or organisations involved in the IulIilment oI pharmacovigilance
obligations and to provide the Competent Authorities and, iI applicable the Agency, with inIormation
on such arrangements in line with the requirements set out in Chapter I.2. The contracted person(s) or
organisation should implement quality assurance and quality control and accept to be audited by or
behalI oI the Marketing Authorisation Holder.
In cases oI contractual arrangements between Marketing Authorisation Holders in relation to
co-marketing oI separately authorised medicinal products which are identical in all aspects apart Irom
their invented names, these arrangements should include measures to avoid the duplicate submission
oI Individual Case SaIety Reports (e.g. literature reports) to EudraVigilance.
2. Requirements for Pharmacovigilance Systems, Monitoring of Compliance
and Pharmacovigilance Inspections
2.1 Introduction
The rapid and eIIective identiIication and assessment oI drug saIety issues is dependent on early
access to complete inIormation. This is Iundamental to Competent Authorities` and Marketing
Authorisation Holders` ability to protect public health in taking appropriate action swiItly. Marketing
Authorisation Holders and Competent Authorities have an obligation to implement medicines
legislation and non-compliance with pharmacovigilance regulatory obligations could have a
potentially serious health impact.
This Chapter sets out the Iramework Ior implementation, in the context oI the revised pharmaceutical
legislation, oI the monitoring oI compliance with pharmacovigilance obligations and oI
pharmacovigilance inspections. In the same context it sets out the inIormation to be supplied in the
application giving a detailed description oI the pharmacovigilance system oI the Marketing
Authorisation Holder and prooI that the Marketing Authorisation Holder has the services oI a
QualiIied Person responsible Ior Pharmacovigilance (QPPV) and the necessary means Ior the
notiIication oI adverse reactions. This guidance is applicable Ior any medicinal product, whatever the
marketing authorisation procedure used. The inspection process described Iocuses on centrally
authorised products, however the principles are generally applicable.
The description oI the risk management system, which includes product-speciIic pharmacovigilance
activity, is not addressed in this Chapter but in Chapter I.3.
2.1.1 Roles of the Marketing Authorisation Holder
The Marketing Authorisation Holders should ensure that they have an appropriate system oI
pharmacovigilance in place in order to assure responsibility Ior their products on the market and to
ensure that appropriate action can be taken, when necessary. This includes the Marketing
Authorisation Holder having at its disposal permanently and continuously an appropriately qualiIied
person responsible Ior pharmacovigilance residing within the European Economic Area, and the
establishment oI a system oI pharmacovigilance.
2.1.2 Roles of the Agency
The roles oI the Agency are set out in Regulation (EC) No 726/2004 and Iurther described in this
Volume 9A. Regarding the monitoring oI compliance with pharmacovigilance regulatory obligations
and pharmacovigilance inspections, the Iollowing are oI particular relevance:
Article 57(1)(c) oI Regulation (EC) No 726/2004 stating 'coordination oI the supervision,
under practical conditions oI use, oI medicinal products which have been authorised within the
Community and the provision oI advice on the measures necessary to ensure the saIe and
eIIective use oI these products, in particular by evaluation, coordination oI the implementation
oI pharmacovigilance obligations and the monitoring oI such implementation;
Article 57(1)(i) oI Regulation (EC) No 726/2004 stating 'coordinating the veriIication oI
compliance with the principles oI good manuIacturing practice, good laboratory practice, good
clinical practice and the veriIication oI compliance with pharmacovigilance obligations.
2.1.3 Roles of the Competent Authorities in Member States
The roles oI the Competent Authorities in Member States are set out in Directive 2001/83/EC, in
Regulation (EC) No 726/2004 and Iurther described in this Volume.
PART I 22/229
Title IX oI Directive 2001/83/EC sets out requirements Ior pharmacovigilance.
2.1.4 Pharmacovigilance Inspections
The legal basis Ior the conduct oI Pharmacovigilance inspections is set out in Article 111 oI Directive
2001/83/EC and in Article 19(1) oI Regulation (EC) 726/2004.
2.1.5 Detailed Description of the Pharmacovigilance System to Be Included in the
Marketing Authorisation Application
The Applicant Ior a marketing authorisation is required (see Article 8(3)(ia) oI Directive 2001/83/EC)
to provide a detailed description oI the system oI pharmacovigilance and, where appropriate, oI the
risk management system which the Applicant will introduce. This Chapter addresses the detailed
description oI the pharmacovigilance system that should be supplied with the application dossier and
supporting documentation that the Applicant should maintain and supply to the Competent Authorities
on request. The description oI the risk management system, which includes the product-speciIic
pharmacovigilance activity, is addressed in Chapter I.3.
2.1.6 Proof of the Services of a QPPV and of the Necessary Means to Notify
Adverse Reactions, to be Included in the Marketing Authorisation
Application
The Applicant is required (Article 8(3)(n) oI Directive 2001/83/EC) to provide prooI that they have
the services oI a QPPV and the necessary means Ior the notiIication oI any adverse reaction occurring
either in the Community or in a third country.
2.2 Detailed Description of the Pharmacovigilance System
2.2.1 Location in the Marketing Authorisation Application and Update of the
Detailed Description
The detailed description oI the pharmacovigilance system, including the prooI oI the availability oI the
services oI the QPPV and the prooI that the Marketing Authorisation Holder has the necessary means
Ior the collection and notiIication oI any adverse reaction, should be provided in Module 1/section
1.8.1 oI the application dossier.
The detailed description should comprise an overview oI the pharmacovigilance system providing
inIormation on the key elements oI that system. Where aspects oI the system such as the
organisational arrangements are particular to the product rather than the main system oI the Marketing
Authorisation Holder/company (Marketing Authorisation Holder or a group oI Marketing
Authorisation Holders sharing the same pharmacovigilance system) this should be indicated in a
product-speciIic addendum.
The detailed description should be supported by documentation maintained by the company.
Updates to the inIormation provided in the detailed description oI the pharmacovigilance system
should be made as type II variations.
2.2.2 Statement of the Marketing Authorisation Holder and the QPPV Regarding
their Availability and the Means for the Notification of Adverse Reactions
The Applicant should provide a signed statement Irom the Marketing Authorisation Holder and the
QPPV to the eIIect that the Applicant has their services available as QPPV and has the necessary
means Ior the collection and notiIication oI any adverse reaction occurring either in the Community or
in a third country. This statement may make reIerence to the detailed description oI the
PART I 23/229
pharmacovigilance system (see Chapter I.2, Section 2.3), indicate what is already in place, and
conIirm which items will be put in place beIore the product is placed on the market in the Community.
2.2.3 Elements of the Detailed Description of the Pharmacovigilance System
All Marketing Authorisation Holders are required to have an appropriate system oI pharmacovigilance
in place. The detailed description oI the pharmacovigilance system should include the Iollowing
elements, as applicable, and be set out in a structured manner consistent with this list. Additional
important elements pertinent to a speciIic situation, should be added:
2.2.3.a) Qualified Person Responsible for Pharmacovigilance (QPPV)
The name oI the QPPV, located in the EEA. The business address and contact details should
be provided in the Marketing Authorisation Application Iorm. Companies might, Ior example,
use a 24-hour telephone number through which the QPPV or their back-up can be reached,
diverting it to the appropriate person according to availability.
A summary Curriculum Vitae oI the QPPV with the key inIormation relevant to their role
(main qualiIications, training and experience).
A summary oI the job description oI the QPPV.
A description oI the back-up procedure to apply in the absence oI the QPPV.
2.2.3.b) Organisation
IdentiIication and location oI the company units or other organisations where the principal
EEA and global pharmacovigilance activities are undertaken (in particular those sites where
the main databases are located, where Individual Case SaIety Reports (ICSRs) are collated and
reported and where PSURs (Periodic SaIety Update Reports) are prepared and processed Ior
reporting to the Competent Authorities). IdentiIication oI aIIiliates may be made in a general
sense, rather than aIIiliate-by-aIIiliate.
IdentiIication oI the point(s) in the Community at which pharmacovigilance data are
accessible (to include access to ICSRs, PSURs and the global pharmacovigilance data).
High-level organisation chart(s) providing an overview oI the global and EEA
pharmacovigilance units and organisations (identiIied above) and, illustrating the relationships
between them, with aIIiliate/parent companies and contractors. The chart(s) should show the
main reporting relationships with management and clearly show the position oI the EEA
QPPV within the organisation. Individual names oI people should not be included. Licensing
partnerships are usually product-speciIic and should be indicated in a product-speciIic
addendum in the application Ior that product, unless a partnership is a consistent Ieature oI the
company`s organisation across most products.
A brieI summary oI the pharmacovigilance activities undertaken by each oI the
organisations/units identiIied above.
Flow diagrams indicating the Ilow oI saIety reports oI diIIerent sources and types. These
should indicate how reports/inIormation are processed and reported Irom the source, to the
point oI receipt by the Competent Authorities. These should be limited to the major processes
identiIied in Volume 9A.
2.2.3.c) Documented Procedures
An essential element oI any pharmacovigilance system is that there are clear, written procedures in
place. The Iollowing list indicates topics that should usually be covered by these written procedures.
The detailed description should indicate Ior which oI these topics there are written procedures in place,
PART I 24/229
but should not list the procedure titles per se. A procedure may cover one or more oI the topics or one
topic may have one or more procedures depending on its complexity and the organisation oI the
company. Care should be taken to ensure that quality control and review are appropriately addressed
anagement), quality control,
view and reporting oI ICSRs:
licensing partners,
ts Ior missing inIormation and Ior inIormation on the progress and
reports;
: Continuous monitoring oI the
cinal products (product-speciIic risk management systems
in the various processes and reIlected in the relevant procedures.
The activities oI the QPPV and the back-up procedure to apply in their absence;
The collection, processing (including data entry and data m
coding, classiIication, medical re
Reports oI diIIerent types:
Organised data collection schemes (solicited), unsolicited, clinical trials, literature
The process should ensure that reports Irom diIIerent sources are captured:
EEA and third countries, healthcare proIessionals, sales and marketing
personnel, other Marketing Authorisation Holder personnel,
Competent Authorities, compassionate use, patients, others;
The Iollow-up oI repor
outcome oI the case(s);
Detection oI duplicate
Expedited reporting;
Electronic reporting;
Periodic SaIety Update Reports (PSURs):
The preparation, processing, quality control, review (including medical review) and
reporting;
Global pharmacovigilance activities applying to all products
saIety proIile oI authorised medi
and pharmacovigilance planning are covered in Chapter I.3.):
mpetent Authorities and healthcare
e oI products, etc;

ducts (signal detection, evaluation,
management systems and
Signal detection and review,
Risk-beneIit assessment;
Reporting and communication notiIying Co
proIessionals oI changes to the risk-beneIit balanc
Interaction between saIety issues and product deIects;
Responses to requests Ior inIormation Irom regulatory authorities;
Handling oI urgent saIety restrictions and saIety variations;
Meeting commitments to Competent Authorities in relation to a marketing authorisation;
Global pharmacovigilance activities applying to all pro
reporting, communication etc.). (Product-speciIic risk
pharmacovigilance planning are covered in Chapter I.3.);
nt and use oI databases or other recording systems;
it oI the pharmacovigilance system;
Training;
global and EEA procedures should be available
within two working days on request by the Competent Authorities. Any additional local procedures
should be available to respond to speciIic requests.
Manageme
Internal aud
Archiving.
The detailed description oI the pharmacovigilance should indicate the processes Ior which written
procedures are available. A list and copies oI the
PART I 25/229
2.2.3.d) Databases
A listing oI the main databases used Ior pharmacovigilance purposes (e.g. compilation oI saIety
reports, expedited/electronic reporting, signal detection, sharing and accessing global saIety
inIormation) and brieI Iunctional descriptions oI these should be provided including a statement
regarding the validation status oI the database systems.
A statement should be included regarding the compliance oI the systems with the internationally
agreed standards Ior electronic submission oI adverse reaction reports as reIerred to in Part III.
A copy oI the registration, oI the QPPV, with the EudraVigilance system and identiIication oI the
process used Ior electronic reporting to the Competent Authorities.
There should be an indication oI the responsibility Ior the operation oI the databases and their location
(with reIerence to the locations identiIied under Chapter I.2, Section 2.3.b above).
2.2.3.e) Contractual Arrangements with Other Persons or Organisations Involved in
the Fulfilment of Pharmacovigilance Obligations
Links with other organisations such as co-marketing agreements and contracting oI pharmacovigilance
activities should be outlined. The company should identiIy the major subcontracting arrangements it
has Ior the conduct oI its pharmacovigilance activities and the main organisations to which it has
subcontracted these (in particular where the role oI the QPPV, the electronic reporting oI ICSRs, the
main databases, signal detection, or the compilation oI PSURs is subcontracted).
A brieI description oI the nature oI the agreements the company establishes with co-marketing
partners and contractors Ior pharmacovigilance activities should be provided.
Co-licensing or co-marketing arrangements within the EEA should be identiIied and the distribution oI
the major responsibilities between the parties made clear.
Since co-licensing or co-marketing arrangements are mainly product-speciIic any inIormation on these
may be provided in a product-speciIic addendum, in the applicable Marketing Authorisation
Application. Likewise iI subcontracting is product-speciIic this should be indicated in a product-
speciIic addendum.
2.2.3.f) Training
StaII should be appropriately trained Ior perIorming pharmacovigilance related activities. This
includes not only staII within the pharmacovigilance units but also staII who may receive or process
saIety reports, such as sales personnel or clinical research staII. Provide a brieI description oI the
training system and indicate where the training records, Curricula Vitae (CVs) and job descriptions are
Iiled.
2.2.3.g) Documentation
Provide a brieI description oI the locations oI the diIIerent types oI pharmacovigilance source
documents, including archiving arrangements. ReIerence can be made to the organisation charts
provided under Chapter I.2, Section 2.3.b above.
2.2.3.h) Quality Management System
Provide a brieI description oI the quality management system, making cross-reIerence to the elements
provided under the above Sections. Particular emphasis should be placed on organisational roles and
PART I 26/229
responsibilities Ior the activities and documentation, quality control and review, and Ior ensuring
corrective and preventive action.
A brieI description oI the responsibilities Ior quality assurance auditing oI the pharmacovigilance
system, including auditing oI sub-contractors, should be provided.
2.2.3.i) Supporting Documentation
The Marketing Authorisation Holder should ensure that the pharmacovigilance system is in place and
documented.
An essential Ieature oI a pharmacovigilance system is that it is clearly documented to ensure that the
system Iunctions properly, that the roles and responsibilities and required tasks are clear to all parties
involved and that there is provision Ior proper control and, when needed, change oI the system.
Documentation supporting the pharmacovigilance system (and its detailed description) may be
required during the pre-authorisation period, or post-authorisation, Ior purposes such as assessment or
inspection.
2.3 Monitoring of Compliance by the Competent Authorities
EEA Competent Authorities have been working Ior many years to Iacilitate Marketing Authorisation
Holders in meeting pharmacovigilance regulatory obligations. This has included the development oI
guidelines, education programmes, responding to enquiries and the development oI electronic
reporting. Competent authorities should monitor Marketing Authorisation Holders Ior compliance
with pharmacovigilance regulatory obligations. Furthermore, Competent Authorities exchange
inIormation in cases oI non-compliance and will take appropriate regulatory action as required. It
should be noted that enIorcement action is within the competency oI individual Member States.
Article 84 oI Regulation (EC) 726/2004 sets out the roles oI the Member States, the Agency and the
Commission with respect to the imposition oI penalties Ior inIringement oI that Regulation or
regulations adopted pursuant to it.
Set out below is an outline oI how compliance monitoring should be perIormed. In this context
compliance monitoring relates to activities that are separate to inspection activities and are carried out
separately to them or as a prelude or Iollow-up to inspection. Where compliance monitoring raises
concerns these should be highlighted to other Competent Authorities and in the case oI centrally
authorised products to the Agency, the Rapporteur/Co-Rapporteur, the CHMP, and the
Pharmacovigilance Working Party as applicable. DeIiciencies identiIied during compliance
monitoring may lead to an inspection request.
Competent authorities will ensure that a system oI pharmacovigilance is in place within Marketing
Authorisation Holders through scrutiny oI the detailed description oI pharmacovigilance, procedures,
saIety reports and through pharmacovigilance inspections.
2.3.1 Qualified Person Responsible for Pharmacovigilance
Competent authorities will maintain a list oI QPPVs within the EEA. This list will include business
address and contact details (including out oI hours contact). Where applicable this will include
national contact points in the Member State concerned.
2.3.2 Availability of Pharmacovigilance Data
Competent authorities should monitor (e.g. by assessment oI the detailed description oI the
pharmacovigilance system and when inspections are carried out) that pharmacovigilance data are
PART I 27/229
collated and accessible by the Marketing Authorisation Holder at least at one point within the
Community.
2.3.3 Change in the Evaluation of the Risk-Benefit Balance of a Product
One oI the key responsibilities oI Marketing Authorisation Holders is to immediately notiIy the
Competent Authorities oI any change in the balance oI risks and beneIits oI their products. Any Iailure
to do so may pose a signiIicant threat to public health. Any evidence oI Iailure to notiIy such changes
will result in consideration oI enIorcement action by the Competent Authorities.
2.3.4 Expedited Adverse Reaction Reporting
Requirements Ior expedited reporting oI ICSRs are given in Chapter I.4. Non-compliance with
expedited reporting may include complete Iailure to report, delayed reporting (i.e. submission beyond
15 days) and submission oI reports oI poor quality (particularly where evidence suggests that this
results Irom inadequate company Iollow-up oI individual cases). Failure to comply with electronic
reporting requirements will be monitored.
Methods available to Competent Authorities Ior prospective monitoring oI compliance with expedited
reporting oI adverse reactions could be:
Monitoring adverse reaction reports received Irom Marketing Authorisation Holders against
other sources to determine complete Iailure to report.
Monitoring the time between receipt by Marketing Authorisation Holder and submission to
Competent Authorities to detect late reporting.
Monitoring the quality oI reports. Submission oI reports judged to be oI poor quality may
result in the Iollow-up procedures oI Marketing Authorisation Holders being scrutinised.
Monitoring that all adverse reactions that are kept electronically comply with the Note Ior
Guidance on the Electronic Data Interchange (EDI) oI ICSRs and Medicinal Product Reports
(MPRs) in Pharmacovigilance in the Pre- and Post-Authorisation Phase in the EEA
8
.
Checking oI Periodic SaIety Update Reports (PSURs) to detect under-reporting (e.g. oI
expedited reports).
Checking interim and Iinal reports oI post-authorisation saIety studies to ensure that all
qualiIying serious reports have been submitted within 15 days.
At inspection there may be a review oI a sample oI reports on the Marketing Authorisation
Holder database to assess the quality oI data, determine whether the relevant reports have been
expedited and are included on the EudraVigilance database, and to conIirm that procedures are
in place to Iollow up reports.
2.3.5 Periodic Safety Update Reports
PSURs are important pharmacovigilance documents. They provide an opportunity Ior Marketing
Authorisation Holders to review the saIety proIile oI their products and ensure that the Summary oI
Product Characteristics (SPC) and Package LeaIlet are up to date. They also provide the Competent
Authorities with a valuable source oI pharmacovigilance data. For these reasons the Competent
Authorities place great importance on compliance with periodic reporting. Non-compliance may
include:

8
Doc.ReI. EMEA/115735/2004 latest version, available on EudraVigilance website
http://eudravigilance.emea.europa.eu.
PART I 28/229
Non-submission: Complete non-submission oI PSURs, submission outside the correct cycle or
outside the correct time Irames (without previous submission oI a type II variation), non-
restart oI the cycle oI submission when necessary.
Incorrect Iormat oI the document: Report not in accordance with Chapter I.6.
Omission oI inIormation required by Chapter I.6 particularly in the Iollowing sections oI the
report: Update oI Regulatory Authority or Marketing Authorisation Holder Actions taken Ior
SaIety Reasons, Changes to ReIerence SaIety InIormation, Patient Exposure, Presentation oI
Individual Case Histories.
Poor quality reports: Poor documentation oI adverse reactions or insuIIicient inIormation
provided to perIorm a thorough assessment in the Presentation oI Individual Case Histories
section, new saIety signals not or poorly assessed in the Overall SaIety InIormation section,
misuse not highlighted, absence oI use oI standardised medical terminology (e.g. MedDRA).
Company core data sheet (CCDS) or SPC: Where changes have been made to the CCDS or
SPC since the submission oI the last PSUR, the covering letter does not highlight the
diIIerences between the CCDS and the EU SPC.
Previous requests Irom Competent Authorities not addressed: Submission oI a report where
previous requests Irom Competent Authorities have not been addressed (e.g. close monitoring
oI speciIic saIety issues).
2.3.6 Information Requested by Competent Authorities
No Iixed time Irames are laid down in EU legislation or guidelines Ior responding to a request Ior
inIormation Irom Competent Authorities. This reIlects the Iact that the appropriate time Irame will
depend mainly on the urgency oI the pharmacovigilance issue and its potential impact on public
health. The Competent Authorities will ensure that all requests Ior inIormation Irom Marketing
Authorisation Holders have a clearly stipulated deadline and this deadline should be appropriate to the
complexity and urgency oI the issue. Competent Authorities will liaise with Marketing Authorisation
Holders regarding the appropriate deadline, as required. Failure oI Marketing Authorisation Holders to
provide the necessary inIormation/data within the deadline may be considered as non-compliance.
2.3.7 Submission of Safety Variations
EU legislation and guidelines do not speciIy deadlines Ior submission oI saIety variation applications.
As with responding to requests Ior inIormation Irom Competent Authorities, deadlines Ior submission
oI saIety variations will depend on the urgency and potential public health impact oI the
pharmacovigilance issue. The Competent Authorities will ensure that requests Ior saIety variations
have a clearly stipulated deadline and this deadline should be appropriate to the complexity and
urgency oI the issue. The Competent Authorities will liaise with Marketing Authorisation Holders
regarding the appropriate deadline, as required. Failure oI Marketing Authorisation Holders to submit
the variation application within the deadline may be considered as non-compliance.
2.3.8 CHMP Commitments in Respect of Centrally Authorised Products
EU legislation and guidelines do not speciIy deadlines Ior the submission oI Iollow-up measures
Iollowing the granting oI a centralised marketing authorisation. The timeIrame Ior submission oI
Iollow-up measures should be clearly stated in a letter oI undertaking signed by the Applicant at the
time oI the CHMP Opinion.
Regulation (EC) No 726/2004 Ioresees a number oI particular possibilities Ior marketing
authorisations and post-marketing activities. Compliance with the provisions oI these measures will be
monitored. These include:
Conditional marketing authorisations;
PART I 29/229
Marketing authorisations under exceptional circumstances;
and the speciIic obligations or Iollow-up measures as applicable to these. Normal marketing
authorisations may also include Iollow-up measures.
Non-compliance may include:
Complete non-submission oI data, including non-submission oI speciIic obligations beIore the
annual re-assessment;
Submission oI data aIter the deadline agreed in the letter oI undertaking Irom the company
(without previous agreement Irom the Competent Authority);
Failure to implement a speciIic obligation;
Failure to implement a Iollow-up measure;
Poor quality oI a report requested as a Iollow-up measure;
Poor quality oI a report requested as a speciIic obligation;
Failure to implement an urgent provisional measure.
2.3.9 Post-Authorisation Safety Studies
Because oI the objectives oI saIety studies there is considerable potential Ior saIety signals to arise or
changes in the balance oI risks and beneIits oI products to be identiIied. ThereIore, expedited reporting
and submission to Competent Authorities oI interim and Iinal study reports Irom such studies has an
important role in protecting public health. Where appropriate, Competent Authorities will scrutinise
protocols prior to initiation oI saIety studies. Competent authorities should check that relevant adverse
reaction reports Irom saIety studies are expedited and monitor the submission oI interim and Iinal
study reports. Guidance on post-authorisation saIety studies is available in Chapter I.7.
2.3.10 Provision of Additional Data on Studies
As part oI their pharmacovigilance system, companies are required to have processes in place to
screen all studies Ior inIormation on saIety or lack oI eIIicacy and to report on this when required (see
also Chapters I.1 and I.8). The Competent Authorities will monitor this by comparison oI inIormation
received Irom diIIerent sources and in the course oI inspections.
2.4 Pharmacovigilance Inspections
To ensure that Marketing Authorisation Holders comply with pharmacovigilance regulatory
obligations and to Iacilitate compliance, Competent Authorities will conduct pharmacovigilance
inspections. There should be collaboration between Competent Authorities to minimise duplication
and maximise coverage. Inspections will be routine as well as targeted to Marketing Authorisation
Holders suspected oI being non-compliant. The results oI an inspection will be routinely provided to
the inspected Marketing Authorisation Holder who will be given the opportunity to comment on the
Iindings. The results will be used to help Marketing Authorisation Holders improve compliance and
may also be used as a basis Ior enIorcement action. The scheduling and conduct oI these inspections
will be driven by routine programs and by risk analysis criteria. The inspection process described
Iocuses on centrally authorised products, however the principles may be generally applicable.
2.4.1 Conduct of Inspections
The Competent Authority Ior inspection oI the Marketing Authorisation Holder`s pharmacovigilance
system will be the Competent Authority oI the Member State in whose territory the Marketing
Authorisation Holder`s QPPV is located. Where an additional Iacility (e.g. a database) in another
PART I 30/229
Member State requires inspection, the inspection will be carried out by the Competent Authority oI the
Member State in whose territory the Iacility is located.
In general, companies have a pharmacovigilance centre in the Community covering multiple products
that are on the market, in the Community. These centres may also be the global pharmacovigilance
centres, or the latter may be located in third countries. Where the global centres, databases etc. are
located in third countries, the same Competent Authority as above will be responsible Ior purposes oI
inspection on behalI oI the community, iI such an inspection is considered necessary. Where relevant
or on request, and in particular Ior product-speciIic issues, they may be assisted, or the inspection may
be conducted, by an inspector and/or expert Irom the Rapporteur/Co-Rapporteur Member State (Ior
centrally authorised products) or the ReIerence Member State (Ior mutual recognition
procedures/decentralised procedures).
2.4.2 Routine Inspections
Routine inspections are carried out by the Competent Authority(ies) reIerred to in Chapter I.2,
Section 4.1. In general, it is anticipated that national inspection programmes will IulIil the need Ior
routine inspections. They may be carried out on a repeated basis. The Iocus oI these inspections is to
determine that the Marketing Authorisation Holder has personnel, systems and Iacilities in place to
meet their regulatory obligations Ior centrally authorised products. These inspections may be
requested with one or more speciIic products selected as examples Ior which speciIic inIormation can
be traced and veriIied through the various processes, in order to provide practical evidence oI the
Iunctioning oI the pharmacovigilance system oI the Marketing Authorisation Holder and their
compliance with their regulatory obligations.
In cases where a Competent Authority has carried out, or intends, within the required timeIrame, to
carry out, an inspection covering the scope oI that requested, this inspection will suIIice and its results
will be made available to the CHMP or applicable reviewing agency.
Such inspections may be speciIically requested by the CHMP.
Where the pharmacovigilance system oI a Marketing Authorisation Holder has not been inspected
previously, the CHMP will request the relevant Competent Authority to carry out and report on an
inspection oI the system within 4 years oI the placing on the market oI the Iirst centrally authorised
product by that Marketing Authorisation Holder. Where the system has previously been inspected, re-
inspection will take place at intervals. The timing oI the Iirst inspection and any Iurther inspection will
be determined on the basis oI risk analysis criteria.
The CHMP, in conjunction with the Competent Authority reIerred to in Chapter I.2, Section 4.1 and
the applicable Pharmacovigilance and Inspectors` Working Parties, will determine a programme Ior
inspection in relation to centrally authorised products. These inspections will be prioritised based on
the potential risk to public health, the nature oI the products, extent oI use, number oI products that the
Marketing Authorisation Holder has on the EEA market, etc and risk Iactors such as those identiIied
under Chapter I.2, Section 4.3. This programme will be separate Irom any targeted inspection, but iI a
targeted inspection takes place it may replace the need Ior one under this programme dependent on its
scope. The Competent Authorities oI the Member States are responsible Ior determining their national
inspection programmes.
2.4.3 Targeted Inspections
Targeted inspections may be conducted as and when the trigger is recognised and the CHMP and/or
the Competent Authority determines that inspection is the appropriate course oI action.
Targeted inspections may arise when one or more oI the Iollowing arise:
PART I 31/229
Triggers Ior the inspection are identiIied which do not relate to speciIic concerns about a
product`s saIety or actual non-compliance, e.g.:
The Marketing Authorisation Holder has not previously been inspected;
The Marketing Authorisation Holder has placed their Iirst product on the market in the
EEA;
The Marketing Authorisation Holder has recently been or is involved in a merger or
takeover process;
The Marketing Authorisation Holder has changed their system signiIicantly (e.g. new
database system, contracting out oI reporting activities).
Triggers Ior the inspection are identiIied which relate to speciIic concerns about a product`s
saIety or actual non-compliance, e.g. signiIicant issues relating to:
Delays in carrying out or Iailure to carry out speciIic obligations or Iollow-up measures
relating to the monitoring oI product saIety, identiIied at the time oI the marketing
authorisation;
periodic reporting; Delays in expedited or
Incomplete reporting;
Submission oI poor quality or incomplete PSURs;
and other inIormation sources; Inconsistencies between reports
Change in risk-beneIit balance;
Failure to communicate change in risk-beneIit balance;

r simultaneous notiIication to the Competent Authorities or the
Product withdrawal with little or no advance notice to the EEA Competent Authorities.
covigilance inspection. The
presence oI a trigger will not always lead to the conduct oI an inspection.
2.4.4 Pharmacovigilance System Inspections
igations. They may use products as examples to test the
system. They may be routine or targeted.
2.4.5 Product-Specific Inspections
and are usually targeted as a result oI triggers
Previous inspection experience;
InIormation received Irom other authorities;
Poor Iollow-up to requests Ior inIormation Irom the Competent Authorities;
Communication oI inIormation on pharmacovigilance concerns to the general public
without giving prior o
Agency as applicable;
The above are examples and other issues may trigger a targeted pharma
These inspections are designed to review the systems, personnel, Iacilities in place and their
compliance with pharmacovigilance obl
These inspections Iocus speciIically on a given product
that have been identiIied (see Chapter I.2, Section 4.3).
2.4.6 Requesting and Reporting of Inspections
Inspection requests are prepared by the Agency`s inspection sector in conjunction with the
Rapporteur/Co-Rapporteur and the relevant Competent Authority. They are presented to the CHMP
Ior adoption and once adopted are carried out by the Competent Authority reIerred to in Chapter I.2,
Section 4.1on behalI oI the Agency.
PART I 32/229
2.4.7 Inspections of Contractors and Licensing Partners
igilance activities in whole or in part on behalI oI, or in conjunction
with, the Marketing Authorisation Holder may be inspected in order to conIirm their capability to
t the M pliance with pharmacovigilance obligations.
Countries
utine inspections when considered
appropriate, particularly where the main pharmacovigilance centre and databases etc. are located
ity requesting the inspection.
An inspection Iee(s) (and inspectors` expenses where applicable) will be charged in accordance with
Any party carrying out pharmacov
suppor arketing Authorisation Holder`s com
2.4.8 Inspections in European Economic Area
These may be routine or targeted.
2.4.9 Inspections in Third
These may be routine or targeted. They will be included in ro
outside the community, Ior the Marketing Authorisation Holder and centrally authorised product(s) in
question. They will be included in targeted inspections whenever this is considered appropriate by the
author
2.4.10 Fees for Inspections Requested by the CHMP
the Council Regulation (EC) No 297/95 on Iees, as amended and implementing rules applicable at the
time.
2.4.11 Procedures for Coordination of Pharmacovigilance Inspection for Centrally
The Agency will establish procedures Ior the administration and review oI inspection requests and
gilance and Inspectors` Working
Parties.
2.4
Pro u
ins to
Pharma
wil
The Procedure Ior Coordinating Pharmacovigilance Inspections Requested by the CHMP
The Procedure Ior Conducting Pharmacovigilance Inspections Requested by the CHMP
CHMP
(INS/PhV/3, latest version)
11
.

Authorised Products
reports in conjunction with the CHMP and relevant Pharmacovi
These procedures will be adopted and published in line with the policies and procedures oI the Agency
on such documents.
.12 Procedures for Pharmacovigilance Inspections
ced res Ior pharmacovigilance inspection are prepared by representatives oI the pharmacovigilance
pec rs oI the national Competent Authorities in association with representatives oI the
covigilance Working Party and the Agency. The Iollowing procedures have been adopted and
l be updated as needed:
9
;
10
;
The Procedure Ior Reportting Pharmacovigilance Inspections Requested by the

9
Available on EMEA website http://www.emea.europa.eu.
10
11
PART I 33/229
2.4.13 Unannounced Inspections
It is anticipated that the majority oI inspections will be announced. However, on occasions, it may be
appropriate to conduct unannounced inspections or to announce an inspection at short notice.
2.4.14 Inspection Reports
Each inspection will result in an inspection report, prepared in accordance with an agreed Iormat. The
. The inspection report will be made available to inspection report will be made available to the CHMP
the Marketing Authorisation Holder. See Chapter I.2, Section 4.12 Ior the procedures.
Where an inspection reveals non-compliances the Marketing Authorisation Holder will be required to
the non-compliances and avoid their recurrence. The
Marketing Authorisation Holder may be required to provide reports and where necessary evidence oI
oups.
Un
pha
com pharmacovigilance regulatory obligations is detected, the necessary action will be
y-case basis. What action is taken will depend on the potential negative public
hea
act Competent Authorities oI the
ntext. ReIerence should also be made to legislation at EU and
nat
In ry options include the Iollowing:
to determine the extent oI non-
pliance is achieved.

lic a list oI Marketing Authorisation
Holders Iound to be seriously or persistently non-compliant.
Urgent SaIety Restriction
In accordance with the guidance and rules set out elsewhere.
Variation oI the Marketing Authorisation
2.4.15 Follow-up of Inspection Findings
prepare a remedial action plan to correct
the progress and completion oI the action plan. There may be re-inspection at an appropriate time to
veriIy the progress and success oI these remedial actions.
2.4.16 Sharing of inspection information
The national Competent Authorities and the European Commission, in co-operation with the Agency,
will establish procedures Ior the sharing oI inIormation on inspections and their outcomes, in
particular through the Pharmacovigilance Working Parties and the Inspection Services Gr
2.5 Regulatory Action
der EU legislation, to protect public health, Competent Authorities are obliged to implement
rmaceutical legislation and to ensure compliance with pharmacovigilance obligations. When non-
pliance with
judged on a case-b
lth impact oI non-compliance but any instance oI non-compliance may be reIerred Ior enIorcement
ion. Action may be taken by the Agency, the Commission or the
Member States as appropriate in the co
ional level on penalties and sanctions and implementing procedures relating to these.
addition, in the event oI non-compliance, regulato
Education and Facilitation
Marketing Authorisation Holders may be inIormed oI non-compliance and advised on how this can
be remedied.
Inspection
Non-compliant Marketing Authorisation Holders may be inspected
compliance and then re-inspected to ensure com
Warning
Co petent Authorities may issue a Iormal warni m ng reminding Marketing Authorisation Holders oI
their pharmacovigilance regulatory obligations.
Naming non-compliant Marketing Authorisation Holders
Competent Authorities will consider a policy oI making pub
PART I 34/229
PART I 35/229
In accord
Suspension oI the Marketing Authorisation
d rules set out elsewhere.
ance with the guidance and rules set out elsewhere.
In accordance with the guidance an
Revocation oI the Marketing Authorisation
In accordance with the guidance and rules set out elsewhere.

3. Requirements for Risk Management Systems
3.1 Introduction
It is recognised that at the time oI authorisation, inIormation on the saIety oI a medicinal product is
relatively limited. This is due to many Iactors including the small numbers oI subjects in clinical trials,
restricted population in terms oI age, gender and ethnicity, restricted co-morbidity, restricted

pre- or post-authorisation data and Irom pharmacological principles.
re, the concept oI risk management should also
management system that they will introduce
de Competent Authorities
co-medication, restricted conditions oI use, relatively short duration oI exposure and Iollow up, and
the statistical problems associated with looking at multiple outcomes.
A medicinal product is authorised on the basis that in the speciIied indication(s), at the time oI
authorisation, the risk-beneIit is judged positive Ior the target population. However, not all actual or
potential risks will have been identiIied when an initial authorisation is sought. In addition, there may
be subsets oI patients Ior whom the risk is greater than that Ior the target population as a whole.
Planning oI pharmacovigilance activities will be improved iI it were more closely based on product-
speciIic issues identiIied Irom
Such planning will also guide the use oI electronic data, which are routinely collected within health
services to provide rapid investigation oI predicted or emerging saIety concerns.
The management oI a single risk can be considered as having Iour steps, risk detection, risk
assessment, risk minimisation and risk communication. However, a typical individual medicinal
product will have multiple risks attached to it and individual risks will vary in terms oI severity, and
individual patient and public health impact. ThereIo
consider the combination oI inIormation on multiple risks with the aim oI ensuring that the beneIits
exceed the risks by the greatest possible margin both Ior the individual patient and at the population
level.
This Chapter
12
aims to provide guidance on how Marketing Authorisation Holders and Applicants
should meet the requirements Ior a description oI a risk
Ior an individual medicinal product, or a series oI medicinal products, in line with new Community
legislation. This guidance also describes how such a risk management system can be presented to
Competent Authorities in the Iorm oI a Risk Management Plan.
EU legislation requires Applicants/Marketing Authorisation Holders to provi
with a description oI pharmacovigilance and risk management systems.
The requirements and Iormat Ior the description oI a pharmacovigilance system are covered in Chapter
I.2 and should be submitted accordingly.
Consideration should also be given to other relevant EU pharmacovigilance guidelines (see Annex 3).
The present Guideline provides guidance to Applicants and Marketing Authorisation Holders in the
European Union on how to meet the requirements Ior a detailed description oI the risk management
system` (see Chapter I.3, Section 2) and the circumstances when it is appropriate (see Chapter I.3,
Sections 4 and 14) to provide it. The risks addressed in this guidance are those related to non-clinical
and clinical saIety. Where the disposal oI the product might pose a particular risk because oI
ce on Harmonisation ICH-E2E Guideline.
remaining active substance (e.g. patches) this should also be addressed. The Guideline is applicable to
products in both the pre-authorisation and post-authorisation phase and whether the product was
authorised through the centralised, decentralised or mutual recognition procedures. It incorporates the
concepts oI the International ConIeren

12
This guidance was Iirst published in 2005 as Guideline on Risk Management Systems Ior Medicinal Products
Ior Human Use (EMEA/CHMP/96268/2005) on the EMEA website.
PART I 36/229
Article 6 oI Regulation (EC) No 726/2004 and Article 8 oI Directive 2001/83/EC lay down the
particulars and documents to be included in an application Ior the authorisation oI a medicinal product
Ior human use. More speciIically and Ior the purpose oI this guidance it requires in accordance with
Article 8(3)(ia) oI Directive 2001/83/EC the inclusion oI a detailed description of the
pharmacovigilance and, where appropriate, of the risk management system which the applicant will
introduce. This provision Iorms the legal basis Ior this guideline. Also relevant to the legal context
Ior EU Risk Management Plans are the Iollowing legal provisions:
In the context oI centrally authorised products Article 9(4) oI Regulation (EC) No 726/2004 requires
Ior a Iavourable opinion that the Iollowing shall be attached to the Opinion:
c) details of any recommended conditions or restrictions with regard to the safe and effective use of
b) details of any conditions or restrictions which should be imposed on the supply or use of the
medicinal product concerned, including conditions under which the medicinal product may be made
available to the patients, in accordance with the criteria in Title VI of Directive 2001/83/EC;
the medicinal product.
In addition to Article 9(4)(c) above, Article 127a oI Directive 2001/83/EC states that When a
medicinal product is to be authorised in accordance with Regulation (EC) 726/2004 and the Scientific
Committee in its opinion refers to recommended conditions or restrictions with regard to the safe and
effective use of the medicinal product [], a decision addressed to the Member States shall be
adopted in accordance with the procedure provided for in Article 33 and 34 of the Directive, for the
implementation of those conditions or restrictions.
The legislation provides Ior additional inIormation to be requested Irom Marketing Authorisation
Holders.
Article 23 oI Regulation (EC) No 726/2004 states [] That qualified person shall reside in the
Community and shall be responsible for the following:
c) ensuring that any request from the competent au
information necessary for the evaluation of the risks and benefits
thorities for the provision of additional
of a medicinal product is answered
l product concerned [];
viding the competent authorities with any other information relevant to the evaluation of the
risks and benefits of a ularly information concerning post-authorisation
saf s
fully and promptly, including the provision of information regarding the volume of sales or
prescriptions for the medicina
d) pro
medicinal product partic
ety tudies.
Similarly
qualified
, Ior nationally authorised products, Article 103 oI Directive 2001/83/EC states '[] That
person shall reside in the Community and shall be responsible for the following:
c) ensuring that any request from the competent authorities for the provision of additional
medicinal product is
ng the provision of information about the volume of sales or

information necessary for the evaluation of the benefits and risks afforded by a
answered fully and promptly, includi
prescriptions of the medicinal product concerned;
d) the provision to the competent authorities, of any other information relevant to the evaluation of
the benefits and risks afforded by a medicinal product, including appropriate information on post-
authorization safety studies.
Article 26 oI Regulation (EC) No 726/2004 states that [] for a period of five years following the
initial placing on the market in the Community, the Agency may request that the Marketing
PART I 37/229
Authorisation Holder arrange for specific pharmacovigilance data to be collected from targeted
groups of patients. [].
Article 34 oI Regulation (EC) No 1901/2006 on medicinal products Ior paediatric use states that []
Where there is a particular cause for concern, the competent authority shall require, as a condition of
granting marketing authorisation, that a risk management system be set up or that specific post-
marketing studies be performed and submitted for review. The risk management system shall comprise
a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or
minimise risks relating to medicinal products including the assessment of the effectiveness of those
interventions.
The detailed description oI a risk management system should be provided in the Iorm oI an EU Risk
Management Plan (EU-RMP) in the situations described in Chapter I.3, Section 4. It is strongly
uthorities on the need Ior, and content oI, an EU-
RMP should take place in advance oI submission.
ties and interventions designed to
to medicinal products, including the
recommended that discussions with the Competent A
3.2 Description of the Risk Management System
A risk na activi ma gement system is a set oI pharmacovigilance
relating identiIy, characterise, prevent or minimise risks
assessment oI the eIIectiveness oI those interventions. The legislation requires that a description oI the
risk management system should be submitted when appropriate. This requirement can be met by the
submission oI an EU-RMP in the circumstances detailed in Chapter I.3, Sections 4 and 14.
The aim oI a risk management system is to ensure that the beneIits oI a particular medicine (or a series
oI medicines) exceed the risks by the greatest achievable margin Ior the individual patient and Ior the
target population as a whole. This can be done either by increasing the beneIits or by reducing the
ut, by its deIinition, risk management Iocuses upon the risk reduction approach. N risk evertheless,
wh v
mo
n the Iorm oI an EU-RMP. The
EU
Part I:
An evaluation oI the need Ior risk minimisation activities;
and iI there is a need Ior additional (i.e. non-routine) risk minimisation activities
ncepts oI ICH-E2E regarding the SaIety SpeciIication, which
s b
ene er possible, increases in beneIits should also be considered and the characteristics oI patients
st likely to beneIit Irom treatment should be better deIined.
3.3 EU Risk Management Plan (EU-RMP)
The description oI a risk management system should be submitted i
-RMP contains two parts:
A SaIety SpeciIication,
A Pharmacovigilance Plan; and
Part II:
A risk minimisation plan.
Part I oI the EU-RMP incorporates the co
summarises the saIety proIile oI the medicinal product at the particular point in time oI its liIe-cycle,
and the Pharmacovigilance Plan which is based on the SaIety SpeciIication. Chapter I.3, Sections 6
and 7 oI this guidance include relevant text Irom ICH-E2E with additional commentary on
implementation within the EU. Chapter I.3, Section 6.2.g also details the particular EU requirements
Ior the SaIety SpeciIication.
PART I 38/229
In Part II oI the EU-RMP, on the basis oI the SaIety SpeciIication, the Applicant/Marketing
Authorisation Holder should consider careIully the need Ior risk minimisation activities to be
introduced. Risk minimisation activities may be 'routine or 'additional (see Chapter I.3, Section 8).
Within the 'evaluation oI the need Ior risk minimisation activities, the Applicant/Marketing
Authorisation Holder should discuss Iully the use oI routine risk minimisation activities and whether
there is a need Ior additional risk minimisation activities. II only routine risk minimisation activities
uired sation
activities are sary, the Applicant/Marketing Authorisation Holder should provide a risk
minimisation plan within Part II oI the EU-RMP. This risk minimisation plan should contain both the
are req there is no need to submit a risk minimisation plan. II additional risk minimi
thought neces
routine and additional activities Ior each saIety concern. Every time the EU-RMP is updated (see
Chapter I.3, Section 14) the Applicant/Marketing Authorisation Holder should reconsider its position
vis-a-vis the need Ior risk minimisation activities and Part II should be updated accordingly.
RMP
rketing authorisation (PUMA);
with an application involving a signiIicant change in a marketing authorisation (e.g. new
tion, new manuIacturing process oI a biotechnologically-
luding a new paediatric indication) unless
isation via the centralised procedure may require an EU-RMP:
Authorisations via the Centralised Procedure
At any stage, but in particular during the pre-authorisation phase, an Applicant/Marketing
Authorisation Holder may request advice on the need Ior, development or content oI an EU-RMP
through the scientiIic advice procedure.
Whether or not the scientiIic advice procedure has been used, discussion on the EU-RMP Ior a
medicinal product seeking a new authorisation through the centralised procedure should take place at
the pre-submission meeting.
3.4 Situations Requiring an EU-
An EU-RMP may need to be submitted at any time oI a product`s liIe-cycle i.e. during both the
pre-authorisation and post-authorisation phases. In particular an EU-RMP should be submitted:
with the application Ior a new marketing authorisation Ior:
any product containing a new active substance;
a similar biological medicinal product;
a generic/hybrid medicinal product where a saIety concern requiring additional risk
minimisation activities has been identiIied with the reIerence medicinal product.
with an application Ior a paediatric use ma
dosage Iorm, new route oI administra
derived product, signiIicant change in indication, inc
it has been agreed with the Competent Authority that submission is not required;
on request Irom a Competent Authority (both pre-and post-authorisation);
on the initiative oI an Applicant/Marketing Authorisation Holder when they identiIy a saIety
concern with a medicinal product at any stage oI its liIe cycle.
In some circumstances, products which are not in the above categories which are seeking a new
author
Known active substances
Hybrid medicinal products where the changes compared with the reIerence medicinal product
suggest diIIerent risks
Bibliographical applications
Fixed combination applications.
For situations where the submission oI an EU-RMP is not mandatory, the need Ior it should be
discussed with the Competent Authority well in advance oI the submission.
3.4.1 Marketing
PART I 39/229
For signiIicant changes to an existing centralised marketing autho
Holder ld discuss the need Ior an EU-RMP with the Agency
risation, the Marketing Authorisation
shou at least two months in advance oI the
ication which will Iorm part oI the Iormal
ass
Agency
3.4 uthorisations via the Mutual Recognition or Decentralised
y oI this country should be consulted.
eting Authorisation should be provided
in Module 1.8.2 oI the Marketing Authorisation Application in a stand-alone Iormat allowing
submission. When it is not mandatory that an EU-RMP is submitted and the Applicant/Marketing
Authorisation Holder thinks it is unnecessary, the Applicant/Marketing Authorisation Holder should
submit a brieI justiIication oI this along with the appl
essment by the Rapporteur. However, it is strongly recommended that this is discussed with the
beIore submission oI the application.
.2 Marketing A
Procedures
The Competent Authority oI the Member State should be contacted regarding the timings oI
discussions on Risk Management Plans. Where there is a ReIerence Member State (RMS), the
Competent Authorit
3.5 Location in the Application
An EU-RMP submitted at the time oI an application Ior a Mark
circulation to, and evaluation by pharmacovigilance and risk management experts. It should be
accompanied by other relevant documents such as study protocols, where applicable.
Updates to the EU-RMP (see Chapter I.3, Section 14) should be presented preIerably in a tab-
separated dossier and in accordance with the appropriate headings and numberings oI the EU-CTD
Iormat. This should be accompanied by a cover letter, detailing which sections oI the EU-RMP have
ation period. The SaIety SpeciIication is intended to help industry and regulators identiIy
any need Ior speciIic data collection and also to Iacilitate the construction oI the Pharmacovigilance
include additional elements,
depending on the nature oI the product and its development programme. Conversely, Ior products
been changed, and study reports (iI appropriate).
3.6 Safety Specification
The SaIety SpeciIication should be a summary oI the important identiIied risks oI a medicinal product,
important potential risks, and important missing inIormation. It should also address the populations
potentially at risk (where the product is likely to be used), and outstanding saIety questions which
warrant Iurther investigation to reIine understanding oI the risk-beneIit proIile during the
post-authoris
Plan.
In the EU-RMP the SaIety SpeciIication will also Iorm the basis oI the evaluation oI the need Ior risk
minimisation activities and, where appropriate, the risk minimisation plan.
It is recommended that Applicants/Marketing Authorisation Holders Iollow the structure oI elements
provided below when compiling the SaIety SpeciIication. The elements oI the SaIety SpeciIication
that are included are only a guide. The SaIety SpeciIication can
already on the market with emerging new saIety concerns, only a subset oI the elements might be
relevant.
PART I 40/229
3.6.1 Non-clinical Part of the Safety Specification
Within the SaIety SpeciIication, this section should present non-clinical saIety Iindings that have not
Th e
use s
exist.
3.6 ety Specification
3.6.2.a)
Lim udy population, study
inc o the implications oI such limitations with
respect to predicting the saIety oI the product in the marketplace should be explicitly discussed.
made to populations likely to be exposed during the intended or
expected use oI the product in medical practice.
atient-years, patient-months) exposed to
the drug. This should be stratiIied, Ior relevant population categories such as age and gender, type oI
I adverse drug reactions detectable given the size oI the
ong-term
t duration
.
Post-marketing (non-study) exposure:
ng oI the medicine has occurred, the applicant / Marketing Authorisation Holder should
provide data on patients exposed post-marketing. Exposure data based on the number oI kilogrammes
ge dose is only valid iI the medicinal product is always
ined by pack size
(e.g. a course oI antibiotics), a simple count oI packs sold may be more appropriate. The inIormation
should be stratiIied by relevant variables such as age, indication, dose and duration oI treatment.
3.6.2.b) Populations Not Studied in the Pre-Authorisation Phase
The SaIety SpeciIication should discuss which populations have not been studied or have only been
se. In particular, iI paediatric development has
been adequately addressed by clinical data, Ior example:
Toxicity (including repeat-dose toxicity, reproductive/developmental toxicity, nephrotoxicity,
hepatotoxicity, genotoxicity, carcinogenicity);
General pharmacology (cardiovascular, including QT interval prolongation, nervous system);
Drug interactions;
Other toxicity-related inIormation or data.
e rel vance oI the Iindings to the use in humans should be discussed. II the product is intended Ior
in pecial populations, consideration should be given to whether speciIic non-clinical data needs
.2 Clinical Part of the Saf
Limitations of the Human Safety Database
itations oI the saIety database (e.g. related to the size oI the st
lusi n/exclusion criteria) should be considered, and
Particular reIerence should be
In order to assess the limitation oI the human saIety database, the size oI the study population should
be detailed using both numbers oI patients and patient time (p
study (e.g. randomised controlled trial, open clinical trial, observational study) and any other relevant
variable, such as dose, indication and duration oI treatment. Limitations oI the database should also be
presented in terms oI the Irequencies o
database. The limitations oI the database should also be discussed with regard to suspected l
adverse reactions (e.g. malignancies) when it is unlikely that exposure data is oI suIIicien
and latency
Where marketi
oI medicinal product sold divided by the avera
taken at one dose level Ior a Iixed length oI time which is not the situation with most medicinal
products. In paediatric populations or mixed populations oI diIIerent indications or age groups, use oI
this measure alone is inappropriate and other measures should be used.
A more accurate breakdown oI drug exposure based on market research should be provided where
possible. When deciding which measure to use Ior exposure data, it is important to consider the way a
medicine is used. For example, Ior medicines used chronically, the appropriate measure may be
patient years oI use. However, when use is typically limited and utilisation is determ
studied to a limited degree in the pre-authorisation pha
PART I 41/229
been limited to certain age categories, then the implications Ior other paediatric age groups should also
be discussed. The implications, with respect to predicting the saIety oI the product in the marketplace,
he relevance oI inclusion and
exclusion criteria in relation to the target population, in particular when exclusion criteria are not
tions Ior the drug. In discussing diIIerences between target populations and
d relevant genetic polymorphism;
e-approval phase should be discussed along with the implications Ior

the Summary oI Product Characteristics.
Identified risks that require further evaluation
n as part oI the Pharmacovigilance
Plan (e.g. Irequency in normal conditions oI use, severity, outcome, at-risk groups).
Potential risk rther evaluation

oI all these populations with limited or no research should be explicitly discussed.
Limitations oI the database should also be presented in terms oI t
proposed as contraindica
those exposed in clinical trials it should be noted that some diIIerences may arise through trial setting
(e.g. hospital or general practice) rather than through explicit inclusion/exclusion criteria.
Populations to be considered Ior discussion should include (but might not be limited to):
Children (Irom birth to 18 years with consideration given to the diIIerent age categories as per
ICH-E11
13
, or, iI justiIied, to other developmentally meaningIul groups);
The elderly;
Pregnant or lactating women;
Patients with relevant co-morbidity such as hepatic or renal disorders;
Patients with disease severity diIIerent Irom that studied in clinical trials;
Sub-populations carrying known an
Patients oI diIIerent racial and/or ethnic origins.
Post Marketing Experience:
For updates to the SaIety SpeciIication, speciIic reIerence should be made to how the realised pattern
oI exposure (including oII-label use) has diIIered Irom that predicted and Irom the indication(s) and
contraindications in the Summary oI Product Characteristics.
Newly identiIied saIety concerns should be mentioned, in particular any issue Iound in relation to a
population not studied in the pr
II regulatory action has been taken in relation to a saIety concern, this should be mentioned.
3.6.2.c) Adverse Events/Adverse Reactions
This section should list the important identiIied and potential risks that require Iurther characterisation
or evaluation.
More detailed inIormation should be included on the most important identiIied adverse events/adverse
reactions, which would include those that are serious or Irequent and that also might have an impact
on the balance oI beneIits and risks oI the medicinal product. This inIormation should include
evidence bearing on a causal relationship, severity, seriousness, Irequency, reversibility and at-risk
groups, iI available. Risk Iactors and potential mechanisms should be discussed. These adverse
events/adverse reactions should usually call Ior Iurther evaluatio
s that require fu
Important potential risks should be described in this section. The evidence that led to the conclusion
that there was a potential risk should be presented. It is anticipated that Ior any important potential
risk, there should be Iurther evaluation to characterise the association.

13
PART I 42/229
Presentation of risk data
When the inIormation is available, detailed risk data should be presented according to the Iollowing
Iormat.
sed population.
When an accurate Irequency is needed Ior an important adverse reaction, this should always be based
als should be provided.
When using patient-time, the underlying assumption is that the hazard Iunction must be nearly
should be split into relevant categories where the
assumption oI constancy holds. Where appropriate, the period oI major risk should be identiIied.
or
relevant population categories.
d relative incidence should be given. Excess incidence (in
comparison to placebo and active comparator; iI available) should be calculated based on the best
s) Ior each population (total controlled, total
Time to event data should be summarised using
pact oI the m st important identiIied and important potential risks should be
example: strength oI evidence, supporting plausibility, nature oI evidence and
burden, rbidity and case Iatality. Recording this in a structured Iorm will
Iacilitate assessment oI the potential signiIicance oI a saIety concern. ClassiIication oI the saIety
er evaluation as part the Pharmacovigilance Plan.
ractions including Food-Drug and Drug-Drug
and pharmacodynamic interactions should be discussed. For
action and possible mechanism should be summarised, and the
IIerent indications and in the diIIerent populations should be
y
The epidemiology oI the indication(s) should be discussed. This discussion should include incidence,
prevalence, mortality and relevant co-morbidity, and should take into account whenever possible
The Irequency oI important adverse reactions should be expressed taking into account the source oI
the data. For a product already on the market, the reporting rate based on the number oI spontaneously
reported adverse events/adverse reactions (in the numerator) and the sales data (in the denominator) is
very likely to underestimate the rate oI occurrence oI an adverse reaction in an expo
on systematic studies (e.g. clinical trials or epidemiological studies) in which both the number oI
patients exposed to the medicinal product and the number oI patients who experienced the respective
adverse event/adverse reaction are known.
The denominator should be expressed using the appropriate measure: e.g. number oI patients or in
patient-time or equivalent units (courses oI treatment, prescriptions, etc.) It should be stated clearly
which Irequency parameter is being used: e.g. incidence proportion (patient units in the denominator)
or incidence rate (patient-time units in the denominator). ConIidence interv
constant over the Iollow-up time. Otherwise it
Adverse event/adverse reaction incidence rates should be presented Ior the whole population and I
For important identiIied risks, the excess an
available evidence (e.g. meta-analytic technique
controlled plus open label extension, total study).
survival techniques which take appropriate account oI inIormative censoring. Cumulative hazard
Iunctions may provide a simple visual comparison oI the competing risks oI diIIerent adverse
reactions. These data can be stratiIied by substance (to investigate the diIIerence in the adverse event
proIile between active and placebo), or by risk Iactors such as dose, gender or age.
The potential im
addressed using Ior
o
mo
oI
potential public health
concern by dose, time and risk Iactors is encouraged. The identiIication oI susceptible patients should
receive speciIic attention, possibly Irom analysis oI cases. It is likely that the adverse reactions will
require Iurth
3.6.2.d) Identified and Potential Inte
Interactions
IdentiIied and potential pharmacokinetic
each, the evidence supporting the inter
potential health risks posed Ior the di
discussed.
It should be stated which interactions require Iurther investigation.
3.6.2.e) Epidemiolog
PART I 43/229
stratiIication by age, sex, and racial and/or ethnic origin. DiIIerences in the epidemiology in the
diIIerent regions should be discussed, where Ieasible, (because the epidemiology oI the indication(s)
dicinal product is indicated (i.e. the
background incidence rates). InIormation on risk Iactors Ior an adverse event would also be useIul to
iI a medicinal product is intended Ior treating prostate cancer the
n the medicinal product.
Class Effects
harmacological class.
II a risk which is common to the pharmacological class is not thought to be a saIety concern with the
me n d.
/Marketing Authorisation Holder is requested to discuss the topics below. II the
potential is thought to be signiIicant, the topic should be identiIied as an important potential risk and
the 'evaluation oI the need Ior risk minimisation
there is a reasonable likelihood that it will occur.
oI overdose in the target
may vary across regions), but the emphasis should be on the epidemiology in the EU.
In addition, Ior important adverse events that may require Iurther investigation, it is useIul to review
the incidence rate oI these events among patients in whom the me
include, iI available. For example:
target population is likely to be men over the age oI 50 years. This population is also at increased risk
oI myocardial inIarction. II it is suspected that the medicinal product might also cause myocardial
inIarction, it would be useIul to know how many cases would be expected amongst prostate cancer
patients (ideally) or men in the same age group, not o
3.6.2.f) Pharmacological
The SaIety SpeciIication should identiIy risks believed to be common to the p
dici al product, this should be justiIie
3.6.2.g) Additional EU Requirements
The Applicant
means Ior reducing or minimising it discussed in
activities. In this context, 'signiIicant means that
Where a particular topic is not relevant to the individual medicinal product, this should be stated along
with the reason.
Potential for overdose
Special attention should be given in particular cases, e.g. where there is a narrow therapeutic margin, a
medicinal product with signiIicant toxicity and/or there is an increased risk
population.
Potential for transmission of infectious agents
The Applicant/Marketing Authorisation Holder should discuss the potential Ior the transmission oI an
inIectious agent in line with Chapter I.5.
limited pack size and
Potential for misuse for illegal purposes
The potential Ior misuse Ior illegal purposes should be considered. II appropriate, the means oI
limiting this, e.g. by the use oI colorants and/or Ilavourings in the dosage Iorm,
controlled distribution should be discussed in the RMP section 'Evaluation oI the Need Ior Risk
Minimisation Activities.
Potential for off-label use
The potential Ior oII-label use should be discussed. This is particularly relevant where a medicinal
product has an indication restricted to a subset oI the population within a disease area or there are
situations where the medicinal product must not be given Ior saIety reasons. The potential Ior use in
other disease areas should also be considered where this is likely.
PART I 44/229
Potential for off-label paediatric use
II the disease or disorder which is being treated or prevented is Iound in the paediatric population, and
the product is not authorised in all paediatric age groups, the potential Ior oII-label paediatric use in
the non-authorised age groups should be discussed.
3.6.3 Summary
At the end oI the SaIety SpeciIication a summary should be provided oI the:
Important identiIied risks;
Important potential risks; and
Important missing inIormation.
Based on this summary the Applicant/Marketing Authorisation Holder should provide a
Pharmacovigilance Plan and an evaluation oI the need Ior risk minimisation activities (see Template in
Annex 5.1.1).
3.7 Pharmacovigilance Plan
According to ICH-E2E, the Pharmacovigilance Plan should be based on the SaIety SpeciIication and
propose actions to address the saIety concerns identiIied. Early discussions between Competent
thorisation Holder are recommended to identiIy
activities are needed. It is important to note that
3.7.1 Routine harmacovigilance
Fo e re no special concerns have arisen, routine pharmacovigilance should be
suI e without the need Ior additional actions (e.g. saIety
stu )
Authorities and the Applicant or Marketing Au
whether, and which, additional pharmacovigilance
only a proportion oI risks are likely to be Ioreseeable and the Pharmacovigilance Plan will not replace
but rather complement the procedures currently used to detect saIety signals.
P
r m dicinal products whe
Iici nt Ior post-authorisation saIety monitoring,
dies .
A r ities is covered elsewhere in Part I, which should be
consulted in developing the Pharmacovigilance Plan.
For medicinal products with important identiIied risks, important potential risks, or important missing
so consider the situations when routine
pharmacovigilance is likely to be inadequate. An example oI this might be when a potential risk with
dividua he target population(s),
leading to diIIiculties in distinguishing between the eIIects oI the medicinal product and the 'normal
ered.
durations oI exposure, to identiIy risk Iactors or to assess a causal association. For important missing
ovide
desc iption oI routine pharmacovigilance activ
3.7.2 Additional Pharmacovigilance Activities and Action Plans
inIormation, additional activities designed to address these saIety concerns should be considered.
Applicants/Marketing Authorisation Holders should al
an in l medicinal product has a signiIicant background incidence in t
incidence. When any doubt exists about the need Ior additional pharmacovigilance activities,
consultation with a Competent Authority should be consid
The objective(s) oI additional pharmacovigilance activities will normally diIIer according to the saIety
concern to be addressed. For important identiIied and potential risks, objectives may be to measure the
incidence rate in a larger or a diIIerent population, to measure the rate ratio or rate diIIerence in
comparison to a reIerence medicinal product, to examine how the risk varies with diIIerent doses and
inIormation, the objective may simply be to investigate the possibility oI a risk or to pr
reassurance about the absence oI a risk.
PART I 45/229
The threshold Ior investigating a saIety concern Iurther will depend upon the indication, the target
population, and the likely impact on public health. For example, a saIety concern with a vaccine might
have a lower threshold Ior investigation than the same issue in a medicine used in the palliative
treatment oI metastatic cancer.
The Table I.7.A lists some oI the epidemiological activities which might be considered Ior inclusion in
a Pharmacovigilance Plan. Additional pharmacovigilance activities included in the Pharmacovigilance
Plan should be designed and conducted according to the recommendations in the Guidelines Ior Good
Pharmacoepidemiology Practices (GPP)
14
. For studies involving children, the Guideline on Conduct
oI Pharmacovigilance Ior Medicines Used by the Paediatric Population (see Annex 3.1.4) should be
3.7.3 Action Plan for Safety Concerns
consulted. The responsibility Ior the scientiIic value oI study protocols remains with Applicants or
Marketing Authorisation Holders, even iI they have been previously discussed with Competent
Authorities.
Within the Pharmacovigilance Plan the action plan Ior each saIety concern should be presented and
justiIied according to the Iollowing structure (see also Annex 5.1.1):
SaIety concern
Objective oI proposed action(s)
Action(s) proposed
Rationale Ior proposed action(s)
Although not explicitly included in this structure, it is also necessary in the EU-RMP to explain the
uation of the Need for Risk Minimisation Activities
der should assess whether any risk
minimisation activities are needed. Some saIety concerns may be adequately addressed by the
sness that risk minimisation activities are needed. It is possible that the risk minimisation
activities may be limited to ensuring that suitable warnings are included in the product inIormation or
e appropriate, supporting
evidence provided.

Monitoring by the Applicant/Marketing Authorisation Holder Ior saIety concern and proposed
action(s)
Milestones Ior evaluation and reporting.
Protocols (draIt or otherwise) Ior any Iormal studies should be provided. Details oI the monitoring Ior
the saIety concern in a clinical trial could include: stopping rules, inIormation on the drug saIety
monitoring board and when interim analyses will be carried out.
decision making processes which will depend on the outcomes oI the proposed actions. The possible
consequences oI the study outcomes should be discussed.
3.8 Eval
On the basis oI the SaIety SpeciIication, the Applicant/Marketing Authorisation Holder should provide
an evaluation oI the need Ior risk minimisation activities.
For each saIety concern, the Applicant/Marketing Authorisation Hol
proposed actions in the Pharmacovigilance Plan, but Ior others the risk may be oI a particular nature
and seriou
by the careIul use oI labelling and packaging, i.e. routine risk minimisation activities. II an
Applicant/Marketing Authorisation Holder is oI the opinion that no additional risk minimisation
activities beyond these are warranted, this should be discussed and, wher

14
International Society Ior Pharmacoepidemiology. Guidelines Ior good pharmacoepidemiology practices
(GPP). Pharmacoepidemiol Drug SaI. 2005; 14 (8): 589-595. Available on the ISPE website
http://www.pharmacoepi.org/resources/guidelines08027.cIm.
PART I 46/229
However, Ior some risks, routine risk minimisation activities will not be suIIicient and additional risk
minimisation activities will be necessary. II these are required, they should be described in the risk
minimisation plan (see Chapter I.3, Section 9) which should be included in Part II oI the EU-RMP.
Within the evaluation oI the need Ior risk minimisation activities, the Applicant/Marketing
Authorisation Holder should also address the potential Ior medication errors (see Chapter I.3, Section
8.1) and state how this has been reduced in the Iinal design oI the pharmaceutical Iorm, product
inIormation, packaging and, where appropriate, device.
As a rule, Applicants/Marketing Authorisation Holders should always consider the need Ior risk
minimisation activities whenever the SaIety SpeciIication is updated in the light oI new saIety
inIormation on the medicinal product. In some circumstances, it may be appropriate to suggest that an
additional risk minimisation activity be stopped because experience with the medicinal product
suggests that it is no longer necessary Ior the saIe and eIIective use.
gn oI the medicinal product Ior marketing,
the Applicant needs to take into account potential reasons Ior medication error. The naming (taking
3.8.1 Potential for Medication Errors
Applicants/Marketing Authorisation Holders are encouraged routinely to consider the likelihood oI
medication errors. In particular, they should assess prior to marketing, common sources oI medication
errors. During the development phase and during the desi
into account the Guideline on the Acceptability oI Invented Names Ior Human Medicinal Products
Processed through the Centralised Procedure ), presentation (e.g. size, shape and colouring oI the
ractice to administer the product at the same time as other medicinal products given by the
hazardous route.
tween strengths oI the same medicinal product and
inimisation plan details the risk minimisation activities which will be taken to reduce the
rn. When a risk minimisation plan is provided within
include both routine and additional risk minimisation
15
pharmaceutical Iorm and packaging), instructions Ior use (e.g. regarding reconstitution, parenteral
routes oI administration, dose calculation) and labelling are among the items to be considered.
II a product has liIe-threatening potential when administered by an incorrect route, consideration
should be given as to how such administration can be avoided. This is particularly important when it is
common p
The need Ior visual (or physical) diIIerentiation be
between other medicinal products commonly administered or taken at the same time should be
discussed. When a medicinal product is likely to be used by a visually impaired population, special
consideration should be given to the potential Ior medication error.
Consideration should be given to the prevention oI accidental ingestion or other unintended use by
children.
Medication errors identiIied during product development should be discussed and inIormation on the
errors, their potential cause(s) and possible remedies given. Where applicable an indication should be
given oI how these have been taken into account in the Iinal product design.
II during the post-marketing period it becomes apparent that adverse reactions are occurring as a result
oI medication errors, this topic should be discussed in the updated EU-RMP and ways oI limiting the
errors proposed.
3.9 The Risk Minimisation Plan
The risk m
risks associated with an individual saIety conce
an EU-RMP, the risk minimisation plan should
activities. A saIety concern may have more than one risk minimisation activity attached to an

15
Doc.ReI. CPMP/328/98 latest version, available on EMEA website http://www.emea.europa.eu.
PART I 47/229
objective. For example, a possible plan Ior a known teratogen could have the objective oI avoiding any
patient taking the drug becoming pregnant. A routine risk minimisation activity might be to emphasise
the need Ior eIIective contraception in the Summary oI Product Characteristics and a recommendation
that patients should have a negative pregnancy test beIore each prescription. One additional risk
minimisation activity might be to develop an educational pack to provide inIormation to the patients
on the risks oI the medicine and the need Ior contraception. It might also be an activity to limit the
pack sizes to one month`s supply oI the medicine.
The risk minimisation plan should list the saIety concerns Ior which risk minimisation activities are
proposed. The risk minimisation activities, i.e. both routine and additional, related to that saIety
concern should be discussed. For each saIety concern the Iollowing headings in the plan will mirror
those Ior saIety concerns listed in Chapter I.3, Section 7.3. In addition, Ior each proposed additional
risk minimisation activity, a section should be included detailing how the eIIectiveness oI it as a
measure to reduce risk will be assessed (see Annex 5.1.1).
3.10 Risk Minimisation Activities
It is diIIicult to provide precise guidance on which risk minimisation activity should be used in a given
situation as each saIety concern needs to be considered on a case-by-case basis. Some oI the risk
minimisation activities are described in the Table I.3.A at the end oI this Chapter, but it is essential
that appropriate specialised experts are consulted at all stages and Marketing Authorisation Applicants
and Holders are also encouraged to discuss risk minimisation plans with the Competent Authorities
early on.
3.10.1 Risk Communication
Accurate and timely communication oI emerging data on risk is an essential part oI
pharmacovigilance. Risk communication is an important step in risk management as well as a risk
minimisation activity. Patients and healthcare proIessionals need accurate and well communicated
inIormation about the risks associated with both the medicinal product, and the condition Ior which it
is being used, so that an inIormed choice can be made about the most appropriate treatment. The
product inIormation in the Iorm oI the Summary oI Product Characteristics and Patient InIormation
LeaIlets is an important means oI inIorming prescribers and patients about the risks associated with a
particular medicine but additional materials may be needed. A short list oI established media Ior such
communication is given in the Table I.3.A (under Additional Educational Material), but the target
audience, levels oI detail required to achieve eIIective results and the most appropriate Iorms oI words
Marketing Authorisation
ctions ation may be used as a risk minimisation
will all vary with circumstances. Whereas Marketing Authorisation Holders may produce educational
material to inIorm and educate Healthcare ProIessionals and Patients, the requirement to do this will
only be included as a condition oI the marketing authorisation when it is deemed necessary Ior the saIe
and eIIective use oI the medicinal product.
Because oI the importance oI risk communication it is recommended that appropriate experts are
consulted.
3.11 The
Restri and conditions within the marketing authoris
activity Table I.3.A. When a marketing authorisation is granted, it will include details oI any
medicinal product may be made available to patients. These conditions
ded in the post-authorisation phase.
l product. It may also restrict where
by whom it can be prescribed (e.g. specialist).
conditions or restrictions imposed on the supply or the use oI the medicinal product, including the
conditions under which the
may also be modiIied when the marketing authorisation is amen
medicina This is commonly reIerred to as the 'legal status oI a
the medicine can be administered (e.g. to a hospital) or
For medicines only available upon prescription, additional conditions may be imposed by classiIying
PART I 48/229
medicines into those available only upon either a restricted medical prescription or a special medical
prescription.
aIIect the Decision addressed to the
Marketing Authorisation Applicant. However, in certain circumstances, the Commission may also
uld be shown to achieve the desired eIIects. In addition, as a
pub h
mini is
oI whic
3.12.1
whether the inIormation is being eIIectively
also allow direct measures oI
or example, concomitant medication
imescales which allow the lessons learned to be used to improve risk management. In
comparison with historical data can be made. Not withstanding the above,
s may be clariIied by a cross-tabulation oI the

The CHMP or national Competent Authorities may also make recommendations on conditions or
restrictions with regard to the saIe and eIIective use oI the medicinal product. In the case oI the
CHMP, these conditions or restrictions will usually only
adopt a Decision addressed to the Member States.
3.12 Ensuring the Effectiveness of Risk Minimisation Activities
The deIinition oI risk management requires assessment oI the eIIectiveness oI the interventions
Iorming part oI the process. It is clearly desirable that activities which may involve substantial
investment oI eIIort and resources sho
lic ealth measure it is imperative that alternative methods be adopted should a particular risk
m ation strategy prove ineIIective. Assessment oI eIIectiveness will also increase understanding
h activities are most appropriate in addressing speciIic types oI saIety concerns.
Assessment of Risk Minimisation
Direct measurement oI risk minimisation should be employed whenever Ieasible. Surrogate measures
should be considered when this is not Ieasible or to provide interim assessments whilst awaiting direct
risk minimisation measurements. For example, Ior measures based on the provision oI inIormation to
proIessionals, descriptive studies or surveys which assess
communicated might be appropriate. The use oI medical databases might
how uniIormly such advice was being adhered to by reviewing, I
or the results oI laboratory tests. Since such studies are likely to be required with increasing Irequency,
the availability oI such databases will be an ever more important Iactor in risk management. II the
prescribing databases are Iurther linked to patient clinical outcome, a study oI the adequacy oI the
prescribing process could be designed to evolve over time into a Iull risk reduction study.
It is clear that, even when risks are oI a type which can be directly measured, ethical and practical
considerations may prevent prospective comparison. It may be scientiIically diIIicult to make direct
comparison between a situation with and without the intervention to be assessed and may not be
achievable in t
particular this will occur when risks associated with long-term exposure or very rare events are to be
reduced. For products where a risk minimisation plan has been introduced aIter some time on the
market a
Applicants/Marketing Authorisation Holders should investigate new methodologies Ior monitoring
and assessment.
3.13 Summary of Activities in the EU-RMP
The EU-RMP should contain an overall summary oI the activities detailed Ior the medicinal product.
This should be in two parts:
Summary oI activities Ior each important saIety concern;
Summary oI all activities and their milestones.
The relationship between activities and saIety concern
two te
Su a
Th h sing the activities (both
pharmacovigilance minimisation) which will be taken. Where
ca gories showing which saIety concerns are addressed by each activity (see Annex 5.1.1).
mm ry of activities for each safety concern:
ty concern and summari is s ould be a simple table, listing each saIe
and, where appropriate, risk
PART I 49/229
appropriate, it should provide a cross-reIerence to the actions in the Pharmacovigilance Plan and the
risk minimisation activities Ior the individual saIety concern.
be organised in terms oI the actions or activities to
be undertaken and their milestones. The reason Ior this is that one proposed activity (e.g. a prospective
more than one oI the saIety concerns. Timelines and milestones
should be included in the summary with a timetable Ior the submission oI Iindings. In developing
el oI risk Ior patients and public health; or
when it will be possible to assess with suIIicient precision the eIIect oI risk Iactors associated
with the occurrence oI an adverse reaction;
when the results oI ongoing or proposed saIety studies are expected to be available;
the seriousness and magnitude oI the risk Ior which risk minimisation activities are being
proposed. Evaluation oI the eIIectiveness oI the activities will need to be carried out earlier
and more Irequently iI the risk is very serious.
3.14 Submission of Updated EU-RMP Documents
As additional inIormation on the saIety oI a medicinal product becomes available, the SaIety
SpeciIication and other sections oI the EU-RMP should be updated accordingly. For example,
spontaneous reports, clinical trials and pharmacoepidemiological studies may all give rise to saIety
signals which need to be investigated or the results Irom a study could provide new inIormation to
update the SaIety SpeciIication. It may be that, based on the new inIormation, it can be concluded that
the saIety concern has been resolved and that no Iurther actions are needed beyond routine
pharmacovigilance. In other cases, additional activities may be proposed and new milestones should
be developed.
The update should include assessment oI the eIIectiveness oI the risk minimisation activities within
the RMP.
At each update, consideration should be given as to whether new risk minimisation activities are
needed. This may be because oI a new saIety concern or with an existing saIety concern because the
data suggests that the current strategy is not eIIective.
Updated EU-RMPs are only required Ior medicinal products where an EU-RMP (or similar document)
Summary of all activities and their milestones:
This section oI the EU-RMP Ior the product should
saIety cohort study) could address
these milestones one should consider:
when it will be possible to detect an adverse reaction with a pre-deIined Irequency at a pre-
deIined conIidence level. This Irequency should be chosen such as to reIlect an acceptable
lev
has already been submitted under the conditions in Chapter I.3, Section 4 or required under the terms
oI the marketing authorisation.
The updated EU-RMP should be submitted at the same time as the next Periodic SaIety Update Report
(PSUR) unless other requirements have been laid down as a condition oI the marketing authorisation.
In addition, an updated EU-RMP should be submitted:
when new inIormation is received that may impact on the current SaIety SpeciIication,
Pharmacovigilance Plan or risk minimisation activities;
within 60 days oI an important (pharmacovigilance or risk minimisation) milestone being
reached or the results oI a study becoming available;
at the request oI the Competent Authority.
A cover letter should be submitted with the updated EU-RMP brieIly summarising the changes Irom
the previous EU-RMP.
PART I 50/229
Where no changes to any part oI the EU-RMP have
this, and the date oI the last EU-RMP submission
occurred since the last submission, a letter stating
should be sent. In this circumstance it is not
n
P
A
ecessary to re-submit the EU-RMP with the letter.
eriodic Safety Update Reports
summary oI any amendments made to the EU-RMP, prior to the data lock point oI the Periodic
S aIety Update Report (PSUR), should be included in the PSUR (see Addendum to ICH-E2C Clinical
S te Reports Ior Marketed Drugs, Section 2.8.3 (see aIety Data Management. Periodic SaIety Upda
Annex 4).
PART I 51/229
TABLE I.3.A: METHODS FOR RISK MINIMISATION
Risk minimisation activities can be divided into those where a reduction in risk is achieved
inIormation and education and those which seek to control the
use oI the medicine. When it is obvious that a risk minimisation activity will be needed post
primarily through the provision oI
authorisation, consideration should be given to piloting the activity during the development phase to
see the eIIectiveness and suitability. When this is done, the outcome should be provided in the risk
minimisation plan under the appropriate action.
1. Provision of Information
Provision oI inIormation to Healthcare ProIessionals and/or Patients on the speciIic risks oI a
product and the measures on how to reduce them is an essential activity oI risk management. This
provision oI inIormation may be conIined to inIormation contained within the Summary oI Product
Characteristics (SPC) and Package LeaIlet (routine risk management) or may be through the use oI
additional educational material (additional risk management). The need Ior additional material
beyond the Summary oI Product Characteristics and Package LeaIlet will depend upon the risk and
should be considered on a case-by-case basis. Experts in risk communication should be consulted as
appropriate.
1.1 Additional Educational Material
The need Ior additional educational material and the Iorm in which it should be provided will
depend upon the speciIic saIety concern. The aim oI a specialised educational programme Ior
care proIessiona health ls and/or patients is to:
Enhance understanding oI the speciIic risk(s);
Enhance understanding oI measures to reduce either the Irequency or severity oI adverse

ss and provide inIormation on the need and use oI
additional precautions.
portion oI visually impaired patients, the use oI Braille or audio media should be given
special consideration. Pre-testing materials in the target audience(s) is highly desirable to help
ods such as readability testing, Iocus groups or surveys could be used.
Sp ic
that pre
pro m
reactions;
Enhance early detection and treatment (iI applicable) oI an adverse reaction;
Enhance patient inIormation, awarene
The educational programme may include but is not limited to the Iollowing materials:
Direct Healthcare ProIessional Communications;
Physician`s Guide to Prescribing;
Pharmacist`s Guide to Dispensing;
Checklists Ior assessing comprehension, knowledge, attitudes, and/or desired saIety
behaviours about the risk(s). These should be tailored to the target audience (e.g.
physicians, pharmacists or patients);
Checklists Ior actions beIore prescribing or dispensing;
Patient InIormation Brochures;
SpeciIic training programmes.
The choice oI media may also need to be considered (written, audio or video) as well as the use oI
drawing/symbols to improve understanding. For medicines where the target population may include
a larger pro
ensure good comprehension and acceptance oI the communication method and contents. A variety
oI testing meth
eciI training programmes may be considered in certain circumstances. However, it is unlikely
scription/dispensing oI the medicine can be limited to people who have undertaken such a
gra me.
PART I 52/229
Th o
Pa
e ab ve educational materials should be in strict compliance with the contents oI the SPC and the
ckage LeaIlet and must be agreed with the Competent Authority.
2. e Legal Status of a Medicin
It is possible that controlling the conditions under which a medicine may be made available could
reduce the risks associated with its use or misuse. This might be achieved by control oI either who
may be permitted to prescribe or dispense a medicine or by controlling who, or the conditions under
which a patient, may receive a medicine.
granted, it must include details oI any conditions or restrictions
to medical prescription. It may also restrict where the medicine can be
inis an be prescribed (e.g. specialist).
edicinal product is intended Ior outpatients but its use may produce very serious
ubmitted in accordance with the
Ior recommending the legal status to the
gh restriction to use in a hospital environment may in practice ensure that the
needs to be balanced against the inconvenience to
every prescription. Care also needs to be taken when
ting where resuscitation equipment is
available.
For classiIication as subject to special medical prescription the Iollowing Iactors should be taken
into account:
the medicinal product contains, in a non-exempt quantity, a substance classiIied as a
narcotic or a psychotropic substance within he meaning oI the international conventions in
Iorce, such as the United Nations Conventions oI 1961 and 1971; or
When a marketing authorisation is
imposed on the supply or the use oI the medicinal product, including the conditions under which the
medicinal product may be made available to Patients. This is commonly reIerred to as the 'legal
status oI a medicinal product. Typically it includes inIormation on whether or not the medicinal
product is subject
adm tered (e.g. to a hospital) or by whom it c
For medicines only available upon prescription, additional conditions may be imposed by
classiIying medicines into those available only upon either a restricted medical prescription or a
special medical prescription. When considering classiIication as subject to restricted medical
prescription the Iollowing Iactors shall be taken into account:
the medicinal product, because oI its pharmaceutical characteristics or novelty or in the
interests oI public health, is reserved Ior treatments which can only be Iollowed in a hospital
environment;
the medicinal product is used Ior the treatment oI conditions which must be diagnosed in a
hospital environment or in institutions with adequate diagnostic Iacilities, although
administration and Iollow up may be carried out elsewhere; or
the m
adverse reactions requiring prescription drawn up as required by a specialist and special
supervision throughout the treatment.
In the case oI an application Ior a marketing authorisation s
Centralised procedure, the CHMP is responsible
Commission. Although the use oI legal status is not an activity that can be used directly by an
Applicant Ior the purposes oI risk reduction, the Applicant could request the Competent Authority
to consider a particular legal status.
However, the deIinition oI what constitutes a specialist is not uniIorm throughout the Member
States so, in practice the provisions oI the last indent are usually phrased in section 4.2 oI the
Summary oI Product Characteristics as: 'treatment by a physician experienced in the treatment oI
the disease~. Althou
medicine is always prescribed by a specialist, this
patients iI they need to attend a hospital Ior
considering where a medicine can be saIely administered. For example the term 'clinic has
diIIerent connotations depending upon the country. For this reason, the type oI equipment needed
may be speciIied rather than a location, e.g. 'use in a set
PART I 53/229
the medicinal prod
abuse, to lead to addiction
uct is likely, iI incorrectly used, to present a substantial risk oI medicinal
or be misused Ior illegal purposes; or
e
the medicinal product contains a substance which, by reason oI its novelty or properties,
could be considered as belonging to the group envisaged in the previous indent as a
precautionary measure.
There is possibility oI implementing Iurther sub-categories at Member State level which permits th
Member States to tailor the broad classiIications described above to their national situation. The
deIinitions and thereIore also the implementation varies in those Member States where the sub-
categories exist.
3. Control at Pharmacy Level
The control oI dispensing is another potential activity Ior risk management. Pharmacists who are
well inIormed about the risks oI a medicine can help educate the Patient and provide an additional
level oI protection.
4. Control of Prescription Size or Validity
Limiting the validity oI a prescription is another activity Ior risk management in the situation where
decision to prescribe depends upon the result oI a test which is only valid Ior a speciIic time. In
some Member Sates it is possible to limit the validity oI a prescription but not in others.
Limiting the number oI units prescribed is another risk minimisation activity. This can be useIul iI
regular testing or review is needed. By limiting the number oI units, the patient will need to see a
Healthcare ProIessional at deIined intervals increasing the opportunity Ior testing and reducing the
length oI time a patient is without review. II this strategy is adopted, it is a pre-requisite that the
appropriate pack size is available and that supply issues are addressed. In extreme cases, making
units available in only one pack size to try to link prescribing to the need Ior review may be
considered.
A small pack size can also be useIul, especially iI overdose is thought to be a major risk or iI the
potential Ior drugs to get into the general population needs to be controlled.
5. Informed Consent and other Patient Aspects
In a clinical trial, patients are given inIormation about the possible beneIits and risks oI the trial
medication and any procedures associated with the trial. The Patient signs a Iorm to say that they
have been given the inIormation, they understand it and agree to take part in the trial. This is known
as inIormed consent. It has potential as a risk management activity to ensure that patients have been
provided with appropriate inIormation regarding the risks oI the medicine and appropriate measures
to reduce the risks. Use oI inIormed consent outside the clinical trial area may not be possible in
some Member States.
6. Restricted Access Programmes
In high-risk situations, it may be necessary to restrict access to a medicinal product to those patients
who agree to take part in a speciIic surveillance programme.
PART I 54/229
PART I 55/229
7. Patient Registries
Patient registries are oIten suggested as a means oI risk management. They have been used
(sometimes very successIully) in individual countries to record the results oI tests, to ensure that the
recommended conditions oI use are being adhered to, and control access to a medicine. However,
there are possible issues about who controls the registry and the conIidentiality oI medical data.
Whereas patient registries could be a very useIul activity Ior pharmacovigilance studies to
characterise risks, use as a means oI controlling access is not currently possible in some Member
States. It is strongly suggested that iI a Marketing Authorisation Holder is contemplating the use oI
a patient registry, this should be discussed with the appropriate regulatory authority at a very early
stage.

4. Requirements for Expedited Reporting of Individual Case Safety Reports
4.1 Introduction
The obligations oI the Marketing Authorisation Holder Ior recording and reporting suspected adverse
cant during the period between submission oI the
Ma ti
reactions associated with a medicinal product Ior which marketing authorisations are held are deIined
in Directive 2001/83/EC and Regulation (EC) No 726/2004. For suspected adverse reactions requiring
expedited reporting, Iurther explanation is provided in this Chapter. Reporting requirements in special
situations, including obligations oI the Appli
rke ng Authorisation application and granting oI the Marketing Authorisation, are described in
Chapter
For authoris
received Iro
should be re
the authorise own Ior
ma ti
identiIie e worldwide-published scientiIic literature should also be reported. Electronic
I.5.
ed medicinal products, independent oI the authorisation procedure, adverse reactions
m Healthcare ProIessionals, either spontaneously or through post-authorisation studies,
ported, regardless oI whether or not the medicinal product was used in accordance with
d Summary oI Product Characteristics (SPC) and/or any other conditions laid d
rke ng oI the product in accordance with applicable legal requirements. Adverse reactions
d Irom th
reportin I
The deIinitio
g o adverse reactions is mandatory, save in exceptional circumstances (see Chapter III.4).
ns oI suspected adverse reaction`, serious adverse reaction` and expected/unexpected
adverse reac ext oI pharmacovigilance,
the m
drug rea
For rep ected transmission via a medicinal product oI an inIectious agent is
tion` are provided in the Glossary (see Annex 1.1). In the cont
ter adverse reaction is considered as synonymous with suspected adverse reaction and adverse
ction.
orting purposes, any susp
also considered a serious adverse reaction and thereIore should be reported in expedited manner (see
Chapter I.5, Section 9). In addition, such cases should be considered Ior reporting as product deIects iI
appropriate (see Compilation oI Community Procedures on Inspections and Exchange oI
InIormation
16
).
When a Marketing Authorisation Holder receives an Individual Case SaIety Report (ICSR) where the
invented name oI the medicinal product is not speciIied but the active substance is included in any oI
eceived Irom Healthcare ProIessionals should be reported
by the Marketing Authorisation Holder iI:
een the event
ationship is at least a reasonable
poss
the medicinal products Ior which a marketing authorisation is held, the Marketing Authorisation
Holder should assume that the report may relate to their product.
Spontaneous reports oI adverse reactions r
the Healthcare ProIessional has made a statement that a causal relationship betw
and the medicinal product is considered to be at least a reasonable possibility; or iI
the Healthcare ProIessional has not made any statement on the suspected causal relationship or
has stated that the causal relationship is unknown; or iI
the Marketing Authorisation Holder considers that a causal rel
ibility.
II the Healthcare ProIessional has made an explicit statement that a causal relationship between the
medicinal product and reaction has been excluded and the Marketing Authorisation Holder agrees with
this, the event should not be reported.
When the Marketing Authorisation Holder is aware that a Healthcare ProIessional may have reported a
reaction to one oI their products directly to the Competent Authority oI a Member State, the Marketing
Authorisation Holder should still report the reaction, inIorming the Competent Authority that the

16
Doc.ReI. EMEA/INS/GMP/3351/03 latest version, available on EMEA website http://www.emea.europa.eu.
PART I 56/229
report may be a duplicate oI a previous report. In this situation, it is essential Ior the Marketing
Authorisation Holder to provide all the available details including all case identiIication numbers
allocated to the case, in order to aid identiIication oI the duplicate case. For Iurther guidance on
reporting oI potential duplicates, reIer to Section A.1.11 'Other case identiIiers in previous
transmission oI ICH-E2B(M) (see Annex 4).
ntiIiable Healthcare ProIessional reporter (see Section A.2 'Primary source(s) oI
The Marketing Authorisation Holder is expected to validate all adverse reactions reported by
Healthcare ProIessionals to ensure, prior to reporting to the Competent Authorities, that the minimum
inIormation required is included in the report:
An ide
inIormation oI ICH-E2B(M) (see Annex 4);
The reporter may be identiIied by name or initials, address or qualiIication (e.g.
physician, dentist, pharmacist, nurse), taking into account EU legislation on data
protection (Directive 95/46/EC, Regulation (EC) No 45/2001) and relevant national
legislation (see also Chapter III.5, Section 4). Contact details Ior a Healthcare
ProIessional should be available Ior the reporter to be considered as identiIiable.
An identiIiable Patient (see Section B.1 'Patient characteristics oI ICH-E2B(M) (see
Annex 4);
The Patient may be identiIied by initials, patient number, date oI birth, age, age group or
sex. The inIormation should be as complete as possible, taking into account EU
legislation on data protection (Directive 95/46/EC, Regulation (EC) No 45/2001) and
relevant national legislation (see also Chapter III.5, Section 4).
At least one suspected active substance/medicinal product (see Section B.4 'Drug(s)
inIormation oI ICH-E2B(M) (see Annex 4);
At least one suspected adverse reaction (see Section B.2 'Reactions(s)/event(s) oI ICH-
E2B(M) (see Annex 4).
For adverse reaction reports relating to biological products, the deIinite identiIication oI the product
e, Marketing Authorisation
Holders should give advice to reporters to provide the name oI the medicinal product (in accordance
with regard to its manuIacturing is oI particular importance. ThereIor
with Article 1(20) oI Directive 2001/83/EC, see Annex 1.3) and the batch number and should Iollow-
up the reports where this inIormation is missing Ior completion.
Reports should be Iollowed-up to obtain additional inIormation relevant to the case as necessary, and
relevant Iollow-up inIormation should be reported to the Competent Authorities (see Chapter III.5,
Section 3). All available clinical inIormation relevant to the evaluation oI the adverse reaction should
be provided (see Chapter III.5, Section 1).
For reports on adverse reactions Irom Patients/Consumers, see Chapter I.4, Section 3.5.
II ICSRs, which do not qualiIy Ior expedited reporting as outlined in this Chapter, provide inIormation
and no later than 15 calendar days Irom receipt. This applies to initial and Iollow-up inIormation.
that may lead to a change in the known risk-beneIit balance Ior the product, this possible change
should be notiIied to the Competent Authorities without delay.
4.2 Reporting Time Frames
The Marketing Authorisation Holder should transmit all ICSRs requiring expedited reporting promptly
The date the Marketing Authorisation Holder becomes aware oI a case which IulIils the minimum
inIormation (see Chapter I.4, Section 1) should be considered day 0. The same applies iI new
inIormation on the case is received by the Marketing Authorisation Holder, i.e. the reporting time
clock begins again Ior the submission oI the Iollow-up report Irom the day the Marketing
Authorisation Holder receives relevant Iollow-up inIormation (see also Chapter III.5, Section 3).
PART I 57/229
The clock Ior expedited reporting starts (day 0) as soon as the minimum inIormation (see Chapter I.4,
Section 1), has been brought to the attention oI any personnel oI the Marketing Authorisation Holder
or an organisation having a contractual arrangement with the Marketing Authorisation Holder,
including medical representatives.
For individual cases described in the worldwide scientiIic literature, the clock starts (day 0) with
awareness oI a publication containing the minimum inIormation (see Chapter I.4, Section 1) by any
personnel oI the Marketing Authorisation Holder or an organisation having a contractual arrangement
with the Marketing Authorisation Holder, including medical representatives. For Iurther guidance see
Chapter III.7.
Contractual arrangements may be made with a person or organisation to perIorm literature searches
and/or report relevant individual cases to Competent Authorities. II another person or organisation is
perIorming these tasks, explicit procedures and detailed agreements should exist between the
Marketing Authorisation Holder and this person or organisation to ensure that the Marketing
Authorisation Holder is promptly made aware oI any individual cases described in the worldwide
where the Marketing Authorisation Holder has set up contractual arrangements with a
person or organisation Ior e.g. the marketing oI, or research on a medicinal product authorised to this
ion that
constitutes a reportable case. Explicit procedures and detailed agreements should exist between the
scientiIic literature to ensure that the Marketing Authorisation Holder can comply with their reporting
obligations.
In general,
Marketing Authorisation Holder, the clock starts as soon as any personnel oI the Marketing
Authorisation Holder or the other person/organisation receives the minimum inIormat
Marketing Authorisation Holder and the person/organisation to ensure that the Marketing
Authorisation Holder can comply with his reporting obligations (see Chapter I.1).
4.3 Requirements by Reporting Source
4.3.1 Spontaneous Reports from Healthcare Professionals
a) Individual Case Safety Reports on adverse reactions occurring within the EU
For all medicinal products, independently oI the authorisation procedure, the Marketing Authorisation
Holder should report, on an expedited basis, all serious adverse reactions occurring within the EU, and
brought to their attention by a Healthcare ProIessional, to the Competent Authority oI the Member
State on whose territory the incident occurred.
For reporting purposes, any suspected transmission via a medicinal product oI an inIectious agent is
also considered a serious adverse reaction and thereIore should be reported in expedited manner (see
Chapter I.5).
For medicinal products authorised through the mutual recognition or decentralised procedures and Ior
medicinal products which have been the subject oI a reIerral procedure, the Marketing Authorisation
Holder is responsible Ior ensuring that all serious adverse reactions received Irom Healthcare
ProIessionals or Competent Authorities within the EU are reported to the ReIerence Member State. To
avoid duplicate reporting, the ReIerence Member State/Rapporteur Member State should not re-
transmit these ICSRs to EudraVigilance iI they did not occur within its territory (see Chapter II.3).
Non-serious adverse reactions occurring within the EU should only be reported in an expedited
manner on request and otherwise in accordance with Chapter I.6 on Periodic SaIety Update Reports.
For centrally authorised products and periodic transmission oI such cases into EudraVigilance see
Chapter III.11, Section 7.
PART I 58/229
For nd an overview on the expedited reporting requirements in Member States, see Annexes 6.1.1 a
6.1
b) ase Safet t urring outside the EU
Fo al produc depe e g Auth tion
Holder should report on an exp cted se ny
suspected transmission via a medi ag ring in the territory oI a
non-EU country, and initially repor are ProIessional, to the Agency and
to he me
Se dverse reactio iss medicinal product oI an
inIectious agent initially reported a equently transmitted by a
regulatory authority outside the EU is subject to
expedited reporting to the Competent Authorities oI the EU by the Marketing Authorisation Holder.
Although ent, er r all
expected serious adverse reactions a e cy,
.2.
Individual C y Repor s on adverse reactions occ
r all medicin ts, in ndent oI the authorisation proc
edited basis, all unexpe
cinal product oI an inIectious
ted (or conIirmed) by a Healthc
dure, the Marketin
rious adverse reactions
ent occur
orisa
and a
all Member States w
rious unexpected a
re the dicinal product is authorised.
ns and any suspected transm
by a Healthcare ProIessional
to the Marketing Author
ion via a
nd subs
ation Holder are also
not a legal requirem Marketing Authorisation Hold
occurring outside the EU on
s are encouraged to also
n expedited basis to th
eport
Agen
provided that reporting takes place th ICH-E2B(M) (see Chapter III.11, electronically in accordance wi
Se
Non-serious adverse reac occu U should onl expedited manner
ction 3).
tions rring outside the E y be reported in
on request and otherwise in accorda dic SaIety Update Reports.
Fo oI non-se adv ucts and periodic
nce with Chapter I.6 on Perio
y r reporting rious erse reactions with centrall authorised prod
tra reports oc ou e, 1, Sectio nsmission oI curring tside the EU to EudraVigilanc see Chapter III.1 n 7.
For an overview on the expedited re er States, see Annex 6.1.3. porting requirements in Memb
PART I 59/229
Expedited Reporting Requirements (shaded in grey: reporting encouraged but not a legal
requirement)
Marketing
Authorisation Type
Origin Adverse Reaction Type Destination Time
line
Centralised EU All serious adverse reactions,
including any suspected
To Member State
where adverse reaction
15
days
transmission via a medicinal
product oI an inIectious agent
occurred
Mutual recognition
or decentralised, or
EU All serious adverse reactions,
including any suspected
To Member State
where adverse reaction
15
subject to reIerral transmission via a medicinal
occurred
and to
ReIerence/Rapporteur
Member State
17
days
Purely national EU All serious adverse reactions, To Member State 15
including any suspected where adverse reaction days
occurred
Centralised Non-
EU
All serious unexpected
adverse reactions
To all Member States
and to
15
and any suspected
Agency days
Centralised Non-
EU
All serious adverse reactions
and any suspected
To the Agency 15
days
National, including
mutual recognition,
Non-
EU
All serious unexpected
adverse reactions
To all Member States 15
decentralised, or
subject to reIerral
and any suspected
authorised and to the
Agency
where product is days
National, including
mutual recognition,
decentralised, or
subject to reIerral
Non-
EU
All serious adverse reactions
and any suspected
To the Agency 15
days

4.3.2 Reports Published in the Worldwide Literature
Individual case reports Irom the worldwide literature in accordance with the provisions oI Chapter I.4,
Section 1 are considered to be reports oI which the Marketing Authorisation Holder can reasonably be
expected to be aware and have knowledge oI.
The Marketing Authorisation Holder is thereIore expected to maintain awareness oI possible
publications by accessing a widely used systematic literature review and reIerence database (e.g.
Medline, Excerpta Medica or Embase) no less Irequently than once a week. In addition, company

17
To avoid duplicate reporting, the ReIerence/Rapporteur Member State should not Iorward the adverse reaction
to EudraVigilance iI the adverse reaction did not occur within its territory. The adverse reaction should be
reported by the Member State in whose territory the adverse reaction occurred.
PART I 60/229
oIIices in each Member State are required to be aware oI publications in their local journals and bring
them to the attention oI the QPPV as appropriate.
the scientiIic and medical literature, including relevant published
abstracts Irom meetings and draIt manuscripts, should be reviewed to identiIy individual cases which
Cases oI adverse reactions Irom
might qualiIy Ior expedited reporting.
As required by legislation, the Marketing Authorisation Holder should report within 15 days published
serious adverse reactions associated with the use oI the active substance(s) oI their medicinal products,
as relevant to the categories identiIied in Chapter I.4, Section 3.1. The procedure Ior handling oI
adverse reaction reports published in the worldwide literature is described in Chapter III.7.
II the medicinal product source and/or the invented name is not speciIied and ownership oI the product
cannot be excluded on the basis oI the active substance(s), Iormulation or route oI administration, the
Marketing Authorisation Holder should assume that it is one oI their products the publication reIers to,
although the report should indicate that the speciIic product source and/or the invented name was not
ied.
al websites Ior inIormation on adverse reactions. However, iI a Marketing
Authorisation Holder becomes aware oI an adverse reaction on any other website the Marketing
identiI
II multiple medicinal products are mentioned in the publication, a report should be submitted only by
the Marketing Authorisation Holder(s) oI the product(s) which is (are) identiIied by the publication`s
author(s) as having at least a possible causal associated with the reaction.
4.3.3 Information on Adverse Reactions from the Internet
The Marketing Authorisation Holder should regularly screen websites under their management or
responsibility, Ior potential reports on adverse reactions. The Marketing Authorisation Holder is not
expected to screen extern
Authorisation Holder should review the case and determine whether it should be reported in expedited
manner in accordance with Chapter I.4, Sections 3.1 and 3.5.
The Marketing Authorisation Holder should consider utilising their websites to Iacilitate adverse
reaction collection, e.g. by providing adverse reaction Iorms Ior reporting or by providing appropriate
contact details Ior direct communication. In relation to such reported adverse reactions, identiIiability
oI the reporter and Patient reIers to the existence oI actual people (see Chapter I.4, Section 3.1)
stems
ed Irom interventional or non-interventional studies.
on the Collection, VeriIication and Presentation oI Adverse Reaction Reports
4.3.4 Reports from Organised Data Collection Sy
Reporting requirements Ior cases derived Irom organised data collection systems (which include
clinical trials, post-authorisation studies, registries, post-authorisation named-patient use programmes,
other patient support and disease management programmes, surveys oI Patients or Healthcare
Providers, and inIormation gathering on eIIicacy or patient compliance) diIIer depending on whether
they are deriv
a) Interventional Studies
Interventional studies Iall under the provisions oI Directive 2001/20/EC on clinical trials and adverse
reactions should be reported in line with that Directive and associated guidance, in particular the
Detailed Guidance
Arising Irom Clinical Trials on Medicinal Products Ior Human Use (ENTR/CT3, Volume 10 oI The
Rules Governing Medicinal Products in the EU, Chapter II
18
), which includes guidance on unblinding,
and the Detailed Guidance on the European Database oI Suspected Unexpected Serious Adverse
Reactions (EudraVigilance Clinical Trial Module) (ENTR/CT4, Volume 10 oI The Rules Governing

18
Available on EC website http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/index.htm.
PART I 61/229
Medicinal Products in the EU, Chapter II). For reporting oI adverse reactions in the Periodic SaIety
Update Reports (PSURs), see Chapter I.6.
b) Non-interventional Studies
Post-authorisation studies that are non-interventional are not covered by the provisions oI Directive
2001/20/EC but by Directive 2001/83/EC and Regulation (EC) No. 726/2004 (see Annex 1.1 Ior the
deIinition oI a non-interventional trial). Serious adverse reactions arising Irom such studies should be
reported on an expedited basis according to the same criteria and timelines as adverse reactions
reported spontaneously by Healthcare ProIessionals (see Chapter I.4, Section 1); this includes any
suspected transmission via a medicinal product oI an inIectious agent. For an overview on the
expedited reporting requirements in Member States, see Annexes 6.1.1, 6.1.2 and 6.1.3. All adverse
reactions, i.e. also non-serious ones, should be included in the Iinal study report. For reporting oI
adverse reactions in the Periodic SaIety Update Reports (PSURs), see Chapter I.6. For Iurther
inIormation on post-authorisation saIety studies see Chapter I.7.
4.3.5 Reports from Patients and Other Consumers
ented as a spontaneous report Irom a
When inIormation is received directly Irom a Patient /Consumer suggesting that an adverse reaction
may have occurred, the Marketing Authorisation Holder should attempt to obtain the Patient's consent
to contact the Healthcare ProIessional involved Ior Iurther inIormation. When such a report has been
conIirmed by the Healthcare ProIessional, it should be docum
Healthcare ProIessional and reported according to Chapter I.4, Sections 1 and 3.1. When a Consumer
the occurrence oI the adverse reaction, this should be submits medical documentation that supports
considered suIIicient to report the individual case iI it provides the minimum inIormation (see Chapter
I.4, Section 1). For requirements to reIlect Consumer reports in Periodic SaIety Update Reports see
Chapter I.6, Section 3.7.
For requirements in relation to reporting oI outcomes oI use oI medicinal products during pregnancy,
originating Irom Consumers, see Chapter I.5, Section 4.
Member States may have additional requirements in place with regard to reports Irom Consumers,
which need to be Iollowed by the Marketing Authorisation Holder (see Annexes 6.1.1, 6.1.2 and
6.1.3). Medically unconIirmed adverse reactions should not be reported to the Agency/EudraVigilance
on expedited basis.
4.3.6 Reports from Other Non-Medical Sources
II a Marketing Authorisation Holder becomes aware oI a case report Irom non-medical sources other
than those mentioned in Chapter I.4, Section 3.5, e.g. the lay press or other media, every attempt
should be made to obtain the minimum inIormation that constitutes an individual case (see Chapter
I.4, Section 1) and to Iollow-up the case as Ior reports Irom a Patient/Consumer (see Chapter I.4,
Section 3.5).
4.4 Data Elements for the Report
The principles in the ICH-E2D Guideline and ICH-E2B(M) Guideline (see Annex 4) should be
Iollowed. Detailed aspects related to the preparation oI ICSRs and the applicable data elements are
deIined in Part III.
For the minimum inIormation constituting a case and Ior the standards relating to the electronic
transmission oI an ICSR, see Chapter I.4, Section 1 and Chapter III.2.
It is essential Ior the Marketing Authorisation Holder to provide as many data elements as possible Ior
cases oI adverse reactions to Iacilitate assessment (see Chapter III.5, Sections 1 and 2). The Marketing
PART I 62/229
PART I 63/229
us adverse reactions to their
ble. Additional inIormation not
Authorisation Holder is expected to Iollow-up all reports oI serio
medicinal product(s) to obtain comprehensive inIormation where availa
available at the time oI the initial report should be provided in the Iorm oI Iollow-up reports (see
Chapter I.4, Section 1 and Chapter III.5, Section 3).
The suspect, interacting and/or concomitant active substance(s)/invented name oI the suspect
product(s) should be reported in accordance with ICH-E2B(M) (see Annex 4) and as outlined in
Chapter III.5, Section 1. The Marketing Authorisation Holder should report ICSRs to the Competent
Authorities oI Member States and EudraVigilance in English (see also Chapter III.11, Section 5). In
addition to the English summary, the original verbatim in the local language may be maintained in the
Iield B.5.1 'Case narrative including clinical course, therapeutic measures, outcome and additional
relevant inIormation oI ICH-E2B(M), iI considered necessary.
The Marketing Authorisation Holder may comment on the causal relationship between the suspect
s oI drug to reaction(s)/event(s) oI ICH-E2B(M).
In a Iit balance oI a medicinal product, the
Ma ti to the Competent Authorities and,
iI a i lation to the marketing authorisation, the
Su a and Patient InIormation LeaIlet. This should in addition be
rec e
4.5
Electronic reporting oI adverse reactions is mandatory, save in exceptional circumstances. The
rdance with
product(s) and the reaction(s) reported and should provide the criteria on which he has made the
assessment in Iield B.4.k.18 'Relatednes
situ tions where ICSRs impact on the known risk-bene
rke ng Authorisation Holder should indicate in a separate letter
ppl cable, to the Agency what action is proposed in re
mm ry oI Product Characteristics
ord d in Iield B.5.4 'Sender`s comments oI ICH-E2B(M).
Method of Reporting
requirements Ior electronic transmission oI ICSRs to be Iollowed are explained in acco
Part III.

5. Requirements for Reporting in Special Situations
5.1 Introduction
Adverse reactions should be reported according to the requirements outlined in Chapter I.4, regardless
oI whether or not the medicinal product was used in accordance with the authorised Summary oI
Product Characteristics (SPC) and/or any other conditions laid down Ior the marketing oI the product.
In addition to routine expedited and periodic reporting requirements as laid out in Chapters I.4 and I.6,
n oI the marketing authorisation application and
the granting oI the marketing authorisation;
on use oI medicinal products in children;
mpassionate/named-patient use;
s;
orting in the Period between the Submission of the Marketing
the Marketing Authorisation Holder should be aware oI the Iollowing additional reporting
requirements relating to worldwide experience with the medicinal product:
Reporting in the period between the submissio
Reporting Iollowing suspension or withdrawal oI the marketing authorisation Ior saIety oI
commercial reasons;
Reporting oI outcomes oI use oI a medicinal product during pregnancy;
Reporting oI adverse reactions during breastIeeding;
Reporting oI data
Reporting Irom co
Reporting oI lack oI eIIicacy;
Reporting oI suspected transmission oI inIectious agent
Reporting in relation to overdose, abuse and misuse;
Reporting oI medication errors;
Reporting in the event oI a public health emergency.
5.2 Rep
Authorisation Application and the Granting of the Marketing Authorisation
In the period between submission oI the marketing authorisation application and the authorisation,
inIormation that could impact on the risk-beneIit balance may become available to the Applicant (see
also Chapter 1, Section 5.1.1 oI Volume 2A (Notice to Applicants) oI The Rules Governing Medicinal
Products in the European Union
19
). It is the responsibility oI the Applicant to ensure that this
inIormation is immediately submitted to the Competent Authorities oI the Member States where the
application is under assessment (including ReIerence Member State and all Concerned Member States
Ior products assessed under the mutual recognition or decentralised procedures). For centralised
applications, inIormation should also be provided to the Agency, the Rapporteur and Co-Rapporteur
(see Chapter II.3, Section 4.1 and Chapter II.2.A).
5.3 Reporting Following Suspension or Withdrawal of the Marketing
Authorisation for Safety or Commercial Reasons
Reporting requirements remain Iollowing suspension oI the marketing authorisation oI a medicinal
product (see Chapters I.4 and I.6). Where a marketing authorisation is withdrawn or revoked, the
Iormer Marketing Authorisation Holder is encouraged to continue to report in line with Chapter I.4 to
e.g. Iacilitate review oI delayed onset adverse reactions and retrospectively notiIied cases. It may be

appropriate to continue submission oI PSURs aIter withdrawal or revocation oI the marketing
authorisation. An agreement should be made on a case-by-case basis with the Competent Authorities
and, where applicable, the Agency.

19
PART I 64/229
5.4 Reporting of Outcomes of Use of a Medicinal Product During Pregnancy
e been exposed to one oI his medicinal products
(either through maternal exposure or transmission oI a medicinal product via semen Iollowing paternal
made to Iollow-up
via the Patient`s Healthcare ProIessional. When a Consumer submits medical documentation that
The Marketing Authorisation Holder should Iollow-up all reports Irom Healthcare ProIessionals
relating to pregnancies where the Ioetus may hav
exposure). Where reports originate Irom Consumers, reasonable attempts should be
supports the occurrence oI a suspected adverse reaction, this should be considered suIIicient to report
the case iI it provides the minimum inIormation (see Chapter I.4, Section 1).
When an active substance, or one oI its metabolites, has a long halI-liIe, this should be taken into
account when considering the possibility oI Ioetal exposure (i.e. medicinal products taken beIore
conception need to be considered) (see Annex 3.1.3).
Individual cases with an abnormal outcome in association with a medicinal product should be reported
on an expedited basis, Iollowing the reporting requirements outlined in Chapter I.4 and in accordance
with the Guideline on Exposure to Medicinal Products During Pregnancy: Need Ior Post-Authorisation
Data (see Annex 3.1.3.) and the ICH-E2B(M) Guidelines (see Annex 4).
This reIers especially to:
Reports oI congenital anomalies in the Ioetus/child;
Reports oI Ioetal death and spontaneous abortion; and
ases requiring expedited reporting, e.g. pregnancy exposure to products
ratogenic potential.
or Competent Authorities requesting inIormation on the teratogenic potential oI
Reports oI adverse reactions in the neonate that are classiIied as serious.
Other cases, i.e. reports oI termination oI pregnancy without inIormation on congenital malIormation
and reports oI pregnancy exposure without outcome data, should not normally be reported on an
expedited basis.
In certain circumstances, the Marketing Authorisation Holder may be requested to treat any reports oI
pregnancy exposure as c
contraindicated in pregnancy because oI a high te
InIormation on exposure to medicinal products during pregnancy should include dates oI exposure
and, as Iar as possible, details oI the period oI gestation at the time oI exposure, speciIied by the
method oI assessment and expressed as weeks and/or days. This inIormation is necessary to establish a
possible causal relationship between the adverse event(s) reported and exposure to the product.
It is also important to collect inIormation on pregnancies, which have a normal outcome. Not
inIrequently, pregnant women or Healthcare ProIessionals will contact either the Marketing
Authorisation Holder
a medicinal product and/or experience oI use during pregnancy (see Annex 3.1.3).
Expedited reports together with other reports on outcome oI exposure during pregnancy should also be
included in the Periodic SaIety Update Report (PSUR) (see Chapter I.6) together with aggregated data
on the overall exposure and details oI normal/abnormal outcomes. Reports Irom prospective registries
on has not (yet) been obtained.
should also be included and evaluated in the PSUR.
II, at any time, the Marketing Authorisation Holder identiIies, or becomes aware oI, a signal oI a
possible teratogenic eIIect (e.g. through a cluster oI similar abnormal outcomes) all Competent
Authorities where a marketing authorisation is held, and also the Agency in the case oI centrally
authorised medicinal products, should be inIormed on an expedited basis. This also applies to possible
signals arising Irom Consumer reports Ior which medical conIirmati
PART I 65/229
5.5 Reporting of Adverse Reactions during Breastfeeding
Adverse reactions suspected in inIants Iollowing exposure to a medicinal product Irom breastIeeding,
should be reported in accordance with Chapter I.4.
5.6 Reporting of Data on Use of Medicinal Products in Children
Collection and evaluation oI data on exposure oI children to medicinal products and associated risks is
an important task and speciIic guidance is thereIore included in the Guideline on Conduct oI
Pharmacovigilance Ior Medicines Used by the Paediatric Population (see Annex 3.1.4). Exposure oI
children should also be considered and addressed in the Risk Management Plan (see Chapter I.3).
5.7 Reporting from Compassionate/Named-Patient Use
ng the medicine and should ideally be the subject oI a protocol.
the Patient are provided with the available inIormation
on the properties oI the medicine with the aim oI maximising the likelihood oI saIe use. The protocol
Companies should continuously monitor the risk-beneIit balance oI medicines used on compassionate
Compassionate or named-patient use oI a medicine should be strictly controlled by the company
responsible Ior providi
Such a protocol should ensure that the Patient is registered and adequately inIormed about the nature
oI the medicine and that both the prescriber and
should encourage the prescriber to report any adverse reactions to the company, and to the Competent
Authority, where required nationally.
or named-patient basis (subject to protocol or not) and Iollow the requirements Ior reporting to the
appropriate Competent Authorities. As a minimum, the requirements laid down in Chapter I.4,
Section 1 apply.
For inclusion oI experience Irom compassionate or named-patient use in Periodic SaIety Update
Reports, see Chapter I.6.
5.8 Reporting of Lack of Efficacy
Reports oI lack oI eIIicacy should not normally be reported on expedited basis, but should be
discussed in the relevant Periodic SaIety Update Report (see Chapter I.6). However, in certain
circumstances reports oI lack oI eIIicacy should be treated as expedited cases Ior reporting purposes.
Me in cines and contraceptives are
exa be considered as cases
requ n
qualiIy
For exa e medicinal product was not in Iact
app r tion where
the k a bacterium
prev u
e reported, in particular with a view to possible signals
oI reduced immunogenicity in a sub-group oI vaccinees, waning immunity and strain replacement.
n and Iurther investigation through post-authorisation saIety studies as appropriate.
dic al products used Ior the treatment oI liIe-threatening diseases, vac
mples oI classes oI medicinal products where lack oI eIIicacy should
iri g expedited reporting. Judgement should be used in reporting, considering iI other cases
Ior reporting.
mple, antibiotics used in liIe-threatening situations where th
rop iate Ior the inIective agent should not be reported. However, a liIe-threatening inIec
lac oI eIIicacy seems to be due to the development oI a newly resistant strain oI
io sly regarded as susceptible should be reported on an expedited basis
For vaccines, cases oI lack oI eIIicacy should b
With regard to the latter, it is considered that spontaneously reported cases oI lack oI eIIicacy as
suspected by a healthcare proIessional may constitute a signal oI strain replacement. Such signals may
need prompt actio
Internationally agreed case deIinitions should be used as available.
PART I 66/229
5.9 Reporting of Suspected Transmission of Infectious Agents
For the purposes oI reporting, any suspected transmission oI an inIectious agent via a medicinal
product is also considered a serious adverse reaction and all such cases should be reported in expedited
manner in accordance with the criteria outlined in Chapter I.4, whether they occur within or outside
the EU.
For cases occurring outside the EU, the legislation includes this reporting requirement speciIically to
ensure that such cases are appropriately reported and to avoid Iailure to report due to interpretation oI
such cases as expected (e.g. given the manuIacturing process). For cases occurring within the EU, the
legal requirement to report any such transmission in expedited manner is addressed by the reporting
requirements Ior all (i.e. expected and unexpected) serious adverse reactions as Chapter I.4.
be classiIied as serious in Iield A.1.5.1, and Iield For electronic reporting, such cases should to
A.1.5.2. 'Seriousness criteria should be set to 'Other medically important condition (see ICH-
E2B(M) in Annex 4).
The requirement to apply MedDRA coding (see Annex 4) is also relevant to the reporting oI cases oI
Because any suspected transmission oI an inIectious agent via a medicinal product is considered a
edically important in the
absence oI other seriousness criteria.
ccurrence oI unknown agents should never be excluded.
oI an inIectious agent via a medicinal product, care
sible, between
se reactions caused by a product in an immunosuppressed patient/vaccinee;
ConIirmation oI contamination (including inadequate inactivation/attenuation oI inIectious agents as
active substances) oI the concerned medicinal product increases the evidence Ior transmission oI an
inIectious agent.
The requirement to report the suspected transmission oI an inIectious agent via a medicinal product

o vaccinees
suspected transmission oI an inIectious agent.
serious adverse reaction, it should be assessed under the category oI m
Any organism, virus or inIectious particle (e.g. prion protein transmitting Transmissible SpongiIorm
Encephalopathy), pathogenic or non-pathogenic, is considered an inIectious agent.
A transmission oI an inIectious agent may be suspected Irom clinical signs or symptoms or laboratory
Iindings indicating an inIection in a patient exposed to a medicinal product. As in the case oI
suspected adverse reactions and adverse reactions, the terms suspected transmission and transmission
are considered synonymous.
Emphasis should be on the detection oI inIections/inIectious agents known to be potentially
transmitted via a medicinal product, but the o
In the context oI evaluating suspected transmission
will have to be taken to discriminate, whenever pos
adverse reactions caused by a product manuIactured as speciIied;
adverse reactions caused by a product with conIirmed contamination;
adverse reactions caused by a medication error, including distribution, storage, prescribing and
administration error;
adverse reactions caused by a product designed in a way that it may insuIIiciently prevent
medication errors or contamination during administration;
adverse reactions caused by the injection oI a product, e.g. injection-site reactions;
adver
adverse reactions caused by a product in close contacts oI the patient/vaccinee.
MedDRA coding also applies in this context.
also applies to vaccines, including live attenuated vaccines. For the latter, e.g. shedding, transmission
oI the attenuated agent to close contacts and reversion to virulence may cause harm t
PART I 67/229
and/or their close contacts. Pregnant women and the Ioetus might be at particular risk. Furthermore, as
with other biological medicinal products, certain batches oI a vaccine may be contaminated and cause
adverse reactions in vaccinees.
Signals arising Irom case reports on suspected transmission oI an inIectious agent should be
investigated as Ior other adverse reactions.
Where a quality deIect is suspected or conIirmed, the procedures laid down in the Compilation oI
Community Procedures on Inspections and Exchange oI InIormation
20
should also be Iollowed. Any
contamination oI a medicinal product should be considered serious and is likely to be classiIied as a
Cla
Th t
ss 1 or Class 2 Product DeIect.
e po ential Ior transmission oI an inIectious agent via a medicinal product should also be addressed
in R
In
the isk Management Plan (see Chapter I.3).
case oI medicinal products derived Irom human b the lood or human plasma, haemovigilance
pro u ced res also apply, in accordance with Directive 2002/98/EC.
Medicin ote Ior Guidance on Minimising the Risk oI al products should also comply with the N
Transmitting Animal SpongiIorm Encephalopathy Agents Via Human and Veterinary Products
21
.
5.10 Reporting in Relation to Overdose, Abuse and Misuse
The Marketing Authorisation Holder should collect any available inIormation on overdose, abuse and
misuse related to his products. Reports oI overdose, abuse and misuse should be routinely Iollowed up
to ensure that inIormation is as complete as possible with regard to early symptoms, treatment and
outcome. The Marketing Authorisation Holder should report cases oI overdose, abuse and misuse that
lead to serious adverse reactions on an expedited basis in accordance with the requirements in
Chapter I.4. This includes cases oI intended suicide. The Marketing Authorisation Holder should
continuously monitor and evaluate the potential impact oI overdose, abuse and misuse on the overall
risk-beneIit balance oI the medicinal product. The potential Ior overdose, abuse and misuse and the
associated risks should also be addressed in the Periodic SaIety Update Reports (see Chapter I.6) and
the Risk Management Plan (see Chapter I.3).
5.11 Reporting of Medication Errors
The Marketing Authorisation Holder should report cases oI medication errors that are associated with
serious adverse reactions on an expedited basis in accordance with the requirements in Chapter I.4,
and as required by national requirements. Cases not associated with adverse reactions and near misses
should only be reported in accordance with national requirements. Cumulative inIormation on
medication errors, resulting in adverse reaction or not, should be discussed in the section oI the
Periodic SaIety Update Report on the overall saIety evaluation (see Chapter I.6). The potential Ior
medication errors and their prevention should be addressed in the Risk Management Plan (see
Chapter I.3).
For reporting oI medication errors due to conIusion oI invented names in relation to centrally
authorised products, see the Guideline on the Acceptability oI Invented Names Ior Human Medicinal
Products Processed through the Centralised Procedure
22
.

20
21
Doc.ReI. EMEA/410/01 latest version, available on EMEA website http://www.emea.europa.eu.
22
Doc.ReI. EMEA/CPMP/328/98, latest version available on EMEA website http://www.emea.europa.eu.
PART I 68/229
PART I 69/229
2 cy
lic health threat duly recognised either by the World Health
5.1 Reporting in the Event of a Public Health Emergen
A public health emergency is a pub
Organization (WHO) or the Community in the Iramework oI Decision No. 2119/98/EC oI the
European Parliament and oI the Council. In the event oI a public health emergency, regular reporting
requirements may be amended. Such arrangements will be considered on a case-by-case basis and
appropriately notiIied.
For anti-inIluenza products used in a pandemic, the Iollowing documents are available on the EMEA
website http://www.emea.europa.eu:
EMEA Pandemic InIluenza Crisis Management Plan Ior the Evaluation and Maintenance oI
Pandemic InIluenza Vaccines and Antivirals (EMEA/214301/2006, latest version);
Guideline on InIluenza Vaccines Prepared Irom Viruses with the Potential to Cause a
Pandemic and Intended Ior Use Outside oI the Core Dossier Context
(EMEA/CHMP/VWP/263499/2006, latest version);
CHMP Recommendations Ior the Pharmacovigilance Plan as part oI the Risk Management
Plan to be submitted with the Marketing Authorisation Application Ior a Pandemic InIluenza
Vaccine (EMEA/32706/2007, latest version).
6. Requirements for Periodic Safety Update Reports
6.1 Introduction
A Periodic SaIety Update Report (PSUR) is intended to provide an update oI the worldwide saIety
experience oI a medicinal product to Competent Authorities at deIined time points post-authorisation.
At these times, Marketing Authorisation Holders are expected to provide succinct summary
inIormation together with a critical evaluation oI the risk-beneIit balance oI the product in the light oI
new or changing inIormation. This evaluation should ascertain whether Iurther investigations need to
d be made to the marketing authorisation and product
tion ( 01/83/EC establish the periodicity Ior submission oI
be carried out and whether changes shoul
inIormation.
Regula EC) No 726/2004 and Directive 20
PSURs, unless other requirements are laid down as a condition Ior the granting oI the marketing
authorisation. This Chapter is consistent with ICH-E2C and the Addendum to ICH-E2C (now ICH-
E2C(R), see Annex 4).
It should be noted that electronic periodic submission oI Individual Case SaIety Reports (ICSRs) Ior
centrally authorised products, described in Chapter III.11, Section 7, is a process that is independent oI
PSUR submission.
Once a medicinal product is authorised in the EU, even iI it is not marketed, the Marketing
Authorisation Holder is required to submit PSURs at 6-monthly intervals. When launch dates are
planned, this inIormation should be reIlected in the upcoming PSUR.
Once marketed, 6-monthly PSUR submissions should be continued Iollowing initial placing on the
market in the EU and until two Iull years oI marketing experience in the EU has been gained. Then,
PSURs should be submitted once a year Ior the Iollowing two years and thereaIter at 3-yearly
intervals.
PSURs should also be submitted upon request oI a Competent Authority or the Agency at any time
aIter granting oI the marketing authorisation.
Moreover, review oI the periodicity is also part oI the Risk Management Plan and its assessment (see
Chapter I.3).
There may be situations where exceptionally the submission oI 6-monthly and subsequent yearly
PSURs may be re-started, or where other amendments oI the periodicity are required. This is Iurther
explained in Chapter I.6, Section 2.4.c.
For medicinal products authorised through the centralised procedure, PSURs should be submitted to
the Competent Authorities oI all Member States and to the Agency in accordance with Regulation
(EC) No 726/2004 Article 24. For medicinal products authorised nationally, PSURs should be
submitted to the Competent Authorities in accordance with Directive 2001/83/EC, Article 104 (see
Distribution Requirements and Address Lists Ior PSURs in Annex 6.2).
II the Marketing Authorisation Holder considers, on the basis oI the data included in the PSUR, that
amendment oI the Summary oI Product Characteristics (SPC) is necessary, a variation application
For products authorised through the centralised, mutual recognition or decentralised procedures,
amendments to the PSUR submission periodicity should be agreed via a type II variation. For
nationally authorised products, amendments to the PSUR submission periodicity should be agreed
should be submitted with the PSUR, or where this is not possible, a timetable Ior submission should be
proposed at the time oI PSUR submission.
according to the national requirements.
PART I 70/229
Fo t
decentr
synchro r many
points are published by the Heads oI Medicines
r na ionally authorised products, including those authorised through the mutual recognition or
alised procedures, initiatives have been taken by the national Competent Authorities to
nise PSUR submission schedules Ior products containing the same active substance. Fo
active substances, harmonised 'virtual birth dates, so-called EU Harmonised Birth Dates (EU HBDs)
and related harmonised data lock points Ior the Iollowing PSURs have been agreed between the
relevant Marketing Authorisation Holders Ior originator products and national Competent Authorities.
These harmonised birth dates and related data lock
Agencies
23
. Marketing Authorisation Holders Ior generic products are encouraged to use the same
PSUR submission schedules as those agreed Ior originator products.
6.2 General Principles
6.2.1 General Scope of Information
The main Iocus oI the PSUR should be the presentation, analysis and evaluation oI new or changing
saIety data received during the period covered by the PSUR. For this purpose, analysis oI adverse
reaction reports, an overview oI cumulative data, saIety data Irom studies and other relevant saIety
inIormation, as well as Iollow-up oI any Risk Management Plan (see Chapter I.3) should be
adequately addressed in the PSUR. Reports oI lack oI eIIicacy (see Chapter I.5, Section 8),
tain
in
speciIically Ior medicinal products used in the treatment oI liIe-threatening conditions and Ior cer
other medicinal products, e.g. contraceptives and vaccines, may represent a signiIicant hazard and
that sense may give rise to a saIety concern. These types oI cases should be discussed within the
PSUR (see Chapter I.6, Section 3.9.a). Moreover, data Irom pregnancy experience and outcome
should also be discussed.
An increase in the Irequency oI Individual Case SaIety Reports (ICSRs) Ior known adverse reactions
is considered as relevant new inIormation. Although increased reporting should be discussed in the
PSUR, it is not possible to provide speciIic guidance as to what constitutes increased reporting or what
ilitate a consistent, broad-based examination oI the saIety inIormation
Ior the active substance(s) in a single document.
osage Iorm, route oI
dy oI the
a
, the Competent Authorities or the Marketing Authorisation Holder
may co de . In such cases, agreement should be obtained at
the time oI a o de:

method should be used Ior quantiIying this. The Marketing Authorisation Holder should provide
details oI the methods that have been used. Judgement should be used in such situations to determine
whether the data reIlect a meaningIul change in occurrence oI adverse reactions or in the saIety proIile
and whether an explanation can be proposed Ior such a change (e.g. population exposed, duration oI
exposure).
6.2.2 One Periodic Safety Update Report for Products Containing an Active
Substance Authorised to One Marketing Authorisation Holder
It is recommended that inIormation on all indications, dosage Iorms, routes oI administration and
regimens Ior a given active substance Ior medicinal products authorised to one Marketing
Authorisation Holder should be included in a single PSUR, with a single data lock point common Ior
all aspects oI product use to Iac
When relevant and possible, data relating to a particular indication, d
administration or dosing regimen should be presented in separate sections within the bo
PSUR and any saIety concerns addressed accordingly without preparing a separate PSUR (e.g.
section dedicated on paediatric use summarising saIety as well as exposure inIormation).
In exceptional cases, the Agency
nsi r it appropriate to have a separate PSUR
uth risation or during the post-authorisation phase, as applicable. Examples inclu

23
Available on Heads oI Medicines Agencies website http://heads.medagencies.com.
PART I 71/229
s to existing medicinal products (e.g. an active
subs ce
Products authorised through line extension
tan in two or more diIIerent Iormulations Ior systemic versus topical administration)
with cros ate (see Chapter I.6, Section 6.2.4.c);
Fixe o bination with
older, the data lock points used Ior the PSURs Ior the Iirst product should normally be
tion, in order to put in place measures Iacilitating work sharing oI PSUR assessment among
er or the Competent Authorities. In this context, submission oI a type II
s-reIerence between PSURs, iI appropri
d c mbinations, where options include either a separate PSUR Ior the com
cross-reIerence to the single-substance PSUR(s) or inclusion oI the Iixed combination data
within one oI the single-substance PSURs.
II a subsequent marketing authorisation is granted to a Marketing Authorisation Holder Ior a product
which contains the same active substance as one previously granted to the same Marketing
Authorisation H
used Ior the Iollowing joint PSURs covering the Iirst and all subsequent products.
In addi
Competent Authorities, harmonisation oI birth dates, renewal dates and/or PSUR submission
schedules Ior medicinal products containing the same active substances may be proposed by the
Marketing Authorisation Hold
variation to amend the schedule is not required, iI the Marketing Authorisation Holder Iollows the
harmonised PSUR submission schedule.
6.2.3 Products Authorised to More Than One Marketing Authorisation Holder
Where a product is authorised to more than one Marketing Authorisation Holder, in the case oI
multiple applications, submission oI common PSURs is acceptable provided that the products remain
identical in all respects apart Irom their invented names and that the PSURs are submitted separately
by each Marketing Authorisation Holder. The data lock point should be based on the birth date used
Ior the Iirst authorised product. The submission cover letter should conIirm that the data in these
PSURs are identical.
Generic products should preIerably have the same PSUR submission periodicity as the corresponding
originator product (see Chapter I.6, Section 6.2.4.c). It is generally considered acceptable that
Marketing Authorisation Holders Ior generic products collaborate on the preparation oI PSURs.
However, each Marketing Authorisation Holder remains responsible Ior the appropriate submission oI
PSURs Ior their products. Where common PSURs are submitted, the Marketing Authorisation Holders
should conIirm in writing that the data in these PSURs are identical.
Marketing Authorisation Holders who have contractual arrangements in place but opt not to submit
common PSURs, should ensure that all data which may meaningIully contribute to the saIety analysis
and inIluence any proposed or eIIected changes in the Product InIormation oI the medicinal product
c Submission of Periodic Safety Update Reports
In acco
and sub
upon request Irom a Competent Authority or the Agency; and
authorised to the reporting Marketing Authorisation Holder, should be included, with the source
indicated, and discussed in the PSUR, even iI it is known that they are included in another Marketing
Authorisation Holder`s PSUR.
6.2.4 Frequency of Review and Reporting
6.2.4.a) Regular and Ad Ho
rdance with the regular periodicity Ior PSUR submission, PSURs are required to be prepared
mitted:
beIore initial placing on the EU market:
immediately
at least every 6 months aIter authorisation;
PART I 72/229
aIter initial placing on the EU market:
6-monthly PSUR submissions should be continued until two Iull years oI marketing
experience in the EU has been gained;
The Iirst PSUR should have a data lock point within 6 months aIter granting oI the marketing
Each PSUR should cover the period oI time since the last PSUR and should be submitted within 60
e time oI
renewal is an opportunity to review and, iI necessary, change the periodicity PSUR, or to request a
yearly PSURs Ior the Iollowing two years; and
thereaIter PSURs should be submitted at 3-yearly intervals;
in addition, PSURs should be submitted immediately upon request Irom a
Competent Authority or, Ior centrally authorised products, Irom the Agency.
authorisation.
The date oI initial placing on the EU market is the date oI launch, Ior the Iirst time, in any Member
State.
days aIter the data lock point.
Because the renewal is an independent process, it does not change the data lock point and submission
schedule Ior the PSURs. It should be noted that re-assessment oI the risk-beneIit balance at th
second renewal.
When yearly or 3-yearly PSURs are due Ior submission, multiple 6-monthly or yearly PSURs are
acceptable, provided that the Marketing Authorisation Holder submits a PSUR Summary Bridging
Report, the content oI which is described in Chapter I.6, Section 4. It should be noted that in such
cases, the Marketing Authorisation Holder should not send 6-monthly or yearly PSURs 60 days aIter
the data lock points oI these 6-monthly or yearly PSURs, but should send them only at the required
due date (yearly or 3-yearly).
II a tim
Authori
e gap occurs between the data lock point oI a regular PSUR and a request Irom a Competent
ty (e.g. renewal, Risk-BeneIit Review, ad hoc PSUR request), a PSUR Addendum Report
should
3 years
the 3-ye ter than 6 months.
Exceptionally, a Marketing Authorisation Holder may make a special request to the Competent
vided that there is no new
and/or
ight require additional
or Iurther analysis.
submitted on the appropriate date in line with their original periodicity.
also be submitted (see Chapter I.6, Section 5). For a PSUR that spans longer time intervals, e.g.
, an Addendum Report would only be considered appropriate iI the time since preparation oI
ar PSUR and the locally required report is grea
For PSURs requested Ior immediate submission by a Competent Authority or the Agency on an ad hoc
basis, the Marketing Authorisation Holder should liaise with the Competent Authority/the Agency to
agree the PSUR submission date, depending on the urgency oI the issue.
Authority Ior 30 additional calendar days to submit a PSUR. Ideally, this request should be made
beIore the data lock point. The Competent Authority should respond as rapidly as possible. The basis
Ior such a request should be justiIied and could include:
a large number oI case reports Ior the reporting period, pro
signiIicant saIety concern;
saIety concerns raised by Competent Authorities in the previous PSUR Ior which the
Marketing Authorisation Holder is preparing additional or Iurther analysis in the next PSUR;
saIety concerns identiIied by the Marketing Authorisation Holder that m
The Marketing Authorisation Holder should make such a request only Ior the speciIic PSUR in
question and not Ior subsequent PSURs. Subsequent PSURs will generally be expected to be
PART I 73/229
6.2.4.b) Submission of Periodic Safety Update Reports for Renewal of Marketing
Authorisations
The Guideline on the Processing oI Renewals in the Centralised Procedure and the Guideline on the
Processing oI Renewals in the Mutual Recognition and Decentralised Procedures deIine the diIIerent
requirements to be respected Ior the purpose oI data submission as part oI the renewal application (Ior
both Guidelines see Volume 2C oI The Rules Governing Medicinal Products in the European
Union
24
).
The Marketing Authorisation Holder should submit saIety data with the renewal application at least 6
ission oI saIety
concept should be
ays beIore
authorisation in any Member State, in order to Iacilitate
months beIore the expiry date oI the marketing authorisation in the EU. For the subm
data as part oI the application Ior renewal oI the marketing authorisation, the PSUR
data no more than 60 d used. The Marketing Authorisation Holder should lock the
submitting the PSUR.
The data lock point Ior submission oI saIety inIormation should be at 4 years and 4 months Iollowing
the marketing authorisation date. Renewal applications may be submitted earlier than 6 months beIore
the expiry date oI the marketing
synchronisation oI the PSUR submission schedule as well as harmonisation oI renewal dates.
For the purpose oI the renewal application, the Marketing Authorisation Holder should submit:
the PSUR, or the PSUR plus a PSUR Addendum Report (see Chapter I.6, Section 5) or plus
line-listings and/or summary tabulations, or only a PSUR Addendum Report, or only line-
listings and/or summary tabulations (see Chapter I.6, Sections 2.4.d and 2.6.c), covering the
t is accepted that previously
submitted PSURs should not be re-submitted, provided that a list oI original submission dates
rity or the Agency concludes that an additional
renewal is needed, this conclusion may also include a requirement Ior an additional period oI 6-
equirements. It should be noted that re-
assessment oI the risk-beneIit balance at the time oI renewal is an opportunity to review and, iI
Th
applications with the relevant Com
agr n
6.2
Submis the normal conditions oI marketing authorisations and
period since the data lock point oI the last PSUR (e.g. Ior the Iirst renewal, the saIety data oI
this PSUR or Addendum Report together with the PSURs previously submitted should cover a
period oI 4 years and 4 months since the marketing authorisation); and
a PSUR Summary Bridging Report, bridging all PSURs (including those already submitted)
covering the period oI 4 years and 4 months. Alternatively, the inIormation which corresponds
by its content with the PSUR Summary Bridging Report may be included in the Clinical
Overview, to be submitted with the renewal application. I
is appended to the Summary Bridging Report.
II at the time oI the Iirst renewal, the Competent Autho
monthly or yearly PSURs. The second renewal application should discuss PSURs data covering a Iive-
year period since the data lock point oI the PSUR(s) submitted with the Iirst renewal application.
Because the renewal is an independent process, it does not change the periodicity and submission
dates Ior PSURs due as part oI pharmacovigilance reporting r
necessary, change the PSUR periodicity, or to request a second renewal.
e Marketing Authorisation Holder may discuss the requirements Ior PSURs Ior the renewal
petent Authorities oI the Member States and/or the Agency, and
ee o the appropriate PSUR documentation required.
.4.c) Circumstances Where the Periodicity May Be Amended
sion oI PSURs is part oI
pharmacovigilance obligations oI the Marketing Authorisation Holder. The periodicity oI PSUR

24
PART I 74/229
submission may be amended, as required by the Competent Authority or proposed by the Marketing
Authorisation Holder. This may result in more or less Irequent submission oI PSURs. However,
submission oI PSURs at a lower Irequency than once every 3 years is not possible.
uld submit, as
part oI the application Ior a marketing authorisation, a reasoned request Ior the amendment, which, iI

Ior such an a owing authorisation, such an application should Iollow the procedures Ior a
type II variation.
ances where less Irequent submission oI PSURs may be appropriate include:
Where an amendment is proposed, the Applicant/Marketing Authorisation Holder sho
granted, becomes part oI the conditions oI authorisation. II a Marketing Authorisation Holder applies
mendment Ioll
Circumst
Products authorised through line-extensions to existing medicinal products;
Newly authorised generic medicinal products.
A priori, a line-extension triggers the restart oI the regular PSUR periodicity, unless a diIIerent
periodicity has been agreed as a condition Ior the granting oI the marketing authorisation (Article
104(6) oI Directive 2001/83/EC).
However, in many cases, there will be no need to restart the regular PSUR periodicity Iollowing the
amendment oI the periodicity, iI
hile the PSUR submission Ior the
indication Ior an existing medicinal product is an example oI a line-
line-extension, as data Ior the newly authorised product may be addressed in the PSURs submitted
according to the existing submission schedule. A justiIication Ior continuing the existing submission
schedule should be provided by the Marketing Authorisation Holder as part oI the line-extension
application, and the conditions Ior the authorisation will include any
required, as part oI the outcome oI the application evaluation.
Where separate PSURs Ior the product approved through the line-extension are considered
appropriate, these should be submitted in accordance with the authorisation date oI the newly
approved product by starting the regular PSUR periodicity, w
previously authorised product(s) continues according to the existing submission schedule. These
requirements should be reIlected in the conditions Ior the authorisation. II/when separate PSURs are
no longer considered necessary, data relevant to the product approved through the line-extension
should be incorporated in a single PSUR covering all related products.
The addition oI a paediatric
extension which would result in re-starting the regular PSUR periodicity Iollowing the authorisation
date oI the newly approved product (see Annex 3.1.4).
For newly authorised generic products or products authorised on the basis oI inIormed consent
applications, application Ior submission oI PSURs on a 3-yearly basis may be included in the
authorisation application. PSURs Ior such products should preIerably have the same data lock points
as the corresponding originator product (see Chapter I.6, Section 2.4.c). Such applications will be
assessed on a case-by-case basis by the Competent Authority.
Circumstances where more Irequent PSUR submission may be required include:
varia ns, populations, dosage Iorms and routes oI
administrations;
rresponding originator product requiring speciIic
tions introducing new indicatio
an active substance which is a diIIerent salt/ester or derivative (with the same therapeutic
moiety);
the presence oI an excipient without an established saIety proIile; and
a Risk Management Plan in place Ior a co
monitoring oI a saIety concern.
In some circumstances, e.g. Ior biological products, a change in the manuIacturing process may
require close monitoring oI possible clinical impact in terms oI saIety. ThereIore, the conditions under
PART I 75/229
which the related variation oI the marketing authorisation is granted, may include a re-start oI the
regular PSUR periodicity.
II the Competent Authority considers it appropriate to amend the PSUR periodicity and submission
schedule, this should be clearly communicated to the Marketing Authorisation Holder.
The IBD is the date oI Iirst marketing authorisation oI a medicinal product granted to the Marketing
on date Ialls.
6.2.4.d) Preparation of Periodic Safety Update Report according to the International
Birth Dates
Medicinal products, which are also authorised outside the EU, will have an International Birth Date
(IBD).
Authorisation Holder (or a contractual partner oI the Marketing Authorisation Holder) anywhere in the
world. For practical reasons, the IBD may be deIined as the last day oI the month in which this Iirst
authorisati
The EU Birth Date (EBD) is the date oI Iirst marketing authorisation granted Ior the medicinal product
in any EU Member State to the Marketing Authorisation Holder (see Glossary in Annex 1.1).
older may use
the IBD to determine the dates oI the datalock points Ior the PSUR submission schedule, provided that
thorised medicinal products that are marketed in Member States, the
Marketing Authorisation Holder may wish to synchronise national birth dates with the IBD. Although
For nationally authorised products, including those authorised through the mutual recognition or
In order to harmonise PSUR submissions internationally, the Marketing Authorisation H
the Iirst datalock point Ialls within the 6 months Iollowing the EBD.
AIter initial placing oI the product on the EU market, the Marketing Authorisation Holder should
submit at least Iour PSURs covering 6 months each, in order to ensure that two Iull years oI
experience with the product on the EU market are covered through provision oI 6-monthly PSURs,
while keeping the data lock point according to the IBD or EBD.
For purely nationally au
such a process may be diIIicult (e.g. multiple applications Ior variations might be required), such a
step may be Ieasible and should be discussed with the Competent Authorities. II Ieasible, this may be
implemented by notiIication.
decentralised procedures, where national birth dates are used to determine the submissions oI PSURs,
the Marketing Authorisation Holders and Competent Authorities may liaise and designate an EU HBD
which may be the IBD (see Chapter I.6, Section 1). AIter such harmonisation oI the birth date, the Iirst
PSUR to be submitted in the EU should be based on the EU HBD and should cover a period in
accordance with the liIe cycle oI the product in the EU (6 months, 1 year or 3 years). When PSURs
have previously been submitted in Member States based on diIIerent national birth dates, Competent
us knowledge oI the medicinal product`s saIety, and to indicate whether
changes should be made to the Product InIormation or the Risk Management Plan. ReIerence
inIormation is needed to carry out this comparison.
Having one reIerence saIety document would Iacilitate a practical, eIIicient and consistent approach to
the saIety evaluation and make the PSUR a unique report also accepted in other regions oI the world.
Authorities should accept that there may be an overlap between the last PSUR based on a national
birth date and the Iirst PSUR based on the EU HBD.
6.2.5 Reference Safety Information
An objective oI a PSUR is to establish whether inIormation recorded during the reporting period is in
accordance with previo
PART I 76/229
It is common practice Ior Marketing Authorisation Holders to prepare their own Company Core Data
Sheet (CCDS), which includes material relating to saIety, indications, dosing, pharmacology and other
practical option Ior the purpose oI the PSUR is Ior each
Marketing Authorisation Holder to use, as a reIerence, the saIety inIormation contained within the
t
pur reporting in the EU.
It is im ingIul diIIerences between the CCSI and the EU or national SPC in
the cover letter accompanying the submission oI the PSUR. The EU or national SPC should also be
pro e
ing oI the period
e reIerence inIormation.
When produ ore than one year or a PSUR Summary Bridging
Report, it is oI listedness on the CCSI that was in eIIect at the
beginni onsiderable variation in listedness over the reporting period.
iod may be used Ior PSURs covering a longer
year, when listedness is assessed at the time oI
UR.
Authorisation Holder should ensure that all changes to the CCSI made over this period are
inIormation concerning the product. A
CCDS, which is reIerred to as Company Core SaIety InIormation (CCSI).
For the purposes oI PSURs, the CCSI Iorms the basis Ior determining whether an adverse reaction is
already listed or is still unlisted (listed and unlisted are terms that are introduced to distinguish them
Irom the usual terminology oI expectedness, which is used in association with the authorised Produc
InIormation). The EU Summary oI Product Characteristics (SPC) or national SPC authorised by a
Member State continues to be the reIerence document upon which expectedness is based Ior the
pose oI expedited post-authorisation saIety
portant to highlight mean
vid d.
For 6-monthly and yearly PSURs the version oI the CCSI in eIIect at the beginn
covered by the PSUR should be used as th
However, there may be valid reasons to use the CCSI in eIIect at the end oI the period:
cing a PSUR covering a period oI m
e analysis oIten impractical to base th
ng oI the period. There may be c
ThereIore, the latest CCSI in eIIect at the end oI the per
period. For PSURs covering a period oI more than one
PSUR preparation aIter the data lock point, it is generally considered appropriate to use the version oI
the CCSI in place at the end oI the reporting period as the reIerence document, as long as that choice is
made clear in the PS
Whether the CCSI valid at the beginning or at the end oI the period covered in the PSUR is used, the
Marketing
described in the relevant section oI the PSUR entitled 'Changes to the ReIerence SaIety InIormation
(see Chapter I.6, Section 3.5).
Marketing Authorisation Holders assessing listedness at case entry or on an ongoing basis throughout
the reporting period should include the current version oI the CCSI and comment on the reasons Ior
any change in listedness assessment over time. In both cases, changes added since the previous PSUR
should be explained in the PSUR sections 'Changes to ReIerence SaIety InIormation (see Chapter
I.6, Sec
The Re
HBD sh s oI the
con n
lock poi
should horisation Holder should indicate in the PSUR which changes
to
examin
tion 3.5) and/or 'Overall SaIety Evaluation (see Chapter I.6, Section 3.10).
Ierence SaIety InIormation to be used Ior PSURs Ior generic medicinal products based on EU
ould consist oI the common saIety inIormation that is included in all current SPC
cer ed generic medicinal product, as authorised in the EU Member States at the time oI the data
nt. In addition, a summary oI the other saIety inIormation that was not included in all SPCs
be submitted. The Marketing Aut
the ReIerence SaIety InIormation as used are considered necessary on the basis oI the data
ed in the PSUR.
PART I 77/229
6.2.6 Presentation of Data on Individual Cases
6.2.6.a) Sources of Information
Generally, adverse reaction data Irom the Iollowing sources are potentially available to the Marketing
s agreements);
The reaction term he MedDRA terminology
Authorisation Holder and should be included in the PSUR:
Adverse reaction reports notiIied directly to the Marketing Authorisation Holder (or through
schemes under its control):
Spontaneous reports Irom Healthcare ProIessionals;
Reports Irom Marketing Authorisation Holder-sponsored studies or named-
patient/compassionate use;
Reports Irom Patients and other Consumers (not medically conIirmed).
Literature
Adverse reaction reports received Irom regulatory authorities worldwide:
Spontaneous and non-spontaneous reports Irom Healthcare ProIessionals;
Reports Irom Patients and other Consumers (not medically conIirmed).
Other sources oI data including:
Exchange oI reports on adverse reactions in the Iramework oI contractual arrangements
(e.g. licensors-licensee
Data Irom special registries;
Reports Irom poison control centres;
Epidemiological databases.
6.2.6.b) Description of the Adverse Reaction
s used in the PSUR should be in accordance with t
(see Annex 3.2.1).
Whenever possible, the original reporter`s reaction terms should be used to des
rea o
However, w m not medically appropriate or meaningIul, the
Marketing Authorisation Holder shoul lternative com atible reaction terms Irom
M ost accurate possible h ms. r such
circum should
ble to make it a the 'verbatim inIormation supplied by the
ter should be kept on I he original language and/or as a medically valid
ranslation, iI applicable).
In the absence oI a dia orter, a sugges d diagnosis Ior a symptom
complex may be made by sation Holder and used to describe the case,
o presenting the reported ind idual signs, symptoms and laboratory data.
Authorisation Hold grees with a diagnosis that is provided by the
such disagreemen indicated within the line-listing oI cases
cribe the adverse
cti n.
hen the original reporter`s ter s are
d use the best a p
edDRA to ensure the m
stances, the Iollowing
representation oI t e original ter Unde
be borne in mind:
vailable on request, In order to be a
original repor ile (in t
English t
gnosis by the original rep
the Marketing Authori
te
in addition t iv
II the Marketing er disa
original reporter, t may be
(see Chapter
The Ma
I.6, Section 2.6.c).
rketing Authorisation Holde d report and try nderstand all i ormation
case report. An example is a laboratory abnormality not addressed/evaluated
r.
riptions oI the signs, symptoms or diagnosis could
the
r shoul to u nI
provided within a
by the original reporte
ThereIore, when necessary and relevant, two desc
be presented in the line-listing: Iirst, the reaction as originally reported; second, when it diIIers,
Marketing Authorisation Holder`s medical interpretation (identiIied by asterisk or other means).
PART I 78/229
6.2.6.c) Line listings and/or Summary Tabulations
Depending on their type or source, available adverse reaction cases should be presented as line-listings
and/or as summary tabulations (see Table below).
arily all the details customarily collected on
individual cases; however, it does serve to help Competent Authorities identiIy cases which they may
im (or under his control), including those Irom persons and
org s
A line-listing provides key inIormation but not necess
wish to examine more completely by requesting Iull case reports.
The Marketing Authorisation Holder should prepare line-listings oI consistent structure and content
Ior cases directly reported to h
ani ations with whom the Marketing Authorisation Holder has set up contractual arrangements, as
we s
should
aut m
suc s keting Authorisation Holder has contractual
ll a those received Irom worldwide regulatory authorities (see Chapter I.6, Section 2.6.a). They
usually do the same Ior published cases (usually well documented; iI not, Iollow-up with the
hor ay be possible). However, inclusion oI individual cases Irom second- or third-hand sources,
anisations with whom the Mar h a persons or org
arr e
sta rd
unn s by the Marketing Authorisation Holder.
Th o iew oI these data are considered acceptable
e reaction), and also on other cases Ior which line-listings are not requested
ang ments and special registries (see Chapter I.6, Section 2.6.a) may not be possible without
nda isation oI data elements, or appropriate due to the paucity oI inIormation, and may represent
ece sary re-entry/re-processing oI such inIormation
sibly a narrative rev ereI re, summary tabulations or pos
nces. under these circumsta
In addition to individual case line-listings, summary tabulations oI adverse reaction terms Ior signs,
symptoms and diagnoses across all patients should usually be presented to provide an overview. Such
tabulations should be based on the data in the line-listings (e.g. all serious adverse reaction and all
non-serious unlisted advers
(e.g. non-serious listed adverse reactions). Details are Iound in Chapter I.6, Sections 3.7.a and 3.7.b.
Presentation of individual case histories in the PSUR:
Source Type of Case Only Summary
Tabulation
Line-Listing and
Summary
Tabulation
1. Direct Reports to MAH
Spontaneous reporting*

serious yes
Post-authorisation saIety
studies and other studies
Compassionate use
programmes
non-serious listed
serious / attributable to drug by
investigator or sponsor

yes**
yes
non-serious unlisted
serious
yes

yes
2. Literature serious
non-serious unlisted
yes
yes
3. Other sources
Regulatory authorities
Contractual partners***
serious
serious

yes
yes
egistries
oison control centres
serious
serious
yes
yes

R
P
E

pidemiological databases serious yes
* Medica irmed reports should be provided as an annex to the PSUR as a line-listing.
** -l
*** t
MAH has in 'Direct Reports
to MAH.
lly unconI
Line isting should be provided as an annex to the PSUR.
For he purpose oI this Table, the term contractual partners does not reIer to persons and organisations to whom the
transIerred pharmacovigilance tasks and Iunctions. Such persons and organisations are included

PART I 79/229
6.3 Model for a Periodic Safety Update Report (PSUR)
The Iollowing Sections are organised as a model PSUR. In each oI these Sections, guidance is
provided on what should be included.
6.3.1 PSUR section Executive Summary
The Marketing Authorisation Holder should prepare a brieI overview oI each PSUR in the Iorm oI an
Executive Summary to provide the reader with a description oI the most important inIormation. The
vered by the PSUR (e.g. any
ata;
Number oI new case reports received during the period covered by the PSUR and the
Particular issues and saIety concerns investigated;
When the Marketing Authorisation Holder has perIormed a review oI one or several speciIic saIety

that have be
g Authorisation Holder should brieIly introduce the product so that the PSUR 'stands
alo b ircumstances.
ReIeren the PSUR but also those excluded.
Ex i Ior example, they may be covered in a separate PSUR (e.g. Ior a
com n
II it is known that a PSUR on the same product(s) will be submitted by another Marketing
Executive Summary should be placed at the beginning oI the PSUR immediately aIter the title page
and should include a summary oI:
The worldwide marketing authorisation status (including a list oI countries where the product
is authorised/marketed and the authorised indications;
Other relevant regulatory inIormation related to the period co
urgent saIety restriction should be highlighted);
Exposure d
cumulative numbers;
Overall Iindings oI the PSUR;
Conclusions.
concern(s), this should be stated in this Executive Summary (as well as the nature oI saIety concerns
en reviewed).
6.3.2 PSUR section Introduction
The Marketin
ne ut is also placed in perspective relative to previous PSURs and c
ce should be made not only to product(s) covered by
clus ons should be explained;
bi ation product).
Au ri hose data are included in the PSUR (see Chapter I.6, Section 2.3),
provided Ior any indication, usually as a table, Ior all countries
ng:
Dates oI marketing authorisation and subsequent renewal (where PSURs are common Ior
Treatment indications and special populations covered by the market authorisation, when
tho sation Holder and some oI w
the possibility oI data duplication should be noted.
6.3.3 PSUR section Worldwide Marketing Authorisation Status
This section oI the PSUR provides cumulative inIormation.
The Iollowing inIormation should be
where a regulatory decision about marketing has been made related to the Iollowi
identical products with diIIerent invented names, or in the case oI generic medicinal products,
the list oI the dates should cover all products separately);
Any qualiIications surrounding the authorisation, such as limits on indications iI relevant to
saIety;
relevant;
PART I 80/229
Lack oI approval, including explanation, by worldwide regulatory authorities;
Withdrawal by the company oI an application Ior authorisation submission iI related to saIety
or eIIicacy;
Dates oI launch (where PSURs are common Ior identical products with diIIerent invented
names or in the case oI generics, the listing oI the dates should cover separately all products);
Dates when the marketing authorisation has been revoked/withdrawn or dates when the
marketing or marketing authorisation has been suspended either by a regulatory authority or
voluntarily by the Marketing Authorisation Holder;
at are related to such diIIerent exposures.
con status tables Ior diIIerent product uses or Iorms
Invented name(s).
Typically, indications Ior use, populations treated (e.g. children vs. adults) and dosage Iorms will be
the same in many or even most countries where the product is authorised. However, when there are
important diIIerences, which would reIlect diIIerent types oI patient exposure, such inIormation
should be noted. This is especially true iI there are meaningIul diIIerences in the newly reported saIety
inIormation th
II more venient and useIul, separate regulatory
should be utilised.
Country entries should be listed in chronological order oI regulatory authorisations.
Annex 5.2.2 provides an example, with Iictitious data Ior an antibiotic, oI how such a table might be
organised. The product was initially developed as a solid oral dosage Iorm Ior out-patient treatment oI
various inIections.
6.3.4 PSUR section Update of Regulatory Authority or Marketing Authorisation
Holder Actions taken for Safety Reasons
This section should include details on the Iollowing types oI worldwide actions relating to saIety that
were taken during the period covered by the PSUR and between data lock point and PSUR
submission:
Marketing authorisation withdrawal, revocation or suspension;
Failure to obtain a marketing authorisation renewal;
Restrictions on distribution;
Clinical trial suspension;
Dosage modiIication;
Changes in target population or indications;
Formulation changes;
Urgent saIety restrictions.
The saIety-related reasons that led to these actions should be described and documentation appended
when appropriate; any communication with Healthcare ProIessionals (e.g. Direct Healthcare
e appended.
y PSURs, the version oI the CCDS with its CCSI coming into eIIect at the
ProIessional Communication (DHPC), commonly called 'Dear Doctor Letter (DDL)) as a result oI
such action should also be described with copies appended. For practical reasons, only a single DHPC
in the English language, or together with an English summary oI the inIormation distributed in one or
more countries should b
6.3.5 PSUR section Changes to Reference Safety Information
For 6-monthly and yearl
beginning oI the period covered by the report should normally be used as the reIerence inIormation.
For a PSUR covering a period oI over one year, the latest CCSI in eIIect at the end oI the period may
be used (see Chapter I.6, Section 2.5).
PART I 81/229
The CCSI used as reIerence should be numbered, dated and appended to the PSUR and include the
date oI the last revision. Changes to the CCSI, such as new contraindications, precautions, warnings,
adverse reactions or interactions, already made during the period covered by the PSUR, should be
clearly described, with presentation oI the modiIied sections. The revised CCSI should be used as the
reIerence Ior the next PSUR and the next period (see also Chapter I.6, Section 2.5).
With the exception oI emergency situations, it may take some time beIore intended modiIications are
introduced in the Product InIormation. ThereIore, during that period the amended reIerence document
(CCSI) may contain more 'listed inIormation than the existing Product InIormation in many
comment should be prepared by the Marketing Authorisation Holder, describing the
local diIIerences and their consequences on the overall saIety evaluation and on the actions proposed
local submission
oI the PSUR.
posure) data Irom the
major monitoring sources are Irequently unavailable. It may also be diIIicult to obtain accurate data
, use is
oIten on an as-required basis, and individual packages are Irequently used by multiple Iamily members
e same period as the interim saIety
data. While it is recognised that it is usually diIIicult to obtain and validate accurate exposure data, an
atients is
impossible to estimate. In its place, other measures oI exposure, such as patient-days, number oI
the diIIiculty oI estimating cases, patient exposure should preIerably be provided as
ould be
II e sed. The
concept oI a
cially paediatric vs. adult) should be provided.
oups. An estimate oI use
in the case oI pregnancy
When an observed patter
locally
presente
nt
countries.
When meaningIul diIIerences exist between the CCSI and the EU/Member State`s Summary oI
Product Characteristics (SPC) (or the oIIicial data sheets/Product InIormation documents approved in
a country), a brieI
or initiated. This commentary may be provided in the cover letter accompanying the
6.3.6 PSUR section Patient Exposure
Estimating patient exposure data Ior marketed medicinal products oIten relies on gross approximations
oI in-house or purchased sales data or volume to determine patient exposure. This is not always
reliable or available Ior all products. For example, hospital-based (in-patient ex
Ior medicinal products oI which generic presentations are in use. For non-prescription products
oI diIIerent ages and weights.
Where possible, an estimate oI patient exposure should cover th
estimate oI the number oI patients exposed should be provided along with the method used to derive
the estimate. An explanation and justiIication should be presented iI the number oI p
prescriptions or number oI dosage units are considered appropriate; the method used should be
explained. Given
person-time oI exposure (days, months, years). The Marketing Authorisation Holder sh
consistent in its method oI calculation across PSURs Ior the same product. II a change in the method is
appropriate, then both methods and calculations should be shown in the PSUR introducing the change.
thes or other more precise measures are not available, bulk sales (tonnage) may be u
DeIined Daily Dose may be used in arriving at patient exposure estimates. When possible
and relevant, data broken down by sex and age (espe
Paediatric population exposure should be broken down according to age gr
outside the terms oI the marketing authorisation should be provided along with the method used to
provide the estimate. Pregnancy exposure should also be estimated specially
registries using the same data lock point as the PSUR.
n oI case reports indicates a potential problem, details by country (with
recommended daily dose) or other breakdowns (e.g. indication, dosage Iorm) should be
d iI available.
When adverse reaction data Irom clinical studies are included in the PSUR, the releva
denominator(s) should be provided. For ongoing and/or blinded studies, an estimation oI patient
exposure may be made.
PART I 82/229
When exposure data are based on inIormation Irom a period that does not Iully cover the period oI the
PSUR, the Marketing Authorisation Holder may extrapolate using the available data. II this is done it
late Ior the PSUR period
porting
or Iurther guidance see explanations provided in
should be clearly indicated what data were used and why it is valid to extrapo
in question (e.g. stable sales over a long period oI time, seasonality oI use oI the product).
In a PSUR Summary Bridging Report, exposure should be presented including the Iull re
period and explaining any diIIerences in this estimation Irom the simple sum oI exposure estimates
included in the separate PSURs covered by the PSUR Summary Bridging Report. In addition,
cumulative exposure estimates should be presented (I
the Risk Management Plan Template in Annex 5.1.1).
6.3.7 PSUR section Presentation of Individual Case Histories
This section should contain a description and analysis oI selected cases containing new or relevant
uent to their inclusion in a PSUR. II such
ssessment oI the case and has not led to relevant coding
Ho e bles and analyses iI relevant.
Wi e r standard, recognised
me l Iety inIormation relevant to their products and/or make use oI one
or e
Publish
include rdless oI the 'primary source.
Wi e
Holders
6.3.7.a
The typ
to avoid te reporting oI cases Irom literature and regulatory sources.
actions (attributable to the medicinal product by either investigator or
dies (including
ed-patient/compassionate use;
saIety inIormation and grouped preIerably by medically relevant headings/MedDRA System Organ
Classes (SOCs).
A description oI the criteria used to select cases Ior presentation should be provided.
Follow-up data on individual cases may be obtained subseq
inIormation is relevant to the interpretation oI the case (e.g. signiIicant impact on the case description
or analysis), the new inIormation should be presented in the next PSUR, and the correction or
clariIication noted relative to the earlier case description. Cases where Iollow-up inIormation is not
considered to have any impact on the overall a
changes Ior the case, do not need to be discussed in the body text oI the PSUR.
wev r, such cases should always be presented in cumulative ta
th r gard to the literature, Marketing Authorisation Holders should monito
dica and scientiIic journals Ior sa
mor literature search/summary services Ior that purpose.
ed cases received Irom other sources (e.g. spontaneous reporting, studies) should only be
d once and literature citation should be provided rega
th r gards to spontaneous reports that originate Irom Patients/Consumers, Marketing Authorisation
should:
ensure review oI data Irom Patients/Consumers or other non-healthcare proIessionals;
include analysis oI this data iI associated with a saIety concern in the PSUR section 'Overall
SaIety Evaluation (clearly identiIying such reports by their source); and
provide the data as a line-listing and summary tabulation (iI considered appropriate).
) Cases Presented as Line-Listings
es oI cases reIerenced below should be included in the line-listings. Attempts should be made
duplica
All serious adverse reactions and non-serious unlisted adverse reactions Irom spontaneous
reporting;
All serious adverse re
sponsor) available Irom post-authorisation saIety studies (PASS) and other stu
those which are part oI the Risk Management Plan) or nam
All serious adverse reactions, and non-serious unlisted adverse reactions Irom the literature;
All serious adverse reactions transmitted to the Marketing Authorisation Holder by worldwide
regulatory authorities.
PART I 83/229
In addition, the types oI cases reIerenced below should be included as line-listings in the Iorm oI an
annex to the PSUR:
All non-serious listed adverse reactions Irom spontaneous reporting ;
All serious and non-serious (listed and unlisted) adverse reactions reported by
Patients/Consumers and other non-healthcare proIessionals (not medically conIirmed).
Suspected transmission via a medicinal product oI any inIectious agent should be considered as a
serious adverse reaction (see Chapter I.5, Section 9).
Line-listing(s) (see Annex 5.2.3 Ior Template) should include each Patient only once regardless oI

d)
yst
how many adverse reaction terms are reported Ior the case. II there is more than one reaction, they
should all be mentioned but the case should be listed according to the most serious adverse reactions
(sign, symptom or diagnosis), as judged by the Marketing Authorisation Holder.
It is possible that the same Patient may experience diIIerent adverse reactions on diIIerent occasions
(e.g. weeks apart during a clinical trial). Such experiences should be treated as separate reports. Under
such circumstances, the same Patient might then be included in a line-listing more than once, and the
line-listings should be cross-reIerenced when possible. Line-Listings should be organised (tabulate
by body s em (MedDRA System Organ Classes (SOCs)).
Where common PSURs are submitted, the line-listings should still reIlect the invented name oI the
medicinal product (or the active substance name iI the invented name oI the medicinal products is not
available) as reported by the original reporter.
The Iollowing headings should usually be included in the line-listings (see Annex 5.2.3):
Mar ase reIerence number;
Country in which the case occurred;
ossible (may go in comments section);
est estimate oI treatment duration;
esc as reported, and when necessary as interpreted by the
keting Authorisation Holder c
Source (e.g. clinical trial, literature, spontaneous, regulatory authority);
Age and sex oI the Patient;
Daily dose oI the suspected medicinal product (and, when relevant, dosage Iorm or route);
Date oI onset oI the adverse reaction(s). II not available, best estimate oI time to onset Irom
therapy initiation. For adverse reactions known to occur aIter cessation oI therapy, estimate oI
time lag iI p
Dates oI treatment. II not available, b
D ription oI adverse reaction(s)
Marketing Authorisation Holder (English translation when necessary) (see Chapter I.6,
Section 2.6.b);
Patient outcome (at case level) (e.g. resolved, Iatal, improved, sequelae, unknown). This
should indicate the consequences oI the adverse reaction(s) Ior the Patient, using the worst oI
the diIIerent outcomes Ior multiple reactions
Comments, iI relevant (e.g. causality assessment iI the manuIacturer disagrees with the
reporter; concomitant medications suspected to play a role in the reactions directly or by
interaction; indication treated with suspect medicinal product(s); dechallenge/rechallenge
nly Ior inIormation that helps to clariIy individual
se
he data.
results iI available). It should be used o
ca s.
Depending on the product or circumstances, it may be useIul or practical to have more than one line-
listing, such as Ior diIIerent dosage Iorms or indications, iI such diIIerentiation Iacilitates presentation
and interpretation oI t
PART I 84/229
6.3.7.b) Cases Presented as Summary Tabulations
An aggregate summary Ior each oI the line-listings should usually be presented. These tabulations
ed and unlisted reactions; other breakdowns
usually contain more terms than patients. It would be useIul to have separate tabulations (or columns)
Ior serious reactions and Ior non-serious reactions, Ior list
might also be appropriate (e.g. by source oI report). See Annex 5.2.4 Ior a sample data presentation on
serious reactions.
The terms used in these tables should ordinarily be those used by the Marketing Authorisation Holder
to describe the case (see Chapter I.6, Section 2.6.b).
Data on serious reactions Irom other sources (see Chapter I.6, Section 2.6.a) should normally be
I useIul, the tabulations may, Ior example, be sorted by source oI
inIormation or country.
rmal table is considered suitable.
ons should be interval data, as should the line-
listings Irom which they are derived. However, Ior adverse reactions that are both serious and unlisted,
uld be provided in the table(s) or as a narrative.
nted on particular serious or unanticipated Iindings (their nature, medical
signiIicance, mechanism, reporting Irequency, etc.). The Iocus here should be on individual case
presented as a summary tabulation. I
When the number oI cases is very small, or the inIormation inadequate Ior any oI the tabulations, a
narrative description rather than a Io
As previously described, the data in summary tabulati
a cumulative Iigure (i.e. all cases reported to date) sho
6.3.7.c) Marketing Authorisation Holders Analysis of Individual Case Histories
This section may be used Ior brieI comments on the data concerning individual cases. For example,
discussion may be prese
discussion and should not be conIused with the global assessment in the PSUR section 'Overall SaIety
Evaluation (see Chapter I.6, Section 3.10).
risation Holder should not routinely catalogue or describe
6.3.8 PSUR section Studies
All studies (non-clinical, clinical and epidemiological) yielding saIety inIormation (this includes lack
oI eIIicacy data) with a potential impact on product inIormation, studies speciIically planned, in
progress and those published that address saIety concerns should be included with a discussion oI any
interim or Iinal results. The Marketing Autho
all the studies. Studies that are part oI the Risk Management Plan should be mentioned (see Chapter
I.6, Section 3.9.c).
6.3.8.a) Newly Analysed Studies
All relevant studies containing important saIety inIormation and newly analysed during the reporting
period should be described, including those Irom epidemiological, toxicological or laboratory
n and results should be clearly and concisely presented with attention to the usual standards oI
data analysis and description that are applied to non-clinical and clinical study reports. Copies oI Iull
authorisation saIety studies and Ior other studies
with a signiIicant saIety Iinding only iI deemed appropriate.
saIety concern (actual or hypothetical)
should be described (e.g. objective, starting date, projected completion date, number oI subjects,
investigations. ReIerence should be made to the Risk Management Plan, where applicable. The study
desig
study reports should be appended, e.g. in case oI post-
6.3.8.b) Targeted New Safety Studies
New studies speciIically planned or conducted to examine a
protocol abstract).
PART I 85/229
When possible and relevant, iI an interim analysis was part oI the study plan, the interim results oI
ongoing studies may be presented. When the study is completed and analysed, the Iinal results should
be presented in a subsequent PSUR as described in Chapter I.6, Section 3.8.a.
Copies oI Iull reports should be appended in the case oI post-authorisation saIety studies and Ior other
studies with a signiIicant saIety Iinding only iI deemed appropriate.
Planned studies should be discussed in the Risk Management Plan (see Chapter I.3) and iI relevant in
the related PSUR section (see Chapter I.6, Section 3.9.c).
tings,
cation
6.3
6.3
For pro treatment oI serious or liIe-threatening diseases
(e. n or products used in healthy Consumers (e.g. contraceptives),
me l
described and explained.
Where d in this
section.
n Ior review and report
preparation may be presented in this section. Examples include signiIicant new cases or important
ken into account in the PSUR section 'Overall SaIety
6.3.8.c) Published Studies
Reports in the scientiIic and medical literature, including relevant published abstracts Irom mee
publi containing important saIety Iindings (positive or negative) should be summarised and
reIerence(s) provided.
.8.d) Other Studies
The Marketing Authorisation Holder should provide any relevant inIormation Irom the data collected
by pregnancy exposure registries and a discussion oI the positive and negative experience oI use oI the
medical product during pregnancy.
6.3.9 PSUR section Other information
.9.a) Efficacy-related Information
ducts used in prevention (e.g. vaccines) or in
g. a tibiotics and antiviral products)
dica ly relevant lack oI eIIicacy reports, which may represent a signiIicant hazard, should be
appropriate, all other medically relevant reports oI lack oI eIIicacy should be discusse
6.3.9.b) Late-breaking Information
Any important, new inIormation received aIter the database was Iroze
Iollow-up data. These new data should be ta
Evaluation (see Chapter I.6, Section 3.10).
Management Plan
ata lock point should be presented
6.3.9.c) Risk
When a speciIic Risk Management Plan is in place, it should be discussed. In this case, the status oI
the Risk Management Plan and its amendments prior to the d
together with all available study results.
The assessment oI the eIIectiveness oI the risk management system should be presented (see Chapter
I.3).
6.3.9.d) Risk-Benefit Analysis Report
When a more comprehensive saIety or risk-beneIit analysis (e.g. all indications reviewed) has been
conducted separately, a summary oI the analysis should be included in this section.
PART I 86/229
6.3.10 PSUR section Overall Safety Evaluation
The Marketing Authorisation Holder should provide a concise analysis oI the data presented, taking
into account any late-breaking inIormation (see Chapter I.6, Section 3.9.b), and Iollowed by the
the data collected during the
period. Discussion and analysis oI the 'Overall SaIety Evaluation should be organised by SOC rather
The Marketing Authorisation Holder should also review the cumulative experience and highlight any
tive the cumulative reports;
ed reporting Irequency oI listed adverse reactions, including comments on whether
Th e on the Iollowing (lack oI
Marketing Authorisation Holder`s assessment oI the signiIicance oI
than by listedness or seriousness; the latter properties should still be covered under each SOC.
Although related terms may be Iound in diIIerent SOCs, they should be reviewed together Ior clinical
relevance.
Standardised MedDRA Queries (SMQs) may be used Ior signal detection and the use oI SMQs is
recommended in order to retrieve and review cases oI interest where signals are identiIied Irom
adverse reaction databases
25
.
new inIormation on:
A change in characteristics oI listed reactions, e.g. severity, outcome, target population;
Serious unlisted adverse reactions, placing into perspec
Non-serious unlisted adverse reactions;
An increas
it is believed the data reIlect a meaningIul change in adverse reactions occurrence.
is s ction should also explicitly address any new saIety concern
signiIicant new inIormation should be mentioned Ior each):
Interactions;
Experience with overdose, deliberate or accidental, and its treatment;
Abuse or misuse;
Positive or negative experiences during pregnancy or lactation;
Experience in special patient groups (e.g. children. elderly, organ impaired, a qualitative
description oI oII-label use should be given);
EIIects oI long-term treatment;
Patient/Consumer and other non-healthcare proIessional reports (see Chapter I.6, Section 3.7),
iI appropriate;
Prescription errors/medication errors, including those associated with invented names or with
, iI available.
the PSUR should deal with use oI the medicinal product in children iI the product has
dren or iI there are
adverse reactions reported in the paediatric population. Data Irom completed or ongoing clinical trials
the presentation oI the medicinal products, that have saIety implications
A subsection oI
a paediatric indication, iI there is evidence oI signiIicant oII-label use in chil
should be presented separately Irom spontaneous reports (see Annex 3.1.4).
6.3.11 PSUR section Conclusion
The 'Conclusion should address the overall risk-beneIit balance in the context oI the data presented
in the PSUR and:
indicate which saIety data are not in accordance with previous cumulative experience and the
reIerence saIety inIormation (CCSI);
speciIy and justiIy any action recommended or initiated.

25
Council Ior International Organizations oI Medical Sciences (CIOMS). Development and rational use oI
Standardised MedDRA Queries (SMQs). Geneva: CIOMS; 2004. Available on CIOMS website
http://www.cioms.ch/.
PART I 87/229
The need to amend the SPC should be addressed in the cover letter Irom the Marketing Authorisation
Holder, where consistency between the CCSI and the SPC is cross-checked and any comment or
planned action is proposed.
d
tim b
6.4
Th S provide a brieI
sum r Rs and PSUR Addendum Reports (e.g. two
con u early PSUR or six consecutive 6-monthly PSURs to compile
3-year PSUR data). It is intended to assist Competent Authorities with a helpIul overview oI the
appended PSURs. The PSUR data should not be repeated but cross-reIerenced to individual PSURs.
The Iormat oI the Summary Bridging Report should be identical to that oI the usual PSUR, but the
content should consist oI summary highlights and an overview oI data Irom the attached PSURs to
which it reIers.
A Summary Bridging Report should contain the Iollowing:
Introduction (a brieI description oI the purpose oI the document speciIying the time periods
covered and cross-reIerencing any appended PSURs);
Worldwide marketing authorisation status (number oI countries which have approved the
product);
Update on regulatory authority or Marketing Authorisation Holder-initiated actions Ior saIety
reasons (an integrated summary oI actions taken iI appropriate);
Changes to the CCSI (signiIicant changes over the entire period);
Exposure data (estimation oI the total number oI patients exposed in the time period);
Individual case histories (brieI statement outlining the total number oI cases presented in the
series oI PSURs). When there is an important speciIic saIety concern that has not been
adequately discussed in one or more PSURs, it is considered appropriate to include a
cumulative line-listing or summary tabulation Ior the types oI cases oI concern presenting
adverse reactions ordered by SOC, seriousness and listedness covering the period oI the
Summary Bridging Report and pointing out any diIIerences Irom prior listings or tabulations.
In this case, there should be a clear understanding that the tables should be generated Irom live
databases, which change over time as cases are updated. These tables should then reIlect the
most up-to-date data available at the time they are generated. It is recognised that the case
counts in these summary tables may diIIer somewhat Irom the contents oI the individual tables
in the appended PSURs. A general statement describing the diIIerences should be provided);
Studies (a brieI summary oI important targeted clinical saIety studies);
Other inIormation (only highly signiIicant saIety inIormation received aIter the data lock
point);
Overview oI the saIety concerns and Conclusion (unresolved key issues).
In addition, the cover letter accompanying the Summary Bridging Report should also contain
inIormation highlighting any signiIicant diIIerences between the approved SPC and the current CCSI.
6.5 Contents of the PSUR Addendum Report
A PSUR Addendum Report is an update to the most recently completed PSUR when a Competent
Authority requests or requires a saIety update outside the usual IBD-based PSUR submission
schedule. An Addendum Report should be provided when more than 3 months Ior a 6-monthly or
yearly PSUR, and more than 6 months Ior a PSUR covering a longer period have elapsed since the
Having made a decision to amend the SPC, the Marketing Authorisation Holder should submit a
variation application at the same time as the PSUR or, where this is not possible, state a propose
eta le Ior submission.
Contents of the PSUR Summary Bridging Report
e P UR Summary Bridging Report should not
URs, or PSU
contain any new data but should
ma y bridging two or more PS
sec tive 6-monthly PSURs Ior a y
PART I 88/229
PART I 89/229
e an Addendum Report data lock point oI the most recent PSUR. It may also be appropriate to provid
to the PSUR Summary Bridging Report (see Chapter I.6, Section 4).
The Addendum Report should summarise the saIety data received between the data lock point oI the
the PSUR);
SigniIicant worldwide regulatory authorities` actions relevant to saIety;
most recent PSUR and the Competent Authority`s requested cut-oII date. It is not intended that the
Addendum Report should provide an in-depth analysis oI the additional cases, as these should be
included in the next regularly scheduled PSUR. Depending on the circumstances and the volume oI
additional data since the last scheduled report, an Addendum Report may Iollow the PSUR Iormat or a
simpliIied presentation.
The proposed simpliIied presentation should include the Iollowing sections, containing any new
inIormation or changes beyond the most recent PSUR to which the Addendum Report reIers:
Introduction (purpose; cross-reIerence to most recent PSUR);
Changes to the CCSI (including a copy oI the most recent CCSI document iI it diIIers Irom the
one in
Line-listing(s) and/or summary tabulations;
Conclusions (brieI overview).
7. Company-Sponsored Post-Authorisation Safety Studies
7.1 Introduction
There is a continuous need to monitor the saIety oI medicinal products as they are used in clinical
practice. Spontaneous reporting schemes provide important early signals oI saIety concerns and also
provide a means oI continuous surveillance. Formal studies to evaluate saIety may also be necessary,
particularly in the conIirmation, characterisation and quantiIication oI saIety concerns identiIied at an
earlier stage oI product development or during post-authorisation use (see Chapter I.8). Such studies
may also be useIul in identiIying previously unsuspected adverse reactions or in conIirming the saIety
proIile oI a medicinal product under normal conditions oI use. In accordance with legal requirements,
post-authorisation saIety studies (PASS) may be required by Competent Authorities either as a
commitment at the time oI authorisation or in the post-authorisation phase to Iurther assess a signal. In
either case, such studies will be considered as a relevant part oI the Risk Management Plan (see
Chapter I.3).
This Chapter oI Volume 9A applies to the conduct oI studies sponsored by the pharmaceutical
industry, which evaluate the saIety oI products with a marketing authorisation Ior human use. They
encompass all studies carried out to evaluate the saIety oI authorised medicinal products and Ior which
a Marketing Authorisation Holder takes responsibility Ior their initiation, management and/or
by the Marketing Authorisation
and in the hospital
Whilst it is recognised that the study design
concerns, this guidance deIines the essential
study methods in this Iield continue to develop
and e s advances made
Iinancing. This includes studies where the medicine is provided
Holder and those where it is prescribed in the normal way, both in general practice
setting. A study Iollows a protocol, which deIines the study population and the design Ior its conduct
and analysis. ThereIore, in this context, databases searches to count e.g. number oI adverse events or
number oI prescriptions are not considered studies.
The present guidance provides a Iramework whereby a variety oI data collection methods may be used
to evaluate the saIety oI authorised medicinal products.
used needs to be tailored to particular products and saIety
principles to be applied in a variety oI situations. The
th reIore there will be a need to regularly review guidance to ensure that it reIlect
in a
A st icle 1(15) oI Directive 2001/83/EC as
'ph
marketing authorisation, conducted with the aim oI identiIying or quantiIying a saIety hazard relating
to u
oI e
ma r
l
include the
deIinitions a Iundamental distinction
w routes oI administration or new combinations, aIter a
product has been authorised, should be considered as interventional. In such cases, Directive
the ssessment oI product saIety (see Table I.7.A at the end oI this Chapter).
po -authorisation saIety study is deIined in Art
armacoepidemiological study or a clinical trial carried out in accordance with the terms oI
an a thorised medicinal product. The deIinition oI non-interventional trial is provided in Article 21
ctive 2001/20/EC: 'A study w Dir here the medicinal product(s) is (are) prescribed in the usual
nne in accordance with the terms oI the marketing authorisation. The assignment oI the patient to a
ar therapeutic st particu rategy is not decided in advance by a trial protocol but Ialls within the current
practice and the prescription oI the medicine is clearly separated Irom the decision to
patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients
and epidemiological methods shall be used Ior the analysis oI the collected data.
In this context it is considered important to clariIy that interviews, questionnaires and blood samples
may be considered as normal clinical practice. Based on these
can be made between non-interventional (observational) and interventional post-authorisation saIety
studies. The latter are considered clinical trials Ialling under the scope oI the Directive 2001/20/EC.
II the deIinition oI non-interventional is not met, the study should be considered as interventional. For
instance, studies exploring new indications, ne
2001/20/EC and the related guidance should be Iollowed (see Volume 10 oI The Rules Governing
PART I 90/229
Medicinal Products in the European Union
26
). The guidance on Good Clinical Practice does not apply
to non-interventional post-authorisation studies.
s where
there is a known saIety issue under investigation and/or where the numbers oI patients to be included
gress at intervals and at study
end as requested by the Authorities.
The guidance below relates principally to those non-interventional post-authorisation studie
in the study will add signiIicantly to the existing saIety data Ior the product(s).
A saIety concern may be unexpectedly identiIied in the course oI perIorming a study on an authorised
medicinal product that would normally Iall outside the scope oI this guidance. In that case, the
Marketing Authorisation Holder and speciIically the QPPV are expected to inIorm the relevant
Competent Authorities immediately and to provide a brieI report on pro
II there is doubt as to whether or not a study comes under the scope oI the present guidance, the
company should discuss the intended protocol with the relevant Competent Authorities oI the Member
State(s) in which the study is to be conducted (see Chapter I.7, Section 4.1).
In addition to the guidance below, Marketing Authorisation Holders should consider the Guidelines
tices issued by the International Society Ior
acoepi
They may also be conducted to quantiIy
established adverse reactions and to identiIy risk Iactors.
appropriate include:
ucture or novel mode oI action;
levance oI a toxic eIIect in animals;
e
Ior Good Pharmacoepidemiology Prac
Pharm demiology (ISPE)
27
.
7.2 Objectives of Post-Authorisation Safety Studies
Post-authorisation saIety studies may be conducted Ior the purpose oI identiIying previously
unrecognised saIety concerns (hypothesis-generation), investigating potential and identiIied risks
(hypothesis-testing in order to substantiate a causal association), or conIirming the known saIety
proIile oI a medicinal product under normal conditions oI use.
Situations where studies may be
a medicinal product with a novel chemical str
where there is uncertainty as to the clinical re
where there is uncertainty as to the saIety proIile;
where there is a need to better quantiIy adverse events identiIied in clinical trials and elucidat
risk Iactors;
where there is a need to conIirm or reIute saIety concerns suggested by other sources
(e.g. spontaneous reporting);
where there is a concern regarding the use oI the medicinal product (e.g. to quantiIy the oII-
label use); and
when there is a need to evaluate the eIIectiveness oI a risk minim isation measure.
A variety oI designs may be appropriate including observational cohort studies, case-control studies or
registries (see Table I.7.A). Clinical trials involving systematic allocation oI treatment (e.g.
randomisation) may also be used to evaluate the saIety oI authorised products. Such clinical trials
should comply with the requirements oI Directive 2001/20/EC.
The design to be used will depend on the objectives oI the study, which must be clearly deIined in the
study protocol. Any speciIic saIety concerns to be investigated should be identiIied in the protocol and
explicitly addressed by the proposed methods. A reIerence to the Risk Management Plan should be
made in the protocol when such a Plan exists.

26
27
Available on ISPE website http://www.pharmacoepi.org/index.cIm.
PART I 91/229
For protocol development consideration should be given to the elements described in Table I.7.B at
the end oI this Chapter.
7.3 Responsibilities for the Conduct of Post-Authorisation Safety Studies
es the study is responsible
Ior its conduct and should meet the pharmacovigilance obligations concerning PASS. The study
The Marketing Authorisation Holder who initiates, manages and/or Iinanc
should be supervised by a designated monitor(s) or monitoring organisation and the names oI the
monitors should be recorded in the study documents. In case the Marketing Authorisation Holder does
not directly conduct the study, detailed and clear contractual agreements Ior meeting
pharmacovigilance obligations should be documented (see Chapter I.1).
The QPPV at EU level and/or, where applicable, the nominated person responsible Ior
pharmacovigilance at national level, should be involved in the review oI protocols Ior all post-
authorisation saIety studies, in order to ensure compliance with pharmacovigilance requirements.
7.4 Liaison with Competent Authorities
to perIorm a post-authorisation saIety study should send
the protocol to the Competent Authority oI the Member State(s) in whose territory the study is to be
n into account in those Member States where these exist, and Directive 2001/20/EC
should be Iollowed when the study qualiIies as a clinical trial.
Tw i
by C
a) Stu
The con
authorised through the mutual recognition or decentralised procedure, the
ssion may take place at PhVWP level.
t points. However, when the need Ior the study has been
consider its appropriateness and the need Ior Iurther evaluation at CHMP and/or PhVWP level.
ReIinements oI exposure and/or case deIinitions will normally not require notiIication.
7.4.1 Evaluation of the Protocol
Marketing Authorisation Holders proposing
perIormed. In case oI products authorised through the mutual recognition or decentralised procedures,
the protocol should also be sent to the ReIerence Member State and, in case oI centrally authorised
products, to the Agency, the Rapporteur and Co-Rapporteur. National legal requirements or guidelines
should be take
o d IIerent situations can be envisaged depending on whether or not the study has been requested
the ompetent Authorities:
dies requested by Competent Authorities
tact point will depend on the procedure by which the product has been authorised in the EU:
For centrally authorised products, the Agency will normally be the contact point. The
(Co-)Rapporteur will initially review the draIt protocol Ior approval by the CHMP. The draIt
protocol may also be discussed at PhVWP level iI so requested by CHMP.
For products
ReIerence Member State will normally be the contact point and the initial reviewer oI the draIt
protocol. A Iurther discu
For purely nationally authorised medicinal products, the Competent Authority oI the Member
State requesting the study and the Competent Authority oI each Member State where the study
is to be conducted will be the contac
discussed at PhVWP level, a Lead Member State may be nominated who will act as the
contact point and initial reviewer Ior the draIt protocol. Further discussions may take place at
PhVWP level when the study is to be conducted in several Member States or the product is
used in several Member States.
Meetings will be organised as appropriate between the designated (Co-) Rapporteur or ReIerence/Lead
Member State and the Marketing Authorisation Holder in order to agree upon a protocol and a
timetable. When the Marketing Authorisation Holder considers that the protocol requires a major
amendment, this should be reported to the (Co-)Rapporteur or ReIerence/Lead Member State who will
PART I 92/229
When the same or a similar study is also requested by other Competent Authorities, e.g. countries
outside the EU Ior centrally authorised or other Member States Ior nationally authorised products, an
eIIort should be made by the Marketing Authorisation Holder to reach agreement on a common
ol.
n Holders initiative
ognition or decentralised procedures. Any major
amendment to the protocol should be reported to the relevant Authorities accompanied by a
For post-authorisation saIety studies that qualiIy as clinical trials, the reporting criteria laid down in
protoc
b) Studies performed at Marketing Authorisatio
When the study has commenced, the Marketing Authorisation Holder should inIorm the relevant
Competent Authorities oI all Member States where the study is being conducted, as well as the
Agency and (Co-)Rapporteur Ior centrally authorised products and the ReIerence Member State Ior
products authorised through the mutual rec
justiIication Ior it. ReIinements oI exposure and/or case deIinitions will normally not require
notiIication.
7.4.2 Reporting of Adverse Reactions
Directive 2001/20/EC and related guidance (see Volume 10 oI the Rules Governing Medicinal
Products in the EU
28
) should be Iollowed as well as the requirements established Ior Periodic SaIety
Update Reports (PSURs) (see Chapter I.6).
For non-interventional post-authorisation saIety studies, conducted inside and outside the EU, the
usual regulatory requirements Ior reporting oI adverse reactions should be IulIilled according to
Chapters I.4. and I.6 (in conjunction with Part III Ior electronic exchange oI pharmacovigilance
inIormation).
This means that
reports oI all serious adverse reactions arising Irom such studies within the EU should be
reports
reported on an expedited basis (i.e. within 15 days), to the Competent Authority oI the
Member State on whose territory the incident occurred, and in addition, Ior products
authorised through the mutual recognition or decentralised procedures and Ior products which
have been the subject oI a reIerral procedure, to the ReIerence Member State. These
should also be included in the PSURs (see Chapter I.6);
reports oI all unexpected serious adverse reactions arising Irom such studies outside the EU
should be reported on an expedited basis to the Agency and to all Member States where the
medicinal product is authorised. These reports should also be included in the PSURs (see
Chapter I.6);
reports on expected serious occurring outside the EU should be reported in accordance with
Chapter I.6 on PSURs;
All adverse reactions/events including those which are considered non-serious, should be summarised
investigator or the Marketing Authorisation Holder to be adverse reactions).
in the Iinal study report in Irequency tables.
Marketing Authorisation Holders should ensure that they are notiIied by the investigator oI serious
adverse reactions and, iI speciIied in the study protocol, oI events (those not suspected by the
In certain study designs, such as case-control or retrospective cohort studies (see Data Sources in
Table I.7.A), in which it is not Ieasible or appropriate to make an assessment oI causality between
medical events recorded and the medicinal products at individual case level, expedited reporting oI
Individual Case SaIety Reports (ICSRs) is not required. In case oI doubt, the Marketing Authorisation

28
PART I 93/229
Holder should clariIy the reporting requirements through the contact point reIerred to in Chapter I.7,
Section 4.1.a, according to the authorisation procedure oI the product.
7.4.3 Progress and Final Study Reports
Marketing Authorisation Holders should provide a study progress report annually, or more Irequently
, a Iinal report should also be submitted, which
will include the reasons Ior stopping the study.
The content oI the progress report should Iollow a logical sequence and should include all the
a) Studies requested by Competent Authorities
as requested by the Competent Authorities (e.g. according to the Risk Management Plan milestones)
or on their own initiative. II the study is discontinued
available data which is judged relevant Ior the progress oI the study; e.g. number oI patients who have
entered the study according to their status (exposure, outcome, etc.), problems encountered and
deviations Irom the expected plan. AIter review oI the report, Competent Authorities may request
additional inIormation.
A Iinal study report should be submitted according to an agreed timetable (e.g. Risk Management Plan
milestones). For the content oI the Iinal report consideration should be given to the recommendations
laid down in Table I.7.C at the end oI this Chapter. The Iindings oI the study should be made public,
preIerably through scientiIic journals.
Both progress and Iinal reports should be sent to the Competent Authorities oI the Member States in
which the study is being conducted and to the Competent Authority that requested the study. In case oI
products authorised through the mutual recognition or decentralised procedures, these reports should
also be sent to the ReIerence Member State and, in case oI centrally authorised products, to the
Agency, the Rapporteur and Co-Rapporteur. For evaluation oI such reports, the same procedure as Ior
evaluation oI the protocol should be Iollowed (see Chapter I.7, Section 4.1).
For post-authorisation saIety studies that qualiIy as clinical trials, the criteria laid down in Directive
2001/20/EC and related guidance (see Volume 10 oI the Rules Governing Medicinal Products in the
EU
29
) should be Iollowed, in addition to the requirements established in the present guidance.
b) Studies performed at the Marketing Authorisation Holders initiative
Progress and Iinal reports should be included or updated in the corresponding PSUR and/or Risk
. The Iindings oI the study should be made public, preIerably through
scientiIic journals.
For post-authorisation saIety studies that qualiIy as clinical trials, the criteria laid down in Directive
Management Plan. When a saIety concern is raised, a report should be submitted immediately to the
relevant Competent Authorities (including the Agency and (Co-) Rapporteur Ior centrally authorised
products and the ReIerence Member State Ior products authorised through the mutual recognition or
decentralised procedures)
2001/20/EC and related guidance (see Volume 10 oI the Rules Governing Medicinal Products in the
EU
30
) should be Iollowed, in addition to the requirements established in this guidance provided in
Volume 9A.
7.5 Promotion of Medicinal Products
Post-authorisation studies should not be planned or conducted Ior the purposes oI promoting the use oI
medicinal products.

29
30
PART I 94/229
Company sales and marketing representatives should not be involved in studies in such
could be seen as a promotional exercise, such as in the recruitment oI patients and physic
a way that it
ians.
7
S
c
N nducement Ior a Healthcare ProIessional to participate in a post-
authorisation be oIIered or given.
7
P
2
Holders and investigators should Ioll ber States where
t xist en here.
T
.6 Participation of Healthcare Professionals
ubject to the Healthcare ProIessional`s terms oI service, payment should be restricted to
ompensation oI the Healthcare ProIessional Ior any additional time and expenses incurred.
o additional payment or i
saIety study should
.7 Ethical Issues
ost-authorisation saIety studies that qualiIy as clinical trials Iall within the scope oI Directive
001/20/EC. For non-interventional post-authorisation saIety studies, the Marketing Authorisation
ow relevant national legislation in those Mem
his e s, in addition to the guidance giv
he highest possible standards oI proIessional conduct and conIidentiality must always be maintained
a
c
s
d
i
P
Authorisation ible Ior the handling oI such inIormation.
It is recommended that non-interventional post-authorisation saIety studies are reIerred to an Ethics
C
(
g
A
c
7
A
(
A
matter within their remit.
nd legislation on data protection Iollowed (see Directive 95/46/EC). The Patient`s right to
onIidentiality is paramount. The Patient`s personal identiIiers should be replaced by a code in the
tudy documents, and only authorised persons should have access to identiIiable personal details iI
ata veriIication procedures demand inspection oI such details. Responsibility Ior the retrieval oI
nIormation Irom personal medical records lies with the Healthcare ProIessional(s) responsible Ior the
atient`s care. Such inIormation Irom medical records should be provided to the Marketing
Holder, who is thereaIter respons
ommittee. Studies conducted entirely using records not containing any personal identiIiers
e.g. anonymised records) may not require an ethical review oI individual study protocols. National
uidelines in this respect should be Iollowed where they exist.
ccording to European data protection legislation, explicit consent is required when the study plans to
ollect data containing personal identiIiers, though some exceptions are envisaged.
.8 Procedure for Complaints
post-authorisation saIety study, the objective, design or conduct oI which gives cause Ior concern
e.g. using the study as a promotional activity), should be reIerred to the relevant Competent
uthorities, and, iI appropriate, to other bodies within Member States which are deemed to have the
PART I 95/229
T S FOR POST-AUTHORISATION SAFETY STUDIES ABLE I.7.A: EPIDEMIOLOGICAL METHOD
Spontaneous reporting schemes are valuable tools Ior providing saIety signals in a continuous
manner. In many situations, however, such passive surveillance should be complemented with more
Iormal approaches in order to increase the sensitivity Ior risk identiIication or to conIirm,
characterise or quantiIy possible saIety concerns. These more Iormal approaches are included under
the term post-authorisation saIety studies`.
1. Study Designs
Post-authorisation saIety studies may adopt diIIerent designs depending on their objectives. A brieI
description oI the Iundamental types oI studies, as well as the types oI data resources available, is
However, this table is not intended to be exhaustive and should be
complemented with other widely available inIormation sources (1-4). The ICH-E2E Guideline has
provided hereaIter.
been Iollowed to a great extent in order to provide a harmonised view on this topic.
1.1 Methods for Active Surveillance
Active surveillance, in contrast to passive surveillance, seeks to ascertain more completely the
number oI adverse events in a given population via a continuous organised process. An example oI
active surveillance is the Iollow-up oI patients treated with a particular medicinal product through a
risk management system. Patients who Iill a prescription Ior this product may be asked to complete
a brieI survey Iorm and give permission Ior later contact. In general, it is more Ieasible to get
comprehensive data on individual adverse event reports through an active surveillance system than
through a passive reporting system.
1.1.1 Sentinel Sites
Active surveillance may be achieved by reviewing medical records or interviewing patients and/or
physicians/pharmacists in a sample oI sentinel sites to ensure complete and accurate data on
reported adverse events. The selected sites may provide inIormation, such as data Irom speciIic
patient subgroups that would not be available in a passive spontaneous reporting system. Further,
collection oI inIormation on the use oI a medicinal product, such as the potential Ior abuse, may be
ajor weaknesses oI sentinel sites are problems with
reased costs. Active surveillance with sentinel sites
targeted at selected sentinel sites. Some oI the m
selection bias, small numbers oI patients, and inc
is most eIIicient Ior those medicinal products used mainly in institutional settings such as hospitals,
nursing homes, and haemodialysis centres. Institutional settings may have a greater Irequency oI use
Ior certain products and may provide an inIrastructure Ior dedicated reporting. In addition,
automatic detection oI abnormal laboratory values Irom computerised laboratory reports in certain
clinical settings may provide an eIIicient active surveillance system.
1.1.2 Intensive Monitoring Schemes
Intensive monitoring is a system oI record collation in designated areas, e.g. hospital units or by
speciIic Healthcare ProIessionals in community practice. In such cases, the data collection may be
undertaken by monitors who attend ward rounds, where they gather inIormation concerning
undesirable or unintended events thought by the attending physician to be causally related to the
medication. Monitoring may also be Iocused on certain major events that tend to be drug-related
such as jaundice, renal Iailure, haematological disorders, bleeding. The major strength oI such
systems is that the monitors may document important inIormation about the events and exposure to
medicinal products. The major limitation is the need to maintain a trained monitoring team over
time.
PART I 96/229
1.1.3 Prescription Event Monitoring
Prescription event monitoring is a method oI active pharmacovigilance surveillance. In prescription
event monitoring, patients may be identiIied Irom electronic prescription data or automated health
insurance claims. A Iollow-up questionnaire can then be sent to each prescribing physician or
patient at pre-speciIied intervals to obtain outcome inIormation. InIormation on patient
demographics, indication Ior treatment, duration oI therapy (including start dates), dosage, clinical
events, and reasons Ior discontinuation can be included in the questionnaire (5-6). Limitations oI
prescription event monitoring include incomplete physician response and limited scope to study
products which are used exclusively in hospitals. More detailed inIormation on adverse events Irom
a large number oI physicians and/or patients may be collected.
1.1.4 Registries
A registry is a list oI patients presenting with the same characteristic(s). This characteristic may be a
disease or an outcome (disease registry) or a speciIic exposure (exposure or drug registry). Both
types oI registries, which only diIIer by the type oI patient data oI interest, may collect a battery oI
inIormation using standardised questionnaires in a prospective Iashion.
Disease/outcome registries, such as registries Ior blood dyscrasias, severe cutaneous reactions, or
congenital malIormations may help collect data on drug exposure and other Iactors associated with
a clinical condition. A disease registry might also be used as a base Ior a case-control study
I cases identiIied Irom the registry and controls selected Irom either
patients within the registry with another condition, or Irom outside the registry.
comparing the drug exposure o
Exposure registries address populations exposed to medicinal products oI interest (e.g. registry oI
rheumatoid arthritis patients exposed to biological therapies) to determine iI a medicinal product has
a special impact on this group oI patients. Some exposure registries address exposures to medicinal
products in speciIic populations, such as pregnant women. Patients may be Iollowed over time and
included in a cohort study to collect data on adverse events using standardised questionnaires.
Single cohort studies may measure incidence, but, without a comparison group, cannot provide
prooI oI association. However, they may be useIul Ior signal ampliIication particularly Ior rare
outcomes. This type oI registry may be very valuable when examining the saIety oI an orphan drug
indicated Ior a speciIic condition.
1.2 Comparative Observational Studies
Traditional epidemiological methods are a key component in the evaluation oI adverse events.
There are a number oI observational study designs that are useIul in validating signals Irom
spontaneous reports or case series. Major types oI these designs are cross-sectional studies, case-
control studies, and cohort studies (both retrospective and prospective).
1.2.1 Cross-sectional Study (Survey)
Data collected on a population oI patients at a single point in time (or interval oI time) regardless oI
exposure or disease status constitute a cross-sectional study. These types oI studies are primarily
used to gather data Ior surveys or Ior ecological analyses. The major drawback oI cross-sectional
studies is that the temporal relationship between exposure and outcome cannot be directly
addressed, which limits its use Ior aetiologic research unless the exposures do not change over time.
These studies are best used to examine the prevalence oI a disease at one time-point or to examine
trends over time, when data Ior serial time-points can be captured. These studies may also be used
to examine the crude association between exposure and outcome in ecologic analyses.
PART I 97/229
1.2.2 Cohort Study
In a cohort study, a population-at-risk Ior an event oI interest is Iollowed over time Ior the
occurrence oI that event. InIormation on exposure status is known throughout the Iollow-up period
Ior each patient. A patient might be exposed to a medicinal product at one time during Iollow-up,
but non-exposed at another time point. Since the population exposure during Iollow-up is known,
incidence rates can be calculated. In many cohort studies involving exposure to medicinal
product(s), comparison cohorts oI interest are selected on the basis oI medication use and Iollowed
re useIul when there is a need to know the incidence rates oI adverse
events in addition to the relative risks oI adverse events. Multiple adverse events may also be
come
over time. Cohort studies a
investigated using the same data source in a cohort study. However, it may be diIIicult to recruit
suIIicient numbers oI patients who are exposed to a product oI interest (such as an orphan drug) or
to study very rare outcomes. The identiIication oI patients Ior cohort studies may come Irom large
automated databases or Irom data collected speciIically Ior the study at hand. In addition, cohort
studies may be used to examine saIety concerns in special populations (the elderly, children,
patients with co-morbid conditions, pregnant women) through over-sampling oI these patients or by
stratiIying the cohort iI suIIicient numbers oI patients exist. Cohort studies may be prospective or
retrospective depending on when the outcome oI interest occurs in relation to the commencement oI
the research: II the outcome occurs aIter the research begins, it would be prospective; iI the out
had already occurred when the investigation began, it would be retrospective.
1.2.3 Case-control Study
In a case-control study, cases oI disease (or events) are identiIied. Controls, or patients without the
disease or event oI interest, are then selected Irom the source population that gave rise to the cases.
The controls should be selected in such a way that the prevalence oI exposure to the medicinal
s ratio, which is an estimate oI the
relative risk oI disease among the exposed as compared to the non-exposed. Patients may be
base or using data collected speciIically Ior the purpose oI the study
oI interest. II saIety inIormation is sought Ior special populations, the cases and controls may be
ll as to identiIy
lationship between the drug
exposure and the adverse event. Under speciIic conditions, a case-control study may also provide
oI the event. II all cases oI interest (or a well-deIined Iraction oI cases) in
the catchment area are captured and the Iraction oI controls Irom the source population is known, an
product among the controls represents the prevalence oI exposure in the source population. The
exposure status oI the two groups is then compared using the odd
identiIied Irom an existing data
stratiIied according to the population oI interest (the elderly, children, pregnant women, etc.). For
rare adverse events, existing large population-based databases are a useIul and eIIicient means oI
providing needed exposure and medical outcome data in a relatively short period oI time. Case-
control studies are particularly useIul when the goal is to investigate whether there is an association
between a medicinal product (or products) and one speciIic rare adverse event, as we
risk Iactors Ior adverse events (or actually, eIIect-modiIiers). Risk Iactors may include conditions
such as renal and hepatic dysIunction, which might modiIy the re
the absolute incidence rate
incidence rate can be calculated. As in cohort studies, case-control studies may be prospective or
retrospective (see 1.2.2. oI this Table).
When the source population within which the case-control study is conducted is a well-deIined
cohort, it is then possible to select a random sample Irom it to Iorm the control series. The name
been coined to designate those studies in which the control
control series represents the person-time distribution oI exposure
(case-control surveillance). This strategy has been Iollowed Ior rare diseases with a relevant
y Iraction attributed to medicinal products, including blood dyscrasias or serious skin
'nested case-control study has
sampling is density-based (e.g. the
in the source population). The case-cohort is also a variant in which the control sampling is
perIormed on those persons who make up the source population regardless oI the duration oI time
they may have contributed to it (4).
A case-control approach could also be set up as a permanent scheme to identiIy and quantiIy risks
aetiolog
disorders.
PART I 98/229
1.2.4 Other Novel Designs
Some novel designs have been described to assess the association between intermittent exposures
and short-term events, including the case-series (7), the case-crossover (8) and the case-time-control
(9) studies. In these designs only cases are used and the control inIormation is obtained Irom past
es themselves. One oI the important strengths oI these designs is
s that do not change within individuals are automatically matched.
person-time experience oI the cas
that those conIounding variable
1.3 Clinical Trials
When signiIicant risks are identiIied Irom pre-approval clinical trials, Iurther clinical studies might
be called Ior to evaluate the mechanism oI action Ior the adverse reaction. In some instances,
pharmacodynamic and pharmacokinetic studies might be conducted to determine whether a
particular dosing instruction can put patients at an increased risk oI adverse events. Genetic testing
may also provide clues about which group oI patients might be at an increased risk oI adverse
reactions. Furthermore, based on the pharmacological properties and the expected use oI the
medicinal product in general practice, conducting speciIic studies to investigate potential drug-drug
interactions and Iood-drug interactions might be called Ior. These studies may include population
pharmacokinetic studies and drug concentration monitoring in patients and normal volunteers.
Sometimes, potential risks or unIoreseen beneIits in special populations might be identiIied Irom
pre-approval clinical trials, but cannot be Iully quantiIied due to small sample sizes or the exclusion
m these clinical studies. These populations might include the
disorder. Children, the elderly, and patients with
oI subpopulations oI patients Iro
elderly, children, or patients with renal or hepatic
co-morbid conditions might metabolise medicinal products diIIerently than patients typically
enrolled in clinical trials. Further clinical trials might be used to determine and to quantiIy the
magnitude oI the risk (or beneIit) in such populations.
In perIorming clinical trials Directive 2001/20/EC and related guidance (Volume 10 oI the Rules
Governing Medicinal Products in the EU
31
) should be Iollowed.
1.3.1 Large Simple Trials
A Large Simple Trial is a speciIic Iorm oI clinical trial where large numbers oI patients are
randomised to treatment but data collection and monitoring is kept to the absolute minimum
consistent with the aims oI the study (10). This design is best used in pharmacovigilance to
elucidate the risk-beneIit proIile oI a medicinal product outside oI the Iormal/traditional clinical trial
setting and/or to Iully quantiIy the risk oI a critical but relatively rare adverse event.
These studies qualiIy as clinical trials and are subject to Directive 2001/20/EC and related guidance
(Volume 10 oI the Rules Governing Medicinal Products in the EU
32
).
1.4 Other Studies
Descriptive studies are an important component oI pharmacovigilance, although not Ior the
detection or veriIication oI adverse events associated with exposures to medicinal products. These
studies are primarily used to obtain the background rate oI outcome events and/or establish the
prevalence oI the use oI medicinal products in speciIied populations.
1.4.1 Occurrence of Disease
The science oI epidemiology originally Iocused on the natural history oI disease, including the
characteristics oI diseased patients and the distribution oI disease in selected populations, as well as
estimating the incidence and prevalence oI potential outcomes oI interest. These outcomes oI
interest now include a description oI disease treatment patterns and adverse events. Studies that

31
32
PART I 99/229
examine spec
Ior the adve
iIic aspects oI adverse events, such as the background incidence rate oI or risk Iactors
rse event oI interest, may be used to assist in putting spontaneous reports into
understand the Irequency at which the event oI interest might occur in speciIic subgroups, such as
perspective (1). For example, an epidemiologic study can be conducted using a disease registry to
patients with concomitant illnesses.
1.4.2 Drug Utilisation Study
Drug utilisation studies (DUS) describe how a medicinal product is marketed, prescribed and used
outc data on speciIic populations, such as the elderly, children, or
and a product is being used in these
adv oI regulatory actions and media
oI a the relationship between recommended and
medicinal product has
ther inappropriate repeat prescribing. Important limitations oI these studies may
include a lack oI clinical outcome data or inIormation oI the indication Ior use oI a product.
in a population, and how these Iactors inIluence outcomes, including clinical, social, and economic
omes. These studies provide
patients with hepatic or renal dysIunction, oIten stratiIied by age, gender, concomitant medication
other characteristics. DUS may be used to determine iI
populations. From these studies, denominator data may be derived Ior use in determining rates oI
erse reactions. DUS have been used to describe the eIIect
attention on the use oI medicinal products, as well as to develop estimates oI the economic burden
dverse reactions. DUS may be used to examine
actual clinical practice. These studies may help to determine whether a
potential Ior abuse by examining whether patients are taking escalating dose regimens or whether
e is evidence oI
2. Data Sources
Pharmacoepid e perIormed using a variety oI data sources. Traditionally,
Iield studies were required Ior retrieving the necessary data on exposure, outcomes, potential
dical records. However, the advent oI automated healthcare
databases has remarkably increased the eIIiciency oI pharmacoepidemiologic research. There are
main comprehensive medical inIormation,
including prescriptions, diagnosis, reIerral letters and discharge reports, and those mainly created
admin
claims da
may not n needed Ior some research, such as validated
diagnostic inIormation or laboratory data, and paper-based medical records should be consulted to
ertain the outcome oI interest, the
validation may require either a case-by-case approach or just the review oI a random sample oI
es. Ot e validation where appropriate. There are many databases in
place Ior potential use in pharmacoepidemiological studies or in their validation phase.
rketin data source according to validity
(e.g. completeness oI relevant inIormation, possibility oI outcome validation) and eIIiciency criteria
en into account: As Iar as
Ieasible the data source chosen to perIorm the study should include the population in which the
saIety co
Holder sh
oI use oI
the poten
With any y to personal data
should be Iollowed.
emiological studies may b
conIounders and other variables, through interview oI appropriate subjects (e.g. patients, relatives)
or by consulting the paper-based me
two types oI automated databases, those that contain
Ior istrative purposes, which require a record-linkage between pharmacy claims and medical
tabases. These datasets may include millions oI patients and allow Ior large studies. They
have the detailed and accurate inIormatio
asc and validate test results and medical diagnoses. Depending on
cas her key aspects may requir
Ma g Authorisation Holders should select the best
(e.g. time span to provide results). External validity should also be tak
ncern has been raised. In case another population is involved, the Marketing Authorisation
ould evaluate the diIIerences that may exist in the relevant variables (e.g. age, sex, pattern
the medicinal product) and the potential impact on the results. In the statistical analysis,
tial eIIect oI modiIication oI such variables should be explored.
data source used, the privacy and conIidentiality regulations that appl
PART I 100/229
ReIerences:
1. Mann
2002
2. Strom
3. Hartz
Cinc
4. Rothman KJ, Greenland S, editors. Modern Epidemiology. 2
nd
ed. Philadelphia: Lippincott-
gress and Iuture horizons. Br J Clin
Pharm
6. Shakir SAW. Prescription event
7.
J Epidemiol. 1996;143:1165-73.
8. McC d Ior studying transient eIIects on the risk oI
acute
9.
10.
RD, Andrews EB, eds. Pharmacovigilance. West Sussex: John Wiley and Sons, Ltd;
.
BL, ed. Pharmacoepidemiology. 4
th
ed. New York: John Wiley and Sons, Ltd; 2005.
ema AG, Porta M, Tilson H, eds. Pharmacoepidemiology: an Introduction. 3
rd
ed.
innati: Harvey Whitney Books; 1998.
Raven Publishers; 1998.
Mann RD. Prescription event monitoring: recent pro 5.
acol. 1998;46:195-201.
monitoring. In: Strom BL, editor. Pharmacoepidemiology. 4
th

ed. New York: John Wiley and Sons, Ltd; 2005. p. 203-216.
Farrington CP, Nash J, Miller E. Case series analysis oI adverse reactions to vaccines: a
comparative evaluation. Am
lure M. The case-crossover design: a metho
events. Am J Epidemiol 1991;133:144-153.
Suissa S. The case-time control design. Epidemiology 1995;6:248-253.
YusuI S, Collins R, Peto R. Why do we need some large simple randomized trials. Stat Med.
1984;3:409-422.

TABLE I.7.B:
(Bas
Society
A
ELEMENTS TO BE CONSIDERED IN THE PROTOCOL OF POST-AUTHORISATION SAFETY
STUDIES AS APPROPRIATE
ed on the Guidelines Ior Good Pharmacoepidemiology Practices issued by the International
Ior Pharmacoepidemiology
33
.)
A descriptive title and version identiIier (e.g. date)
B The names, titles, degrees, addresses and aIIiliations oI all responsible parties, including
the principal investigator, co-investigators and a list oI all collaborating primary
institutions and other relevant study sites
C n Holder The name and address oI the Marketing Authorisatio
D An abstract oI the protocol
E Th and timelines e proposed study tasks, milestones
F
Res
Spe ypotheses to be tested. The
priori research hypotheses and hypotheses that are
ach
A statement oI research objectives, speciIic aims and rationale
earch objectives describe the knowledge or information to be gained from the study.
cific aims list the measurements to be made and any h
protocol should distinguish between a
generated based on knowledge of the source data. The rationale explains how
ievement of the specific aims will further the research objectives.

ISPE website
33
Available on http://www.pharmacoepi.org/index.cIm.
PART I 101/229
G A c
The
to pass relevant animal and human experiments,
stu
ritical review oI the literature to evaluate pertinent inIormation and gaps in knowledge
literature review should describe specific gaps in knowledge that the study is intended
fill. The literature review might encom
clinical studies, vital statistics and previous epidemiologic studies. The literature review
should also cite the findings of similar studies and the expected contribution of the current
dy.
H A d

e, time period and selection criteria.
files, abstracts of
igibility files, prescription
story record reviews or
e in the proposed study. For example, "PCP episode" is not an operational
data
anagement
statistical software programmes and hardware to be
ta analysis comprises comparisons and methods for analysing and
presenting results, categorisations as well as procedures to control sources of bias and
their influence on results, e.g. possible impact of biases due to selection,
escription oI the research methods, including:
1. The overall research design, strategy and reasons Ior choosing the proposed study
design
Research designs include case-control, cohort, cross-sectional, nested case-control or
hybrid designs.
2. The population or sample to be studied
The population is defined in terms of persons, plac
The rationale for the inclusion and exclusion criteria and their impact on the number
of subjects available for analysis should be described. If any sampling from a base
population is undertaken, details of sampling methods should be provided.
3. The strategies and data sources Ior determining exposures, health outcomes and all
other variables relevant to the study objectives, such as potential conIounding variables
and eIIect modiIiers, using validated measurements whenever possible
Data sources might include questionnaires, hospital discharge
primary clinical records, administrative records such as el
drug files, biological measurements, exposure/work hi
exposure/disease registries.
4. Clear operational deIinitions oI health outcomes, exposures and other measured risk
Iactors as well as selection criteria and comparison groups
An operational definition is one that can be implemented independently using the data
availabl
definition, whereas a better description would be "hospitalisation with a primary
discharge diagnosis of ICD-9-CM code 136.3".
5. Projected study size, statistical precision and the basis Ior their determination
Describe the relation between the specific aims of the study and the projected study
size in relation to each outcome.
6. Methods used in assembling the study
This should include a description of or reference to any pre-testing procedures for
research instruments and any manuals and formal training to be provided to
interviewers, abstractors, coders or data entry personnel.
7. Procedures Ior data m
Describe data management and
used in the study.
8. Methods Ior data analysis
Data analysis includes all the major steps that lead from raw data to a final result,
including methods used to correct inconsistencies or errors, to impute values or to
modify raw data. Da
PART I 102/229
miscla
applie
ssification, confounding and missing data. The statistical procedures to be
d to the data to obtain point estimates and confidence intervals of measures of
9. A description oI quality assurance and quality control procedures Ior all phases oI the
study
be described, including,
design, data sources and analytic methods
m, issues relating to confounding, misclassification, selection,
considered. The likely success of efforts
educe errors should be discussed.
occurrence or effect, for instance, should be presented. Any sensitivity analyses
undertaken should also be described.
Mechanisms to ensure data quality and integrity should
abstraction of original documents. As appropriate, include certification and/or
qualifications of any supporting laboratory or research groups.
10. Limitations oI the study
At a minimu
generalisability and random error should be
taken to r
I A description oI plans Ior protecting human subjects
This section should include information about whether study subjects will be placed at risk
as a result of the study, provisions for maintaining confidentiality of information on study
subjects and potential circumstances and safeguards under which identifiable personal
y. Conditions under which the
be described. Procedures for
ive studies consider using a Data
information may be provided to entities outside the stud
study would be terminated (stopping rules) should
monitoring results should be described; for prospect
Safety Monitoring Board (DSMB) for this purpose.
J Management and reporting oI adverse events/adverse reactions
This section should include the procedures for collecting, management and reporting of
, as appropriate. If an exemption to
Authorities, a mention
individual cases of adverse events or adverse reactions
the individual case reporting has been granted by the Competent
should be made in this section along with a justification (the waiver must be attached as
an annex).
K g study results, including the
presence or absence oI any restrictions on the extent and timing oI publication
ngs of potential scientific or public
A description oI plans Ior disseminating and communicatin
There is an ethical obligation to disseminate findi
health importance (e.g. results pertaining to the safety of a marketed medicinal product).
L
Describe time, personnel and equipment required to conduct the study, including a brief
e of each of the personnel assigned to the research project.
Resources required to conduct the study
description of the rol
M Bibliographic reIerences
N Dated amendments to the protocol
Significant deviations from the protocol, such as any changes in the population or sample
ocumented in writing.
Any changes made after data analysis has begun should be documented as such and the
rationale provided.
that were implemented after the beginning of the study, should be d
PART I 103/229
O Annexes
For any additional or complementary information on specific aspects not addressed in the
body text (e.g. questionnaires, case report forms).

TABLE I.7.C: ELEMENTS TO BE CONSIDERED IN THE FINAL STUDY REPORT
(Based on the Guidelines Ior Good Pharmacoepidemiology Practices issued by the International
Society Ior Pharmacoepidemiology
34
.)
1 A descriptive title
2 An abstract
3 Purpose (objectives) oI the research, as stated in the protocol
4 The names, titles, degrees, addresses and aIIiliations oI the principal investigator and all
co-investigators
5 Name and address oI the Marketing Authorisation Holder
6 Dates on which the study was initiated and completed
7 Introduction with background, purpose and speciIic aims oI the study
8 A description oI the research methods, including:
a) Source population and selection oI study subjects;
b) Data collection methods and, iI questionnaires or surveys are involved, complete
copies (including skip patterns);
c) TransIormations, calculations or operations on the data;
d) Statistical methods used in data analyses.
9 A description oI circumstances that may have aIIected the quality or integrity oI the data
Describe the limitations of study approach and the methods used to address them (e.g.
response rates, missing or incomplete data).
10 Analysis oI the data
Include sufficient tables, graphs and illustrations to present the pertinent data and to
reflect the analyses performed.
11 Management and reporting oI adverse events/adverse reactions
12 A statement oI the conclusions drawn Irom the analyses oI the data

34
Available on ISPE website http://www.pharmacoepi.org/index.cIm.
PART I 104/229
PART I 105/229
A
contrast to present findings. Discuss possible
biases and limitations in present research.
13 discussion oI the implication oI study results
Cite prior research in support of and in
14 ReIerences

8. Overall Pharmacovigilance Evaluation and Safety-Related Regulatory Action
8.1 Introduction
Granting oI a marketing authorisation Ior a medicinal product indicates that it is considered to have a
satisIactory risk-beneIit balance under the conditions deIined in the Summary oI Product
Characteristics (SPC) and in accordance with the Risk Management Plan (where applicable) (see
Chapter I.3), on the basis oI the inIormation available at that time.
diverse populations than those during the
er and the Competent Authorities must keep abreast oI all
Iollowing responsibilities:
risk-beneIit balance.
or Consumers; epidemiological studies; clinical
be used Ior
oI interest
databases.
35
Rarely, even a single report oI an
signal on or establish a
The responsibilities oI the Marketing Authorisation Holder, and in particular oI the QPPV, are
During the post-authorisation period, larger and more
development phase oI the product are likely to be exposed. New inIormation on the beneIits and risks
oI the product will be generated, and evaluation oI this inIormation and any saIety concerns should be
an on-going process, both by the Marketing Authorisation Holder and the Competent Authorities.
Both the Marketing Authorisation Hold
relevant inIormation in order to IulIil the
Ensuring that all sources oI inIormation are screened regularly to identiIy any potential
signals;
Ensuring that appropriate action is taken in response to new evidence which impacts on the
known risk-beneIit balance;
Keeping the Competent Authorities, Healthcare ProIessionals and Patients inIormed.
This Chapter
outlines the responsibilities oI Marketing Authorisation Holders in signal detection;
provides the principles on which an assessment oI the risk-beneIit balance should be based;
and
outlines the steps that may be taken by Marketing Authorisation Holders in order to address a
change in the
8.2 Signal Detection and Evaluation
Signals oI possible unexpected adverse reactions or changes in severity, characteristics or Irequency oI
expected adverse reactions may arise Irom any source including preclinical and clinical data (e.g.
spontaneous reports Irom Healthcare ProIessionals
trials), published scientiIic and lay literature. Standardised MedDRA Queries (SMQs) may
signal detection and the use oI SMQs is recommended in order to retrieve and review cases
where signals are identiIied Irom adverse reaction
unexpected adverse reaction may contain suIIicient inIormation to raise a
causal association with the suspected medicinal product and impact on the risk-beneIit balance.
pro e ibility oI the QPPV to provide the Competent
Au ri the evaluation oI beneIits and risks aIIorded by a medicinal
vid d in Chapter I.1, Section 2. It is the respons
tho ty with any inIormation relevant to
product, including appropriate inIormation on post-authorisation saIety studies.
The Marketing Authorisation Holder should immediately inIorm the Competent Authorities in all
Member States where the product is authorised and additionally, Ior centrally authorised products, the
Agency oI any prohibition or restriction imposed by the Competent/regulatory authorities oI any
country in the world in which the medicinal product is marketed and oI any other new inIormation
which might inIluence the evaluation oI the beneIits and risks oI the medicinal product.

35
PART I 106/229
The Marketing Authorisation Holder and the Competent Authority should agree on the appropriate
scope and timelines Ior evaluation, taking account oI the authorisation procedure (see Chapters II.2.A
and II.3) and agreed responsibilities Ior review. The Marketing Authorisation Holder should provide
a comprehensive evaluation oI the issue and the risks in the context oI the beneIits at the earliest
peciIied in the written communications between the
Competent Authority and the Marketing Authorisation Holder. It should be sent to the Competent
8.3
Ov l
to w
populati
8.3.1
Wh a
pro t
dis
to whic
the resp
beneIit idered as the reduction oI the expected severity or incidence oI the disease. With
er words, Ialse
negative and Ialse positive rates. Any available inIormation on misuse oI the product and on the level
mplian mpact on the evaluation oI its beneIits, should
also be considered. The quality and degree oI the evidence oI beneIit should be taken into account.
opportunity and no later than the agreed date s
Authorities in all Member States where the medicinal product is authorised, and additionally to the
Agency in the case oI centrally authorised products.
Principles of Risk-Benefit Assessment
eral risk-beneIit assessment should take into account and balance all the beneIits and risks reIerred
belo . Risk-beneIit assessment should be conducted separately in the context oI each indication and
on, which may impact on the conclusions and actions.
Assessment of Benefits
en new or changing risk is identiIied, it is important to re-evaluate the beneIit oI the medicinal
duc using all available data. The beneIit oI a medicinal product can be seen as the decrease in
ease burden associated with its use. BeneIit is composed oI many parameters including: the extent
h the medicinal product cures or improves the underlying condition or relieves the symptoms;
onse rate and duration and quality oI liIe. In the case oI prophylactic medicinal products, the
may be cons
diagnostics, the beneIit will be deIined in terms oI sensitivity and speciIicity or, in oth
oI co ce in clinical practice, which may have an i
BeneIit should, as Iar as possible, be expressed in quantitative terms in a way that makes it comparable
to the risks.
8.3.2 Assessment of Risks
Assessment oI risk involves a stepwise process requiring identiIication, conIirmation, characterisation
(including identiIication oI risk Iactors), and quantiIication oI the risk in the exposed population.
Overall assessment oI risk should consider all available sources oI inIormation, including:
Spontaneous adverse reaction reports;
Adverse reaction data Irom studies which may or may not be company-sponsored;
In vitro and in vivo laboratory experiments;
Epidemiological data (see Table I.7.A);
Registries, Ior example oI congenital anomaly/birth deIects;
Im
oI c sa
may all
account. In the assessment oI risks and consideration oI regulatory action, it is important to note that
Data published in the worldwide scientiIic literature or presented as abstracts, posters or
communications;
Investigations on pharmaceutical quality, and
Data on sales and product usage.
portant issues, which should be addressed in the assessment oI adverse reactions, include evidence
au l association, seriousness, absolute and relative Irequency and presence oI risk Iactors, which
ow preventive measures. The quality and degree oI evidence oI risk should be taken into
rarely even a single case report may establish a causal association with the suspected medicinal
product and impact on the risk-beneIit balance. Risk assessment should also take account oI the
potential Ior overdose, misuse, abuse, oII-label use and medication errors.
PART I 107/229
When new saIety concerns are identiIied, which, could have an impact on the overall risk-beneIit
balance oI a medicinal product, the Marketing Authorisation Holder should propose appropriate
studies to Iurther investigate the nature and Irequency oI the adverse reactions. A new or updated Risk
Management Plan should be proposed accordingly (see Chapter I.3). The studies should comply with
the guidance provided in Chapter I.7.
8.3.3 Risk-Benefit Assessment
Whenever possible, both beneIits and risks should be considered in absolute terms and in comparison
to alternative treatments. The magnitude oI risk that may be considered acceptable is dependent on the
seriousness oI disease being treated and on the eIIicacy oI the medicinal product. For example:
In the treatment oI a disease with high mortality, a high risk oI serious adverse reactions may
be acceptable providing the beneIits associated with treatment have been shown to be greater.
main beneIit is symptom relieI Ior minor illnesses in otherwise healthy
are treated not only Ior their own beneIit but also Ior the
ust be extremely low.
8.4 Improving the Risk-Benefit Balance
The Marketing Authorisation Holder should aim to optimise the saIe use and the risk-beneIit balance
oI an individual product and ensure that the adverse eIIects oI a medicinal product do not exceed the
beneIits within the population treated. The risk-beneIit balance oI a medicinal product cannot be
considered in isolation but should be compared with those oI other treatments Ior the same disease.
The risk-beneIit balance may be improved either by increasing the beneIits (e.g. by restricting use to
identiIied responders), or by reducing the risks by risk minimising measures (e.g. by contraindicating
the use in patients particularly at risk, reducing dosage, introducing precautions oI use and warnings
and, iI appropriate, pre-treatment tests to identiIy patients at risk, monitoring during treatment Ior
For medicines used in chronic diseases or in prevention oI disabling diseases, some level oI
risk may be acceptable iI there is a substantial improvement in the prognosis or quality oI liIe.
In situations where the
individuals or where individuals
beneIit oI the community (e.g. vaccination), risk levels m
In cases where therapeutic beneIit is limited, even a Iew cases oI a serious adverse reaction
may suIIice to render the risk-beneIit balance as unIavourable.
II, Ior two medicinal products with essentially similar eIIicacy and types oI adverse reactions,
one or more serious adverse reactions were shown to diIIer in Irequency, the risk-beneIit
balance oI the product with the higher adverse reaction Irequency may no longer be
acceptable.
The populations being treated must also be taken into account, as should oII-label use.
early diagnosis oI adverse reactions (see Table I.3.A Ior overview on risk minimisation methods).
When proposing measures to improve the risk-beneIit balance oI a product, their Ieasibility in normal
conditions oI use should be taken into account. II dose reduction is considered as a method oI risk
minimisation, the impact oI dose reduction on eIIicacy should be careIully evaluated.
The Iollowing types oI action may be necessary and may be initiated by the Marketing Authorisation
Holder or by the Competent Authorities:
Variation oI marketing authorisation(s) in respect oI the indication, dosing recommendations,
contraindications, warnings and precautions Ior use or inIormation about adverse reactions or
other sections oI the SPC and the Package LeaIlet (PL);
Direct provision oI important saIety inIormation to Healthcare ProIessionals and Patients/the
public (e.g. through letters and/or bulletins or via electronic media) (see Chapter I.8,
Section 6).
II there are important new saIety concerns requiring urgent action, the Marketing Authorisation
Holder, should initiate an urgent saIety restriction (USR) in accordance with Commission Regulations
PART I 108/229
PART I 109/229
C) No 1084/2003 and (EC) No 1085/2003 Iollowed by a type II variation. These measures should
e immediately communicated to the relevant Competent Authorities and in addition to the Agency in
ase oI a centrally authorised product. II no objections are raised within 24 hours aIter receipt oI an
pplication, the USR may be introduced and the corresponding application Ior the variation should be
ubmitted without delay to the Competent Authorities and, with respect to centrally authorised
(E
b
c
a
s
medicinal products, the Agency. See also Chapter II.1, Section 7, and Chapters II.2.A and II.3.
.5 Withdrawal of a Product from the Market on Risk-Benefit Grounds
the event that the overall risk-beneIit balance is considered to be unIavourable and proposed risk
inimisation measures are considered inadequate to redress the balance, the medicinal product should
be withdrawn Irom the market and onals and Patients/the public should be
8
In
m
Healthcare ProIessi
inIorm untarily by
Ma iscussed at
an early stage with all Competent Authorities concerned. All concerned Competent Authorities and the
Agency should be inIormed immediately oI any deIinite action.
For reporting requirements Ior Individual Case SaIety Reports Iollowing withdrawal oI a marketing
ed as appropriate (see Chapter I.8, Section 6). Such action may be taken vol
rketing Authorisation Holders. It is recommended that any such intended measure be d
authorisation see Chapter I.5.
8.6 Communication
In the event oI a product withdrawal, an urgent saIety restriction or an important variation, the content
oI Public Statements, Direct Healthcare ProIessional Communication (DHPC) and other
communication Irom the Marketing Authorisation Holder to Healthcare ProIessionals, Patients and the
general public, including the time Irame Ior the distribution oI such communication, should be agreed
with the relevant Competent Authorities. Marketing Authorisation Holders are reminded oI their legal
obligations under Article 104(9) oI Directive 2001/83/EC not to communicate inIormation relating to
pharmacovigilance concerns to the public without notiIication to the Competent Authorities. For
Iurther guidance see Part IV.

PART II:
Guidelines Ior Competent Authorities and the Agency
110/229
1. Undertaking of Pharmacovigilance Activities by Competent Authorities in
Member States
1.1 Introduction
The basis Ior undertaking oI pharmacovigilance activities is established in EU legislation, as described
in Directive 2001/83/EC (mainly Title IX) and Regulation (EC) No 726/2004 (particularly Articles 21-
29). The aim oI this Chapter is to provide overall guidance Ior nati
principles described and in accordance with the Mandate oI the
onal Competent Authorities on the
Pharmacovigilance Working Party
(PhVWP) (see Appendix II.1.A at the end oI this Chapter).
For centrally authorised products, the European Commission is the Competent Authority. As the
Agency co-ordinates some oI the pharmacovigilance activities on behalI oI the European Commission,
the Agency should be understood as included in the term 'Competent Authorities Ior the purposes oI
this guidance.
To meet their legal requirements, Member States should undertake all appropriate activities, including
the Iollowing:
To encourage reporting oI suspected adverse reactions by Healthcare ProIessionals;
To Iacilitate reporting oI adverse reactions by Patients either directly to national Competent
Authorities, or via patient organisations, or via Healthcare ProIessionals, as appropriate in
accordance with the national system;
To maintain awareness oI relevant pharmacovigilance publications through regular monitoring
oI the scientiIic literature;
To initiate, as appropriate investigation and assessment oI saIety concerns;
To oblige Marketing Authorisation Holders to systematically collect inIormation on risks
related to their medicinal products and to transmit this inIormation to the Competent
Authorities and the Agency as appropriate in accordance with Part I;
To ensure that Marketing Authorisation Holders implement appropriate Risk Management
Plans to eIIectively monitor and manage risks associated with the saIety oI their products;
To monitor the impact and eIIectiveness oI such Risk Management Plans and regulatory
action taken to enhance saIe and appropriate use oI medicinal products;
To monitor the compliance oI Marketing Authorisation Holders in relation to their
pharmacovigilance activities;
To implement conditions and restrictions with regard to the saIe and eIIective use oI centrally
authorised products, or products subject to reIerral procedures, on the basis oI Commission
Decisions;
To interact with relevant international organisations, particularly the World Health
Organization (WHO), in accordance with agreed guidance and procedures (see Chapter II.6);
To communicate the outcome oI evaluation oI saIety concerns as appropriate to Healthcare
ProIessionals and as necessary to the public, through timely and appropriate methods oI
communication and to assess the impact oI such communications;
To make Individual Case SaIety Reports (ICSRs) available to the Agency, Competent
Authorities oI other Member States and to the concerned Marketing Authorisation Holders
according to the criteria laid down in legislation, and also described in this Chapter and
Chapters II.2.A and II.3 and in Part III on the Electronic Exchange oI Pharmacovigilance
InIormation;
To record electronic data and paper-based ICSRs in a database managed by the national
Competent Authority. Data storage should ensure on-line accessibility in line with
recommendations speciIied in Part III.
The requirements and procedures involved in a phamacovigilance system are described in this
Chapter, which relates to medicinal products authorised in the EU (using either centralised, mutual
PART II 111/229
recognition, decentralised or purely national procedures) and covers collection and evaluation oI all
inIormation useIul in the surveillance oI medicinal products. This Chapter should be read in
association with other relevant Chapters included in this Volume, in particular Chapter II.2.A on the
conduct oI pharmacovigilance Ior centrally authorised products and Chapter II.3 on the conduct oI
pharmacovigilance Ior medicinal products authorised through the mutual recognition or decentralised
procedure, Part III on electronic reporting, Chapter II.2.B on the Crisis Management Plan Ior centrally
authorised products, Chapter II.4 on the Rapid Alert/Non-Urgent InIormation System, Chapter I.3 on
Risk Management Systems and Part IV on communication to the public.
1.2 Establishment of a Pharmacovigilance System
Each Member State should have in place systems Ior receipt and evaluation oI all pharmacovigilance
data and to ensure that appropriate regulatory action may be taken. Such systems, whether involving
distribution oI activities through regional centres or operated Iully by a single national centre, within
the Competent Authority, should ensure that pharmacovigilance data are managed in a way that is
compatible with the procedures undertaken in other Member States and the Agency in order that
pertinent data may be shared between Member States and the Agency.
In accorda e with Article 102a oI Directive 2001/83/EC, the nc management oI Iunds intended Ior
activities connected with pharmacovigilance, the operation oI communication networks and market
surveillance should be under the permanent control oI the Competent Authorities in order to guarantee
their ind n
pharma g
adequat b
Each Membe
and po u
pharmacovig
ompliance with
pha a
submiss
appropr
epe dence. According to Article 67(4) oI Regulation (EC) No 726/2004, activities relating to
covi ilance, operation oI communication networks and market surveillance should receive
e pu lic Iunding commensurate with the tasks conIerred.
r State should ensure appropriate procedures and systems exist between pre-authorisation
st-a thorisation Iunctions to ensure the availability oI comprehensive and integrated
ilance systems.
Each Member State should monitor Marketing Authorisation Holder c
rm covigilance obligations (e.g. timely reporting oI expedited adverse reaction reports, timely
ion oI Periodic SaIety Update Reports in accordance with agreed Iormats and content,
iate and comprehensive responses to ad hoc queries Irom Competent Authorities) and should
underta hapter ke monitoring oI compliance and pharmacovigilance inspections in accordance with C
I.2 on m
The CH
onitoring oI compliance and pharmacovigilance inspections.
MP Pharmacovigilance Working Party (PhVWP) has been given a Mandate, Objectives and
Rules o
medicin oI adverse reactions to enable
eII v
liIe oI a
nationa
appropr vigilance issues at EU
level. Each Member State should ensure that it actively participates in and cooperates with the PhVWP
with international bodies, in particular the World Health
Or iz borating Centre Ior International Drug Monitoring through
I Procedure (see Appendix II.1.A at the end oI this Chapter) to provide advice on the saIety oI
al products authorised in the EU and on the investigation
ecti e identiIication, assessment, management and communication oI risk at any time during the
medicinal product and to provide recommendations Ior regulatory action to the CHMP and the
l Competent Authorities. This requires interaction with the CHMP and specialised experts as
iate, as well as consensus development and coordination oI pharmaco
in order to IulIil its pharmacovigilance obligations at EU level.
All Member States should cooperate
gan ation (WHO) and the WHO Colla
the a keeping with the guidance provided in Chapter II.6 on
pri l WHO.
Co should also cooperate with regulatory authorities outside the
EU t ments in place Ior exchange oI data and other inIormation.
ir n tional Competent Authorities, in
ncip es oI collaborating with
mpetent Authorities and the Agency
on he basis oI any Iormal arrange
PART II 112/229
1.3 Management of Spontaneous Reporting Programmes
1.3.1 General Principles
Each Member State should have in place a system Ior the collection oI spontaneous suspected adverse
reaction reports Irom Healthcare ProIessionals, Marketing Authorisation Holders (see also Chapter
I.4) and, where appropriate, Irom Patients/Consumers (see Chapter 1.4, Section 3.5). Competent
Authorities should liaise with Healthcare ProIessionals in their territory, to increase awareness oI the
reporting system, stressing its importance and encouraging reporting.
To this end, it is desirable that each Member State should ensure the Iollowing:
That reporting oI adverse reactions is straightIorward and accessible to Healthcare
ProIessionals and, where appropriate, to Patients/Consumers (by providing a user-Iriendly
reporting system, e.g. Iree post, telephone and/or web-based systems);
That all adverse reaction reports are acknowledged where appropriate and Iurther inIormation
is Iorwarded as requested; and
That regular contact is maintained between the national/regional pharmacovigilance centre(s)
and Healthcare ProIessionals, Ior example by:
.
y in the
otential signals and analyse data in order to e.g.
Publication oI regular pharmacovigilance bulletins;
Circulation oI Direct Healthcare ProIessional Communications, where appropriate, (either
by the Competent Authority and/or the Marketing Authorisation Holder);
Provision oI inIormation in response to speciIic requests Irom Healthcare ProIessionals
and other stakeholders;
Provision oI lectures and talks to Healthcare ProIessionals during scientiIic meetings and
conIerences; and
Availability oI comprehensive websites that Iacilitate and encourage reporting oI
suspected adverse reactions
The Iollowing recommendations concern spontaneous reporting system procedures:
A Healthcare ProIessional or a Marketing Authorisation Holder reports a suspected adverse
reaction, related to one or more medicinal products, to the Competent Authorit
Member State where the reaction occurred. Reports may be made in writing (e.g. using report
Iorms), by telephone, or electronically in the case oI Marketing Authorisation Holders.
Reports are collected and validated by the regional centre or national Competent Authority
and are entered into a database. Serious reactions should be handled with the highest priority.
The database should be used to identiIy p
clariIy risk Iactors and apparent changes in reporting proIiles.
Case reports should be made accessible to the Agency, to the Competent Authorities oI other
Member States, and to the concerned Marketing Authorisation Holders according to the
criteria laid down in legislation, and described in this Chapter, Chapters II.2.A and II.3, and in
Part III on the electronic exchange oI pharmacovigilance inIormation.
ember States and are independent
oI the structure oI the national pharmacovigilance systems (centralised or regionalised). The
ments
Quality management; and
ConIidentiality and security.
The Iollowing requirements relate to the Competent Authorities oI M
require are described as Iollows:
Receipt and validation oI ICSRs;
Processing oI ICSRs;
Evaluation oI ICSRs;
Reporting oI ICSRs;
PART II 113/229
1.3.2 Receipt and Validation of Individual Case Safety Reports (ICSRs)
This concerns receipt and validation oI primary data, i.e. the data transmitted Irom the original reporter
to the Competent Authority. For validation and management oI electronically transmitted reports, the
speciIic requirements should be Iollowed (see Part III).
A single case report concerns one Patient, one or more identiIiable reporter(s), one or more suspected
adverse reaction(s) and one or more suspected medicinal product(s). Cases that meet the criteria Ior
expedited reporting should be submitted in accordance with the requirements speciIied in Chapter I.4.
Validation of ICSRs received directly from Healthcare Professionals and Patients/Consumers
prior to
reporting to the Marketing Authorisation Holders and the Agency, that the minimum inIormation
National Competent Authorities should attempt to validate all ICSRs submitted to ensure,
required (see Chapter I.4, Section 1) is included in the ICSR.
This minimum inIormation allows the case to be entered onto a database and become available Ior
signal detection. Every eIIort should be made to obtain complete case inIormation.
ut are considered
, including signs and
ain additional inIormation relevant to the case as necessary, and
eported to the Marketing Authorisation Holder and the Agency. All
II the original notiIication oI a case is made orally or by telephone to the national Competent
Authority, it should be conIirmed in writing by a Healthcare ProIessional. When several suspected
adverse reactions to one or more suspected medicinal products occur in one Patient, b
to be independent reactions, they should be treated as separate cases. II considered appropriate,
especially in the case oI serious or unexpected adverse reactions, data in the report concerning the
Patient, the medicinal products taken, the adverse reactions experienced
symptoms and laboratory reports, and the dates should be conIirmed by copies oI the most important
and relevant original documents (e.g. hospital discharge Iorms, specialist reports, laboratory tests,
prescriptions and post mortem reports).
Reports should be Iollowed-up to obt
Iollow-up inIormation should be r
available clinical inIormation relevant to the evaluation oI the reaction should be provided.
For adverse reaction reports relating to biological products, the deIinite identiIication oI the product
with regard to its manuIacturing is oI particular importance. ThereIore, Competent Authorities should
give advice to reporters to provide the name oI the medicinal product (in accordance with Article
1(20) oI Directive 2001/83/EC, see Annex 1.3) and the batch number and should Iollow-up the reports
where this inIormation is missing Ior completion.
When inIormation is received directly Irom a Patient/Consumer suggesting that an adverse reaction
has occurred, the regional/national pharmacovigilance centre should attempt to obtain consent to
t a He mer Ior Iollow-up inIormation. Such contac althcare ProIessional nominated by the Patient/Consu
cases should be managed in accordance with the guidance described in Chapter I.4 and any relevant
national legal requirements and/or guidance.
With regard to interpretation oI the term suspected, see Chapter I.4.
1.3.3 Processing Individual Case Safety Reports
Paper-based ICSRs should be stored and treated in the same way as other medical records, with
appropriate respect Ior conIidentiality and in accordance with the requirements speciIied by
Directive 95/46/EC on protection oI personal data.
PART II 114/229
Electronic data and paper-based ICSRs should be recorded in a database by the national Competent
Authority, taking account oI the relevant legal requirements. Data storage should ensure on-line
accessibility oI data in line with the recommendations speciIied in Part III.
Terminologies
The internationally agreed medical terminology (MedDRA) and other terminologies reIerred to in
Part III should be used (see Annex 3.2). All coding used in national pharmacovigilance databases
should be compatible with or automatically transIerable to the Iormat oI the ICH-E2B(M) standard
(see Annex 4).
Reaction terms should be entered as the closest term available in the terminology using the appropriate
MedDRA Lowest Level Terms (LLTs), and, iI possible, also in the original reporter's words.
s and destinations oI transmitted data.
eport CSRs, as well as identiIication oI
ty
case reports contain suIIicient inIormation to identiIy such
appropriate), addresses, date oI birth and/or
Use oI terminologies should be monitored and validated, either systematically or by regular random
evaluation. Data entry staII should be instructed in the use oI the terminologies, and their proIiciency
veriIied.
Data Entry
ConIormity oI stored data with initial and Iollow-up reports should be ensured by a quality control
procedure, which provides Ior validation against the original data or images thereoI.
Storage should ensure traceability (audit trail) oI all data entered or modiIied, including dates and
sources oI received data, as well as date
Case r processing also concerns evaluation oI data Irom I
individual cases requiring speciIic handling, signal detection and evaluation and any other processing
oI aggregate data deemed necessary.
Management of Duplicate Reports
Some ICSRs, especially those which are serious, may be reported to Competent Authorities Irom more
than one source, or Irom a single source through more than one channel. The Competent Authori
should make every eIIort to ensure that
duplicates, e.g. Irom Patient/reporter initials (or names, iI
other dates and should liaise with relevant Marketing Authorisation Holders to Iacilitate identiIication
oI possible duplicate cases. Databases should be reviewed regularly to identiIy duplicates in
accordance with national Competent Authority and Agency procedures. AIter identiIication, duplicates
should be merged into a single new (or merged) ICSR, in accordance with ICH-E2B(M) guidance (see
Part III).
1.3.4 Reporting of Individual Case Safety Reports
ICSRs that meet the criteria Ior expedited reporting to other Competent Authorities, the Agency or
Marketing Authorisation Holders should be transmitted in accordance with approved Iormats and
timelines, as deIined in Chapter I.4.
All serious adverse reactions, occurring within a Member State and notiIied to the national Competent
Authority by a Healthcare ProIessional should be transmitted to the Marketing Authorisation Holder
and to the Agency within 15 calendar days oI their receipt by the regional/national centre. The clock
Ior expedited reporting starts (day 0) as soon as the minimum inIormation (see Chapter I.4) has been
brought to the attention oI the national or regional pharmacovigilance centre.
PART II 115/229
The data transmitted should be as complete as possible in order to Iacilitate assessment, but it is not
obligatory Ior national Competent Authorities to have made a Iormal evaluation beIore this
transmission (see also Chapter II.4 and Part III).
National Competent Authorities should ensure that ICSRs are transmitted electronically to the
Agency, as required (see Part III).
ICSRs associated with use oI medicinal products authorised through the mutual recognition or
RMS or Rapporteur by the Marketing Authorisation Holder should only be
transmitted to EudraVigilance by the Competent Authority in the Member State where the case
should
decentralised procedures and Ior medicinal products which have been the subject oI a reIerral
procedure, provided to the
occurred. To avoid duplicate reporting, the ReIerence Member State/Rapporteur Member State
not re-trans igilance (see Chapter II.3).
ion should be
mit these ICSRs to EudraV
In the case oI centrally authorised medicinal products, it is the responsibility oI the Agency to inIorm
each Member State oI serious reports received Irom other Member States. InIormat
transmitted within the timeIrame outlined in Chapter II.2.A. ICSRs should also be transmitted to the
WHO Collaborating Centre Ior International Drug Monitoring by the Competent Authority in whose
territory the reaction occurred, as described in Chapter II.6.
Data Irom non-serious, expected or unexpected, adverse reaction reports that are received Irom all
r transmission to sources should not be reported on an expedited basis, but should be available Io
relevant parties (Marketing Authorisation Holder, Member States and the Agency), as necessary (see
Chapter II.4 and Part III).
1.3.5 Evaluation of Individual Case Safety Reports
ludes assessment oI the seriousness and expectedness oI
ness and expectedness) have speciIic meanings in
Following validation, evaluation oI ICSRs inc
the suspected adverse reaction. These terms (serious
the context oI adverse reaction report evaluation (see Glossary in Annex 1.1). Evaluation oI the
probability oI a causal relationship between the medicinal products and the suspected reaction(s) may
be undertaken, when considered appropriate. All methods used to evaluate these parameters should be
documented. Evaluators should be trained in the methods used and their training should be veriIied.
1.3.6 Signal Detection
MQs) may be used Ior
signal detection and the use oI SMQs is recommended in order to retrieve and review cases oI interest
Database Iunctionality should enable users to search and retrieve data to Iacilitate cumulative data
review, signal detection and trend analysis. Standardised MedDRA Queries (S
where signals are identiIied Irom adverse reaction databases
36
. When a signal is identiIied, the
possibility oI a causal relationship should be considered and in these circumstances, all relevant
adverse reaction data should be Iurther analysed. All ICSRs IulIilling the minimum inIormation
requirements (see Chapter I.4, Section 1) should be included in the overall analysis. Certain analyses
(Ior example those concerning the role oI risk Iactors) may be conIined to cases where suIIicient
inIormation is available, but it should be made clear that this is a subset oI the data.
thorities and Marketing Authorisation Holders should inIorm each other oI identiIied
signals, which may impact on the known risk-beneIit balance oI nationally authorised medicinal
e centralised, mutual recognition or
Competent Au
products and in the case oI products authorised through th
decentralised procedures in accordance with relevant guidance (see Chapters II.2A and II.3). Overall
pharmacovigilance evaluation and relevant regulatory action should be initiated by Competent

36
PART II 116/229
Authorities in accordance with the criteria and guidance described below and in Chapter I.8. The
PhVWP Mandate provides a Iorum Ior discussion and Iinalisation oI regulatory proposals by the
PhVWP at the request oI a Member State or the CHMP, Iollowing initial review and evaluation oI a
signal at national level or by the Rapporteur. The Rapid Alert/Non-Urgent InIormation System should
be used by Competent Authorities when applicable and Competent Authorities should communicate
with Marketing Authorisation Holders in accordance with the requirements speciIied (see
Chapter II.4).
It is essential that signals/saIety concerns are communicated at an early stage, preIerably beIore a
nat a
1.3 orld Health Organization and Other
Co t ation is provided to the World
ion l decision is taken.
.7 Provision of Information to the W
International Bodies
mpe ent Authorities should ensure that appropriate and timely inIorm
He O in Chapter II.6.
inIormation.
Reporting Healthcare Professionals
ber and, iI appropriate, additional
petent Authorities, who should devise, document and
rmacovigilance data, measures should be taken to
olves strict control oI access to documents and to
re that a QualiIied Person Ior Pharmacovigilance
ailable and that an appropriate system oI
alth rganization (WHO), in accordance with the guidance provided
Competent Authorities should also interact regularly and as required with relevant national and
international bodies (e.g. national haemovigilance centres, centres Ior disease control, poison centres),
regarding exchange oI appropriate and timely
1.3.8 Feedback Information to
National Competent Authorities should ensure that the original reporter(s) oI a case is (are) inIormed
oI its receipt and are provided with the allocated reIerence num
inIormation should be requested.
1.3.9 Quality Management
Quality management concerns every step in the processes described above. Quality control and quality
assurance should be ensured by national Com
implement appropriate procedures.
1.3.10 Confidentiality and Security
ConIidentiality oI Patients' records including personal identiIiers, iI provided, should always be
maintained. IdentiIiable personal details oI reporting Healthcare ProIessionals should be kept in
conIidence, as appropriate and in keeping with national and EU legislation.
At each stage oI storage and processing oI pha
ensure data security and conIidentiality. This inv
databases to authorised personnel sharing the medical and administrative conIidentiality oI the data.
This security extends to the complete data path. Case report inIormation should only be transmitted to
stakeholders, or otherwise provided by Competent Authorities in an anonymous Iorm.
In addition, procedures should be implemented to ensure security and non-corruption oI data during
data transIer.
1.4 Company-Derived Pharmacovigilance Data
The Marketing Authorisation Holder should ensu
(QPPV) is permanently and continuously av
pharmacovigilance is in place in order to ensure responsibility and liability Ior marketed products to
ensure that appropriate action can be taken, in accordance with the legal requirements described in
Article 103 oI Directive 2001/83/EC and Article 23 oI Regulation (EC) No 726/2004. Guidance Ior
PART II 117/229
Marketing Authorisation Holders on the implementation and practical procedures involved in
complying with legal requirements is described in Part I and Part III. Competent Authorities should
ensure that the inIormation and contact details Ior QPPVs and back-up services are documented and
accessible to Iacilitate interaction between the Competent Authority and the Marketing Authorisation
Holders via QPPVs, as appropriate. Competent Authorities should also ensure that the descriptions oI
Marketing Authorisation Holders` pharmacovigilance systems are reviewed and assessed, as described
in Chapter I.2.
Reports (ICSRs);
relevant data arising Irom post-authorisation commitments; and
This subchapter deals with the procedures to be undertaken by Competent Authorities in reviewing
Applicants and Marketing Authorisation Holders should submit product-speciIic Risk Management
Company-derived pharmacovigilance data includes the Iollowing:
Risk Management Plans;
Individual Case SaIety
Periodic SaIety Update Reports (PSURs);
data Irom company-sponsored post-authorisation saIety studies;
Risk-BeneIit Reviews;
other relevant data, e.g. proposed communication texts.
company-derived pharmacovigilance data.
1.4.1 Risk Management Plans
Plans in accordance with the requirements speciIied in Chapter I.3.
Risk Management Plans should be thoroughly assessed by the Competent Authorities in terms oI
complexity, content and adequacy. Feedback and comments should be provided to Applicants and
agement Plans
should be provided to Marketing Authorisation Holders, which may impact on and/or Iacilitate
ed by the national Competent
Authority or Lead Member State Ior purely nationally authorised products, or by the ReIerence
Marketing Authorisation Holders, as appropriate. Assessment Reports on Risk Man
discussion with other Competent Authorities.
Risk Management Plans serve as a basis Ior post-authorisation pharmacovigilance activities; thereIore
they should be stored in a way that allows rapid and complete access to the documentation.
An Assessment Report on a Risk Management Plan should be prepar
Member State or the Rapporteur Ior products authorised via the mutual recognition, decentralised or
centralised procedures respectively.
1.4.2 Individual Case Safety Reports
Each Competent Authority should ensure that ICSRs submitted by Marketing Authorisation Holders
conIorm to the requirements described in Chapter I.4, in order to ensure compliance with reporting oI
suspected adverse reactions by Marketing Authorisation Holders. Furthermore, each national
Competent Authority should ensure that suspected, serious adverse reaction reports are Iollowed up by
Marketing Authorisation Holders in accordance with the requirements described in Chapter I.4.
Competent Authorities should ensure that they have the capability to send and receive ICSRs
electronically and should ensure that Marketing Authorisation Holders do so in accordance with
agreed legal requirements, procedures and guidance (see Part III).
1.4.3 Periodic Safety Update Reports
A Periodic SaIety Update Report (PSUR) is intended to provide an update oI the worldwide saIety
experience oI a medicinal product to Competent Authorities at deIined times post-authorisation (see
PART II 118/229
also Chapter I.6). Assessment oI PSURs should be undertaken by Competent Authorities in
accordance with agreed procedures and taking account oI the authorisation process Ior a medicinal
product.
Competent Authorities should liaise with Marketing Authorisation Holders regarding submission oI
PSURs Ior centrally authorised products are evaluated by the Rapporteur and Assessment Reports are
PSURs, particularly to Iacilitate harmonisation oI PSUR periodicity Ior medicinal products containing
the same active substance and to consider circumstances where the PSUR periodicity may be
amended.
circulated to Member States and the Agency according to a timetable agreed by the CHMP (see
Chapter II.2.A).
PSURs Ior products authorised via the mutual recognition or decentralised procedure are evaluated by
the ReIerence Member State. An Assessment Report is circulated by the ReIerence Member State to
all Concerned Member States within 6 weeks oI receipt oI the PSUR (see Chapter II.3).
In the case oI PSURs requested Ior immediate submission by Competent Authorities (i.e. outside the
nd maximise use oI available resources, Competent
Authorities are encouraged to participate in the PSUR work-sharing project on assessment oI PSURs
It is the responsibility oI the national Competent Authorities to evaluate PSURs Ior purely nationally
authorised products in accordance with agreed procedures, as appropriate.
regular reporting periodicity), the requesting Competent Authority should liaise with the Marketing
Authorisation Holder regarding the timescale Ior submission and assessment, taking account oI the
urgency oI the issue.
In order to reduce duplication oI eIIort a
via a Lead Member State Ior nationally authorised products and to Iollow relevant guidance
37
.
PSUR Assessment Reports should be provided to the Marketing Authorisation Holder.
1.4.4 Data from Company-Sponsored Post-Authorisation Safety Studies
Competent Authorities requesting post-authorisation saIety studies (PASS) should liaise with the
relevant Marketing Authorisation Holders on preparation and review oI study documentation as
described in Chapter I.7. In addition, Competent Authorities should ensure that they are notiIied oI
PASS undertaken at the initiative oI Marketing Authorisation Holders.
For PASS that Iall under the provisions oI Directive 2001/20/EC on clinical trials, Competent
Authorities should Iollow the relevant provisions accordingly.
Serious adverse reactions occurring in non-interventional PASS should be reported on an expedited
Competent Authorities should assess, as appropriate, Study Reports Irom Marketing Authorisation
Competent Authorities may maintain a register oI PASS conducted on their territory, as appropriate.
basis by Marketing Authorisation Holders and processed as such by Competent Authorities.
Holders on the progress and completion oI PASS (see Chapter I.7, Section 4.3) Any impact oI the
Iindings on the Product InIormation should be evaluated and an Assessment Report prepared and

circulated, as appropriate.
InIormation on medically or scientiIically relevant conclusions (e.g. signiIicant change in Irequency oI
a known adverse reaction, new unexpected adverse reaction, new interaction) should be appropriately
reIlected in the Product InIormation (SPC, Package LeaIlet and Labelling). The timeIrame Ior

37
PART II 119/229
incorporation oI such changes should be proposed by the Marketing Authorisation Holder with the
submission oI the study report and agreed by the Competent Authority. II rapid dissemination and
discussion oI the new inIormation at EU level is deemed necessary by a Competent Authority
Iollowing assessment oI the submitted report (see below), the procedures described in Chapter II.4
In the case oI studies conducted Ior purely nationally authorised medicinal products, the relevant
oI Member States, a Lead Member State may be appointed by the PhVWP Ior this
evaluation and generation oI an Assessment Report.
In the case oI medicinal products authorised through mutual recognition or decentralised procedures,
should be Iollowed.
Member State(s) is (are) responsible Ior evaluation oI the Study Reports. Where a PASS is conducted
in a number
evaluation oI the Study Reports will normally be carried out by the ReIerence Member State (see
Chapter II.3).
In the case oI medicinal products authorised through the centralised procedure, the Rapporteur will
normally assess the Iinal Study Report (see Chapter II.2.A).
The Assessment Report should be distributed to the Marketing Authorisation Holder, to the CHMP,
ent Authorities within three months oI receipt oI the
report Irom the Marketing Authorisation Holder.
the Agency and as appropriate, to other Compet
In the case oI PASS undertaken at the Marketing Authorisation Holder`s initiative, progress and Iinal
study reports should be included or updated in the corresponding PSUR and/or Risk Management Plan
(see also Chapters I.3 and 1.6).
1.4.5 Risk-Benefit Reviews
Risk-BeneIit Reviews requested by Competent Authorities should always be thoroughly evaluated by
the Competent Authorities and an Assessment Report prepared in accordance with agreed timelines,
taking account oI the urgency oI the issue. As such reviews are prepared and submitted Ior important
reasons, they should be prioritised Ior assessment. In accordance with the PhVWP Mandate,
Risk-BeneIit Reviews may be considered by the PhVWP at the request oI the CHMP or a Member
ging to the same therapeutic
class. A Lead Member State(s) may be appointed by the PhVWP to carry out evaluation oI
he medicinal products
concerned. Competent Authorities designated as Lead Member State Ior the purposes oI assessment oI
Assessment Reports should be provided to the Marketing Authorisation Holder and as appropriate, to
n deemed necessary Iollowing evaluation oI such Reviews should
State. In these circumstances, consideration may be given to review oI generic medicinal products
containing the same active substance, or other medicinal products belon
Risk-BeneIit Reviews, taking account oI relevant authorisation procedures Ior t
such reviews should liaise regarding assignment oI products, development oI a List oI Questions Ior
Marketing Authorisation Holders, the Iormat and content oI Assessment Reports and to determine the
timeIrame Ior receipt and evaluation oI the data.
other Competent Authorities and the Agency.
Changes to the Product InIormatio
be notiIied to other Competent Authorities in accordance with the criteria described in Chapter II.4.
1.4.6 Reports on Post-Authorisation Commitments
Com etent A plement tracking systems to monitor compliance and progress oI p uthorities should im
pos Chapter I.2). The system should ensure that any
com it
ma i
pro t
t-authorisation commitments (see also
m ment speciIied at the time oI granting oI the marketing authorisation is IulIilled. The EMEA
inta ns the tracking system Ior post-authorisation commitments related to centrally authorised
duc s.
PART II 120/229
Re s Authorisation Holder should be assessed and the Assessment
Re s propriate, to other Competent
Authorities and the Agency.
When a product is centrally authorised, the Agency and all Member States should be inIormed by the
orteur.
, such as data on volume oI sales and prescription oI medicinal products. These data should
be evaluated and the outcome reIlected in Assessment Reports, as appropriate.
n oI certain medicinal products to
impose speciIic requirements in respect oI reporting serious or unexpected reactions on the prescribing
oI use oI the product under the terms oI the
marketing authorisation.
port submitted by the Marketing
port provided to the Marketing Authorisation Holder and, as ap
When a product is authorised via the mutual recognition or decentralised procedure, the Concerned
Member States should be inIormed by the ReIerence Member State.
Rapp
1.4.7 Other Data
Competent Authorities should consider all other pharmacovigilance-related data submitted by or
requested Irom Marketing Authorisation Holders to Iacilitate assessment oI signals or emerging saIety
concerns
1.5 Pharmacovigilance Data from Other Sources
1.5.1 Intensive Monitoring Schemes
Intensive Monitoring is a system oI record collection Irom designated areas, e.g. hospital units or by
speciIic healthcare proIessionals in community practice. Competent Authorities may be involved in
the preparation oI protocols to Iacilitate data collection or may be inIormed that such monitoring is
taking place. As the national Competent Authority is usually the liaison point Ior such systems,
relevant adverse reaction reports identiIied should be processed and managed appropriately, with
relevant reports notiIied to the Agency and Marketing Authorisation Holders on an expedited basis.
Furthermore, it may be considered appropriate in the authorisatio
physician and to make these requirements a condition
The relevant national Competent Authority should ensure that data and reports are collected at agreed
intervals and in an appropriate Iormat (see also Chapters I.4, I.6 and I.7).
1.5.2 Data on Medication Errors, Overdose, Misuse and Abuse
the national Competent Authorities (e.g. directly Irom
Healthcare ProIessionals or via Marketing Authorisation Holders or poison centres) should be handled
Reports oI suspected adverse reactions due to medication errors, overdose, misuse and abuse oI
medicinal products, which are received by
in th ay as other Individual Case SaIety Reports (see Chapter I.4 and Chapter II.1, Section 3). e same w
Competent Authorities in Member States should ensure cooperation with other national agencies
responsible Ior collation oI data associated with medication errors, overdose, misuse and abuse, as
appropriate (see also Chapter I.5).
1.5.3 Other Information Sources Relevant to Pharmacovigilance
These inIormation sources may include the Iollowing:
Drug usage data;
Published adverse reaction reports;
Data Irom pharmacoepidemiology studies conducted by organisations other than the
Marketing Authorisation Holder;
PART II 121/229
Data Irom pre-clinical studies;
SigniIicant quality data; and
Reports on products not currently marketed in Member States.
Such inIormation may be important Ior determining Ior example Irequency, occurrence oI unexpected
adverse reactions, new interactions and overall risk-beneIit balance. In cases where signiIicant
inIormation is received Irom these sources, these Iindings may be transmitted to other Member States
and the Agency (see Chapter II.1, Section 6 and Chapter II.4).
1.6 Procedures for Data Exchange
This Section describes the procedures that should be implemented in order to Iacilitate communication
oI pharmacovigilance inIormation between Competent Authorities in Member States, between
ensure that their pharmacovigilance personnel are Iamiliar with the
Competent Authorities and the Agency and between Competent Authorities and Marketing
Authorisation Holders, to optimise use oI resources Ior detection and evaluation oI pharmacovigilance
signals.
Where a national Competent Authority identiIies new inIormation which may inIluence the overall
risk-beneIit assessment it is usually appropriate that they communicate this concern to the Marketing
Authorisation Holder at the time that such inIormation is shared with other Competent Authorities and
the Agency. A comprehensive Assessment Report evaluating the issue and the risks in the context oI
the beneIits should be submitted by the Competent Authority at the earliest opportunity and no later
than the agreed date speciIied in the written communications between the Competent Authority and
the Marketing Authorisation Holder. It should be sent to the Marketing Authorisation Holder, all
Competent Authorities in Member States where the medicinal product is authorised, and usually in
addition to the Agency Ior discussion at EU level, as appropriate. The Competent Authority should
discuss the outcome oI the evaluation with the Marketing Authorisation Holder, or in the case oI
products authorised through EU assessment procedures, with the Rapporteur/ReIerence Member State.
Liaison between Competent Authorities and the Marketing Authorisation Holder on
pharmacovigilance related issues should take place via the QPPV.
1.6.1 Technologies for Data Transmission
For data exchange and communication between Competent Authorities in Member States, the Agency
and Marketing Authorisation Holders, only appropriate secure communication systems (e.g. EudraNet
and EudraVigilance) should be used. EudraLink should only be used when transmission via EudraNet
is not possible.
Competent Authorities should
rules and procedures involved in the use oI these systems and with the requirements Ior electronic
reporting oI adverse reactions (see Part III).
1.7 Overall Pharmacovigilance Evaluation and Safety-Related Regulatory Action
The Competent Authority in each Member State, as part oI its obligation to undertake ongoing
evaluation oI the risk-beneIit balance oI medicinal products, should ensure that all pharmacovigilance
data received and evaluated, as outlined above, are taken into account on an ongoing basis.
New data on the beneIits and risks oI medicinal products will become available during the post-
authorisation period and evaluation oI this inIormation should be carried out on an on-going basis by
Marketing Authorisation Holders and Competent Authorities, taking account oI the relevant
authorisation procedures and/or any arrangements in place Ior work-sharing in respect oI product
speciIic/class related reviews (see also Chapter I.8). As a consequence oI such evaluations, a
marketing authorisation may be varied, suspended, revoked, withdrawn or not renewed, as necessary
PART II 122/229
and according to the appropriate procedure. Criteria Ior such regulatory action are set out Ior example
in Articles 116 and 117 oI Directive 2001/83/EC.
In the case oI centrally authorised medicinal products, changes to the marketing authorisation status or
Summary oI Product Characteristics (SPC) are undertaken according to Commission Regulation (EC)
No 1085/2003 and as outlined in Chapter II.2.A.
The procedure to be Iollowed Ior changes to the marketing authorisation status or the SPC Ior
medicinal products authorised via the mutual recognition or decentralised procedure is described in
Commission Regulation (EC) No 1084/2003 and in Chapter II.3. It is the responsibility oI the
ReIerence Member State to coordinate the procedure, with changes implemented simultaneously in all
Concerned Member States. National decisions should take eIIect on the day agreed aIter discussion
between the ReIerence Member State and the Marketing Authorisation Holder in consultation with the
Concerned Member States. Every eIIort should be made to implement these changes as soon as
As provided Ior in Commission Regulations (EC) No 1084/2003 and 1085/2003, provisional urgent
possible.
In the case oI purely nationally authorised medicinal products, where updated pharmacovigilance data
are considered to impact on the risk-beneIit proIile oI the medicinal product, the Competent Authority
in the Member State may request a variation to the marketing authorisation status or the SPC in
accordance with national procedures.
saIety restrictions may be taken in the event oI a risk to public health. An urgent saIety restriction may
be taken by the Marketing Authorisation Holder iI the Competent Authority in the Member State or,
Ior centrally authorised products, the Agency does not raise any objection within 24 hours aIter the
Marketing Authorisation Holder`s notiIication. The Competent Authority may also impose an urgent
saIety restriction. In the case oI a centrally authorised product, the Agency will act in accordance with
Chapter II.2.A and notiIy all Member States, circulating a Rapid Alert (see Chapter II.4). In case oI a
non-centrally authorised product, the national Competent Authority will notiIy any urgent saIety
restriction to the other Member States and the Agency circulating a Rapid Alert (see Chapter II.4).
Should this concern a product authorised via the mutual recognition or decentralised procedure, the
agreed guidance in Chapter II.3 should be Iollowed. An urgent saIety restriction should be Iollowed by
submission by the Marketing Authorisation Holder oI a variation application immediately and in no
lder may reIer a pharmacovigilance matter relating to
a nationally authorised product(s), including those authorised through the mutual recognition and
oI the Community are involved. These
matters may be reIerred by the CHMP to the PhVWP Ior consideration. The Commission Decision
case later than 15 days aIter the initiation oI the urgent saIety restriction.
Under the terms oI Articles 31, 36 and 37 oI Directive 2001/83/EC, a Member State, the European
Commission or the Marketing Authorisation Ho
decentralised procedures, to the CHMP whenever the interests
issued on the basis oI the CHMP Opinion is binding on all Member States (see Chapter II.5 Ior
reIerence to Iurther guidance).
Any signiIicant change to the marketing authorisation status or SPC considered or undertaken
nationally should be notiIied to the other Member States, the European Commission and the Agency
(see Chapter II.4).
In the case oI centrally authorised products, where urgent action to protect human health or the
environment is considered essential, a Member State may suspend the use oI a medicinal product on
its territory, in accordance with Article 20(4) oI Regulation (EC) 726/2004. In such cases, the Member
State should inIorm the European Commission and the Agency immediately and no later than the
Iollowing working day, providing the reasons Ior its action. In order to meet this legal requirement and
to inIorm the other Member States, the Member State should circulate a Rapid Alert as described in
Chapter II.4. The European Commission should immediately consider the reason given by the
PART II 123/229
PART II 124/229
limit, determined in Member State and shall request the Opinion oI the CHMP within a speciIied time
accordance with the urgency oI the issue (see Chapter II.2.A).
For nationally authorised medicinal products, including those authorised through the mutual
cognition, decentralised and ex-concertation procedures, where a Member State considers, Iollowing
valuation oI pharmacovigilance data, suspension or revocation oI a marketing authorisation, or its
re
e
variation resulting in important changes to the Product InIormation as described in Chapter II.4, the
Rapid Alert System should be used to notiIy the other Member States and the Agency immediately in
accordance with Article 107(1) oI Directive 2001/83/EC as well as the European Commission.
Where a Member State suspends the marketing authorisation Ior a nationally authorised product (this
includes products authorised through the mutual recognition and decentralised procedures), in order to
urgently protect public health on its territory, the Member State should circulate a Rapid Alert (see
Chapter II.4) at the latest one working day aIter the suspension, inIorming the other Member States,
the Agency and the European Commission oI this action in accordance with Article 107(2) oI
Directive 2001/83/EC.
Where the Agency is inIormed oI a revocation or suspension oI a marketing authorisation by a
Member State, the CHMP should prepare an Opinion within a timeIrame to be determined depending
on the urgency oI the matter. In the case oI a variation resulting in important changes to the Product
InIormation as described in Chapter II.4, the CHMP may be requested by a Member State to prepare
such an Opinion. On the basis oI the Opinion, the European Commission may request Member States
to take temporary measures immediately and Iinal measures may be taken in accordance with Article
121(3) oI Directive 2001/83/EC (see Article 107(2) oI Directive 2001/83/EC and Chapter II.5).
II suspension, withdrawal or variation resulting in important changes to the Product InIormation as
described in Chapter II.4 seems likely, the Marketing Authorisation Holder should be inIormed oI any
intended action at an early stage. In the case oI medicinal products authorised through purely national
procedures, it is the responsibility oI the Competent Authorities in the Member States concerned to
inIorm the Marketing Authorisation Holder. For products authorised through mutual recognition or
decentralised procedures, this task is usually undertaken by the ReIerence Member State. For centrally
authorised products, the Agency, in consultation with the Rapporteur should inIorm and liaise with the
Marketing Authorisation Holder.
1.8 Sanctions
In accordance with Directive 2001/83/EC Article 104(9) and Regulation (EC) 726/2004 Article 24(5)
and 84, Member States are required to take the necessary measures to ensure that Marketing
Authorisation Holders who Iail to discharge their obligations are subject to eIIective, proportionate
and dissuasive penalties (see also Chapter I.2).
1.9 Public Communication and Transparency
Competent Authorities should ensure that Healthcare ProIessionals, Patients/Consumers and the
general public are inIormed, where appropriate, oI any signiIicant changes in the Product InIormation
(Summary oI Product Characteristics and Package LeaIlet) and oI any suspected saIety concerns
requiring vigilance. Competent Authorities should ensure their compliance with requirements Ior
transparency and public communication (see Part IV).
APPE : MANDATE, OBJECTIVES AND RULES OF PROCEDURE OF THE PHVWP NDIX 1.A
Available on EMEA website http://www.emea.europa.eu, see under EMEA Committees, CHMP;
Doc.ReI. EMEA/CHMP/PhVWP/88786/04.

PART II 125/229
2.A Conduct of Pharmacovigilance for Centrally Authorised Products
Note: Procedures Ior the conduct oI pharmacovigilance Ior centrally authorised products are currently
under review and an updated version oI this Chapter will be subject to public consultation. A
ReIlection Paper on the Criteria Ior Requiring One Additional Five-Year Renewal Ior Centrally
Authorised Products (EMEA/131973/2006)
38
has been made available in 2007.
2.A.1 Introduction
The objective oI this Chapter is to describe a Iramework whereby all centrally authorised products are
closely monitored to allow timely evaluation oI new inIormation relevant to the risks and beneIits oI
these products, so that appropriate action may be taken, when necessary, to protect public health.
oducts;
product. However, there may be situations where the
e
conIronted with a class-related eIIect and diIIerent Rapporteurs were involved in the pre-authorisation
assessment oI the various centrally authorised products, the CHMP would need to appoint a 'leading
Rapporteur.

The conduct oI pharmacovigilance Ior centrally authorised products is based on obligations and
activities placed, through legislation, on a number oI parties,notably the Member States, the European
Commission, the Agency and the Marketing Authorisation Holders. In order to ensure that the
obligations are met, it is necessary to clariIy the respective roles and responsibilities oI the various
parties.
This Chapter presents:
Principles relevant to the conduct oI pharmacovigilance Ior centrally authorised pr
The Iunctions and procedures Ior conducting pharmacovigilance Ior these products;
The speciIic roles oI the Member States, the CHMP, the Pharmacovigilance Working Party
(PhVWP), the (Co-)Rapporteur(s), the Agency, the Marketing Authorisation Holders and the
European Commission, in carrying out Iunctions and procedures Ior the conduct oI
pharmacovigilance Ior centrally authorised products.
2.A.2 Legal Framework
The legal provisions regarding the conduct oI pharmacovigilance Ior centrally authorised products are
set out in Regulation (EC) No 726/2004, notably but not exclusively in Chapter 3 oI Title II, as well as
Commission Regulation (EC) No 540/95. The examination oI variations to the terms oI marketing
authorisation and urgent saIety restrictions is the subject oI Commission Regulation (EC) No
1085/2003.
2.A.3 Principles
The responsibilities and Iunctions oI the various partners involved in the centralised procedure have
been well deIined Ior the coordination and evaluation oI centralised marketing authorisation
applications and subsequent variation applications. This Iramework should also be applied to the
conduct oI pharmacovigilance Ior centrally authorised products. As a matter oI principle, the handling
and analysis oI pharmacovigilance data should always be done in close cooperation between the (Co-)
Rapporteur(s), the Agency and any Member State(s) who has (have) identiIied a possible issue.
The pre-authorisation Rapporteur should take the lead in pharmacovigilance, acting to evaluate all
issues relevant to the centrally authorised
original Rapporteur is not able to IulIil the Iunctions oI such evaluation. In such cases the Co-
Rapporteur could take this responsibility. II this is not possible, the CHMP would need to appoint
another Rapporteur who could take on these responsibilities. In the particular case that one would b

38
Available on EMEA website http://www.emea.europa.eu,
PART II 126/229
In view oI the large number oI issues to be handled in the post-authorisation period Ior centrally
authorised products, the Rapporteur will have the responsibility Ior evaluating and reaching
issues
which need to be considered by PhVWP and CHMP, in close cooperation with the Agency.
trally authorised products need to be continuously
ember State that identiIied the issue
under investigation.
rting in accordance with current
legislation. Meetings Ior Marketing Authorisation Holders will be organised at the Agency at regular
verse reaction reporting to the Agency. The PhVWP will
be inIormed oI such meetings in advance and will be given the opportunity to participate.
s or Irequency oI expected adverse reactions.
ucts, enabling eIIective risk identiIication, assessment and management in the
conclusions on these issues in accordance with an agreed timetable, and Ior determining the
InIormation relevant to the risks and beneIits oI cen
collected in all Member States. ThereIore, each Member State plays an important role in collecting
inIormation on adverse reactions and in identiIying and evaluating possible saIety concerns Ior
centrally authorised products. The scientiIic expertise oI the Member States will be utilised by the
Rapporteurs in carrying out pharmacovigilance evaluations. The Rapporteur will generally use the
expertise oI the Member State Irom which he originates. However, iI considered more appropriate, the
Rapporteur may work with another Member State, e.g. the M
In accordance with current legislation the Agency should collect all inIormation about serious
suspected adverse reactions and distribute this inIormation to the Member States. The role oI the
Agency, thereIore, is one oI continuous coordination oI the pharmacovigilance system Ior centrally
authorised products. The Agency will ensure that Marketing Authorisation Holders Ior centrally
authorised products adhere to the requirements Ior saIety repo
intervals in order to provide guidance on ad
The Agency, in close cooperation with the Rapporteur, will inIorm the CHMP/PhVWP oI any saIety
concern wherever there is a need Ior discussion and subsequent action to be taken. It will, in
agreement with the Rapporteur, participate in the identiIication oI signals oI possible unexpected
adverse reactions or changes in severity, characteristic
The PhVWP evaluates potential signals, investigates adverse reactions and provides advice on the
saIety oI medicinal prod
pre-and post-authorisation phase (see Appendix II.1.A). Following a CHMP request, their
and is
reviewed at each meeting oI the PhVWP. In addition speciIic issues relating to Periodic SaIety Update
o assure the saIety oI their
product. The Marketing Authorisation Holder is obliged to adhere to the legal provisions as to the
ission oI PSURs and other
on, Iurther inIormation or speciIic actions by the
o be clearly presented to the Marketing Authorisation Holder in
writing. Such requirements oI the Marketing Authorisation Holder should be prepared in collaboration
ings with the Marketing Authorisation Holder should
involve the Rapporteur, the Agency and others as considered necessary. Minutes oI such meetings
A su oI the parties involved in the pharmacovigilance
recommendations on centrally authorised products are transmitted to the CHMP Ior consideration. A
Drug Monitor, including centrally authorised products, is in place to track saIety issues
Reports, speciIic obligations, Iollow-up measures or the need Ior saIety variations may be discussed
by the PhVWP at the request oI the Rapporteur.
The primary responsibility oI the Marketing Authorisation Holders is t
spontaneous reporting oI adverse reactions as well as to the subm
inIormation. Furthermore, issues requiring clariIicati
Marketing Authorisation Holder need t
between the Rapporteur, the Agency and any Member State requesting Iurther inIormation, and
endorsed where necessary by the CHMP. Meet
should be taken and distributed to attendees.
mmary oI the role and responsibilities oI each
system ided in the Table II.2.A.A at the end oI this Chapter. Ior centrally authorised products is prov
PART II 127/229
2.A.4 Functions and Procedures
2.A.4.1 Reporting of Adverse Reactions and Other Safety-Related Information
aluation may become available Irom the Applicant, or
Member States where the product is already in use on a compassionate basis, or Irom third countries
In the period between the CHMP reaching a Iinal Opinion and the Commission Decision there need to
he time oI the Opinion. It is essential Ior this
he Opinion may need to be amended as a consequence.
Phase
g up the Individual Case SaIety Reports
Th d Iorward to the Agency serious suspected adverse reactions occurring
wit t
ed
2.A.4.1.a) Pre-Authorisation Phase
Once an application Ior a marketing authorisation is submitted to the Agency, in the pre-authorisation
phase, inIormation relevant to the risk-beneIit ev
where the product is already marketed. Since it is essential Ior this inIormation to be included in the
assessment carried out by the (Co-)Rapporteur(s) assessment teams, the Applicant is responsible Ior
inIorming immediately the Agency and the (Co-)Rapporteur(s).
be procedures in place to deal with inIormation relevant to the risk-beneIit balance oI centrally
authorised products, which were not known at t
inIormation to be sent to the Agency and (Co-)Rapporteur(s) so that it can be rapidly evaluated to an
agreed timetable and considered by the CHMP to assess what impact, iI any, it may have on the
Opinion. T
2.A.4.1.b) Post-Authorisation
Suspected adverse reactions related to centrally authorised products are reported directly by
Healthcare ProIessionals, to each Member State. Marketing Authorisation Holders report serious
suspected adverse reactions to the Member State in which the reactions occurred, within 15 calendar
days oI receipt. Each Member State is responsible Ior Iollowin
it receives to obtain Iurther inIormation as necessary.
e Member States shoul
hin heir territories.
The Agency and all Member States should receive directly Irom the Marketing Authorisation Holders
suspected serious and unexpected adverse reactions that occur in a country outside oI the EU.
The Agency should ensure that all relevant inIormation about suspected serious unexpected adverse
reactions Irom outside the EU are entered into the EudraVigilance database, and Member States
should ensure that data on suspected serious adverse reactions occurring in their territory are upload
into the EudraVigilance database. For details see Chapter I.4 and Part III.
2.A.4.2 Monitoring of the Safety Profile
A signal oI possible unexpected hazards or changes in severity, characteristics or Irequency oI
mber States;
2.A.4.2.a) Signal Identification
It is likely that many potential signals will emerge in the early stages oI marketing and it will be
important Ior these to be eIIectively evaluated.
expected adverse eIIects may be identiIied by:
the Marketing Authorisation Holders;
the Rapporteur;
the Me
the Agency in agreement with the Rapporteur.
PART II 128/229
It is the responsibility oI each Member State to identiIy signals Irom inIormation arising in their
territory. However, it will be important Ior the Rapporteur and the Agency to have the totality oI
inIormation on serious adverse reactions occurring inside and outside the EU in order to have an
As a matter oI routine, the Rapporteur should continually evaluate the adverse reactions included in
I
inIormation le on the product, to determine the emerging adverse reactions proIile.
Additional inIormation should be requested Irom the Marketing Authorisation Holder and Member
mation Irom the Marketing
Authorisation Holder (apart Irom routine Iollow-up oI cases occurring on their own territory) Ior the
ich include centrally authorised products.
As signals oI possible unexpected adverse reactions or changes in the severity, characteristics or
carried out by:
oI the signal to evaluate the issue. Agreement
unnecessary duplication oI eIIort.
overall view oI the experience gathered with the concerned centrally authorised product.
the EudraVigilance system and all other inIormation relevant to risk-beneIit balance in the context o
already availab
States as necessary, in liaison with the Agency.
When a Member State other than the Rapporteur wishes to request inIor
purposes oI signal identiIication, the request should be made in agreement with the Rapporteur and the
Agency.
Member States will inIorm the Rapporteur(s) and the Agency when perIorming class-reviews oI saIety
issues wh
The PhVWP should regularly review emerging saIety issues which will be tracked through the Drug
Monitor.
2.A.4.2.b) Signal Evaluation
Irequency oI expected adverse reactions may emerge Irom many diIIerent sources oI data (see above),
the relevant inIormation needs to be brought together Ior eIIective evaluation, over a time scale
appropriate to the importance and likely impact oI the signal.
Irrespective oI who identiIied the signal, a signal evaluation should be
the Rapporteur; or
the Member State where a signal originated.
The Rapporteur should work closely with the identiIier
needs to be reached in each case on the responsibility Ior the Assessment Report on the risk-beneIit
balance, by the Rapporteur or the Member State where the signal originated Irom, or jointly.
A Member State other than that oI the Rapporteur should not start a Iull evaluation prior to having
contacted the Agency and the Rapporteur, in order to prevent any
At request oI the CHMP, the PhVWP evaluates signals arising Irom any source and keeps any
potential saIety issues under close monitoring.
2.A.4.2.c) Evaluation of Periodic Safety Update Reports
The Marketing Authorisation Holder is required to provide Periodic SaIety Update Reports (PSURs)
to all the Member States and the Agency, as detailed in Chapter I.6. It is the responsibility oI the
Agency to ensure that the Marketing Authorisation Holder meets the deadlines.
The Marketing Authorisation Holder should submit any consequential variations simultaneously with
the PSUR at the time oI its submission, in order to prevent any unnecessary duplication oI eIIort.
Variations may, however, also be requested subsequently by the Rapporteur, aIter agreement by the
CHMP.
PART II 129/229
It is the responsibility oI the Rapporteur to evaluate and provide a report in accordance with the agreed
timetable and to determine what issues iI any need to be reIerred to the PhVWP and CHMP.
Where changes to the marketing authorisation are required, the CHMP will adopt an Opinion which
Ior preparation oI a Decision.
ide Literature and Other
Information
other countries at times in between PSURs.
As above, the Rapporteur should determine what issues iI any need to be reIerred to the PhVWP and
marketing authorisation are required, the CHMP will adopt an Opinion which
will be Iorwarded to the European Commission Ior preparation oI a Decision.
th
the data, in order to prevent any unnecessary duplication oI eIIort. Variations may, however, also be
, aIter agreement by the CHMP.
It is the responsibility oI the Agency to ensure that the Marketing Authorisation Holder meets the
ations and Iollow-up measures, and that the inIormation
pro e
on oI eIIort. Variations may, however, also be requested
nually, and should be
s) Iollow-up measures may be established, which are annexed to the CHMP Assessment
Actions required Iollowing the evaluation oI a PSUR will be determined by the Rapporteur and the
Marketing Authorisation Holder will be inIormed by the Agency, aIter agreement by the CHMP.
will be Iorwarded to the European Commission
2.A.4.2.d) Evaluation of Post-Authorisation Studies, Worldw
Final and interim reports oI Marketing Authorisation Holder sponsored post-authorisation studies and
any other studies, and other relevant inIormation, may emerge Irom the Marketing Authorisation
Holder, the Member States or
The Rapporteur should receive and assess any relevant inIormation and provide an Assessment Report
where necessary.
CHMP.
The actions required Iollowing an evaluation will be determined by the Rapporteur and the Marketing
Authorisation Holder will be inIormed by the Agency, aIter agreement by the CHMP.
Where changes to the
The Marketing Authorisation Holder should submit any consequential variations simultaneously wi
requested subsequently by the Rapporteur
2.A.4.2.e) Evaluation of Post-Authorisation Commitments
deadlines Ior the IulIilment oI speciIic oblig
vid d is available to the Rapporteur and the CHMP.
The Marketing Authorisation Holder should submit any consequential variations simultaneously with
the requested inIormation Ior the IulIilment oI speciIic obligations/Iollow-up measures, in order to
prevent any unnecessary duplicati
subsequently by the Rapporteur, aIter agreement by the CHMP.
For marketing authorisations granted under exceptional circumstances, speciIic obligations will be set
out in Annex II.C oI the CHMP Opinion. SpeciIic obligations should be reviewed by the Rapporteur,
at the interval indicated in the Marketing Authorisation and at the longest an
subsequently agreed by the CHMP. As above, the Rapporteur should determine what issues iI any
need to be reIerred to the PhVWP and CHMP.
For marketing authorisations granted under exceptional circumstances, the annual review will include
a re-assessment oI the risk-beneIit balance. The annual review will in all cases lead to the adoption oI
an Opinion which will be Iorwarded to the European Commission Ior preparation oI a Decision.
For all marketing authorisations (whether or not the authorisation is granted under exceptional
circumstance
PART II 130/229
Report. These will be reviewed by the Rapporteur, and will be considered by PhVWP and CHMP at
the Rapporteur`s request.
eciIic obligations or Iollow-up measures, the CHMP will have to
consider the possibility oI recommending a variation, suspension, or withdrawal oI the marketing
ing of Safety Concerns
aIety Reports or other inIormation relevant to the risk-
cy and the (Co-)Rapporteur(s), the latter should assess these
nd is reviewed on a regular basis by the PhVWP at its meetings. This summary document
at do not IulIil the criteria Ior a Rapid Alert should be brought to the attention oI
Where changes to the marketing authorisation are required, the CHMP will adopt an Opinion which
will be Iorwarded to the European Commission Ior preparation oI a Decision.
In the case oI non-IulIilment oI sp
authorisation.
2.A.4.3 Handl
2.A.4.3.a) Safety Concerns in the Pre-Authorisation Phase
Following the receipt oI Individual Case S
beneIit balance oI a product by the Agen
pharmacovigilance data. The outcome oI the evaluation should be discussed at the CHMP Ior
consideration in the Opinion.
II pharmacovigilance Iindings emerge Iollowing an Opinion but prior to the Decision, a revised
Opinion, iI appropriate, should be immediately Iorwarded to the European Commission to be taken
into account beIore preparation oI a Decision.
2.A.4.3.b) Safety Concerns in the Post-Authorisation Phase
A Drug Monitor, including centrally authorised products, is in place as a tracking system Ior saIety
concerns a
also records relevant actions that have emerged Irom PSURs, speciIic obligations, Iollow-up measures
and saIety variations.
Following the identiIication oI a signal the relevant inIormation needs to be brought together Ior
eIIective evaluation, over a time scale appropriate to the importance and likely impact oI the signal:
a) Non-urgent safety concerns
Potential concerns th
the Rapporteur and the Agency only in the Iirst instance.
Further inIormation may be requested Irom:
other Member States by the originator oI the concern, issuing a Non-Urgent InIormation (see
Chapter II.4);
the Marketing Authorisation Holder by the Agency, in agreement with the originator oI the
Th a
Fo i
the p

concern and the Rapporteur.
e R pporteur should work closely with the originator oI the concern to evaluate it.
llow ng evaluation, the need Ior Iurther discussion at the PhVWP and CHMP will be determined by
Ra porteur, and any necessary actions will be agreed by CHMP.
The Agency is responsible Ior transmitting the outcome oI the evaluation to the Marketing
Authorisation Holder.
iI lance However, deemed necessary, the CHMP should Iormulate an Opinion on the pharmacovigi
data and Iorward it to the European Commission accordingly in order to take a Decision.
PART II 131/229
These issues will be included in the Drug Monitor by the Agency iI a Non-Urgent InIormation has
been issued.
b) Urgent safety concerns
A Rapid Alert (see Chapter II.4) should be issued by the Rapporteur, the Member States or the Agency
cussion should be held at the PhVWP and subsequently at the CHMP
me situations one or a number oI Member States may consider it
necessary to take immediate suspensive action beIore such coordinated action occurs.
Crisis Management:
when a signal is identiIied which leads to concern about the risk-beneIit balance oI a centrally
authorised product and which could lead to major changes Ior the status oI the authorisation. II it is the
Marketing Authorisation Holder who Iirst identiIies a potentially urgent and serious issue, he needs to
inIorm the Agency without delay.
The Rapid Alert should be transmitted to the contact points oI the Member States, the Agency and the
European Commission, and to the Rapporteur oI the centrally authorised product which is the subject
oI the Rapid Alert.
The Agency, in agreement with the Rapporteur, should promptly start an inquiry and inIormation
exchange with the Marketing Authorisation Holder(s).
The Agency will coordinate the process.
The Rapporteur should work closely with the originator oI the concern to evaluate the issue.
Agreement needs to be reached in each case on the responsibility Ior the Assessment Report on the
risk-beneIit balance, by the Rapporteur, the Member State where the signal originated Irom, or jointly.
Following risk evaluation a dis
within a deIined timeIrame.
Any resulting CHMP Opinion on the measures to ensure the saIe and eIIective use oI the centrally
authorised product will be transmitted by the Agency to the European Commission, in order to take a
Decision.
In some cases immediate action is essential to protect public health. In such cases the basic steps
outlined above need to be Iollowed, but within a much shorter time Irame, with the involvement oI
PhVWP and CHMP at a much earlier stage, and with particular mechanisms in place to provide a
CHPMP Opinion and Commission Decision rapidly. Rapid actions will need to be coordinated across
all Member States, however in so

Following detection oI an urgent saIety concern, which could have a serious impact on public
health, immediate action needs to be taken to evaluate and consider the options and timescale
Ior action. An urgent saIety restriction to be completed within 24 hours may be initiated by the
Marketing Authorisation Holder or the European Commission iI necessary. A Crisis
Management Plan, agreed with the CHMP, has been implemented by the Agency in close
consultation with the European Commission (see Chapter II.2.B).
Action taken by a Member State:
Upon detection oI a saIety concern where urgent action is deemed essential to protect human
health, a Member State may suspend the use oI a medicinal product on its territory.
The Member State must inIorm the Agency, the European Commission and other Member
States no later than the Iollowing working day oI the reasons Ior its action. A Rapid Alert
should be issued Ior this purpose (see Chapter II.4).
PART II 132/229
The European Commission will request the Opinion oI the Agency within a time Irame which
it shall determine depending on the urgency oI the matter. In that respect two possible
procedures can be envisaged Ior implementation by the Agency depending on the time Irame:
the Iirst procedu

re d
the second is the conv he
Agency, aIter uropean
Commission ion on the measures.
2.A.4.4 Informa
Healthcare ProIession ut saIety
issues relevant to centrally t
InIormation. It is importa provided in all Member States. II there is
such a requirement the e
Rapporteur should propo ation Ior consideration by the PhVWP and
sion distributed in
r ex the Marketing
Authorisation Holder, or b ug
bulletins. In some cases co ay
be necessary. The text and ti inIormation should be agreed by all parties prior
to their despatch. The ve, the Agency
at an early stage oI any inIorm
the PhVWP and adoption by th e
with the degree oI urgency. Marke
under Article 24(5) oI Regulation
pharmacovigilance concerns to e ncy
is escribed in the Crisis Management Plan (see Chapter II.2.B);
ening oI an extraordinary CHMP by the Executive Director oI t
consultation with the CHMP Chairperson, in order to provide the E
with a recommendat
tion to Healthcare Professionals and the Public
als and, iI considered appropriate, the public need to be inIormed abo
authorised products, in addition to the inIormation provided in Produc
nt that consistent inIormation is
Rapporteur or the Marketing Authorisation Holder in cooperation with th
se the content oI inIorm
subsequent discus
Member States, Io
and adoption by the CHMP. The agreed inIormation may be
ample, by Direct Healthcare ProIessional Communication Irom
y Competent Authorities in Member States or through Member States` dr
ordinated press releases, in addition to the CHMP Public Statements, m
ming Ior release oI such
Marketing Authorisation Holder should notiIy, at his own initiati
ation he intends to make public, in order to Iacilitate consideration by
e CHMP as well as agreement about timing Ior release, in accordanc
ting Authorisation Holders are reminded oI their legal obligations
(EC) No 726/2004 to not communicate inIormation relating to
th public without notiIication to the Competent Authorities/Age
(see Part IV).
2.A.4.5 Advertising
Title VIII oI Directive al
products. Because co r
across the EU, considerati ber
States in the event oI an im ions
occurring with a centrally porteur should be inIormed by
t er States oI suc issues
in order to ensure that wh any is making misleading claims with saIety
implications in several M MP
should be inIormed subsequentl
2001/83/EC lays down the legal base Ior the control oI advertising medicin
mpany marketing strategies Ior centrally authorised products may be simila
on should be given to what interactions should take place between Mem
portant advertising concern with potential public health implicat
authorised product. The Agency and the Rap
he Memb h concerns. The PhVWP may be an appropriate Iorum to discuss such
en it is considered that a comp
ember States, consistent action is taken whenever possible. The CH
y.
PART II 133/229
TABLE II.2.A.A: ROLES AND THE R PARTNERS INVOLVED IN THE CONDUCT OF
PHARMACOVIGI
Holder

ing the preparation and the
luation oI the beneIits and risks

ion
ESPONSIBILITIES OF
LANCE FOR CENTRALLY AUTHORISED PRODUCTS
Establish and maintain a system, accessible at a single point in
the EU, to collect, collate, and evaluate pharmacovigilance data
Meet legal obligations Ior reporting oI suspected adverse
reactions
Meet legal obligations regard
submission oI Periodic SaIety Update Reports
Respond Iully to requests Irom authorities Ior additional
inIormation necessary Ior the eva
oI a medicinal product
Ensure the marketing authorisation is maintained and reIlects the
latest inIormat
Member States gilance systems
gency, the
ny

rs/Co-
ecisions
the use
, in
tion, the Agency and the European
Have in place national pharmacovi
InIorm the European Commission, the CHMP, the A
Member States and the Marketing Authorisation Holders oI a
relevant actions
Collect and collate data on the risk-beneIit balance
Provide serious adverse reaction cases which have occurred in its
territory to the Agency and the relevant Marketing Authorisation
Holder within 15 calendar days oI receipt
IdentiIy and evaluate saIety concerns and conduct beneIit-risk
evaluations
Provide representation on CHMP, PhVWP and Rapporteu
Rapporteurs
Implement Commission D
In case oI urgent action to protect public health, suspend
y and inIorm oI the product in the Member State`s territor
accordance with the legisla
Commission oI the basis Ior action
Agency
Monitor the legal obligations oI the Marketing Authorisation
Holders
Receipt oI serious adverse reaction reports and provision to the
Member States and the Rapporteur
In agreement with the Rapporteur, identiIy signals oI possible
unexpected adverse reactions or changes in severity,
characteristics or Irequency oI expected adverse reactions
In agreement with the Rapporteur, inIorm all involved parties oI
any saIety concern
Coordination oI the evaluation oI data by the Rapporteurs and
consideration by the CHMP to reach Opinions
Communication oI Opinions to the European Commission
Communication with the Marketing Authorisation Holder on all
relevant issues in consultation with the Rapporteur
Maintenance oI the crisis management system Ior centrally
Coordination oI the pharmacovigilance system Ior centrally
authorised products
PART II 134/229
PART II 135/229
authorised products
Rapporteur Responsible Ior evaluating all saIety concerns and risk-beneIit
ther risk-beneIit data
on receipt, Periodic SaIety Update Reports, company reports and
variation applications to agreed timetables, obtaining additional
inIormation Irom the Marketing Authorisation Holder and
proposals on appropriate action
issues Ior centrally authorised products
Regularly evaluate adverse reactions and o
Member States as necessary
Provide Assessment Reports to agreed timetables Ior
consideration by the PhVWP and CHMP as necessary, with
CHMP
Pharmacovigilance
Working Party
Evaluation oI potential signals arising Irom spontaneous
reporting, including those identiIied Irom EudraVigilance, and all
other sources
Investigation oI adverse reactions
Regularly review Drug Monitor oI saIety concerns
Discussion oI emerging saIety concerns at the request oI the
Recommendations to the CHMP on risk-beneIit evaluations and
Rapporteur
Discussion oI PSURs at the request oI the Rapporteur
Providing advice to the CHMP on saIety, enabling eIIective risk
identiIication, assessment and management in the pre- and post-
authorisation phase
actions necessary to minimise risk and maximise beneIit
CHMP Discussion oI the risk-beneIit balance on the basis oI the
Rapporteur`s Assessment Report
Formulation oI Opinions
European Commission Competent Authority Ior centrally authorised products
Formulation oI Decisions
lders
EnIorcement oI legal requirements and enIorcement oI the
implementation oI Decisions by Member States and Marketing
Authorisation Ho
2.B Crisis Management Plan regarding Centrally Authorised Products
Note: Procedures Ior crisis management Ior centrally authorised products are currently under review
and an updated version oI this Chapter will be subject to public consultation.
2.B.1 Introduction
This Chapter outlines the principles underlying a Crisis Management Plan which allows rapid and
eIIicient handling oI crisis situations involving a centrally authorised product. In order to achieve this
ance with all the involved parties, how the crisis will
ollowed in order to deal with the crisis and
ctures and systems to be set up. These procedures will be Iollowed
in response to new inIormation in the context oI procedures on how to
dea dverse eIIects are included in the
objective, it is necessary to plan and agree in adv
be managed.
The ris e procedures to be I C is Management Plan outlines th
also highlights the management stru
pharmacovigilance while the
l with new quality-related inIormation with potential a
Compilation oI Community Procedures on Insp
the European Commission.
ections and Exchange oI InIormation
39
, on behalI oI
e European Commission and the Marketing
ent as an event which occurs when new inIormation, which
duct, and which
In e
problem
mation but media exposure leads to
serious publi implementation oI the Crisis Management Plan
may be r
There are tw
iI needed, public communication has to be provided.
oI crises should always involve a close cooperation between all
uthorities oI the Member States, the European Commission,
2.B.2 Principles of the Crisis Management Plan
The objective oI the Crisis Management Plan is to deIine and implement a strategy Ior the rapid and
eIIicient handling oI crisis situations by the Agency in liaison with the CHMP, the Rapporteur, the
Competent Authorities oI the Member States, th
Authorisation Holder(s).
A crisis is deIined in the present docum
could have a serious impact on public health, is received Ior a centrally authorised pro
requires immediate action.
som cases the new inIormation can be related to both quality and saIety concerns (Ior instance
s oI viral contamination with biological products).
Crises may be subdivided into those where, at the time the crisis is identiIied, the inIormation has not
become public, and those where it has. In the latter case, the handling oI communications becomes
crucial especially when public conIidence is at risk.
Sometimes a crisis may be triggered when there is no new inIor
c concerns about a product. In this case
app opriate.
o possible outcomes to a crisis:
Urgent regulatory action is needed; in this case, a recommendation on the action to be taken
and, iI needed, on the public communication has to be provided;
Urgent regulatory action is not required; in this case, a recommendation on the Iollow-up and,
In both cases the basis oI the conclusion should be documented.
As a matter oI principle, the handling
parties concerned, i.e. the Competent A
the Agency, the CHMP, the Rapporteur and the Marketing Authorisation Holder(s). In accordance

39
PART II 136/229
with the principles laid down in Chapter II.2.A on the conduct oI pharmacovigilance Ior centrally
authorised products, the Rapporteur should have a key role when there is a saIety issue, in close
cooperation with the Agency.
ng which a crisis should be dealt with, will depend upon the urgency oI the matter.
The proposed procedure should, however, be Ilexible enough to allow Ior immediate action to be
, in the case oI urgent action required to protect public health, Member States
ma
seen, i.e.:
A European Crisis Group;
In r crisis, a European Crisis Group needs to be created. For logistical
up
should be kept to a minimum. Due to logistical and time constraints, some meetings may need to take
tional members and expertise may be co-
opted into the European Crisis Group as need arises.
Th r
vigilance Working Party (PhVWP);
, supported by his/her scientiIic assessment team;
II appropriate, a representative oI the Member State where the signal originated;
s oI the Agency Crisis
The timeIrame, duri
taken (e.g. an urgent product recall), iI considered necessary by the European Commission and/or the
Member States. However
y need to take pre-emptive action in accordance with the legislation.
2.B.3 Crisis Management Structures
Three diIIerent management structures are Iore
An Agency Crisis Team;
An advisory network at the level oI the Member States.
2.B.3.1. European Crisis Group
orde to deal successIully with a
reasons and rapid and eIIicient issue management, the core members oI the European Crisis Gro
place without all members being present. OI course addi
e co e European Crisis Group comprises:
The Chairperson oI the CHMP;
The Chairperson oI the CHMP Pharmaco
The Rapporteur oI the product concerned
The Executive Director oI the Agency, as well as the other member
Team (Ior Iurther details, see Chapter II.2.B, Section 3.2).
The primary role oI the European Crisis Group is to deal with cont
This will be achieved by:
aining and controlling the situation.
ry, or reIerring the matter to the
hat possible action should be taken
levant Marketing Authorisation Holders
Iully inIormed;
ate communication strategy towards the public, including
European Crisis Group will be taken by the Executive Director, in
consultation with the CHMP Chairperson.
2.B.3.2 Agency Crisis Team
The availability oI an internal Agency crisis management structure involves the creation oI an Agency
Crisis Team, which should become operational within the shortest possible timeIrame. It should be set
ConIirming the crisis;
Managing the crisis situation by:
DeIining a strategy to handle the crisis;
Convening an extraordinary CHMP meeting, iI necessa
next regular CHMP meeting, in order to deIine w
considering the seriousness oI the crisis;
Ensuring that all Competent Authorities and re
are rapidly and
Developing the appropri
Patients and Healthcare ProIessionals.
The decision to convene the
PART II 137/229
up in suc way that it is also able to deal with crises arising during weeke h a nds or public holidays. The
Agency Crisis Team should consist oI an identiIied group oI individuals.
st-authorisation Evaluation oI Medicines Ior Human Use;
The ance and Post-authorisation SaIety & EIIicacy oI
Med
itional participants may be co-opted as necessary; Ior example a legal administrator, other
Pro t
and ling be needed.
The role
The Ioll owing speciIic tasks:
dec P Chairperson, to convene a European Crisis Group;
liais mmission.
The Head oI Unit Post-authorisation Evaluation oI Medicines Ior Human Use:
liais Press
OII
c resources.
centralising all updated inIormation related to the crisis;
A list oI all crisis contact points within the Agency is available.
The Agency Crisis Team is normally chaired by the Executive Director, or, in his absence, a
designated deputy.
It has a core membership with optional/additional participants. The core members, in addition to the
Executive Director, are:
The Head oI Unit Po
Head oI Sector Pharmacovigil
icines;
The Product Team Leader concerned;
The Agency`s Press OIIicer.
Optional/add
duc Team Members or Product Team Leaders, as well as support personnel (technical, secretarial
uistic support) will
oI the Agency Crisis Team consists oI:
co-ordinating all activities;
acting at all stages in cooperation with the other participants oI the European Crisis Group.
owing Members have the Ioll
The Executive Director (or, in his absence, a designated deputy):
iding, together with the CHM
chairing the Agency Crisis Team;
deciding upon the Communication Plan;
ing with the European Co
ing with the Executive Director, the Chairperson oI the CHMP and the Agency`s
icer;
providing all necessary scientiIi
The Head of Sector Pharmacovigilance and Post-authorisation Safety & Efficacy Medicines:
acting as overall coordinator, responsible Ior:
organising and coordinating the actions oI the Agency Crisis Team Members;
preparing all documents Ior public communication;
inIorming the Executive Director and the Head oI Unit Post-authorisation Evaluation oI
Medicines Ior Human Use oI all developments.
The Product Team Leader:
collecting internal and external inIormation on an ongoing basis;
writing Iile notes on meetings and ensure that key action points and recommendations are
documented and Iiled.
PART II 138/229
PART II 139/229
.3.3
A prerequisit ts within the Member States.
involvement oI the national pharmacovigilance systems in case
t in the whole EU; this
implies the availability oI eIIicient immediate links with the Heads oI Medicines Agencies;
s oIIicers
available in Member States.
entation oI the reasons Ior the
al that public relations are handled sensitively and in a timely Iashion. Failure
ell the crisis is managed Irom a saIety and regulatory perspective,
pub c
For this reason, the responsibility Ior press brieIing and the preparation oI Public Statements is at the
ideal is that press releases should be coordinated between the Member States, the
wever in some situations, this ideal may not be
between the Agency and the Member States should ensure that
the messages coming Irom them are consistent.
2.B Advisory Network at the Level of the Member States
e in this respect is the availability oI designated contact poin
This network should also Ioresee the
oI saIety concerns.
A consolidated list oI all contact points at the level oI the Member States has been prepared. This list
is continuously updated. It is the responsibility oI the Member States to inIorm the Agency oI any
changes to be implemented.
2.B.4 Key Points of the Procedure
In addition to the management structures, management systems are put in place at the level oI the
Agency and the Competent Authorities oI the Member States. They aim to meet the Iollowing
objectives:
To activate all available networks and to coordinate the diIIerent activities between the
interested parties;
To arrive at a common conclusion and, where regulatory action is considered necessary, an
Opinion, and to implement the regulatory action at the same momen
To convey a uniIied message to the public, including Patients and Healthcare ProIessionals;
this requires eIIicient contacts with the European Commission and with the pres
In order to achieve these objectives, a close cooperation between all the diIIerent parties involved and
the Iollowing steps should be ensured:
1. ConIirmation oI the crisis;
2. Initiation, iI considered necessary, oI the crisis procedure;
3. Rapid scientiIic re-appraisal oI the risk-beneIit balance oI the product concerned;
4. DeIinition oI strategy;
5. Recommendation on action or no action with docum
recommendation;
6. In case oI regulatory action, monitoring oI the implementation in all Member States;
7. Development oI an action plan to monitor the sequelae.
2.B.5 Public Relations
In all cases it is essenti
to do so may mean that, however w
lic onIidence will be lost and the image oI the Competent Authorities will be damaged.
highest levels. A Communication Plan will be decided by the Agency`s Executive Director on the
basis oI the communication strategy proposed by the European Crisis Group, with the Head oI Sector
Pharmacovigilance and Post-authorisation SaIety & EIIicacy oI Human Medicines being responsible
Ior draIting the communication documents, and the Agency`s Press OIIicer acting as the public
spokesperson. The
Agency and the Marketing Authorisation Holder(s). Ho
met. In such cases, close cooperation
3. Conduct of Pharmacovigilance for Medicinal Products Authorised through
the Mutual Recognition or Decentralised Procedure
3.1 Introduction
The objective oI this guidance is to develop
use which Iall under the mutual recognition
a Iramework whereby all medicinal products Ior human
procedure (MRP) or the decentralised procedure (DCP)
oI new inIormation relevant to the risks and beneIits
be taken, when necessary, to protect public health.
l Member States who have granted the authorisation.
ooth Iacilitated by the Coordination Group Ior the Mutual
orking Party (PhVWP) is the Iorum
are closely monitored to allow timely evaluation
oI these products, so that appropriate action may
Products covered by these procedures include those authorised through MRP, DCP or ex-concertation
procedure and those previously reIerred under Articles 30 and 31 oI Directive 2001/83/EC.
Article 31(2) oI Directive 2001/83/EC provides the Agency with the option to limit the procedure to
certain parts oI the authorisation iI the reIerral to the CHMP concerns a range oI products or a
therapeutic class. In that case, Iollowing completion oI such a reIerral procedure, all subsequent
variations, renewals and other maintenance activities oI the relevant Marketing Authorisations granted
through national procedures remain to be handled at national level. That means that aIter the reIerral,
products authorised through MRP or DCP will Iollow the MRP and DCP, and purely nationally
authorised products will be handled through purely national procedures again.
The responsibility Ior the conduct oI pharmacovigilance oI any MRP or DCP product rests with the
Competent Authorities oI all individua
The sm running oI MRP and DCP is
Recognition and Decentralised Procedures (CMD(h)) in accordance with Article 27 oI Directive
2001/83/EC. The CMD(h) acts to support the development oI consensus where diIIerences oI view
arise so as to minimise the need Ior arbitration at the level oI the Committee Ior Medicinal Products
Ior Human Use (CHMP). The Member States have agreed that Ior pharmacovigilance issues arising
with MRP and DCP products, the CHMP Pharmacovigilance W
Ior exchange oI inIormation, evaluation and views and that the PhVWP advises the CMD(h) on
actions to be taken (see PhVWP Mandate in Appendix II.1.A).
Becaus he need to coordinate the process oI pharmacovigilance and an
action across all relevant Member States, best practice guidance has be
e oI t y consequential regulatory
en made available on the
cooperation between the CMD(h) and the PhVWP (see MRFG Best Practice Guide on the Cooperation
between Mutual Recognition Facilitation Group and Pharmacovigilance Working Party
40
). This will
Iacilitate harmonised actions in the Member States.
This Chapter presents:
Principles relevant to the conduct oI pharmacovigilance Ior MRP and DCP products; and
The speciIic roles oI the diIIerent parties involved in carrying out these Iunctions.
P
and DCP and Ior pharmacovigilance procedures and obligations oI Marketing Authorisation Holders,
The responsibilities and Iunctions oI the various parties involved in the handling oI marketing
authorisation and subsequent variation applications in the MRP and DCP are deIined in the legislation.

Directive 2001/83/EC outlines the basis Ior the authorisation oI medicinal products through the MR
Competent Authorities and the Agency thereaIter. Commission Regulation (EC) No 1084/2003
provides the legislative basis Ior variation oI MRP and DCP marketing authorisations including urgent
saIety restrictions.
3.2 Principles

40
PART II 140/229
Memb tes have accordingly agreed principles that should be applied Ior the c er Sta onduct oI
pharmacovigilance Ior MRP and DCP products, with the ReIerence Member State (RMS) taking the
the RMS and CMS. The roles oI the
relevant parties are presented below.
Article 104(5) oI Directive 2001/83/EC stipulates that the Marketing Authorisation Holder should

accessible to the RMS and that the RMS shall assume the responsibility oI analysing and monitoring
sons, Member States have agreed that the RMS should
be assigned responsibility Ior evaluating all saIety concerns relevant to MRP or DCP products, Ior
eed between the national Competent Authorities to
undertake this task. In situations where a class-related eIIect is identiIied Ior products with diIIerent
ween the relevant RMSs to take Iorward
evaluation oI the class-related eIIect.
IIerences arise
between Member States.
The PhVWP is the Iorum Ior discussing all saIety concerns relevant to MRP and DCP products. Items
lead on pharmacovigilance in close co-operation with the Concerned Member States (CMS). Any
reIerence to Member States below should be taken to mean both
3.3 Roles and Responsibilities
3.3.1 Reference Member State
ensure that all serious adverse reactions occurring in the EU are reported in such a way as to be
such serious adverse reactions. For practical rea
providing Assessment Reports to the CMS according to an agreed timetable and presenting the saIety
concerns which need to be considered by the PhVWP. The RMS will be responsible Ior liaising with
the Marketing Authorisation Holder on all such matters. In cases where the RMS is unable to carry out
these Iunctions, another Member State may be agr
RMSs, a Lead-RMS may be appointed by agreement bet
3.3.2 Concerned Member States
The Competent Authorities oI all CMS have a responsibility to continuously collect inIormation on
adverse reactions and play an important role in identiIying and evaluating possible saIety concerns Ior
MRP and DCP products. The CMS will work closely with the RMS on such concerns, and will
respond to proposals Irom the RMS within the agreed timetable.
All Competent Authorities are responsible Ior ensuring implementation oI regulatory action in their
Member State.
3.3.3 CHMP Pharmacovigilance Working Party (PhVWP)
The PhVWP Iacilitates coordination oI pharmacovigilance oI MRP and DCP products across Member
States and the development oI consensus on conclusions and proposed actions where di
Ior discussion may be raised by the RMS or CMS. The Mandate oI the PhVWP (see Appendix II.1.A)
encompasses consideration oI items at the request oI the CHMP or a Member State.
3.3.4 Coordination Group for Mutual Recognition and Decentralised Procedures
The Coordination Group Ior Mutual Recognition and Decentralised Procedures (CMD(h)) will be kept
closely inIormed on issues relevant to it, e.g. variations Ior saIety reasons, by provision oI the agendas
and minutes oI the PhVWP or otherwise as appropriate (see PhVWP Mandate, Appendix II.1.A) and
MRFG Best Practice Guide on the Cooperation between Mutual Recognition Facilitation Group and
Pharmacovigilance Working Party
41
).

41
PART II 141/229
3.3.5 Agency and the Committee for Medicinal Products for Human Use
The Agency will be kept inIormed about saIety data and (proposed) regulatory actions by the Member
7. States according to Directive 2001/83/EC, Articles 105 and 10
The CHMP will become involved in the discussion on saIety concerns relevant to MRP or DCP
products whenever there is a procedure according to Directive 2001/83/EC, Articles 29(4), 31 or
36(1). The Agency will coordinate all activities in the event oI reIerral to the CHMP, see Chapter II.5
and Chapter 3, Volume 2A (Notice to Applicants) oI The Rules Governing Medicinal Products in the
European Union
42
.
For CHMP Opinions according to Article 107(2) oI Directive 2001/83/EC, see Chapters II.1 and II.5.
3.3.6 European Commission
The European Commission takes the Iinal decision relating to medicinal products on any CHMP
Opinion adopted as a result oI reIerrals according to the procedures laid down in Articles 32, 33 and
34 oI Directive 2001/83/EC and oI CHMP Opinions according to Article 107(2) oI Directive
2001/83/EC, see also Chapters II.1 and II.5.
3.3.7 Marketing Authorisation Holders
According to Article 104(5), the Marketing Authorisation Holder should report all serious adverse
in the EU in such a way as to be accessible to the
RMS. The Marketing Authorisation Holder is Iurther obliged to adhere to the other legal requirements
the EU, submission oI
dies) Ior
g oI the PhVWP. In the case oI bilateral contact between a CMS and
the Marketing Authorisation Holder, the relevant CMS should keep the RMS inIormed.
Functions and Procedures for the Conduct of Pharmacovigilance
In the period between an application Ior a marketing authorisation through the DCP or MRP and
reactions with MRP and DCP products occurring
Ior pharmacovigilance (e.g. reporting oI adverse reactions occurring outside
Periodic SaIety Update Reports and other inIormation including post-authorisation saIety stu
MRP and DCP products, as Ior any other nationally authorised products. This inIormation should be
provided to all Member States at the same time. Member States have agreed that the RMS will
normally act as the primary liaison with the Marketing Authorisation Holder, speciIying issues
requiring clariIication, Iurther inIormation or speciIic actions by the Marketing Authorisation Holder.
This will be clearly presented in writing to the Marketing Authorisation Holder by the RMS working
closely with CMS. Meetings with the Marketing Authorisation Holder should involve the RMS, and
any other CMS by request. The conclusions oI such meetings should be distributed to the PhVWP and
the CMD(h). The RMS may also ask the Marketing Authorisation Holder to present Iurther
clariIication to the plenary meetin
3.4
3.4.1 Pre-Authorisation Phase
granting oI the marketing authorisation, inIormation relevant to the saIety oI the product may become
available to the Applicant/Marketing Authorisation Holder. Since it is essential Ior this inIormation to
be included in the assessment oI the risk-beneIit balance, the Applicant/Marketing Authorisation
Holder is responsible Ior the immediate submission oI any inIormation that may impact on this
assessment to the RMS and the other CMS (see also Chapter 1, Section 5.1.1, Volume 2A (Notice to
Applicants) oI The Rules Governing Medicinal Products in the European Union
43
). The RMS should
take the new inIormation into account when draIting the preliminary or Iinal Assessment Report as
applicable. II the Assessment Report has already been distributed, the RMS should prepare and

42
43
PART II 142/229
distribute either an amended or a supplementary Assessment Report. For reporting requirements see
Chapter I.5, Section 2.
3.4.1.a) Risk Management Plans
nt
II the Applicant/Marketing Authorisation Holder has submitted a Risk Management Plan as part oI the
application dossier, the RMS will include an assessment oI it in the Assessment Report. The role and
responsibilities oI the RMS, the options Ior the CMS to contribute and the options Ior the
Applicant/Marketing Authorisation Holder to respond to questions and to liaise with the Compete
Authorities are described in Chapter 2, Volume 2A (Notice to Applicants) oI The Rules Governing
Medicinal Products in the European Union
44
(see also relevant CMD(h) Standard Operating
Procedures
45
). The Assessment Report will be discussed at a PhVWP meeting at the request oI the
RMS considers that a signiIicant risk has emerged to change the risk-beneIit
discussed at the PhVWP. The PhVWP will report the
D(h).
and
Marketing Authorisation Holders on the expedited reporting oI serious adverse reactions. Member
RMS or a CMS. When the Marketing Authorisation(s) are granted the Marketing Authorisation Holder
should appropriately execute the Iinal agreed Risk Management Plan.
3.4.1.b) Concerns during the ongoing Mutual Recognition or Decentralised
Procedure
II, in the course oI a MRP or DCP and Iollowing the assessment oI all inIormation relevant to the
saIety oI a product, the
balance, the outcome oI the evaluation should be
outcome oI the discussion to the CM
3.4.2 Post-Authorisation Phase
3.4.2.a) Expedited Reporting of Individual Case Safety Reports
Directive 2001/83/EC lays down speciIic obligations Ior national Competent Authorities
States are responsible Ior collecting, collating and evaluating reports occurring in their respective
territories. Member States are Iurther obliged to Iorward reports oI serious adverse reactions received
to the respective Marketing Authorisation Holders, see also Chapter II.1. In accordance with Article
104(5) oI Directive 2001/83/EC, Ior products which have been the subject oI a MRP or DCP, the
Marketing Authorisation Holder should additionally transmit these reports to the RMS (see also
Chapter II.3, Section 3.1 and Chapter I.4). To avoid duplicate reporting the RMS should not retransmit
these reports to EudraVigilance.
The responsibility to collate and evaluate these reports has been assigned to the RMS by the Member
n
is required to provide all Competent Authorities with Periodic
and
States.
3.4.2.b) Periodic Safety Update Reports and Other Relevant Post-Authorisation
Informatio
The Marketing Authorisation Holder
SaIety Update Reports (PSURs) and relevant saIety inIormation Irom post-authorisation
commitments, post-authorisation studies, worldwide literature, or other sources as outlined in the
Directive 2001/83/EC and guidance documents Ior Marketing Authorisation Holders. Any
consequential variation should be submitted by the Marketing Authorisation Holders to the RMS
all CMS at the same time. The RMS will evaluate the inIormation and circulate a preliminary
Assessment Report to the CMS and Marketing Authorisation Holder within 6 weeks oI receipt oI the
inIormation. The CMS should respond within 3 weeks oI receipt oI the RMS Assessment Report. The
RMS will distribute the Iinal Assessment Report aIter a Iurther 3 weeks. This Assessment Report will,

44
45
PART II 143/229
iI requested by the RMS or a CMS, be discussed at a PhVWP meeting. The PSUR submission
schedule to be Iollowed in the CMS is the one in place in the RMS, unless otherwise agreed during the
MRP or DCP. This should be decided on a case-by-case basis, see also Chapter I.6, Section 2.4.
For the assessment oI PSURs within the scope oI the PSUR Work Sharing initiative the Iollowing
timetable has been agreed: The preliminary Assessment Report will be distributed by the P-RMS
(Member State responsible Ior the assessment oI the PSUR) to the CMS and the Marketing
Authorisation Holder(s) within 60 days. The CMS may comment within 30 days aIter receipt oI the
3.4.2.c) Risk Management Plans
II the Marketing Authorisation Holder has submitted a new or updated Risk Management Plan in the
RMS will distribute an Assessment Report and collect comments Irom
the CMS. ThereaIter the RMS will distribute the Iinal Assessment Report, which will also be sent to
Assessment Report. The P-RMS will distribute the Iinal Assessment Report aIter a Iurther 30 days.
post-authorisation phase, the
the Marketing Authorisation Holder. The Marketing Authorisation Holder may be requested to revise
the Risk Management Plan. The Risk Management Plan and the Assessment Report will, iI requested
by the RMS or CMS, be discussed at a PhVWP meeting. Results oI post-authorisation studies
perIormed in the Irame oI the Pharmacovigilance Plan should be processed in a similar way by the
RMS (see Chapter I.3).
3.4.2.d) Signal Detection
It is possible that potential signals will emerge in the early stages oI the marketing oI a MRP or DCP
product especially Ior a new active substance. It will be important Ior these signals to be evaluated
eIIectively. A signal oI a possible unexpected adverse reaction or a change in severity, characteristics
ected adverse reaction may be identiIied Irom many diIIerent sources oI or Irequency oI an exp
inIormation held by the Marketing Authorisation Holders, the RMS, or any CMS or the Agency.
It is the responsibility oI each Member State to transmit reports oI serious adverse reactions to the
EudraVigilance database in an expedited way and to identiIy signals Irom inIormation arising in its
territory. It is important Ior the RMS to have the totality oI inIormation in order to have an overall
view oI the experience gathered in relation to the concerned MRP or DCP product. Additional
inIormation requested Irom the Marketing Authorisation Holder should be provided to the RMS and
all CMS simultaneously. The EudraVigilance database services are a very important source oI
inIormation, since all reports oI serious adverse reactions are included in the database in accordance
with the Community legislation (see also Part III).
As a matter oI routine, the RMS should continually evaluate all newly submitted inIormation in the
context oI inIormation already available on the product, to determine the emerging adverse reaction
proIile. Signals oI a possible saIety concern will, iI requested by the RMS or a CMS, be discussed at a
meeting oI the PhVWP.
3.4.2.e) Signal Evaluation
As signals oI possible unexpected adverse reactions or changes in severity, characteristics or
Irequency oI expected adverse reactions emerge, the relevant inIormation needs to be analysed Ior
eIIective evaluation over a timescale appropriate to the importance and likely impact oI the signal.
Any risk evaluation prompted by a signal should normally be carried out by the RMS unless other
arrangements are agreed with another Member State, this could be Ior example the CMS where the
in any case work closely with the originator oI the
on the responsibility Ior the risk-beneIit Assessment
original signal was identiIied. The RMS should
alert. Agreement needs to be reached in each case
Report, by the RMS or the originating Member State, or jointly. The RMS should liaise with the
Marketing Authorisation Holder as appropriate Ior the provision oI additional relevant inIormation, iI
PART II 144/229
available, to ensure that all relevant data is taken into account in the Assessment Report. The
Assessment Report should be distributed to all Member States through the EudraNet
Pharmacovigilance mailbox and may be discussed at a PhVWP meeting at request oI the RMS or
CMS. According to Article 23 IiIth subparagraph oI Directive 2001/83/EC the Marketing
Non-Urgent Safety Concerns
Authorisation Holder may be asked to provide data demonstrating that the risk-beneIit balance
remains Iavourable. All data to be provided by the Marketing Authorisation Holder to the RMS should
simultaneously be distributed to all CMS.
A Member State other than the RMS should not start a Iull evaluation prior to having contacted the
RMS, in order to prevent any unnecessary duplication oI eIIort.
3.4.2.f) Proceedings in Case of Safety Concerns
SaIety concerns that do not IulIil the criteria Ior a Rapid Alert (see Chapter II.4) should be brought to
ting Authorisation Holder as appropriate Ior the provision oI additional
relevant inIormation, iI available, to ensure that all relevant data is taken into account in the
ent InIormation
the attention oI the RMS. The RMS should work closely with the Member State who identiIied the
issue to evaluate the matter. Agreement needs to be reached in each case on the responsibility Ior the
risk-beneIit Assessment Report, by the RMS or the originator Member State, or jointly. The RMS
should liaise with the Marke
Assessment Report. The Assessment Report should be distributed to all Member States through the
EudraNet Pharmacovigilance mailbox. The RMS should consider sending a Non-Urg
request (see Chapter II.4). Following evaluation, the need Ior Iurther discussion at the PhVWP will be
at the request oI the RMS or CMS. The CMD(h) should be inIormed by the RMS.
Urgent Safety Concerns
The Rapid Alert System should be used to communicate inIormation on saIety concerns with MRP
and DCP products which meet the criteria described in Chapter II.4. The RMS should preIerably take
the lead, but in case the concern was raised in a CMS, agreement needs to be reached who will
transmit the Rapid Alert. The Rapid Alert should be transmitted to the contact points oI the RMS, the
CMS, the European Commission and the Agency (see Chapter II.4). The Marketing Authorisation
Holder should also be inIormed by the RMS at the same time. The RMS should work closely with the
CMS where the concern was raised (iI not the RMS) and responsibilities Ior management and
assessment oI the saIety concern should be agreed between them. They should also decide what
additional inIormation should be requested Irom the Marketing Authorisation Holder and CMS.
alising an
agreed position between the RMS and all CMS. In cases oI particular urgency a special meeting oI the
ay Member State may
initiate immediate suspension oI the marketing and use oI the medicinal product concerned iI
Following risk evaluation, a discussion should be held at the PhVWP with the aim oI Iin
PhVWP m need to be set up. The RMS should keep the CMD(h) inIormed. Any
considered necessary (see below under b) Ior actions by Competent Authorities).
Actions Consequential to Safety Concerns
SaIety concerns may emerge Irom the many sources oI inIormation considered above which warrant
amendment to the conditions oI the marketing authorisation, through a short type II variation
procedure, or urgent saIety restriction procedure. In the case oI serious risk, which is considered to
outweigh the beneIit oI a product, there may be a need to withdraw the product Irom the market or
Competent Authorities as described below.
Variations oI the marketing authorisation submitted by the Marketing Authorisation Holder because oI
ures Ior MRP and DCP
revoke the marketing authorisation. Such actions may be taken either by Marketing Authorisation
Holder or by
a) Actions by the Marketing Authorisation Holder
saIety concerns should be handled through the 30 day-type II variation proced
PART II 145/229
products with the RMS evaluating the variation and circulating an Assessment Report to the CMS
within the standardised timetable. For urgent saIety concerns, the Marketing Authorisation Holder
may submit an urgent saIety restriction.
In the case oI a Marketing Authorisation Holder wishing to withdraw its product Irom the market Ior
timetable will depend on the urgency oI the
saIety reasons, action needs to be coordinated across the CMS. It is recommended that the Marketing
Authorisation Holder notiIies the intention Ior a withdrawal to all Competent Authorities concerned at
the same time and at an early stage. The RMS should normally take the lead and coordinate the
actions. The RMS and CMS should use the Rapid Alert system to communicate with each other. The
RMS and Marketing Authorisation Holder should wherever possible agree on the timetable to be used
Ior the diIIerent steps and actions to be taken. The
situation (see Chapter I.8, Section 5). It is important that the same action is Iollowed in all Member
States including communication to Healthcare ProIessionals (see Part IV).
b) Actions by the Competent Authorities
II Iollowing risk evaluation by the RMS, it is considered that action is necessary to vary the terms oI,
or to suspend, revoke or withdraw, the marketing authorisation oI a medicinal product, the RMS
should inIorm the CMS, the Agency and the Marketing Authorisation Holder. The RMS should also
keep the CMD(h) inIormed.
Where possible, in order to ensure a coordinated approach, eIIorts should be made to reach a
consensus on the proposed action to be taken, through discussion within the PhVWP.
Where appropriate, the RMS should communicate with the Marketing Authorisation Holder on the
reasons Ior the conclusions reached by the Member State and the action that should be taken by the
Marketing Authorisation Holder. II the Marketing Authorisation Holder does not voluntarily vary,
withdraw or suspend the marketing authorisation, an urgent saIety restriction procedure should be
started by the RMS, or a reIerral according to Directive 2001/83/EC Article 36 to the CHMP should be
initiated (see Chapter II.5). The resulting CHMP Opinion will be Iollowed by a single Decision oI the
European Commission binding on all Member States and the Marketing Authorisation Holder.
In urgent cases, any Member State may initiate immediate suspension oI the marketing and use oI a
medicinal product on its territory, inIorming all Member States, the European Commission and the
Agency within 24 hours. Such action should preIerably be taken in all Member States in a coordinated
manner Iacilitated by a proposal Irom the PhVWP to the Competent Authorities oI Member States.
For CHMP Opinions according to Article 107(2) oI Directive 2001/83/EC, see Chapter II.5.
3.4.2.g) Communication to Healthcare Professionals and the Public
When a marketing authorisation is issued, according to Article 21(4) oI Directive 2001/83/EC, the
Competent Authorities should make publicly accessible without delay the Assessment Report, together
with the reasons Ior their opinion, aIter deletion oI any inIormation oI a commercially conIidential
nature. Thus the RMS is obliged to prepare a Public Assessment Report (PAR). The preliminary PAR
should be provided to the Marketing Authorisation Holder in particular Ior consideration oI any
commercially sensitive data or inIormation. See also CMD(h) Best Practice Guide Ior the Public
Assessment Report in the Decentralised and Mutual Recognition Procedures
46
.
Such a PAR needs updating, without delay, once regulatory action in response to a saIety concern has
been taken.
In case oI a reIerral to the CHMP, the CHMP Opinion should be made publicly accessible.

46
PART II 146/229
PART II 147/229
aIety
ional
ments). It is important that consistent inIormation is provided in
ed on the need Ior and timing oI
In addition it may be appropriate to inIorm Healthcare ProIessionals and the public about s
concerns related to MRP and DCP products in other ways (e.g. Direct Healthcare ProIess
Communication (DHPC), Public State
all Member States.
In such cases, the RMS should propose the content oI the inIormation to be provided, and whenever
possible, this should be agreed by the CMS and, iI necessary considered by the PhVWP. There should
be agreement whenever possible, on the method and timing oI distribution oI the inIormation e.g. by
letters Irom Marketing Authorisation Holder or Member States` Competent Authorities, or through
Competent Authorities' bulletins. Agreement should also be reach
Public Statements and the reaction to press enquiries.
For guidance on pharmacovigilance communication, see Part IV.
4. Rapid Alert and Non-Urgent Information System in Pharmacovigilance
4.1 Introduction
During the marketing period oI a medicinal product, urgent measures to saIeguard public health may
priate degree oI urgency.
State or the receipt oI any other relevant important inIormation should be shared with
oI saIety concerns and exchange oI inIormation required to take
tent Authorities oI Member States, the Agency and the European
ert and Non-Urgent InIormation System in accordance with the
ter. In order to avoid multiplication oI eIIort and to ensure more
The pur ate degree oI urgency, the Competent
Au ri armacovigilance data related to
State.
A RA r inIorming the Competent Authorities oI other
Member Stat nd the Agency in accordance with Articles 107(1) and (2)
and 36( I ) oI Regulation (EC) 726/2004.
mber State concerned inIorms the
r
at the CHMP; or
within procedures laid down in Articles 31, 36 and 37 or Article 107(2) oI Directive
be necessary. Within the EU pharmacovigilance system it is essential that inIormation regarding saIety
concerns, particularly those which may result in major changes to the marketing authorisation status or
revocation or withdrawal oI a product, is exchanged between the Member States, the Agency and the
European Commission with the appro
In general, any saIety concern identiIied by a Member State aIter evaluation oI the data available in
that Member
other Member States, the Agency and the European Commission. This should also include any action
initiated by the Marketing Authorisation Holder(s).
Early exchange oI inIormation will enable the Competent Authorities oI Member States to initiate data
research and seek specialist expertise, so that appropriate action may be taken in a co-ordinated
manner as soon as possible.
To support rapid notiIication
appropriate action, the Compe
Commission operate a Rapid Al
procedures laid down in this Chap
eIIicient resource utilisation oI national systems, inIormation during the phase oI signal detection may
also be exchanged in order to support inIormal communication between Member States (pre-signal
inIormation exchange). The Marketing Authorisation Holder should be inIormed oI suspected signals
deemed to require Iurther analysis, as appropriate.
pose oI a Rapid Alert (RA) is to alert, with an appropri
tho ties, the Agency and the European Commission about ph
medicinal products, which indicate that action may be needed urgently to protect public health. It is
essential that communication oI such problems occurs at an early stage, normally beIore a decision is
taken in a Member
should also be used by Member States Io
es, the European Commission a
2) o Directive 2001/83/EC and Article 20(4
It should be noted that Article 107(1) also requires that the Me
Marketing Authorisation Holder.
RAs should not be circulated Ior the exchange oI less urgent inIormation. For this purpose, a Non-
Urgent InIormation (NUI) should be used.
A NUI supports collection and exchange oI pharmacovigilance inIormation between the Competent
Authorities and the Agency, which does not IulIil the criteria Ior an RA.
A RA or NUI may also be initiated by the Agency.
Following an RA or NUI, the saIety concern may then be reviewed as Iollows:
at the PhVWP on the basis oI the Drug Monitor and an Assessment Report iI applicable; o
2001/83/EC or Article 20 oI Regulation (EC) No 726/2004.
PART II 148/229
An RA/NUI should primarily be used to highlight concerns relating to the risk-beneIit balance oI a
medicinal product authorised according to Directive 2001/83/EC or Regulation (EC) No 726/2004.
In case oI saIety concerns Ior products not authorised as medicinal products, e.g. chemical products,
the system may also be used iI the inIormation could be relevant to medicinal products.
Occasionally, an NUI may be circulated to solicit inIormation on national policies or views on draIt
l product or speciIic batches oI a medicinal
guidance documents or certain organisational matters, in order to prepare Ior discussions on such
matters at the level oI the PhVWP.
An RA/NUI may be also used Ior sharing inIormation on major Iindings Irom pharmacovigilance
inspections.
Rapid Alerts regarding quality problems oI a medicina
product are not considered in this Chapter, but guidance Ior this is available in the Compilation oI
Community Procedures on Inspections and Exchange oI InIormation
47
. However, in cases oI an
adverse reaction, lack oI eIIicacy, or suspicion thereoI, which are associated with quality issues,
liaison with Inspectorate colleagues should be initiated to assess the saIety implications oI the quality
problem.
4.2 Criteria
An
a m
pro
thorisation
;
oI
s;
y.
data related to a medicinal product
aut is or revocation oI the
ma ti portant changes to the SPC such as listed above,
an ncy immediately in accordance
wit r
Where
order to
latest o Iter the suspension, inIorming the other Member States, the Agency and the
Eu a on in accordance with Article 107(2) oI Directive 2001/83/EC.

4.2.1 Rapid Alert
RA should be used when a Member State or the Agency has a saIety concern which potentially has
ajor impact on the known risk-beneIit balance oI a medicinal product and which could warrant
mpt regulatory action and communication to Healthcare ProIessionals/the general public, such as:
Urgent saIety restriction, suspension, revocation or withdrawal oI the marketing au
and/or recall oI the medicinal product Irom the market;
Suspension oI marketing and/or use oI a medicinal product
Action Ior human blood- and plasma-derived medicinal products Iollowing occurrence
vCJD in a blood donor (with speciIication oI batches on the market as well as expired
batches);
Important changes in the Summary oI Product Characteristics (SPC), e.g.:
Introduction oI new contraindication
Introduction oI new warnings;
Reduction in the recommended dose;
Restriction oI the indications;
Restriction in the availability oI a medicinal product;
Need to inIorm Healthcare ProIessionals or Patients about an identiIied risk without dela
Where as a result oI the evaluation oI pharmacovigilance
hor ed through national procedures, a Member State considers suspension
rke ng authorisation or its variation resulting in im
RA should be used to inIorm the other Member States and the Age
h A ticle 107(1) oI Directive 2001/83/EC as well as the European Commission.
a Member State suspends the marketing authorisation Ior a nationally authorised product in
urgently protect public health on its territory, the Member State should circulate a RA at the
ne working day a
rope n Commission oI this acti

47
PART II 149/229
Wh duct authorised through the
mutual recognition or decentralised procedure on their territory Ior urgent protection oI public health,
ne working day aIter the suspension providing the reasons Ior the
action, thereby inIorming the other Member States and the European Commission in accordance with
al req 3/EC as well as inIorming
the Agency.
e
legal requirements, Member States should circulate a RA, thereby inIorming the European
notiIy
the occurrence oI variant CreutzIeldt-Jakob disease (vCJD) in a blood donor, the RA system in
ere a Member State suspends the marketing and use oI a medicinal pro
a RA should be used at the latest o
the leg uirements oI both Articles 107 and 36(2) oI Directive 2001/8
In the case oI centrally authorised products, where urgent action to protect human health or the
environment is considered essential, a Member State may suspend the use oI a medicinal product on
its territory, in accordance with Article 20(4) oI Regulation (EC) 726/2004. In such cases, the Member
State should inIorm the European Commission and the Agency immediately and no later than the
Iollowing working day, providing the reasons Ior its action. In such cases and in order to IulIil th
Commission, the Agency and the other Member States.
Where a RA is used with regard to medicinal products derived Irom human blood or plasma to
pharmacovigilance should be used in addition to the OIIicial Medicines Control Laboratories (OMCL)
Alert and, iI a batch recall is necessary, the Inspection Rapid Alert (see Compilation oI Community
Procedures on Inspections and Exchange oI InIormation
48
).
In addition to the above criteria, a RA may also be used when there are concerns about a change in the
risk-beneIit balance oI a medicinal product or an active ingredient, Iollowing:
a series oI reports (or rarely a single well documented case) oI an unexpected and serious
adverse reaction;
reports oI an expected adverse reaction which suggest greater severity or long-term sequelae
than previously known, or which identiIy new risk Iactors;
a signiIicant increase in the reporting rate oI an expected serious adverse reaction;
evidence Irom studies (clinical trials or non-interventional studies) indicative oI an unexpected
articular product are greater than alternatives with similar
eIIicacy.
4.2
An
cri
pharma ere additional
Provision oI emerging pharmacovigilance inIormation at an early stage;
st to other Member States, but does not require a response
t

risk, or a change in Irequency or severity oI a known risk;
knowledge that the eIIicacy oI a medicinal product is not established as assumed to date; or
evidence that the risks oI a p
.2 Non-Urgent Information
NUI should be used Ior inIormation exchange in relation to saIety concerns not IulIilling the
teria Ior an RA as deIined above. For example, an NUI should be used to communicate
covigilance data which do not require immediate or urgent action and/or wh
inIormation is required Irom other Member States to support the evaluation oI the concern.
In each case the reason Ior sending an NUI should be provided:
InIormation on a potential new saIety signal;
InIormation on status oI implementation oI regulatory action;
InIormation which may be oI intere
(e.g. the withdrawal oI a product Ior reasons other than saIety, the outcome oI discussions
Irom national saIety committees, when to expect an Assessment Report on certain items,
Public Statements (press releases), Direct Healthcare ProIessional Communication, curren
media activity);
Request Ior inIormation;

lable on EMEA website http://www.emea.europa.eu
48
Doc.ReI. EMEA/INS/GMP/3351/03 latest version, avai .
PART II 150/229
Organisational matters;
Facilitation oI data collection Ior interaction with external parties.
4.3 Procedures
4.3.1 Sending a Rapid Alert or a Non-Urgent Information
erious adverse
he EU. RAs
ing network.
To d
use
and e
Fo i gency, the Member States and the European
Commis Iax system used in the past to exchange this
lure, the Iormer teleIax system needs to be maintained and should be used as an alternative.
e not connected via EudraNet, i.e. Marketing
d Health Organization (WHO), should be perIormed in a way that
gua t
In accordance with Article 26 oI Regulation (EC) No 726/2004 and Article 105 oI Directive
2001/83/EC, the Agency, in consultation with Member States and the European Commission, has set
up a data-processing network Ior the rapid transmission oI data between the Competent Authorities in
the event oI an alert relating to Iaulty manuIacture resulting in adverse reactions, s
reactions and other pharmacovigilance data regarding medicinal products marketed in t
and NUIs Iall under other pharmacovigilance data and use EudraNet as the data-process
sen a RA or NUI, the established EudraNet RA mailbox (address list "All Human RA") should be
d, which reIers to the contact points oI the Competent Authorities oI Member States, the Agency
th European Commission. The latest adopted EudraNet E-mail policy applies accordingly.
llow ng successIul implementation between the A
sion, electronic submission has replaced the tele
kind oI inIormation. However, Ior emergencies, e.g. EudraNet access is not available or there is a
network Iai
Changes related to the Iax numbers should be notiIied immediately to the Agency, the European
Commission and the contact points in Member States. The Agency and all Competent Authorities
should dedicate a Iax machine to the Rapid Alert and Non-Urgent InIormation System which allows
storage oI the Iax numbers and process group dialling.
Electronic communication with partners that ar
Authorisation Holders and the Worl
ran ees security and conIidentiality oI the data exchanged, e.g. via EudraLink
49
.
Templa
availabl
tes Ior RAs and NUIs are annexed (see Annexes 5.3.1 and 5.3.2). These templates are also
e on the EudraNet website (http://www.eudra.org/eudraportal/) and may be accessed via the
hed pharmacovigilance domain. establis
Wh p en reparing a RA or NUI, the Iollowing rules apply:

an NUI.
he Iirst instance.
oduct should be speciIied, i.e. iI the product is centrally authorised,
natio or reIerral procedure, or
The Template (see Annexes 5.3.1 and 5.3.2) chosen should comply with the criteria either Ior
a RA or Ior
Clear and concise inIormation on the saIety concern and reasons Ior sending the RA or NUI
should be provided so that there is no need Ior clariIication in t
a) The product(s) concerned should be identiIied by the International Non-Proprietary Name (INN)
and when available and relevant, its strength, Iormulation and the name oI the Marketing Autorisation
Holder.
b) The authorisation status oI the pr
purely nally authorised, subject to mutual recognition or decentralised
the nature oI the product iI not authorised.
c) The Competent Authority generating the RA/NUI should transmit at least the minimum inIormation
listed in Table II.4.A at the end oI this Chapter and use the Templates (see Annexes 5.3.1 and 5.3.2).

49
See EudraLink website https://eudralink.emea.eu.int.
PART II 151/229
d) Any inIormation required Irom recipients should be clearly speciIied, together with the timeIrame
Ior response.
e) Annexes to the RA/NUI, where necessary, should also be transmitted electronically, iI available.
The Iormat to be used Ior the electronic transmission oI the annexes is the one speciIied in the latest
adopted EudraNet E-mail policy. II the annexes are not available electronically, the RA/NUI Template
should be completed including a reIerence that the reIerred annexes will be submitted separately via
teleIax, and should be sent via the deIined address list to the dedicated mailboxes. A hardcopy oI this
I) The RA/NUI should be transmitted to the nominated contact points oI the Member States, the
g) The title line in the e-mail message which contains the completed Template should:
or another appropriate
. 'GI tox Ior gastrointestinal toxicity);
iden
provide the deadline Ior response iI requested.
h) I ca
oI a me m the market in order to protect
public health, the Agency
Sta s
i) When

g Authorisation Holder(s) concerned in their country adequately and promptly with
y in agreement with the Rapporteur will
Iication to the World
completed Iorm should be attached to the Iaxed annexes.
Agency, the CHMP Chairperson and the European Commission. In case oI a centrally authorised
product, the RA/NUI also needs to be sent to the Rapporteur. In cases where teleIax transmission is
used, the Iax should be transmitted to the established contact points as indicated above.
identiIy the product(s) concerned by INN, name oI the product class
name;
provide a key word identiIying the saIety concern or other reason Ior sending the RA or NUI,
using commonly understandable abbreviations (e.g
tiIy iI the message is a RA or NUI;
Title lines would thereIore look Ior example like 'INN-GI tox-RA or 'INN-Eye disorder-NUI - by
ddmmyy.
n se oI urgency, when the Concerned Member State has suspended the marketing authorisation
dicinal product or has withdrawn the medicinal product Iro
, the European Commission and all Competent Authorities in the Members
tes hould be inIormed on the Iollowing working day at the latest.
a Rapid Alert is circulated
in relation to a nationally authorised product, the initiating Member State should inIorm the
Marketin
view to start an inquiry and inIormation exchange. Receiving Member States are responsible
Ior inIorming Marketing Authorisation Holder(s) in their own country. In case oI products
authorised through the mutual recognition or decentralised procedure, the ReIerence Member
State should inIorm the Marketing Authorisation Holder adequately and promptly.
in relation to a centrally authorised product, the Agenc
promptly start an inquiry and inIormation exchange with the Marketing Authorisation
Holder(s).
the initiator should consider iI the Rapid Alert meets the criteria Ior noti
Health Organization (WHO) in accordance with Chapter II.6.
j) An RA may be used Ior the preparation and conduct oI an urgent saIety restriction in line with the
relevant guidance on post-authorisation procedures (Ior centrally authorised products this is the CHMP
Post-Authorisation Guidance Human Medicinal Products
50
and Ior products authorised through the
mutual recognition an decentralised procedures this is the Urgent SaIety Restriction Member State
Standard Operating Procedure
51
.

50
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51
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PART II 152/229
4.3.2 Responses to a Rapid Alert or Non-Urgent Information
.
In case oI an NUI, requested NUI Responses should be provided to the initiating Competent Authority
and the Agency only and within the time Irame indicated by the initiator, unless otherwise speciIied. A
document compiling all NUI Responses should be circulated by the initiator oI the NUI to all Member
States, the European Commission and the Agency.
A compilation oI RA/NUI Responses should at least include the original RA/NUI and all Responses
Irom Member States.
The title line in the e-mail message which contains the completed response should identiIy iI the
Responses to an RA should be sent to all Member States, the Agency and the European Commission
no later than one week aIter the receipt oI the RA, unless otherwise speciIied. The initiator oI an RA
requesting inIormation should compile the RA Responses and circulate the compilation to all Member
States, the European Commission and the Agency as quickly as possible
message is a RA or NUI Response (e.g. 'INN-GI tox-RA Response; analogous to Chapter II.4, Section
3.1.g). The RA or NUI Response should reIer to the original message (name oI sender, date oI original
message, alert reIerence).
The inIormation requested by the initiator oI the RA/NUI should be provided.
The Agency will summarise the issues raised in the RAs and NUIs in the Drug Monitor, which will be
discussed and updated at each meeting oI the PhVWP.
4.3.3 Assessment of a Rapid Alert
AIter transmission oI the initial RA, an interim Assessment Report should be prepared Ior the next
meeting oI the PhVWP:
For a purely nationally authorised medicinal product, the initiating Member State, taking into
account all inIormation, including that received and collated Irom other Member States,
prepares the Assessment Report on the risk-beneIit balance.
For a product authorised through the mutual recognition or decentralised procedure, any risk
evaluation should normally be carried out by the ReIerence Member State unless other
arrangements are agreed between Member States. In each case agreement needs to be reached
on the responsibility Ior the management oI the RA and the Assessment Report on the risk-
beneIit balance by the ReIerence Member State, or initiating Concerned Member State, or
jointly.
For a centrally authorised product, the Rapporteur should work closely with the initiator oI the
RA to provide an assessment in relation to the saIety concern. Agreement needs to be reached
in each case on the responsibility Ior the Assessment Report on the risk-beneIit balance, by the
Rapporteur or the initiating Member State, or jointly.
When the collated inIormation provides evidence oI a serious saIety concern, a Iull Assessment Report
on the risk-beneIit balance should be prepared, Ior consideration by the PhVWP.
The Assessment Report should be sent to all Competent Authorities in Member States, the Agency and
the European Commission and the Marketing Authorisation Holder and should be discussed at the
next meeting oI the PhVWP.
The Assessment Report should be distributed electronically using the established EudraNet
Pharmacovigilance mailbox (address list 'All Human Pharmacovigilance) as indicated in the latest
adopted EudraNet E-mail policy.
PART II 153/229
Consideration will need t be given to whether the matter is oI Community interest and should be o
reIerred under Article 31, 36 or 37 oI Directive 2001/83/EC (see Chapter II.5 Ior reIerence to Iurther
guidance).
4.3.4
On the basis oI the Drug Monitor the PhVWP will discuss all topics on which inIormation was
exchanged as a NUI and will agree on a case-by-case basis how to process the saIety concern. In the
event that preparation oI an Assessment Report is considered necessary, the same assessment
Assessment of Non-Urgent Information
procedure applies as indicated Ior a RA (see Chapter II.4, Section 3.3).
PART II 154/229
PART II 155/229
LE II.4.A
1. Ide
TAB : MINIMUM INFORMATION FOR TRANSMISSION OF A RAPID ALERT OR NON-URGENT
INFORMATION ALWAYS TO BE PROVIDED
ntification
- Type oI message
- Document reIerence
- Initiator
- Recipients
- Date oI message
2. Medicinal Product
- Active substance(s) by INN (and name oI class iI applicable)
- Invented name(s)
- Marketing authorisation procedure oI the medicinal product:
Centrally Authorised Product
Mutual Recognition
Decentralised Product
Purely Nationally Authorised Product
Product which has been subject to a reIerral process
- Pharmaceutical Iorm and dosage iI appropriate
- Marketing Authorisation Holder(s)
- ManuIacturer iI essential
3. Reason for the Rapid Alert/Non-Urgent Information
4. Action(s)
- Action(s) proposed
- Action(s) taken (steps taken to collect more inIormation at national level and temporary
measure taken to protect public health)
5. Information Exchange
- InIormation requested
5. Referrals in Case of Safety Concerns Related to Products Authorised in the
EU and Commission Decisions Following Suspension, Revocation or
Variation of a Medicinal Product by a Member State
Guidance on Community ReIerrals is provided in Chapter 3, Volume 2A (Notice to Applicants) oI The
Rules Governing Medicinal Products in the EU
52
.
Guidance on Opinions issued by the Committee Ior Medicinal Products Ior Human Use (CHMP) in
accordance with Article 107(2) oI Directive 2001/83/EC Iollowing notiIication oI consideration oI
suspension, revocation or variation oI the marketing authorisation Ior a medicinal product by a
Member State and on subsequent Commission Decisions is anticipated Ior public consultation. With
regard to the procedure to be Iollowed by the Competent Authorities in Member States Ior inIorming
the Agency, the Commission and the other Member State in accordance with Article 107(1) and (2) oI
Directive 2001/83/EC, in case a Competent Authority considers suspension, revocation or variation oI
a marketing authorisation as a result oI pharmacovigilance data evaluation or has suspended the
marketing authorisation oI a medicinal product in order to urgently protect public health, see Chapter
II.4. With regard to the Member State`s obligation to inIorm the Marketing Authorisation Holder
according to Article 107(1), see Chapter II.1.

52
PART II 156/229
6. Principles of Collaboration with the World Health Organization in Matters
acovigilance
mit
/
certain an use intended exclusively Ior markets outside the EU.
of International Pharm
6.1 Introduction
As laid down in Article 27 oI Regulation (EC) No 726/2004, the Agency shall collaborate with the
World Health Organization (WHO) in matters oI international pharmacovigilance and shall sub
promptly to WHO appropriate and adequate inIormation regarding the measures taken in the EU
which may have a bearing on public health protection in countries outside the EU.
In addition, it should be noted that the Agency, in accordance with Article 58 oI Regulation (EC) No
726 2004, may give a scientiIic opinion, in the context oI cooperation with WHO, Ior the evaluation oI
medicinal products Ior hum
A guideline on the related procedural aspects (Guideline on Procedural Aspects regarding a CHMP
ScientiIic Opinion in the Context oI Cooperation with the World Health Organization (WHO) Ior the
Evaluation oI Medicinal Products Intended Exclusively Ior Markets Outside the Community
53
) also
addresses the conduct oI pharmacovigilance Ior such products.
This Chapter describes the principles Ior providing WHO with pharmacovigilance inIormation on
measures taken Ior medicinal products in the EU and other collaboration with WHO in the Iield oI
pharmacovigilance
54
. The Competent Authorities oI the EU Member States are members oI the WHO
Programme Ior International Drug Monitoring and should IulIil their membership obligations
accordingly (see also Chapter II.1). The principles below have been agreed between the Competent
I the EU pharmacovigilance system Ior the medicinal products authorised in
the EU.
or International Drug Monitoring. This applies to adverse reaction case reports
Ior centrally and non-centrally authorised medicinal products submitted to the Competent Authorities
r by He
6.3 Review of Signals Raised by the WHO Collaborating Centre
tre as Ieedback
inIormation Irom their case report database Vigibase. This database may be consulted by all countries
national Drug Monitoring.

Authorities and the Agency at the level oI the PhVWP, reIlecting their respective roles and
responsibilities as part o
6.2 Provision of Individual Case Safety Reports
Cases oI adverse reactions occurring in the EU should be reported to the WHO Collaborating Centre
by the Competent Authority oI the Member State in whose territory the reaction occurred, in
accordance with the agreements between the WHO Collaborating Centre and countries participating in
the WHO Programme I
eithe althcare ProIessionals or by the Marketing Authorisation Holders
55
.
Competent Authorities in Member States and, Ior centrally authorised products, the Agency, should
consider the summary document on signals provided by the WHO Collaborating Cen
participating in the WHO Programme Ior Inter

53
Doc.ReI. EMEA/CHMP/5579/04 latest version, available on EMEA website http://www.emea.europa.eu.
as WHO
Collaborating Centre.
55
Adverse reactions occurring in Luxembourg will be transmitted to the WHO Collaborating Centre by the
French Competent Authority.
54
Unless otherwise speciIied below, any inIormation is provided to the WHO Headquarters in Geneva and the
WHO Collaborating Centre Ior International Drug Monitoring in Uppsala, thereaIter reIerred to
PART II 157/229
PART II 158/229
.4 Provision of Information on Safety-Related Regulatory Action in the EU
) Centrally authorised products
its to WHO EMEA Public Statements on saIety-related regulatory action Ior
entrally authorised products prior to the embargo date. The Agency will also transmit any other
MEA Public Statements concerning centrally authorised products prior to the embargo date.
he Agency should provide responses to Vigimed
56
queries in relation to centrally authorised products
s appropriate.
b) Nationally authorised products, incl horised through the mutual recognition
or the decent
InIormation on saIe products will be
tran ch
ma are
implemented or a Public Statement or a Direct Healthcare ProIessional Communication is issued by,
or in agreement, with the Competent Authority.
For products authorised through mutual recognition or the decentralised procedure, the ReIerence
Member State is responsible Ior provision oI such inIormation on behalI oI the Concerned Member
States.
Member States or the ReIerence Member State respectively should provide responses to Vigimed
queries as appropriate.
In addition, Member States should provide any additional inIormation to WHO Ior nationally
authorised products according to requirements speciIied by national legislation and agreements.
Occasionally, the Agency issues EMEA Public Statements on saIety-related matters Ior nationally
authorised products which have been discussed at the level oI the CHMP in the context oI legal
proceedings as per Community legislation. Such inIormation will also be sent to WHO by the Agency
prior to embargo date.
6.5 Participation in the Annual Meetings of the WHO Programme for
International Drug Monitoring
Member States and the Agency should attend regularly the Annual Meetings oI the WHO Programme
Ior International Drug Monitoring, participating, as appropriate, in the exchange oI inIormation and
data on topics oI common concern and oI interest to international pharmacovigilance.
6.6 Other Collaboration
Other collaboration with WHO and their Collaborating Centres will be considered, as need arises, by
the Agency or the Competent Authorities oI Member States.

6
a
The Agency transm
c
E
T
a
uding those aut
ralised procedure
ty-related regulatory action Ior purely nationally authorised
smitted to WHO by the Competent Authority oI the Member State iI measures related to su
rketing authorisations (restrictive measures, variations, suspension, revocation, withdrawal)

56
Vigimed is an e-mail-based system Ior inIormation exchange between the countries participating in the WHO
Programme Ior International Drug Monitoring maintained by the WHO Collaborating Centre.

PART III:
Guidelines Ior Marketing Authorisation Holders,
Competent Authorities and the Agency on
Electronic Exchange oI Pharmacovigilance InIormation in the EU
159/229
1. Introduction
Part III reIlects the requirements Ior mandatory electronic reporting oI adverse reactions, save in
All applicable ICH Guidelines and Standards Ior electronic reporting oI Individual Case
exceptional circumstances, as deIined in Regulation (EC) No. 726/2004 and Directive 2001/83/EC.
During the revision oI the previous Volume 9, Part III has been updated to incorporate:
SaIety Reports (i.e. ICH-E2A, ICH-E2B(M), ICH-E2C(R), ICH-E2D, ICH-M1, ICH-M2; see
Annex 4).
The Note Ior Guidance on the Electronic Data Interchange (EDI) oI Individual Case SaIety
Reports (ICSRs) and Medicinal Product Reports (MPRs) in Pharmacovigilance during the Pre-
A/115735/2004, and Post-authorisation Phase in the European Economic Area (EEA)` (EME
adopted at EU level in September 2004, see Annex 3.1.1).
The EMEA Guidance Technical Documentation EudraVigilance Human Version 7.0
Processing oI SaIety Messages and ICSRs` (EMEA/H/20665/04, adopted at EU level in July
2004, see Annex 3.1.2).
Detailed Guidance on the European database oI Suspected Unexpected Serious Adverse
Reactions` (EudraVigilance Clinical Trial Module), (ENTR/CT4, Revision 1, adopted at EU
level in April 2004, Volume 10 oI The Rules Governing Medicinal Products in the EU,
Chapter II
57
The reco MEA proposal as endorsed
Th p

The ma
in Regu
authoris
).
mmendations oI the EudraVigilance Ad Hoc Group and E
by the Heads oI Human Medicines Agencies in February 2005 and the EMEA Management
Board in March 2005.
is u dated Part III replaces the Iollowing previous Guidelines:
Note Ior Guidance on Electronic Exchange oI Pharmacovigilance InIormation Ior Human and
Veterinary Medicinal Products in the European Union (CXMP/PhVWP/2056/99).
Note Ior Guidance on Regulatory Electronic Transmission oI Individual Case SaIety Reports
(ICSRs) in Pharmacovigilance (EMEA/H/31387/01).
ndatory electronic reporting oI adverse reactions, save in exceptional circumstances, is deIined
lation (EC) No. 726/2004 and Directive 2001/83/EC and applies to all medicinal products
ed in the European Union (EU), independent oI the authorisation procedure. For Iurther details
reIerenc
Par II
provide and electronic transmission oI Individual Case SaIety Reports
(IC s
reIerred
The sta
deIined in the Irame oI the International ConIeren
Registration oI Pharmaceu
Taking
uniIorm
is oI ut and EU guidelines. This applies in
par l

e should be made to Chapter I.2.
t I oI Volume 9A reIers to the electronic exchange oI pharmacovigilance inIormation and
s a reIerence to the preparation
SR ). It applies to national Competent Authorities, the European Medicines Agency (hereaIter
to as the Agency) and Marketing Authorisation Holders in the EU.
ndards to support the electronic transmission oI ICSRs on an expedited and periodic basis are
ce oI Harmonisation oI Technical Requirements Ior
ticals Ior Human Use (reIerred to as ICH).
into account the international dimension oI adverse reaction reporting and the need to achieve
ity and high quality with regard to content and Iormat oI ICSRs between all involved parties it
most importance that all parties Iollow the applicable ICH
ticu ar to electronic reporting, which requires strict adherence to uniIorm standards.

ble on EC website http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/index.htm
57
Availa .
PART III 160/229
Th q
are deIi
recital 5
Ele n e Iollowing electronic data interchange (EDI)
par rs
Marketi
To sup
collabo n
and data-pro
and Dir v
Assi
e re uirements Ior the electronic reporting obligations oI ICSRs on an expedited and periodic basis
ned in EU legislation Regulation (EC) No. 726/2004, Article 24(2) and Directive 2001/83/EC,
6 and Article 104(1).
ctro ic reporting oI ICSRs should be conducted by th
tne : Competent Authorities in Member States as well as Iceland, Liechtenstein and Norway,
ng Authorisation Holders and the Agency.
port the IulIilment oI these electronic reporting obligations, the European Commission, in
ratio with the Agency established EudraVigilance, the European pharmacovigilance database
cessing network as deIined in Regulation (EC) No. 726/2004, Article 26 and Article 57(d)
ecti e 2001/83/EC Article 105, with the Iollowing main objectives:
st the rapid and secure transmission oI ICSRs between all EDI partners;
Fully ective ICH and EU guidelines and standards as outlined in Chapter comply with the resp
III.2;
litate the electronic reporting by providing the necessary technical tools to the EDI
ers;
Faci
partn

Prov
a
2.
The electron
according to the Iollowing
The
Expedited Reporting`, which presents the standard deIinitions and terminology Ior key aspects
oI clinical saIety reporting and provides guidance on the appropriate mechanism Ior handling
Assist the administration and management oI ICSRs;
ide signal detection Iunctionalities and support scientiIic evaluation oI ICSRs;
blish a central repo Est sitory oI highest quality data on electronically reported adverse
reactions occurring within and outside the EU.
Applicable Electronic Reporting Guidelines
ic transmission and management oI ICSRs should be carried out by all EDI parties
Guidelines and speciIications:
ICH-E2A Guideline Clinical Data Management: DeIinitions and the Standards Ior
expedited reporting in the investigational phase (see Annex 4).
The ICH-E2B(M) Guideline Maintenance oI the ICH guideline on c linical saIety data
2000 by the ICH Steering Committee (including the Post-Step 4
management: data elements Ior transmission oI Individual Case SaIety Reports`
(recommended Ior adoption at Step 4 oI the ICH Process on 17 July 1997 and amended Ior
maintenance on 10 November
corrections agreed by the Steering Committee on 5 February 2001), CPMP/ICH/287/95
modiIication corr.), which extends the above Guideline to standardise the data elements Ior the
transmission oI all types oI ICSRs, regardless oI their source and destination (see Annex 4).
The ICH-E2B(M) Implementation Working Group Questions & Answers, Version 1.1`
(3 March 2005) (see Annex 4).
The ICH-E2C Guideline Clinical SaIety Data Management: Periodic SaIety Update Reports
Ior Marketed Drugs` (CPMP/ICH/288/95) and its Adden

dum (CPMP/ICH/4679/02), which
provides guidance on the Iormat and content oI saIety updates, which need to be provided to
regulatory authorities, at deIined intervals, aIter the medicinal products have been authorised
(see Annex 4).
The ICH-E2D Guideline Post-Approval SaIety Data Management: DeIinitions and Standards
Ior Expedited Reporting` (November 2003, CPMP/ICH/3945/03), which provides Iurther
guidance on deIinitions and standards Ior post approval expedited reporting, as well as good
case management practices (see Annex 4).
The ICH-M1 Standard Medical Dictionary Ior Regulatory Activities (MedDRA)` in the latest
version and related guidelines and Points-to-Consider Documents. The MedDRA terminology
PART III 161/229
is designed to support the classiIication, retrieval, presentation and communication oI medical
inIormation throughout the medicinal product regulatory liIe cycle (see Annex 4).
The ICH-M2 Standard Electronic Transmission oI Individual Case SaIety Reports Message
SpeciIication (ICH ICSR DTD Version 2.1)` (CPMP/ICH/285/95 modiIication), which
provides the standards Ior the saIety messages, which can contain one or more ICSRs (see
Annex 4).
The
EWG M2 Recommendation to the ICH Steering Committee Electronic Standards Ior the
endation to the ICH Steering Committee Electronic Standards Ior the
H Steering Committee Electronic Standards Ior the
ESTRI) Physical Media Recommendation DVD-
ttee Electronic Standards Ior the
TransIer oI Regulatory InIormation (ESTRI) File Format Recommendation XML
ICH Steering Committee Electronic Standards Ior the
mation TransIer Recommendation
ocabulary` (CHMP/ICH/175860/2005),
ICH-M2 Recommendations (see Annex 4):
TransIer Ior the Regulatory InIormation (ESTRI) General Recommendation Procedure
(10NOV2005)
TransIer oI Regulatory InIormation (ESTRI) General Recommendation ESTRI
Gateway (10NOV2005)
EWG M2 Recomm
TransIer oI Regulatory InIormation (ESTRI) Physical Media Recommendation Floppy
Disks (10NOV2005)
TransIer oI Regulatory InIormation (ESTRI) Physical Media Recommendation CD-R
10NOV2005
EWG M2 Recommendation to the IC
TransIer oI Regulatory InIormation (
RAM 10NOV2005
TransIer oI Regulatory InIormation (ESTRI) File Format Recommendation PDF
10NOV2005
EWG M2 Recommendation to the ICH Steering Commi
10NOV2005
EWG M2 Recommendation to the
TransIer oI Regulatory InIormation (ESTRI) InIor
EDIINT AS1 10NOV2005.
The ICH-M5 Routes oI Administration Controlled V
which provides standard terms Ior routes oI administration (see Annex 4).
The ICH-M5 Units and Measurement Controlled Vocabulary`,
(EMEA/CHMP/ICH/175818/2005), which provides standard terms Ior units and
measurements (see Annex 4).
The Standard Terms on Pharmaceutical Dosage Forms as published by the Council oI Europe
as Standard Terms on Pharmaceutical Dosage Forms, Routes oI Administration and
Containers` in the latest version.
The Note Ior Guidance on the Electronic Data Interchange (EDI) oI Individual Case SaIety
Reports (ICSRs) and Medicinal Product Reports (MPRs) in Pharmacovigilance during the Pre-
and Post-authorisation Phase in the European Economic Area (EEA)` (EMEA/115735/2004,
adopted at EU level in September 2004, see Annex 3.1.1).
The EMEA Guidance Technical Documentation EudraVigilance Human Version 7.0
Processing oI SaIety Messages and ICSRs` (EMEA/H/20665/04, adopted at EU level in July
2004, see Annex 3.1.2).
PART III 162/229
Det dverse ailed Guidance on the European database oI Suspected Unexpected Serious A
Reactions` (EudraVigilance Clinical Trial Module), (ENTR/CT4, adopted at EU level in
Apri oducts in the EU, Chapter II
58
).
e Format and Message Processing
l 2004, Volume 10 oI The Rules Governing Medicinal Pr
As technical standards are evolving over time, the above reIerence documents may require revision
and maintenance. In this context, the latest version oI these documents should always be taken into
account.
For general terms and deIinitions reIerence should be made to the relevant chapters oI the documents
listed above.
3. Messag
SaIety Messages including one or several ICSRs need to Iollow the speciIications as outlined in the
EMEA Guidance Technical Documentation EudraVigilance Human Version 7.0 Processing oI
SaIety Messages and ICSRs` (EMEA/H/20665/04, adopted at EU level in July 2004, see Annex 3.1.2).
Medicinal Product Messages including one or several medicinal product reports need to Iollow the
speciIications as outlined in the
EudraVigilance Medicinal Product Dictionary (EVMPD) Version 2.0 Technical SpeciIications
(9 November 2004, EMEA/140190/2004); and the
EudraVigilance Medicinal Product Dictionary (EVMPD) Version 2.0 Message and
Acknowledgement SpeciIications (8 December 2004, EMEA/178966/2004).
For details reIer also to Chapter III.11, Section 6.
With regard to the SaIety and Medicinal Product Report Message processing, the speciIications as
outlined in the Note Ior Guidance on the Electronic Data Interchange (EDI) oI Individual Case
SaIety Reports (ICSRs) and Medicinal Product Reports (MPRs) in Pharmacovigilance during the Pre-
and Post-authorisation Phase in the European Economic Area (EEA)` (EMEA/115735/2004, adopted
at EU level in September 2004, see Annex 3.1.1) should be Iollowed.
y Reports and Definition of
Exceptional Circumstances
ovember 2005, electronic reporting, save in exceptional circumstances, is mandatory Ior all
authorised medicinal products in the EU. Non-adherence to this requirement constitutes non-
4. Electronic Reporting of Individual Case Safet
Since 20 N
compliance with EU legislation as reIerred to in Chapter III.1.
With regard to the provisions set out in Regulation (EC) No. 726/2004, Article 24(2) and Directive
2001/83/EC, Article 104(1), exceptional circumstances` are deIined as mechanical, programme,
electronic or communication Iailures that prevent electronic reporting as described in Chapter IV oI
the Note Ior Guidance on the Electronic Data Interchange (EDI) oI Individual Case SaIety Reports
e during the Pre- and Post-
authorisation Phase in the European Economic Area (EEA)` (EMEA/115735/2004, adopted at EU
(ICSRs) and Medicinal Product Reports (MPRs) in Pharmacovigilanc
level in September 2004, see Annex 3.1.1).
Technical tools (EVWEB) have been made available by the Agency to interested EDI partners,
speciIically Small and Medium-Sized Enterprises (SMEs), to Iacilitate compliance with the electronic
reporting requirements as deIined in EU legislation. In addition, local reporting arrangements should
be discussed with the national Competent Authorities. However, with regard to the electronic

58
PART III 163/229
reporting obligations oI adverse reactions towards the Agency, these need to be maintained
independent oI any local arrangements.
In accordance with EU legislation as outlined in Chapter III.1, the national Competent Authorities in
the EU are responsible Ior electronic reporting oI adverse reactions occurring within their respective
territory to the Agency (EudraVigilance).
nd administrative data related to individual cases, which qualiIy Ior expedited and periodic
reporting, should be provided in line with ICH-E2A, ICH-E2B(M), ICH-E2D, ICH-M1, ICH-M2 and
5. Preparation of Individual Case Safety Reports and Data Privacy Laws
5.1 How to Prepare Individual Case Safety Reports
Medical a
EU guidelines and standards as reIerred to in Chapter III.2. These data should be reported
electronically in a Iully structured Iormat using all applicable and relevant E2B(M) data elements and
standard terminologies. Any supporting inIormation related to the individual case should be
suIIiciently described within an individual case saIety report (ICSR) with reIerence to the documents
that are held by the sender (ICH A.1.8.2: List oI documents held by sender`), which may need to be
provided on request.
It i icult to obtain all details on a speciIic case. However, complete
inIormation Ior an individual case, that is available to the sender, should be reported in each ICSR.
se, Iollow-up
s recognised that it is oIten diII
This applies to all types oI ICSRs, i.e. reports with initial inIormation on the ca
inIormation and cases highlighted Ior nulliIication (ICH-E2B(M) A.1.13: Report nulliIication` set to
yes` and ICH-E2B(M) A.1.13.1: Reason Ior nulliIication` completed see also Chapter III.6 on
nulliIication oI individual cases).
In accordance with the international guideline on pharmacovigilance (ICH-E2D), a case narrative, i.e.
a c p
course,
least Io ning all known relevant
clin l
clin l
evidenc
reaction
inIorma
chronol erience. Furthermore, the available inIormation should be entered in
stru r
In Iollo
provide 2B(M) Iields.
Ab v
and uni
Key inI
should ocuments held by
om lete medical description oI the case (ICH-E2B(M) B.5.1: Case narrative including clinical
therapeutic measures, outcome and additional relevant inIormation`) should be provided at
r all serious cases. This case narrative should be a medical report contai
ica and related inIormation, including patient characteristics, therapy details, medical history,
ica course oI the event(s), diagnosis, adverse reactions including the outcome, relevant laboratory
e (including normal ranges) and any other inIormation that supports or reIutes an adverse
. The narrative should serve as a comprehensive, stand-alone 'medical report. The
tion should be presented in a logical time sequence; ideally this should be presented in the
ogy oI the patient`s exp
ctu ed Iormat in the applicable ICH-E2B(M) Iields, which should be repeated as necessary.
w-up reports, new inIormation should be clearly identiIiable in the case narrative section and
d in structured Iormat in the applicable ICH-E
bre iations and acronyms should be avoided, with the possible exception oI laboratory parameters
ts.
ormation Irom supplementary records should be included in the report, and their availability
be mentioned in the narrative as well as in section ICH A.1.8.2: List oI d
sender`. Any relevant autopsy or post-mortem Iindings should also be summarised in the narrative and
related documents should be provided according to national regulation and iI allowed by the national
data privacy laws.
PART III 164/229
CIOMS V
59
. An example oI a standard narrative template is provided in
In situations where it is unclear or evident that the sender has not transmitted the complete inIormation
available on the case in an ICSR in line with the instructions provided in this chapter, the receiver may
request the sender to re-transmit the ICSR with the complete case inIormation in electronic ICH-
E2B(M) Iormat as described in Chapter III.2 within 24 hours.
This should be seen in the light oI qualitative signal detection and evaluation, where it is important Ior
the receiver to have all available inIormation on a case to perIorm the medical assessment.
The use oI EU languages in adverse reaction reporting is described in Chapter III.11, Section 5 and
Chapter I.4.
The suspect, interacting and/or concomitant active substance(s)/invented name oI the reported
medicinal product(s) should be reported in accordance with the ICH-E2B(M) and as outlined in this
Section. For combination medicinal products, which contain more than one active substance, each
active substance(s) or the invented
name, e.g. in case only the therapeutic class is reported by the primary source, or in case oI other
5.2 How to Prepare Individual Case Safety Reports Related to Parent-
1 Iields Patients characteristics` apply to the
reaction/event (other than early spontaneous
abortion/Ioetal demise) the inIormation provided in this section applies only to the
child r Iather), who was the source

active substance needs to be reIlected individually in section B.4.k.2.2 Active substance name(s)` oI
ICH-E2B(M), which needs to be repeated Ior each active substance contained in the combination
product.
Where medicinal products cannot be described on the basis oI the
administered therapies that cannot be structured, this inIormation should be reIlected in section B.5.1
Case narrative including clinical course, therapeutic measures, outcome and additional relevant
inIormation`.
Child/Foetus Cases
With regard to parent-child/Ioetus cases, the Iollowing principles should be adhered to:
In cases where a Ioetus or nursing inIant is exposed to one or several medicinal products
through the parent and experiences one or more adverse reactions/events, inIormation on both
the parent and the child/Ioetus should be provided in the same report. Reports oI these cases
are reIerred to as parent-child/Ioetus reports.
II there has been no reaction/event aIIecting the child/Ioetus, the parent-child/Ioetus report
does not apply; i.e. the ICH-E2B(M) B.1 Iields Patients characteristics` apply only to the
parent (mother or Iather) who experienced the adverse reaction/event.
For those cases describing miscarriage or Ioetal demise or early spontaneous abortion, only a
parent report is applicable, i.e. ICH-E2B(M) B.
mother. However, iI suspect medicinal product(s) were taken by the Iather this inIormation
should be indicated in the section B.4.k.13 Time intervals between drug administration and
start oI reaction/event`.
II both the parent and the child/Ioetus sustain adverse reactions, two separate reports, i.e. one
Ior the parent (mother or Iather) and one Ior the child/Ioetus, should be provided but they
should be linked by using the ICH-E2B(M) Iield A.1.12 IdentiIication number oI the report
which is linked to this report` in each report.
II only the child/Ioetus has an adverse
/Ioetus, and characteristics concerning the parent (mother o

http://www.cioms.ch/
59
Council Ior International Organizations oI Medical Sciences (CIOMS). Current Challenges in
Pharmacovigilance: Pragmatic Approaches (CIOMS V). Geneva: CIOMS; 2001. Available on CIOMS website
.
PART III 165/229
oI exposure to the suspect medicinal product should be provided in ICH-E2B(M) B.1.10
section For a parent-child/Ietus report, inIormation concerning the parent`.
) then the case should reIlect the mother`s
5.3
ICS
dep e
ICH-E2
report`
and the
each rec y whether the report being transmitted is an initial or Iollow-up report. For this
rea ritical Ior each transmission. A precise date should be used (i.e.
day, mo
This da
New in
Iormat i
The sender should report Iollow-up inIormation on an expedited basis, iI signiIicant new medical
rmation ormation relates e.g. to new adverse reaction(s), a
change in the causality assessment and any new or updated inIormation on the case that impacts on the
e also considered
as signiIicant change and thus reported on an expedited basis.
In i
adm
identiIie
(ICH-E
speciIic
E2B(M
have be y be relevant Ior the medical assessment oI the case.
In tr ,
doe o s oI dates (e.g. the
day oI t
should
implica
In e
oI the m
recent i
II both parents are the source oI the suspect drug(s
inIormation in ICH-E2B(M) B.1.10 section For a parent-child/Ietus report, inIormation
concerning the parent` and the case narrative (section B.5.1) should describe the entire case,
including the Iather`s inIormation.
How to Report Follow-up Information
Rs are sent at diIIerent times to multiple receivers. ThereIore the initial/Iollow up status is
end nt upon the receiver. For this reason an item to capture Iollow-up status is not included in the
B(M) data elements. However, the Iield date oI receipt oI the most recent inIormation Ior this
ICH-E2B(M) (A.1.7) taken together with the Iield sender identiIier` ICH-E2B(M) (A.3.1.2)
Iield sender`s (case) report unique identiIier` ICH-E2B(M) (A.1.0.1) provide a mechanism Ior
eiver to identiI
son these items are considered c
nth, year).
te should be changed each time Iollow up inIormation is received by the sender.
Iormation should be clearly identiIiable in the case narrative section and provided in structured
n the applicable ICH-E2B(M) Iields.
inIo has been received. SigniIicant new inI
medical interpretation oI the case. ThereIore, the identiIication oI signiIicant new inIormation
requiring expedited reporting always requires medical judgement.
Situations where the seriousness criteria and/or the causality assessment related to an individual case
are downgraded (e.g. Iollow up inIormation leads to a change oI the seriousness criteria Irom serious
to non-serious; causality assessment is changed Irom related to non-related) should b
add tion, the sender should also report Iollow-up inIormation on an expedited basis, where new
inistrative inIormation is available, that could impact on the case management e.g. new case
rs have become known to the sender, which may have been used in previous transmissions
2B(M) Iield A.1.11 Other case identiIiers in previous transmissions`); this inIormation may be
ally relevant Ior the receiver to manage potential duplicates. Another example reIers to ICH-
) Iield A.1.8 Additional available documents held by sender`, whereby new documents that
come available to the sender ma
con ast, non-signiIicant inIormation, which does not impact on the medical evaluation oI the case
s n t require expedited reporting. This may reIer Ior example to minor change
he birth date) or corrections oI typos in the previous case version. Naturally, medical judgment
be applied, as a change to the birth date may constitute a signiIicant change (e.g. with
tions on the age inIormation oI the patient).
thes situations where the case is amended without requiring expedited reporting, the date oI receipt
ost recent inIormation reported in the Iield ICH-E2B(M) A.1.7 Date oI receipt oI the most
nIormation Ior this report` should not be changed.
Similarly, a change oI the status oI a MedDRA code/term Irom current to non-current due to a version
change oI MedDRA can be considered as a non-signiIicant change as long as this change has no
impact on the medical content oI a case. However, a change in the MedDRA coding due to a change in
PART III 166/229
the interpretation oI a previously reported adverse reaction may constitute a signiIicant change and
thereIore should be reported on an expedited basis.
5.4 What to Take into Account for Data Privacy Laws
To comply with EU legislation on the protection oI individuals with regard to the processing oI
personal data as reIerred to in Chapter I.7, Section 7, electronic transmission oI ICSRs should operate
es oI anonymised inIormation, on the principl whereby the ICH guidelines should be adhered to as
Iollows:
ICH-E2B(M) Iield B.1.1 Patient name or initials`:
ation should be provided whe n conIormance with the conIidentiality

atient are unknown t
'UNKNOWN.
ICH-E2B(M) Iield B1.2.1 Patient birth dat
time oI the onset oI reaction/event` or ICH-E
Only one oI the elements describing age sho
most precise inIormation available and in
requirements.
Narratives in ICH-E2B(M)
When inIormation on individuals is reIlect
Relevant medical history and concurrent co
Ior the identiIication oI the
6.
In line w tion oI individual cases should be used to indicate
that a p sidered completely void (nulliIied), Ior example
when the whole case was Iound to be erroneous or in case oI duplicate reports. It is essential to use the
s e ca rt unique identiIier`
and ICH ber`) previously submitted.
A nulliI idered Ior scientiIic evaluation.
When n to be taken into account:
A.1.13 Report nulliIication` should be set to Yes` and the
.1.13.1 Reason Ior
be clear and concise to explain why this report is
port. For example a nulliIication reason stating, the

he case cannot be reactivated.
II it becomes necessary to resubmit the case that has been previously nulliIied, a new ICH-
E2B(M) A.1.0.1 Sender`s (case) saIety report unique identiIier` and ICH-E2B(M) A.1.10
Worldwide unique case identiIication number` should be assigned.
The inIorm n it is i
requirements. This also applies to medical r
the initials are known to the sender bu
requirements, this Iield should be populated w
II the initials oI the p
ecord number(s) ICH-E2B(M) Iield (B.1.1.1). II
t cannot be transmitted due to data privacy
ith 'PRIVACY.
o the sender, this Iield should be populated with
e`, ICH-E2B(M) Iield B.1.2.2 Patient age at the
2B(M) Iield B.1.2.3 Patient age group`:
uld be used. The choice should be based upon the
conIormance with the national conIidentiality
ed in narratives (e.g. ICH-E2B(M) section B.1.7
nditions` ICH-E2B(M) section B.1.10.7 Relevant
parent` ICH-E2B(M) section B.5 Narrative case
be provided in such a way that it can support the
er, but does not allow
medical history and concurrent conditions oI
summary and Iurther inIormation`), it should
case evaluation and assessment by the receiv
individual concerned. Taking the example o
age or age group in accordance with nationa
I age, no date oI birth should be provided but the
l conIidentiality requirements.
Nullification of Individual Cases
ith the ICH-E2B(M) guideline, the nulliIica
reviously transmitted report should be con
am se report number (ICH-E2B(M) Iield A.1.0.
-E2B(M) Iield A.1.10 Worldwide unique case identiIication num
ied case is one that should no longer be cons
ulliIying a case the Iollowing principles need
The Ilag ICH-E2B(M) Iield
1 Sender`s (case) saIety repo
nulliIication reason should be provided in
nulliIication`. The nulliIication reason should
no longer considered to be a valid re
the Iield ICH-EB(M) Iield A
report no longer meets the reporting criteria` or
detailed enough explanations.
An individual case can only be nulliIied by the sending organisation.
Once an individual case has been nulliIied, t
report sent previously in error` are not
PART III 167/229
Individual versions oI ICSRs cannot be nulliIied, only the individual case to which they reIer.
Individual cases that have been nulliIied should not be used Ior scientiIic evaluation, however
d remain in the database Ior auditi ses.
I ddi
remaini
this rep . name oI the company,
name o
with the
The Table below gives examples Ior diIIerent scenar
be carried out. It will also provide inIormation on wh
T LE I NS SHOULD AND
they shoul ng purpo
n a tion, in case oI duplicate reports where one
ng case should be perIormed in the Iorm oI a
ort ICH-E2B(M) Iield A.1.11.1 Source(s) o
I regulatory agency)` and ICH-E2B(M) Iiel
case identiIication numbers oI the nulliIied c
report needs to be nulliIied, the update oI the
Iollow-up report. The duplicate number Iields in
I the case identiIier (e.g
d A.1.11.2 Case identiIier(s)` should be updated
ase.
ios Ior which nulliIications should and should not
at to do in speciIic situations.
II.6.A: EXAMPLES OF DIFFERENT SCENARIO
SHOULD NOT BE CARRIED OUT
S FOR WHICH CASE NULLIFICATIO AB
1. Scenarios for which individual cases should be nullified:
Ex. Scenario Action
1 d as One oI the individual cases should be nulliIied.
levant to the
low-up report. The
liIied case.
An individual case has been identiIie
a duplicate oI another individual case
previously submitted.
The remaining valid case should be updated with
any additional inIormation as re
nulliIied case.
The update oI the remaining case should be
perIormed in Iorm oI a Iol
duplicate number Iields in this report ICH-
E2B(M) A.1.11.1 Source(s) oI the case
identiIier (e.g. name oI the company, name oI
regulatory agency)` and ICH-E2B(M) A.1.11.2
Case identiIier(s)` should be updated with the
case identiIication numbers oI the nul
2
A wrong ICH-E2B(M) A.1.10
Worldwide unique case identiIication
number` was accidentally used. This
wrong ICH-E2B(M) A.1.10 Worldwide
2B(M) A.1.10
ated based on an ICSR
unique case identiIication number did not
reIer to any existing case.
The report with the wrong ICH-E
Worldwide unique case identiIication number`
should be nulliIied.
A new case should be cre
with the correct ICH-E2B(M) A.1.10
Worldwide unique case identiIication number`.
The case should be nulliIied. 3 On receipt oI Iurther inIormation it is
conIirmed that that the adverse reaction
occurred beIore the suspect drug(s) was
taken.
The case should be nulliIied. 4 On receipt oI Iurther inIormation on an
individual case, it is conIirmed that the
patient did not receive the suspect drug
and the minimum reporting criteria Ior an
ICSR as outlined in the ICH-E2B(M)
guideline are no longer met.
5 On receipt oI Iurther inIormation it is
conIirmed that the reported adverse
reaction(s) did not occur to the patient.
The case should be nulliIied.
PART III 168/229
conIirmed that there was no valid patient
Ior the individual case minimum reporting
criteria Ior an ICSR as outlined in the
ICH-E2B(M) guideline are no longer met.
irmation oI the II it is not possible to obtain conI
patient`s existence, then the case should be
nulliIied.

2. Scenarios, for which individual cases should NOT be nullified
Ex. Scenario Action
7
A wrong ICH-E2B(M) A.1.10
Worldwide unique case identiIication
number` was accidentally used. This
wrong ICH-E2B(M) A.1.10 Worldwide
unique case identiIication number`
reIerred to an existing case.
The report with the wrong ICH-E2B(M) A.1.10
should not be nulliIied.
A Iollow-up report should be created to correct
the inIormation previously submitted.
A new ICSR should be created and submitted
with the correct ICH-E2B(M) A.1.10
Worldwide unique case identiIication number`.
8 On receipt oI Iurther inIormation on an
CSR as outlined in the
ICH-E2B(M) guideline are still met.
be nulliIied. The case should not
individual case, it is conIirmed that the
patient did not receive the MAH`s suspect
drug. However, the patient received other
suspect drugs and the minimum reporting
criteria Ior an I
conIirmed that the individual case was not
medically conIirmed.
se medically
a health
`.
The case should not be nulliIied.
A Iollow-up report should be submitted within
the appropriate timeIrame with the primary
source inIormation updated:
The Iield ICH-E2B(M) A.2.1.4 QualiIication`
should be set to Consumer or other non health
proIessional` or Lawyer` as applicable; the Iield
ICH-E2B(M) A.1.14 Was the ca
conIirmed, iI not initially Irom
proIessional?` should be set to No
10
A Iollow-up report should be submitted within
the appropriate timeIrame with the updated
inIormation on the case.
On receipt oI Iurther inIormation the
reporter has conIirmed that the reported
adverse reaction is no longer considered
to be related to the suspect drug(s).
11 Change oI the individual case Irom
serious to non-serious (downgrading).
The case should not be nulliIied. A Iollow-up
lso be set to No`.
report should be submitted with the seriousness
Ilags ICH-E2B(M) Iield A.1.5.1 Seriousness`
set to No` without selection oI a value Ior the
ICH-E2B(M) Iield A.1.5.2 Seriousness
criteria`. The Ilag ICH-E2B(M) Iield A.1.9
Does this case IulIil the local criteria Ior an
expedited report?` should a
PART III 169/229
12 The reported adverse reaction was
considered to be a post-study event (it
occu
inclu p period).
trial, a new case should be created and submitted
rred outside oI the study period,
ding Iollow-u
II the adverse reaction is no longer reportable
under the terms oI an investigational clinical
with the appropriate report type selected Ior the
Iield ICH-E2B(M) A.1.4 Type oI report`.
13 The primary source country has changed, The case should not be nulliIied.
t Iollow this policy, then the sender should
was nulliIied should be reIlected in Iields
E2B(M) A.1.11.1 Source(s) oI the case
and ICH-E2B(M) A.1.11.2
which has an impact on the ICH-E2B(M)
convention regarding the creation oI the
ICH-E2B(M) A.1.10 Worldwide unique
case identiIication number`.
The ICH-E2B(M) A.1.0.1 Sender`s (case)
saIety report unique identiIier` can be updated
on the basis oI the new primary source country
code. However, the ICH-E2B(M) A.1.10
should remain unchanged.
II, Ior some technical reason, the sender`s local
system is not Iully ICH-E2B(M) compliant and
canno
nulliIy the original case. A new case should be
created with a new ICH-E2B(M) A.1.10
reIlecting the changed primary source country
code. The ICH-E2B(M) A.1.10 Worldwide
unique case identiIication number` oI the case
that
ICH-
identiIier (e.g. name oI the company name oI
regulatory agency)`
Case identiIier(s)`.
14
se
used). The original
case and speciIy in the Iields ICH-E2B(M)
y)` and ICH-E2B(M) A.1.11.2 Case
identiIier(s)` the reIerence case number and the
The drug taken belongs to another MAH
(e.g. a product with the same active
substance but marketed under a diIIerent
invented name).
It is recommended that the initial sender inIorms
the other MAH about this case (including the
ICH-E2B(M) A.1.10 Worldwide unique ca
identiIication number`
organisation should also submit a Iollow-up
report to provide this new inIormation.
The other concerned MAH should create a new
A.1.11.1 Source(s) oI the case identiIier (e.g.
name oI the company name oI regulatory
agenc
name oI the initial sending MAH.
15
Th
the
MA
the medicinal product i
uld not be nulliIied.
llow-up report with
e suspect drug taken does not belong to The case sho
MAH (same active substance, the
The MAH should submit a Io
invented name is unknown and the report
originates Irom a country, where the
H has no marketing authorisation Ior
n question).
this inIormation (see Chapter I.4)
PART III 170/229
16 The case is mistakenly reported by MAH The case should not be nulliIied.
A although MAH B as co-marketer is
responsible Ior reporting the case.
An explanation should be sent by the MAH A to
the co-marketer MAH B that the case has
already been reported. The MAH B should
provide any additional inIormation on the case
as a Iollow-up report with the same ICH-
E2B(M) A.1.10 Worldwide unique case
identiIication number`.

7. Handling of Adverse Reaction Reports Published in the Worldwide
Literature
General requirements in relation to adverse reaction reports published in the worldwide literature are
described in Chapter I.4, Section 3.2.
When reports Irom the world-wide literature are submitted as ICSRs, the literature reIerences should
be provided in the Vancouver Convention (known as 'Vancouver style) as developed by the
International Committee oI Medical Journal Editors in the Iield ICH-E2B(M) A.2.2 Literature
reIerence(s)`. The standard Iormat as well as those Ior special situations can be Iound in the Iollowing
reIerence, which is in the Vancouver style
60
.
For initial reporting oI a case described in the literature in the Iorm oI an ICSR, a summary oI the case
in English (English abstract oI the literature article) is regarded as suIIicient to meet the expedited
reporting criteria. This case summary should be provided in the Iield ICH-E2B(M) B.5.1 Case
narrative including clinical course, therapeutic measures`.
II considered necessary, a national Competent Authority may request a Iull translation oI the copy oI
the literature article Irom the sender.
In addition to the ICSR, a copy oI the literature article should be provided. Until standards Ior the
electronic transmission oI attachments (e.g. copies oI literature articles) are developed in the Irame oI
ICH, the sender should Iollow the rules outlined below:
Mailing address and Iormat oI literature articles:
- Literature articles reportable to the Agency should be provided in PDF Iormat and sent via e-
mail to the Iollowing e-mail address: EVLITemea.europa.eu.
- Literature articles reportable to the national Competent Authorities should be provided in
PDF Iormat and sent according to the local requirements.
With regard to potential copyright issues in relation to copies oI articles Irom the worldwide
published literature, senders may wish to Iollow the non-binding recommendations Irom the
Pharma Documentation Ring (P-D-R). These recommendations apply only to the transmission
and handling oI electronic copies oI literature articles in the Irame oI regulatory activities.
File name oI literature articles sent in electronic Iormat to the Agency:
The Iile name oI a literature article sent in PDF Iormat should match exactly the World-Wide
Unique Case IdentiIication Number` (ICH-E2B(M) A.1.10.1 or A.1.10.2 as applicable)
assigned to the individual case, which is described in the article and which is reported in the
E2B(M) ICSR Iormat.

60
International Committee oI Medical Journal Editors. UniIorm requirements Ior manuscripts submitted to
biomedical journals. N Engl J Med. 1997;336:309-15. The Vancouver recommendations are also available on the
International Committee oI Medical Journal Editors website http://www.icmje.org.
PART III 171/229
II there is a Iollow-up article to the individual case published in the literature, the Iile name
with the World-Wide Unique Case IdentiIication Number must be maintained but should
Exam
ICSR: FR-ORGABC-23232321 (ICH-E2B(M) Iield A.1.10.1 World-Wide Unique Case
dentiIication Number);
232
or
n one patient, the
copy oI the literature article should
The Iile name oI a literatu orld-Wide
Unique Case IdentiIication Num
assigned to the Iirst reportable individ
In addition, all ICSRs which relate to ed in
the section ICH-E2B(M)
this report` and the section should
See Table below Ior an example Ior th dwide literature
reIerring to more than one patient.
include a sequence number separated with a dash.
ple:
I
File name: FR-ORGABC-2323
Follow-up inIormation published
ICSR: FR-ORGABC-23232321
IdentiIication Number remains
File name: FR-ORGABC-2323
Reporting oI cases reported in the w
When the worldwide literat
2321.pdI.
in the literature in a separate article:
(ICH-E2B(M) Iield A.1.10.1 World-Wide Unique Case
unchanged);
1-1.pdI.
ldwide literature reIerring to more than one patient:
ure article reIers to the description oI more tha
be sent only once.
re article sent in PDF Iormat should match exactly the W
ber` (ICH-E2B(M) Iield A.1.10.1 or A.1.10.2 as applicable)
ual case described in the article.
be cross reIerenc the same literature article should
Iield A.1.12 IdentiIication number oI the report which is linked to
be repeated as necessary to cross reIer all related cases.
ted in the worl e reporting oI cases repor
PART III 172/229
PART III 173/229

TABLE III.7.A: EXAMPLE FOR THE REPORTING OF CASES ORIGINALLY REPORTED IN THE WORLDWIDE
LITERATURE REFERRING TO MORE THAN ONE PATIENT
Example Action
A literature article describes serious
adverse reactions that have been
experienced by 3 patients. For this
scenario 3 ICSRs should be submitted,
reporting Ior each ind
For Case 1 described in the literature article:
ICH-E2B(M) A.1.10.1 World-Wide Unique Case
IdentiIication Number`:
UK-ORGABC-0001
ividual patient
the adverse reactions and all other
ICH-E2B(M) A.1.12 Linked Report:
N Engl J Med. 1997;336:309-15.
available inIormation on the case.
UK-ORGABC-0002
UK-ORGABC-0003
ICH-E2B(M) A.2.2 Literature reIerence(s):
Literature reIerence in line with uniIorm requirements
Ior manuscripts submitted to biomedical journals:
File name Ior the copy oI literature article to be sent
via e-mail to EVLITemea.europa.eu:
UK-ORGABC-0001.pdI
Unique Case
BC-0002
.
le required since the
submitted Ior case 1.
copy was already submitted Ior case 1.
ICH-E2B(M) A.1.10.1 World-Wide
UK-ORGA
UK-ORGABC-0001
UK-ORGABC-0003
N Engl J Med. 1997;336:309-15
literature artic No copy oI the
copy was already
ICH-E2B(M) A.1.10.1 World-Wide Unique Case
UK-ORGABC-0003
UK-ORGABC-0001
UK-ORGABC-0002
N Engl J Med. 1997;336:309-15.
No copy oI the literature article required since the

8. Compliance with Required Reporting Timeframes
Marketing Authorisation Holders and Competent Authorities in Member States as well as Iceland,
Liechtenstein and Norway should ensure that the timeIrames regarding the expedited reporting
requirements as deIined in EU legislation and in Chapter I.4, Section 2 are adhered to.
Fal c
Ior Gui
Medicin
in the E onomic Area (EEA)` (EMEA/115735/2004, adopted at EU level in September
l-ba k procedures in case oI system Iailure Ior electronic case reporting are described in the Note
dance on the Electronic Data Interchange (EDI) oI Individual Case SaIety Reports (ICSRs) and
al Product Reports (MPRs) in Pharmacovigilance during the Pre- and Post-authorisation Phase
uropean Ec
2004, see Annex 3.1.1).
re-transmission oI cases reIers to the electronic transmission oI ICSRs between
multiple senders and receivers, e.g. where a case was Iirst reported by a Marketing Authorisation
nd Norway
and Irom there to the Agency.
Based on the reporting obligations in pharmacovigilance, ICSRs are re-transmitted between diIIerent
ntiIier` (ICH-E2B(M) A.1.0.1);
on` (ICH-E2B(M) A.1.3);
.1.7);
Relatedness oI drug to reaction(s)/event(s) (ICH-E2B(M) section B.4.k.18: repeat B.4.k.18.1
thro
Send osis/syndrome and/or reclassiIication oI reaction/event (ICH-E2B(M) Iield
B.5.3);
e to the ICH-E2B(M) rules regarding the provision oI
Iollow-up inIormation, i.e. the Worldwide unique case identiIication number` (ICH-E2B(M) A.1.10)
ided.
as Iceland,
h the reporting rules deIined in EU legislation. II
electronic reporting oI the ICSRs (e.g. reporting
thro h th uarters), it is the Marketing Authorisation Holder`s (e.g. the local
aIIi e) r re submitted electronically to the Competent Authority
ica
he Iollowing should be taken into account:
9. Electronic Re-transmission of Cases between Multiple Senders and Receivers
The electronic
Holder to the Competent Authorities in Member States as well as Iceland, Liechtenstein a
senders and receivers. During this re-transmission process, inIormation on the case should not be
omitted or changed iI no new inIormation on the case is available to the re-transmitting sender.
Exceptions are the Iollowing:
Sender`s (case) saIety report unique ide
Date oI this transmissi
Date report was Iirst received Irom source` (ICH-E2B(M) A.1.6) Ior initial reports;
Date oI receipt oI the most recent inIormation Ior this report` (ICH-E2B(M) A
Sender and receiver details (ICH-E2B(M) A.3: InIormation on sender and receiver oI case
saIety report`);
ugh B.4.k.18.4 as necessary);
er's diagn
Sender`s comments (ICH-E2B(M) Iield B.5.4: Sender's comments`);
English translation oI the Iree text Iields in the ICSRs.
In addition, any EDI partner should adher
should be maintained in accordance with the ICH-E2B(M) guideline. Non-adherence to these
administrative requirements endangers the electronic case management, leads to unnecessary
duplication oI reports at the receiver`s database and should thereIore be avo
10. Electronic Reporting through Companys Headquarters
The Marketing Authorisation Holder`s QPPV should ensure that all ICSRs are submitted
electronically to the relevant Competent Authorities in Member States as well
Liechtenstein and Norway and the Agency in line wit
a p mac ides to centralise the har eutical company dec
pany`s headq ug e com
liat esponsibility to ensure that ICSRs a
ppl ble. as a
T
PART III 174/229
The arrangement should be clearly speciIied in the Marketing Authorisation Holder`s internal
ion Holder
nt Ior all pharmacovigilance-related matters and
U
11. or the Electronic Reporting to EudraVigilance
11.1 ase Modules
Standard Operating Procedures (SOPs).
The Agency and the Competent Authorities in the EU should be notiIied in writing about the
arrangement (a template is available at the EudraVigilance website).
The Marketing Authorisation Holder should be registered with EudraVigilance.
Whoever is the physical sender oI the electronic ICSRs, the Marketing Authorisat
(i.e. local aIIiliate) will remain the contact poi
responsible Ior the compliance with the pharmacovigilance obligations as deIined in E
legislation.
For the reporting Irom the Competent Authorities in the EU to the Marketing Authorisation Holder,
the same principles apply, i.e. Competent Authorities in Member States as well as Iceland,
Liechtenstein and Norway report electronically to the address oI the headquarters instead oI that oI the
local aIIiliate.
Specific Provisions f
EudraVigilance Datab
On the basis oI the requirements deIined in EU legislation to set up a data-processing network and a
pharmacovigilance database as described in Chapter III.1, two EudraVigilance modules Ior medicinal
products Ior human use were established to address the collection oI the diIIerent types oI adverse
reactions reportable in the Irame oI the EU pharmacovigilance activities.
ective 2001/20/EC and implementing texts).
These modules are as Iollows:
EudraVigilance Post-Authorisation Module (EVPM) (in line with the requirements as deIined
in Regulation (EC) No. 726/2004, Directive 2001/83/EC and EU guidelines);
EudraVigilance Clinical Trial Module (EVCTM) (in line with the requirements deIined in
Dir
11.1.1 Adverse Reaction Data Collected in EudraVigilance Post-Authorisation
Module
DiIIerent types oI adverse reaction reports related to all medicinal products authorised in the EU (see
Chapter I.2, Legal Framework Ior Pharmacovigilance) are currently collected in the EudraVigilance
Post-Authorisation Module based on the reporting obligations oI national Competent Authorities and
Marketing Authorisation Holders in the EU.
The reporting obligations oI Marketing Authorisation Holders with regard to the Agency/EVPM are
described in Chapters I.4 and I.5. The reporting obligations oI national Competent Authorities with
reg t
Th v
interventional studies. R
ard o the Agency via EVPM are described in Chapter II.1, Section 6.1.
e ad erse reaction reports collected in EVPM reIer to spontaneous reports and reports Irom non-
eports that need to be prepared in relation to the reporting in special situations
(as described d be also submitted to EVPM. Depending on their nature, these
Spontaneous report
Other
Not available to sender (unknown)
Or
in Chapter I.5 shoul
reports should be classiIied according to ICH-E2B(M) as one oI the Iollowing categories:
Category I: ICH-E2BM) Iield A.1.4 Type oI report:

PART III 175/229

Category II: ICH-E2BM) Iield A.1.4 Type oI report:
compassionate use or named-patient basis),
- Other studies (e.g. pharmacoepidemiology, pharmacoeconomics, intensive
All suspected unexpected serious adverse reactions (SUSARs) related to Investigational Medicinal
(EVCTM). These reports should be classiIied according to ICH-E2B(M) as the
Iol in
Categor

The reportin ons oI sponsors oI clinical trials concerned with the monitoring oI adverse
Report Irom study and
ICH-E2B(M) Iield A.2.3.3 Study type in which the reaction(s)/event(s) where observed`
relates to
- Individual patient use; (e.g.
monitoring, PMS, etc.).
11.1.2 Adverse Reaction Data Collected in EudraVigilance Clinical Trial Module
Products (IMPs) studied in interventional clinical trials, are collected in the EudraVigilance Clinical
Trial Module
low g category:
y: ICH-E2BM) Iield A.1.4 Type oI report:
Report Irom study and
ICH-E2B(M) Iield A.2.3.3 Study type in which the reaction(s)/event(s) where observed`
relates to Clinical Trials.
g obligati
reactions occurring in clinical trials with IMPs are outlined in Directive 2001/20/EC and the related
implementing texts and do not Iall within the scope oI pharmacovigilance activities as described in
these Guidelines (see Chapter I.2).
To avoid duplicate reports in EVCTM, only the sponsor oI the clinical trial in the EU should report all
SUSARs electronically to EVCTM in line with the Detailed Guidance on the European Database oI
Suspected Unexpected Serious Adverse Reactions (EudraVigilance Clinical Trial Module)`
(ENTR/CT4, Volume 10 oI The Rules Governing Medicinal Products in the EU, Chapter II
61
),
adopted at EU level in April 2004. This includes electronic reporting oI 3
rd
country (non-EU)
SUSARs.
11.2 Data Quality of Individual Case Safety Reports Transmitted Electronically
EudraVigilance should contain all reports oI adverse reactions reportable according to EU legislation
to support pharmacovigilance activities and the European Risk Management Strategy. This applies to
all medicinal products, i.e. IMPs or authorised medicinal products regardless oI the authorisation
procedure.
In addition, EudraVigilance should be based on the highest internationally recognised data quality
standards. To achieve these objectives, all Competent Authorities in Member States as well as Iceland,
Liechtenstein and Norway and Marketing Authorisation Holders should Iully adhere to:
The electronic reporting requirements as deIined in EU legislation;
The concepts oI data structuring, coding and reporting in line with the guidelines and
standards reIerred to in Chapter III.2 and the principles outlined in Chapters III.3 to Chapter
III.11.
This is a pre-requisite to establish a properly Iunctioning European pharmacovigilance system
(EudraVigilance) intended to support the European Risk Management Strategy.

61
PART III 176/229
11.3 Reporting of all Serious Cases from outside the European Union
According to Directive 2001/83/EC and Regulation (EC) No 726/2004, the Marketing Authorisation
Holder is required to report all suspected serious unexpected adverse reactions that occur in third
countries on an expedited basis to the Agency and to all national Competent Authorities in the EU and
where the medicinal product is authorised.
However, Ior non-centrally authorised medicinal products, Marketing Authorisation Holders
exp e
decide i Iact that Ior non-centrally authorised
tual recognition procedures).
11.4 EudraVigilance Post-Authorisation
The ret
eIIort between all invo y, agreed
eri nce problems to determine the expectedness Ior serious cases Irom outside the EU and to
I the case is reportable to the Agency. This is due to the
medicinal products the SPCs vary in the diIIerent Member States.
To Iacilitate the overall reporting process to the Agency, Marketing Authorisation Holders are
encouraged to
report electronically to EudraVigilance all suspected serious adverse reactions that occur in a
third country, Ior all medicinal products authorised in the EU, regardless oI the authorisation
procedure (national, centralised, decentralised or mu
Retrospective Electronic Population of
Module
rospective population oI EudraVigilance has to be seen in the light oI the best collaborative
lved stakeholders to support the European Risk Management Strateg
by the Heads oI Human Medicines Agencies ('Implementation oI the Action Plan to Further Progress
the European Risk Management Strategy: Rolling Two-Year Work Programme (Mid 2005 Mid
2007)
62
), and the protection oI public health. It is an eIIort to retrospectively populate the system
electronically with the ICSRs that were reportable to the Agency during the post-authorisation phase
in line with EU legislation since 1 January 1995
63
(the date when the Agency was established).
Furthermore,
Regulation (E
the retrospective population oI EVPM is considered vital in the context oI Article 28 oI
C) No 726/2004.
rts oI serious cases and non-interventional studies Irom within or outside
To start with ICSRs that occurred since 1 January 1995, which have not been submitted yet
elec ed
to c cts and mutually recognised medicinal products; as a
next step ICSRs related to suspected serious adverse reactions Ior other nationally authorised
For cases published in the worldwide literature, it is not required to provide a copy oI the
nationally authorised products that are no longer
A phased approach should be Iollowed in the retrospective population oI EudraVigilance Post-
Authorisation Module (EVPM) based on the Iollowing principles:
All spontaneous repo
the EU (without the need to reassess expectedness according to the current Summary oI
Product Characteristics) should be submitted based on the responsibilities outlined below:
tronically in the ICH-E2B(M) Iormat involving suspected serious adverse reactions relat
entrally authorised medicinal produ
medicinal products should be provided;
Only the most recent version oI the case report should be transmitted electronically;
original literature article;
It is not required to transmit cases involving
authorised in the EU;

62
Doc.ReI.: EMEA/372687/2005, available on EMEA website http://www.emea.europa.eu.
63
Regulation (EC) No 726/2004 and Directive 2001/83/EC.
PART III 177/229
Unless otherwise speciIied in contractual agreements between partners, all the cases involving
tional trials that occurred in their territory. Where no electronic reports

divested marketed medicinal products should be transmitted by the current Marketing
Authorisation Holder.
From a practical point oI view, the retrospective population oI EudraVigilance should be achieved as
Iollows:
National Competent Authorities in the EU should provide all spontaneous reports oI serious
cases and non-interven
or only limited data are available in structured Iormat by national Competent Authorities,
those national Competent Authorities should see to it that the data are entered in
EudraVigilance.
Marketing Authorisation Holders should provide all spontaneous reports oI serious cases and
non-interventional studies that occurred outside the EU.
With regard to the Member States that joined the EU in May 2004, Marketing Authorisation
Holders should provide all spontaneous reports oI serious cases and non-interventional studies
Ior the period 1 January 1995 to 1 May 2004.
w the recommendations outlined in Chapter III.11, The handling oI EU languages should Iollo
Section 5. In order to maintain homogeneity in the database and to Iacilitate signal detection,
ICSRs should preIerably be transmitted in English.
ICSRs already reported electronically to EudraVigilance should not be included as part oI the
retrospective data transmission.
All Marketing Authorisation Holders and national Competent Authorities in the EU are
requested to take the necessary steps to ensure that the complete retrospective population oI
EudraVigilance is completed no later than 1 February 2008.
context it needs to be recognised that the retrospectively transmitted data may vary Irom the
inIormation submitted on expedited basis in accordance with EU legislation at the time the
s initially reported, Ior example due to the conversion oI the legacy data

In this
original
case wa to the ICH-E2B(M)
and M1 n rospectively to populate EudraVigilance should
not be used
compliance.
The retrosp
sta dards. As a result, the data submitted ret
Ior retrospective pharmacovigilance inspections and checking oI previous reporting
ective electronic population oI the EudraVigilance Post-Authorisation Module should
Iollow the applicable ICH standards and guidelines reIerred to in Chapter III. 2. As a general principle,
the inIo uld be provided in the ICSR Iormat based on the
ICH
The technical speciIications regarding the retrospective transmission rules are described in
rmation available on the case to the sender sho
-E2B(M) data elements.
Chapter III.11, Section 4.1.
11.4.1 Retrospective Electronic Population of EudraVigilance Post-Authorisation
Module: Transmission Rules
The ICSRs to be transmitted in the Irame oI the retrospective population oI EudraVigilance (see
Chapter III.11, Section 4) should Iollow the ICH and EU guidelines and standards as described in
Chapter III.2 including the medical inIormation coded in MedDRA.
The retrospectively transmitted ICSRs need to be clearly Ilagged in EudraVigilance to exclude these
reports Irom expedited reporting compliance checks.
PART III 178/229
To achieve a consistent Ilagging oI these ICSRs, the ICH-E2B(M) message header Iield M.1.1
(Message Type`) should include the speciIication backlog` instead oI ichicsr`. The Iield value is
case-sensitive and should be reported in lower case.
ll not be applied.
All backlog` messages should be addressed to the message receiver identiIier EVHUMAN`.
The Iollowing rules will be applied to the ICSR transmissions Ilagged according to this rule:
The 15-day (expedited) reporting compliance, as set out in EU legislation, wi
The business rules will be applied in line with the EMEA Guidance Technical Documentation
EudraVigilance Human Version 7.0 Processing oI SaIety Messages and ICSRs`
(EMEA/H/20665/04, adopted at EU level in July 2004, see Annex 3.1.2).
th a MedDRA ICH-E2B(M) Iields requiring MedDRA coding will accept MedDRA LLTs wi
version 4.0 or higher.
The inIormation provided in the ICSRs related to the retrospective population oI the
EudraVigilance system, should Iollow the speciIications outlined in Chapters III.2 to III.11.
Backlog messages` should not contain more than 100 retrospective ICSRs.
The sender oI retrospectively transmitted ICSRs as described in Chapter III.11, Section 4
should perIorm some initial testing with the Agency, using the EudraVigilance test system
r Ior
ia physical media in line with the
ospective ICSRs
n and return oI acknowledgement messages Ior retrospectively
g` Iollows the ICH-E2B(M)/M2 standards reIlecting as message
practice this should be handled as Iollows:
Loaded) in the saIety messages; only those ICSRs with the acknowledgement code 02,
corrected saIety message.
The E2B(M) concept is based on the Iact that structured and coded inIormation in the ICSRs is used
ICH-E2B(M) B.5: Narrative case summary and Iurther inIormation` is
normally required.
(EVTEST) beIore transmitting the retrospective ICSRs to the EudraVigilance production
environment.
The retrospective ICSRs should be transmitted through the EudraVigilance Gateway o
non-gateway users by means oI EVWEB.
Alternatively, retrospective ICSRs can be transmitted v
applicable ESTRI recommendations (Iloppy disks, CD-R, DVD).
The Agency will return acknowledgement messages to the sender oI the retr
always via the EudraVigilance Gateway, independent oI the media used Ior the ICSR
transmission. The Agency gives priority in the processing oI messages to expedited ICSRs. As
a result, the generatio
transmitted ICSRs may take longer than two business days. The acknowledgement message
Ior the message type backlo
type backlog`. The sender is requested by the Agency to retransmit saIety messages and
ICSRs in case oI a transmission ACK code 02 or 03 Iollowing the receipt oI the
acknowledgement message. In
ICH-E2B(M) Iield A.1.6 ACK code 02:
ICSR Error, not all reports loaded into the database; reIer to the acknowledgement code
Ior the reports (ICH-E2B(M) B.1.8 01 Report Loaded SuccessIully; 02Report Not
which caused the error at message acknowledgement level, need to be corrected and re-
transmitted.
XML parsing error, no data extracted: all the ICSRs need to be transmitted again via a
11.5 Handling of Languages
Ior data outputs oI pharmacovigilance systems (e.g. listings) and Ior signal detection. However, Ior
scientiIic case assessment and signal evaluation, the medical summary provided in the case narrative
Iields, speciIically in section
PART III 179/229
Taking into account the international dimension oI pharmacovigilance, English translations oI ICSRs
ed by the Marketing Authorisation Holders. M are perIorm arketing Authorisation Holders should
thereIore report ICSRs to EudraVigilance and national Competent Authorities in English. In addition
The summary should Iocus on the most relevant medical inIormation applicable to the case and
can report case
narratives to EudraVigilance and to the Marketing Authorisation Holders in the national language. For
-E2B(M) A.1.8.2: List oI documents held by sender`. These documents should only be
translated iI requested by the receiver.
edicinal Product Dictionary
necessary to permit
roducts in ICSRs is to ask all Marketing
ications:
EudraVigilance Medicinal Product Dictionary (EVMPD) Version 2.0 Message and

Eud Forms Documentation, 31 January
e documents may require revision and
ma n should always be taken into
acc t
With re
MAH with
medicinal p
procedures a
to the English summary, the original verbatim text in the local language may be maintained in the
ICH-E2B(M) B.5.1 Case narrative including clinical course, therapeutic measures, outcome and
additional relevant inIormation`.
required Ior the case assessment.
Competent Authorities in Member States as well as Iceland, Liechtenstein and Norway
these reports, Competent Authorities should provide case translations in the English language when
requested by the EMEA or other national Competent Authorities Ior the evaluation oI potential
signals. Such translation must be provided within 24 hours or the next working day.
Additional documents held by the sender, which may be only available in a local language, should be
listed in ICH
11.6 Population of the EudraVigilance M
The population oI the EudraVigilance Medicinal Product Dictionary (EVMPD) is
the correct identiIication oI medicinal products, related to adverse reactions reported in line with the
reporting obligations set out in EU legislation, as well as data analysis and signal detection. The best
way oI achieving the correct identiIication oI medicinal p
Authorisation Holders to enter each medicinal product Ior which they hold a marketing authorisation
within the EU, in the EudraVigilance Medicinal Product Dictionary (EVMPD).
From a practical point oI view, Marketing Authorisation Holders are thereIore requested by national
Competent Authorities and the Agency to enter inIormation on the medicinal products, Ior which they
hold a license in the EU, in the EVMPD in line with the Iollowing guidelines and speciI
EudraVigilance Medicinal Product Dictionary (EVMPD) Version 2.0 Technical
SpeciIications, 9 November 2004 (EMEA/140190/2004).

Acknowledgement SpeciIications, 8 December 2004 (EMEA/178966/2004).
EudraVigilance (EV) Access Simple Database Version 2.0 8 November 2004
(EMEA/140327/2004).
raVigilance (EV) Access Simple Database Version 2.0
2005, (EMEA/35416/2005).
EudraVigilance (EV) Access Simple Database Version 2.0 Step by Step Guide, 8 December
2004, (EMEA/191986/2004).
As technical standards are evolving, the above reIerenc
inte ance. In this context, the latest version oI these documents
oun .
gard to the timeIrames Ior the population oI the EVMPD, a timetable can be discussed by the
the Agency. As a general principle, priority should be given to centrally authorised
roducts, medicinal products authorised through the mutual recognition or decentralised
nd other nationally authorised medicinal products, Ior which ICSRs are reportable.
PART III 180/229
In addition, the MAH should attempt, where possible, to provide the EVMPD medicinal product data
to the Agen pter III.11, cy beIore the retrospective electronic transmission oI ICSRs in line with Cha
Section 4.
The EVMPD is also a Iundamental component oI the EudraVigilance system Ior signal detection and
data analysis. ThereIore medicinal product data should be submitted concomitantly to the submission
11.7
In
should
and nat t Authorities in the EU. The requirements Ior the preparation oI PSURs are
oI a Risk Management Plan.
Periodic Transmission of Individual Case Safety Reports not Transmitted on
an Expedited Basis in Electronic Format
line with Regulation (EC) No. 726/2004, Article 24 (3), Periodic SaIety Update Reports (PSURs),
be transmitted Ior centrally authorised medicinal products at deIined intervals to the Agency
ional Competen
des e
The obj
describe n
analysis e independently.
To il ed
me n
com o
ele n
product
applicab
Fro a
transmi
crib d in Chapter I.6.
v ecti e oI the periodic transmission oI ICSRs is to obtain a complete set oI adverse reactions as
d i the PSUR line listings. These data, which are used to Iacilitate the data review and
, ar submitted complementary to the PSUR, which is assessed
Iac itate the scientiIic evaluation oI the saIety data as reIerred to in PSURs Ior centrally authoris
dici al products, it is important to collect this inIormation in one common repository and one
m n Iormat. ThereIore, Marketing Authorisation Holders are encouraged to conduct a periodic
ctro ic transmission oI these suspected adverse reaction data Ior centrally authorised medicinal
s to EudraVigilance in the Iormat oI ICSRs (hereaIter reIerred to as periodic ICSRs) as
le.
m practical point oI view, the Iollowing principles should be taken into account Ior the
ssion oI periodic ICSRs in electronic Iormat:
Periodic ICSRs should be transmitted Ior Centrally Authorised Products.
Periodic ICSRs (initial and Iollow-up) should be transmitted at regular intervals by the
Marketing Authorisation Holder but at the latest at the time oI submission oI the PSUR in line
with the time Irames deIined in the EU legislation.
Transmissions oI periodic ICSRs should include all suspected adverse reactions reportable in a
PSUR, which are/were not transmitted on expedited basis in electronic Iormat to EVPM or
EVCTM. Taking into account that the MAH is requested to annex also medically unconIirmed
spontaneous reports that originate with Consumers or other non-health care proIessionals,
these should be included systematically in the transmission oI periodic ICSRs.
Transmissions oI periodic ICSRs should exclude:
all suspected adverse reactions reportable in a PSUR, that were reported on expedited
basis by the Marketing Authorisation Holder to EVPM or EVCTM (see Chapter III.11,
Sections 1.1 and 1.2);
all suspected serious adverse reactions that occur in the EU (they are reportable by the
national Competent Authorities to the Agency in line with EU legislation); and
all SUSARs and suspected serious adverse reactions (SARs) that relate to interventional
clinical trials and which have been reported electronically in the Irame oI Directive
2001/20/EC and the implementing texts to EVCTM.
In case oI the submission oI several PSURs Ior the same medicinal product (e.g. Ior diIIerent
ral active substances, Ior product authorised to more indications, Ior the combinations oI seve
than one MAH), the MAHs should ensure that the periodic ICSRs are transmitted only once in
electronic Iormat to EudraVigilance (see Chapter I.6, Sections 2.2 and 2.3 Ior the
Requirements Ior Periodic SaIety Update Reports).
PART III 181/229
Periodic ICSRs should be reported to EVPM iI they qualiIy as:
Spontaneous reports`, Others` or Not available to the sender` (see ICH-E2B(M) A.1.4);
B(M) A.1.4) and Report Irom study` (see ICH-E2 the Study type in which the
iology, pharmacoeconomics, intensive monitoring, PMS, etc.);
Periodic ICSRs should be reported to EVCTM iI they qualiIy as:
Report Irom study` (see ICH-E2B(M) A.1.4) and
reaction(s)/event(s) were observed` (ICH-E2B(M) A.2.3.3) is Individual patient use`
(e.g. compassionate or named-patient basis) or Other studies`
(e.g. pharmacoepidem
the Study type in which the
reaction(s)/event(s) were observed` (ICH-E2B(M) A.2.3.3) is Clinical trials`.
11.7.1 Periodic Transmission of Individual Case Safety Reports in Electronic
Format
With regard to the transmission rules oI periodic ICSRs as outlined above in this Chapter, the
Iollowing principles should be adhered to:
Periodic ICSRs should reIer to an active substance or a combination oI active substances as
reportable in the relevant PSUR (ICH-E2B(M) Iield B.4.k.2.2 Active substance name(s)`).
The case inIormation available to the sender should be submitted in Iully structured Iormat as
ICSRs using the ICH-E2B(M) data elements and other applicable standards as outlined in
Chapter III.2.
Periodic ICSRs should Iollow the message speciIications as outlined in Chapter III.3. The
Iield Message Type (ICH-M2: M.1.1) should display the value:
'psur Ior ICSRs related to spontaneous reports and reports Irom non-interventional
studies;
'ctasr Ior ICSRs related to interventional clinical trials.
All 'psur messages should be addressed to the message receiver identiIier EVHUMAN`.
All 'ctasr messages should be addressed to the message receiver identiIier EVCTMPROD`.
The business rules are applied as speciIied in the The EMEA Guidance Technical
Documentation EudraVigilance Human Version 7.0 Processing oI SaIety Messages and
ICSRs` (EMEA/H/20665/04, adopted at EU level in July 2004, see Annex 3.1.2).
ICH-E2B(M) Iields requiring MedDRA coding accept MedDRA LLTs with MedDRA version
4.0 or higher. Senders are encouraged to use the latest version oI MedDRA.
Periodic ICSRs should be transmitted through the EudraVigilance Gateway or Ior non-
gateway users by means oI EVWEB.
Alternatively, periodic ICSRs can be transmitted via physical media in line with the applicable
ESTRI recommendations (Floppy Disks, CD-R, DVD).
The sender oI periodic ICSRs as described above in this Chapter should perIorm some
initial testing with the Agency, using the EudraVigilance test system EVTEST regarding
periodic ICSRs to be transmitted to EVPM and the EudraVigilance test system EVCTMTEST
regarding periodic ICSRs to be transmitted to EVCTM.
'psur and 'ctasr messages should not contain more than 100 periodic ICSRs.
EudraVigilance will return an acknowledgment message Ior each 'psur or 'ctasr message. The
Agency will always return acknowledgement messages to the sender oI the periodic ICSRs via the
EudraVigilance Gateway, independent oI the media used Ior the ICSR transmission. The Agency
gives priority in the processing oI saIety messages related to expedited ICSRs. As a result, the
generation and return oI acknowledgement messages Ior periodic transmitted ICSRs may take longer
than two business days. The acknowledgement message Ior the message type 'psur or 'ctasr Iollows
PART III 182/229
PART III 183/229
e ICH-E2B(M)/M2 standards reIlecting as message type 'psur or 'ctasr as applicable. The sender
requested by the Agency to retransmit saIety messages and ICSRs in case oI a transmission ACK
ode 02 or 03 Iollowing the receipt oI the acknowledgement message. In practise this should be
andled as Iollows:
ICSR Error, not all reports loaded into the database; reIer to the acknowledgement code Ior the
reports (ICH-E2B(M) B.1.8 01 Report Loaded SuccessIully; 02Report Not Loaded) in the
saIety messages; only those ICSRs with the acknowledgement code 02, which caused the error
at message acknowledgement level, need to be corrected and re-transmitted.
XML parsing error, no data extracted: all the ICSRs need to be transmitted again via a
th
is
c
h
corrected saIety message.

PART IV:

Guidelines Ior Marketing Authorisation Holders
and Competent Authorities on Pharmacovigilance Communication
184/229
1. Introduction
In addition to the guideline 'Direct Healthcare ProIessional Communications it is anticipated that
Iurther guidance Ior marketing authorisation holders and competent authorities on pharmacovigilance
communication will be developed. Any new guideline will be subject to public consultation.

PART IV 185/229
2. Direct Healthcare Professional Communications
2.1 Introduction
The aim oI this guidance is to establish principles Ior the content and Iormat oI Direct Healthcare
ith medicinal products are
outside the scope oI this guidance.
Dir egulation (EC) No 726/2004 impose requirements on Competent
Authorities in Member States and the European Medicines Agency ('the Agency) Ior communication
medicinal products.
ProIessional Communications (DHPCs) (commonly called 'Dear Doctor-letters (DDL)), as well as
describing situations where dissemination oI DHPCs should be considered. The guidance also aims to
describe the main requirements and procedures Ior such communications on the saIe and eIIective use
oI medicinal products Ior human use. DHPCs relating to quality deIects w
ective 2001/83/EC and R
to the public on matters relating to pharmacovigilance and the saIe use oI
In addition, such communication is considered as part oI the risk management process (see
Chapter I.3).
2.2 Definition of Direct Healthcare Professional Communication
A Direct Healthcare ProIessional Communication (DHPC) is deIined as inIormation aimed at ensuring
Healthcare ProIessionals). Such DHPCs should not
roducts
Th l
general
supports

saIe and eIIective use oI medicinal products which is delivered directly to individual Healthcare
ProIessionals by a Marketing Authorisation Holder, or by a Competent Authority (this excludes direct
personal replies to requests Irom individual
include any material or statement which might constitute advertising within the scope oI Title VIII oI
Directive 2001/83/EC, or which is considered to be promotional or commercial by the Competent
Authority.
2.3 Key Principles for Public Communication on Medicinal P
e Io in low g key principles should be considered Ior public communication on medicinal products in
and by means oI DHPCs in particular:
Provision oI inIormation about the saIe and eIIective use oI medicinal products
appropriate use and should be considered as a public health responsibility.
Communication oI such inIormation needs to be considered throughout the risk management
process (see Chapter I.3).
It is essential that such inIormation is communicated to Healthcare ProIessionals and relevant
partners including Patient and Healthcare ProIessional organisations, learned societies and
tion to Patients and the general public is
the right message is delivered to the right

pharmaceutical wholesalers.
In principle, signiIicant new or emerging inIormation should be brought to the attention oI
Healthcare ProIessionals beIore the general public, in order to enable them to take action and
respond to Patients adequately and promptly. The important Iunction oI Healthcare
ProIessionals in disseminating such inIorma
recognised and should be supported.
The overriding principle should be to ensure that
persons at the right time.
EIIective communication on saIe and eIIective use oI medicinal products authorised in the
European Union (EU) entails:
co-operation oI all partners;
co-ordination between relevant partners, within and, iI possible, outside the EU; and
PART IV 186/229
a strategy which meets the requirements resulting Irom the urgency to communicate and
the expected public health impact oI the inIormation.
as
re
inate a DHPC prior to completion oI a procedure. For centrally
rmation, recipients and the timetable. The agreed timetable Ior
2.4
Dissem llowing situations:

oI the indications, restriction in the

y or, in the case oI centrally authorised product, at the request
Other s

eous reports that identiIy a previously
nowledge that the medicinal product is not as eIIective as previously
point in
d encourage close monitoring
A need Ior communication oI other important inIormation, in particular where the issue has
been/is the subject oI signiIicant media coverage.
In cases where a regulatory agency outside the EU independently requests dissemination oI a
DHPC in their territory Ior a product also authorised in the EU, the Marketing Authorisation
A DHPC should not usually be distributed beIore the corresponding regulatory procedure h
been completed, however, exceptionally (e.g. in the case oI an urgent saIety restriction) the
may be a need to dissem
authorised products, the appropriate point in time Ior dissemination oI a DHPC is usually once
the CHMP Opinion has been adopted.
In general, an agreement between the Marketing Authorisation Holder and the national
Competent Authority(ies)/the Agency (and other partners as appropriate) is needed on the
Iormat and content oI the inIo
release oI the inIormation should be Iully respected by all partners.
Situations Where a Direct Healthcare Professional Communication Should
Be Considered
ination oI a DHPC is usually required in the Io
Suspension, withdrawal or revocation oI a marketing authorisation with recall oI the medicinal
product Irom the market Ior saIety reasons; or
Important changes to the Summary oI Product Characteristics (SPC), Ior instance those
introduced by means oI an urgent saIety restriction (e.g. introduction oI new contraindications,
warnings, reduction in the recommended dose, restriction
availability oI the medicinal product); or
Completion oI a reIerral procedure triggered Ior saIety concerns which results in a signiIicant
change to the product inIormation; or
In other situations relevant to the saIe and eIIective use oI the medicinal product at the request
oI a national Competent Authorit
oI the Agency or European Commission.
ituations where dissemination oI a DHPC may be appropriate include:
A change in the outcome oI the evaluation oI the risk-beneIit balance due to:
new data, in particular Irom a study or spontan
unknown risk or a change in the Irequency or severity oI a known risk; or
new data on risk Iactors and/or on how adverse reactions may be prevented; or
substantiated k
considered ; or
evidence that the risks oI a particular product are greater than those oI alternatives with
similar eIIicacy;
or
Availability oI new recommendations Ior treating adverse reactions; or
Ongoing assessment oI a possible signiIicant risk, but insuIIicient data at a particular
time to take any regulatory action (in this case, the DHCP shoul
oI the saIety concern in clinical practice and encourage reporting, or provide inIormation
about means to minimise the potential risk); or
PART IV 187/229
Holder should notiIy the appropriate Competent Authority/the Agency in the EU. The need Ior
any subsequent action in the EU should be considered and agreed on a case-by-case basis.
A DHPC rmation which does not require urgent
comm unicated to Healthcare ProIessionals at
uct.
should not be used to provide saIety inIo
unication or is otherwise important to be comm
individual level, such as changes to the SPC which do not impact on the conditions oI appropriate use
oI the medicinal prod
2.5 Key Principles for Preparation of Texts for Direct Healthcare Professional
Communications
When draIting a DHPC, the Template (see Annex 5.4) and the guidance provided there should be
The reason Ior dissemination oI a DHPC at a particular point in time should be explained.
he context oI the overall beneIit oI the treatment and
not be presented as stand-alone inIormation.
and Ior nationally authorised products,
ing oI the risk and expected adherence to the recommendations provided in the
so include the content oI any inIormation communicated directly to the
level, date oI recall).
need to report suspected adverse reactions in
ms.
(ies)/the Agency or the Marketing Authorisation Holder should be provided.
Iollowed as appropriate, together with the principles described below:
The message oI the DHPC should be clear and concise with regard to the saIety concern. It
should not exceed two pages.
Recommendations to Healthcare ProIessionals on how to minimise the risk should be provided
iI known.
The saIety concern should be placed in t
The Marketing Authorisation Holder should ensure that pharmacovigilance inIormation to the
general public (this includes Healthcare ProIessionals) is presented objectively and is not
misleading. This requirement is legally binding in accordance with Article 24(5) oI Regulation
(EC) No 726/2004 Ior centrally authorised products
including those authorised through the mutual recognition or decentralised procedures, in
accordance with Article 104(9) oI Directive 2001/83/EC.
In general, the texts oI DHPCs should be reviewed by, or iI the timetable allows, tested among
representatives oI the target groups oI Healthcare ProIessionals in order to assess clarity and
understand
DHPC. Alternatively, standard phrases may be tested and subsequently used, as appropriate,
particularly in urgent situations.
In order to allow Healthcare ProIessionals to prepare responses to questions Irom Patients, the
DHPC should al
general public. In case oI suspension, withdrawal or revocation oI a marketing authorisation,
the DHPC should detail the type and procedure oI recall oI the medicinal product(s) Irom the
market (e.g. pharmacy or patient
Public communication oI the saIety inIormation issued to any target population by other
Competent Authorities and other public bodies, ideally within and outside the EU, should be
taken into account.
The DHPC should include a reminder oI the
accordance with national spontaneous reporting syste
The estimated timeschedule Ior Iollow-up action, iI any, by the national Competent
Authority
A list oI contact points Ior Iurther inIormation, including website address(es), telephone
numbers and a postal address to write to, should be provided at the end oI the DHPC.
A list oI literature reIerences should be annexed, when relevant.
The DHPC may include a statement indicating that the DHPC has been agreed with the
national Competent Authority/the Agency.
PART IV 188/229
2.6 The Processing of Direct Healthcare Professional Communications
2.6.1 The Roles and Responsibilities of Marketing Authorisation Holders, the
Committee Ior Medicinal Products Ior Human Use (CHMP)) normally deals with DHPCs
Competent Authorities and the Agency
The Competent Authorities are those who have issued a marketing authorisation Ior the medicinal
product concerned.
For centrally authorised products, the Competent Authority is the European Commission, however the
Agency (the
on behalI oI the Commission.
For products authorised through the mutual recognition or decentralised procedures, the Competent
Authorities are those oI the ReIerence Member State (RMS) and the Concerned Member State(s)
(CMS(s)); Ior practical reasons, the RMS usually takes over co-ordination oI consistent and
synchronised DHPCs in the RMS and all CMSs (see Chapter IV.2, Section 6.3 Ior translations).
or the Marketing Authorisation Holders with regard to DHPCs are
ber States);
e mutual recognition or decentralised procedures: the RMS
proc
betw
CMS
Ior p
i
auth
Ior p
Com
this
Authority nt national Competent Authority(ies)/the
For purely nationally authorised products, the Competent Authorities are those oI the Member States
where the product is authorised, but it is suggested that one Member State may take the lead in co-
ordinating the process with the Marketing Authorisation Holder and apply synchronised timetables
across the relevant Member States.
Consequently, the contact points I
as Iollows:
Ior centrally authorised products: the Agency together with the Rapporteur (with parallel
submission oI documentation to all Mem
Ior products authorised through th
or, in case oI several products authorised through the mutual recognition or decentralised
edures with the same active substance and diIIerent RMSs, the Lead Member State agreed
een the RMSs and CMS(s) (with parallel submission oI documentation to all RMS(s) and
(s));
urely nationally authorised products: the Member States where the product is authorised
I agreed between th or, ese Member States, the designated Lead Member State Ior the saIety
concern (with parallel submission oI documentation to all Member States where the product is
orised); and
roducts subject to reIerral procedures: the Agency in relation to CHMP Opinions and
mission Decisions and otherwise the RMS or the Agency, as appropriate (see below in
Section Ior Iurther details).
Where the Marketing Authorisation Holder proposes or is requested by the national Competent
/the Agency to disseminate a DHPC, the releva
Agency should be provided with:
the proposed Communication Plan; including
the proposed communication text oI the DHPC; and
the proposed texts oI any related communication documents (see Chapter IV.2, Section
6.2.(2)).
The timing oI the submission should allow national Competent Authority(ies)/the Agency (CHMP)
pro days
should take
reasonable time (a minimum oI two working days) to comment on the Communication Plan and the
posed communication texts prior to their Iinalisation. Exceptionally, less than two working
may be acceptable in the case oI some urgent saIety restrictions. The Marketing Authorisation Holder
into account comments Irom the national Competent Authority(ies)/the Agency and
PART IV 189/229
discuss any outstanding issues when Iinalising these proposals. Ideally, the Marketing Authorisation
DH
Com
Holder should closely co-operate with the Rapporteur/RMS/Member State(s) to Iinalise the text oI the
PC. The Iinal Communication Plan and communication texts should be submitted to the national
petent Authorities/the Agency.
Memb ta er S tes and the Agency should use the Rapid Alert-Non-Urgent InIormation System (see
Chapter II.4) in order to keep each other and the European Commission inIormed during all the phases
unication process.
national Competent Authorities and the Agency should keep their Press OIIicers inIormed about
DHPC.
rketing Authorisation Holders are reminded oI the legal obligations described in Article 24(5) oI
ulation (EC) No 726/2004 and Article 104(9) oI Directive 2001/83/EC. With the except
oI the comm
The
any
Ma
Reg ion oI the
ucts and the Competent Authority Ior
here Ior ease
'Th
pha
with
2001/
In
obje
Member States shall take the necessary measures to ensure that a marketing authorisation holder who
in Member States to IulIil
P) on the Communication Plan and the proposed communication texts.
centrally
disseminated in its own territory, the Agency (CHMP)
ys prior to the proposed dissemination day and
ination
in only one or more Member States is suIIicient (taking into account e.g. availability oI
commendations on DHPCs Irom its
WP).
irements in relation to the communication texts,
nation mechanism, the Marketing Authorisation
harmacovigilance contact points at the national
anner Ior discussion and Iinalisation oI the
requirement to notiIy the Agency Ior centrally authorised prod
nationally authorised products, the requirements in both legal texts are identical and are reproduced
oI reIerence:
e holder of a marketing authorisation may not communicate information relating to
rmacovigilance concerns to the general public in relation to its authorised medicinal product
out giving prior or simultaneous notification to the competent authority |Directive
83/EC|/Agency |Regulation (EC) No 726/2004|.
any case, the marketing authorisation holder shall ensure that such information is presented
ctively and is not misleading.
fails to discharge these obligations is subject to effective, proportionate and dissuasive penalties.
In addition, the Iollowing should be considered:
For centrally authorised products:
In order to enable the Agency and the Competent Authorities
their roles in public health protection, Marketing Authorisation Holders should give prior
notiIication, allowing a minimum oI two working days Ior comments by the Agency
(CHM
Exceptionally, less than two working days may be acceptable in case oI some urgent
saIety restrictions.
When a Member State considers it necessary that a DHPC concerning a
authorised product should be
should be inIormed at least two da
consider whether EU-wide dissemination oI such a DHPC is necessary or dissem
an interacting medicinal product in only a Iew Member States or diIIerences in medical
practice).
The CHMP will normally request re
Pharmacovigilance Working Party (PhV
With regard to Member States` requ
recipients and the proposed dissemi
Holder should contact the relevant p
Competent Authorities in a timely m
Communication Plan and communication texts including relevant translations (see
Chapter IV.2, Section 6.3).
For products authorised through the mutual recognition or decentralised procedures:
Where a CMS considers dissemination oI a DHPC is necessary, this CMS should contact
the RMS to liaise with the Marketing Authorisation Holder prior to dissemination.
PART IV 190/229
Rarely, it may only be necessary to send a DHPC in one/some Member States. However,
the RMS and the CMS should always keep each other inIormed oI any proposed action.
The PhVWP should provide recommendations at the request oI a Member State.
Member States may have approval procedures Ior DHPCs Ior nationally authorised
products in place, which may also apply to products authorised through the mutual
recognition or decentralised procedures.
For purely nationally authorised products:
Member States may have approval procedures Ior DHPCs in place. Also Ior purely
nationally authorised products, Member States should inIorm the other Member States
and the Agency using the Rapid Alert/Non-Urgent InIormation System (see Chapter II.4).
At the request oI a Member State, a synchronised timetable Ior communication
throughout the EU may be agreed by the PhVWP Ior purely nationally authorised
products. Such agreement may be oI particular importance in the case oI DHPCs planned
Ior purely nationally authorised products containing the same active substance as a
through the mutual recognition or decentralised
Ierral Rapporteur and the Agency closely
activities. The involvement oI the CHMP
I active substances authorised through
diI n
Authori
needed
such co
product authorised through the mutual recognition or decentralised procedures.
For products subject to an ongoing reIerral procedure:
The review oI comments on the proposed Communication Plan and communication texts
will be undertaken by the Agency (CHMP) iI such communications reIer to outcomes oI
discussion at the level oI the CHMP and subsequent Commission Decisions, i.e. in
particular to CHMP ReIerral Opinions and review oI monitoring conditions Ior marketing
set out in the Commission Decision. Otherwise, the (post-reIerral) RMS co-ordinates
DHPCs as Ior products authorised
procedures. The RMS needs to keep the Re
inIormed about any planned communication
will be considered on a case-by-case basis.
When a DHPC concerns an active substance or a class o
Iere t procedures and/or involving overlapping roles and responsibilities oI the Competent
ties and the Agency, the relevant partners should co-ordinate their respective activities, as
within the EU pharmacovigilance system. The PhVWP should provide recommendations Ior
-ordination at the request oI the CHMP/EMEA or a Member State.
For le ro s and responsibilities regarding the process oI translation oI communication texts, see Chapter
IV.2, Se
In cases
Authori h
the C

ction 6.3.
where a DHPC is disseminated by a Competent Authority in a Member State, the Competent
ty s ould provide the Iollowing to the Marketing Authorisation Holders concerned:
ommunication Plan; including
the communication text oI the DHPC; and
the t Chapter IV.2, Section 6.2.(2)).
Nat a
should
exts oI any related communication documents (see
ion lly established procedures should be Iollowed in such cases, and the Communication Plan
be circulated Ior inIormation to the other Member States and the Agency using the Rapid
Alert/N
2.6
The processing oI a DHPC consists oI Iour phases:
1.
Th r er or a national Competent
Authority/the Agency/the European Commission.
on-Urgent InIormation System (see Chapter II.4).
.2 Phased Approach to Processing
Consideration phase: Initiation of the process
e p ocess may be initiated by the Marketing Authorisation Hold
PART IV 191/229
Wh t
Compet
oI the State, the
Eu a
rec
urgency ted by telephone and/or
e-m
provide . When a request letter is
rec d designate a contact point within the company Ior
liaison with t .
es where agreement cannot be reached regarding dissemination oI a
older is involved in the
PC is conIirmed, the Marketing Authorisation Holder should
draIt DHPC, iI the Iinal revised
Product InIormation is available) as well as the key message to the public;
unication, communication and post-
en he Marketing Authorisation Holder considers that a DHPC may be necessary, the national
ent Authority/the Agency should be contacted and the documents required Ior the preparation
DHPC submitted, as set out below. When a Competent Authority in a Member
rope n Commission or the Agency (CHMP) considers that a DHPC may be necessary, it is
ommended that the national Competent Authority/the Agency sends a request letter (in case oI
the Marketing Authorisation Holder may additionally be contac
ail) requesting preparation oI a draIt DHPC and a Communication Plan. This request letter should
the rationale Ior the request and the timetable Ior submission
eive , the Marketing Authorisation Holder should
he national Competent Authority/the Agency
II the Marketing Authorisation Holder considers that a DHPC is not appropriate or requires additional
clariIication, a written request may be submitted to the national Competent Authority/the Agency/ the
European Commission. In cas
DHPC by the Marketing Authorisation Holder, a DHPC and/or a Public Statement may be issued by
the national Competent Authority/the Agency/the European Commission.
There may be situations in which more than one Marketing Authorisation H
dissemination oI a DHPC, e.g. where an interaction, a class-eIIect or generic medicinal products are
concerned. In such situations, the objective is to provide consistent inIormation to Healthcare
ProIessionals and to avoid multiple DHPCs on the same saIety concern Irom diIIerent Marketing
Authorisation Holders which may lead to conIusion. Where the number oI Marketing Authorisation
Holders involved is limited to two or three, they should work together to issue a single DHPC. For a
larger number oI Marketing Authorisation Holders or iI a single joint DHPC is not agreed, the national
Competent Authority may opt to issue the DHPC.
2. Pre-communication phase: Preparation of a DHPC
Once the intention to disseminate a DH
submit a draIt Communication Plan including the Iollowing:
the objective oI the DHPC and the draIt DHPC and other communication texts (including
amendments to the Product InIormation (SPC, Package LeaIlet and Labelling), either
mentioned in the DHPC text or, preIerably, appended to the
a proposed timetable covering the pre-comm
communication phases with regard to all communication and other relevant documents
including translations (see Chapter IV.2, Section 6.3). This timetable should include:
timelines Ior comments on the Communication Plan and draIt communication texts by
national Competent Authority(ies) and/or the Agency (CHMP);
timelines Ior agreement on Iinal texts between the Marketing Authorisation Holder and
the Competent Authority(ies)/the Agency (CHMP);
timelines Ior agreement on the date and time oI release oI the DHPC and inIormation to
the general public (synchronised across the EU).
n with other any draIt Communication Plans and communication texts under discussio
Competent Authorities (outside the EU Ior centrally authorised products and products
authorised through the mutual recognition or decentralised procedures; within and outside the
EU Ior purely nationally authorised products);
a list oI proposed recipients (target groups, e.g. general practitioners, specialists, coroners,
pharmacists, nurses; hospitals/ambulatory care/other institutions), including Member States`
speciIicities, iI appropriate;
a description oI the dissemination mechanism in the Member State(s) where the DHPC is
planned to be disseminated (e.g. by post);
PART IV 192/229
a plan Ior user testing oI the communication text, iI appropriate;
a list oI related communication documents, iI appropriate, e.g. press release, questions &
answers document, patient inIormation sheet, and a description oI their dissemination
mechanisms in each Member State where the DHPC is planned to be disseminated;
a description oI the strategy Ior the post-communication phase, including the evaluation oI the
eIIectiveness oI the DHPC, as outlined below in this Section, No 4.;
an outline oI proposed Iollow-up action and a draIt Letter oI Undertaking Irom the Marketing
Authorisation Holder on Iurther investigations, iI applicable; and
levant partners.
press release/Public Statement Irom either national Competent Authority(ies),
the Agency or the Marketing Authorisation Holder should be disseminated at the same date in all
ose Healthcare ProIessionals who will be able or likely to prescribe or administer
the medicinal product, but also to those who may diagnose adverse reactions, e.g. emergency units,
general public, in particular where media interest has
arisen. The national proIessional associations oI physicians, nurses and pharmacists should
The dissemination mechanism should take into account national policies Ior prompt identiIication oI
uraged to Iacilitate
and Iocus Healthcare ProIessionals` attention.
3. Communication phase: Dissemination of the DHPC
Implementation oI the communication phase should adhere to the Communication Plan agreed
between the Marketing Authorisation Holder and the national Competent Authority(ies)/the Agency
and should be accompanied by close monitoring oI events by all partners. Any signiIicant event or
problem occurring during the communication phase should be communicated immediately between all
relevant partners. II this reveals a need to change the Communication Plan or a need Ior Iurther
communication to Healthcare ProIessionals, this should be agreed between the Marketing
Authorisation Holder and the national Competent Authority(ies)/the Agency.
4. Post-communication phase: Follow-up of the DHPC
AIter dissemination oI a DHPC, a closing review should be perIormed by the Marketing Authorisation
Holder, identiIying any event or problem occurring during the communication phase requiring a
change to the Communication Plan, any non-adherence to the Communication Plan as well as any
diIIiculties experienced during any oI the above phases. Such diIIiculties may relate e.g. to the list oI
recipients or the date and mechanism oI dissemination. The national Competent Authority(ies)/the
Agency should be inIormed oI the outcome oI this closing review and should also inIorm the
Marketing Authorisation Holder oI diIIiculties they identiIied. II the national Competent Authority/the
a list oI contact details oI re
The proposed time and date Ior distribution should be considered careIully, with dissemination oI a
DHPC at the beginning oI a week considered ideal; however the release oI urgent inIormation should
not be delayed Ior this reason.
Usually, any planned
Member States, ideally at an agreed time oI the day speciIied as London time.
When deIining the target groups oI recipients, it should be recognised that it is not only important to
communicate with th
poison centres, or to appropriate specialists, e.g. cardiologists. It is also important to consider
provision oI DHPCs to relevant pharmacists who serve as inIormation providers within healthcare
systems and provide assistance and inIormation to Patients, Healthcare ProIessionals, including
hospital wards and poison centres, as well as the
systematically receive DHPCs Ior Iurther dissemination oI the inIormation to their members beyond
the primary target groups oI recipients.
DHPCs, such as speciIic identiIiers on the envelope (e.g. prominent red box warning) or use oI a
speciIic colour oI notepaper. The use oI such speciIic identiIiers is enco
identiIication
PART IV 193/229
PART IV 194/229
gency is not satisIied, a written request should be made to the Marketing Authorisation Holder to
orrect the situation. On the basis oI this inIormation, action should be taken to prevent or anticipate
imilar problems in the Iuture. All partners should also perIorm internal reviews oI their perIormance
s part oI integrated quality management and take appropriate action Ior improvement as needed. In
the public health impact and the eIIectiveness oI DHPCs should be perIormed in
rder to evaluate iI the DHPCs have been received in a timely manner (check in a small sample oI the
rget population) and iI the recommendations and key messages have been understood and Iollowed
means oI healthcare proIessional surveys or other study designs). This evaluation should be
erIormed by the Marekting Authorisation Holder and is speciIically relevant where DHPCs are part
A
c
s
a
general, evaluation oI
o
ta
(e.g. by
p
oI risk minimisation activities in accordance with the applicable Risk Management Plan (see
Chapter I.3).
2.6.3 Translations
For centrally authorised products and in most cases also Ior products authorised through the mutual
recognition or decentralised procedures, the proposed communication texts will be submitted in
English as working language. For products authorised through the mutual recognition or decentralised
procedures, the working language could be another oIIicial Community language iI agreed by the
RMS and all CMSs.
Once the communication texts are agreed with the Agency/RMSCMS(s), the Marketing
Authorisation Holder should prepare translations oI the DHPC in all oIIicial EU languages, oI the
Member States where the product is marketed or, iI appropriate, is made available by other means (e.g.
compassionate use).
The draIt translations should be submitted to all Member States/RMSCMS(s) Ior a language review
within a reasonable time (minimum oI one working day). The Marketing Authorisation Holder should
take account oI comments Irom the national Competent Authorities/the Agency and discuss any
outstanding issues when Iinalising translations.
In the case oI a centrally authorised product, the Marketing Authorisation Holder should provide the
Agency with a complete set oI all Iinal language versions oI the DHPC and any related
communication documents.
In Member States with more than one oIIicial language, similar processes Ior language review by the
national Competent Authority may be in place Ior nationally authorised products.

ANNEXES
195/229
1. Glossary
ym: Drug abuse
nym: Adverse experience
clinical-trial subject administered a medicinal
a medicinal product which is noxious and unintended and which occurs at doses
an Ior the prophylaxis, diagnosis or therapy oI disease or Ior the restoration,
his context means that a causal relationship between a medicinal product and an adverse
ast a reasonable possibility (see ICH-E2A Guideline
65
).
also includes adverse clinical consequences associated with use oI the product
outside the terms oI the Summary oI Product Characteristics or other conditions laid down Ior the
I the product (including prescribed doses higher than those recommended,
overdoses or abuse).
tion, Unlisted adverse reaction
Clinical
An n
and/or o
identiIy verse reactions to one or more investigational medicinal product(s) and/or to study
abs t
with the
out in e Directive
An investigational medicinal product is a pharmaceutical Iorm oI an active substance or placebo being
Ierence in a clinical trial, including products already with a marketing
authorisation but used or assembled (Iormulated or packaged) in a way diIIerent Irom the authorised
1.1 General
Abuse of a medicinal product, synon
Persistent or sporadic, intentional excessive use oI medicinal products which is accompanied by
harmIul physical or psychological eIIects (Article 1(16). oI Directive 2001/83/EC).
Adverse event (AE), syno
Any untoward medical occurrence in a patient or
product and which does not necessarily have to have a causal relationship with this treatment (Article
2(m) oI Directive 2001/20/EC). An adverse event can thereIore be any unIavourable and unintended
sign (e.g. an abnormal laboratory Iinding), symptom, or disease temporally associated with the use oI
a medicinal product, whether or not considered related to the medicinal product.
Adverse reaction, synonym: Adverse drug reaction (ADR), Suspected adverse (drug) reaction
A response to
normally used in m
correction or modiIication oI physiological Iunction (Article 1(11) oI Directive 2001/83/EC)
64
.
Response in t
event is at le
Adverse reaction
marketing and use o
See also under Adverse event, Serious adverse reaction, Unexpected adverse reaction, Listed adverse
reaction, Reportable adverse reac
trial
y i vestigation in human subjects intended to discover or veriIy the clinical, pharmacological
ther pharmacodynamic eIIects oI one or more investigational medicinal product(s), and/or to
any ad
orp ion, distribution, metabolism and excretion oI one or more investigational medicinal product(s)
objective oI ascertaining its (their) saIety and/or eIIicacy; This includes clinical trials carried
ither one site or multiple sites, whether in one or more Member State (Article 2(a) oI
2001/20/EC).
tested or used as a re
Iorm, or when used Ior an unauthorised indication, or when used to gain Iurther inIormation about the
authorised Iorm (Article 2(d) oI Directive 2001/20/EC).

64
Please note that Ior the reporting oI adverse reactions occurring in clinical trials all untoward and unintended
responses to an investigational medicinal product related to any dose administered are considered adverse
reactions (Article 2(n) oI Directive 2001/20/EC).
65
ANNEXES 196/229
Consumer
A person who is not a Healthcare ProIessional such as a Patient, lawyer, Iriend or
atient.
er inIormation concerning
the product.
Company Core Safety Information (CCSI)
thorisation Holder requires to be listed in all
the product, except when the local regulatory authority
the reIerence inIormation by which listed and unlisted are
ose oI periodic reporting Ior marketed products, but not by which expected and
ed Ior expedited reporting.
as the cut-oII date Ior data to be included in a Periodic SaIety Update Report.
Dr b
See d
EU Birt
The date oI medicinal product granted in the EU to the
r:
gh the mutual recognition or decentralised procedure,
edicinal products authorised through purely national procedures (outside the mutual
centralised procedure), the Marketing Authorisation Holder may propose a
an be applied to reporting requirements across the Member States.
irth Date
A document providing the most complete inIormation related to an individual case at a certain point oI
time. An individual case is the inIormation provided by a primary source to describe suspected adverse
relative/parents/children oI a P
Company Core Data Sheet (CCDS)
A document prepared by the Marketing Authorisation Holder containing, in addition to saIety
inIormation, material relating to indications, dosing, pharmacology and oth
All relevant saIety inIormation contained in the company core data sheet prepared by the Marketing
Authorisation Holder and which the Marketing Au
countries where the company markets
speciIically requires a modiIication. It is
determined Ior the purp
unexpected are determin
Data lock point
The date designated
ug a use
un er Abuse
h Date (EBD)
the Iirst marketing authorisation Ior a
Marketing Authorisation Holde
For medicinal products authorised through the centralised procedure, the EU Birth Date is the
date oI the marketing authorisation granted by the European Commission, i.e. the date oI the
Commission Decision.
For medicinal products authorised throu
the EU Birth Date is the date oI the marketing authorisation granted by the ReIerence Member
State.
For m
recognition or de
birth date which c
See also International B
Healthcare Professional
For the purposes oI reporting suspected adverse reactions, Healthcare ProIessionals are deIined as
medically qualiIied persons, such as physicians, dentists, pharmacists, nurses and coroners.
Individual Case Safety Report (ICSR), synonym: Safety report
ANNEXES 197/229
reaction(s) related to the administration oI one or more medicinal products to an individual Patient at a
particular point oI time
66
.
arketing authorisation Ior a medicinal product granted to the Marketing
Authorisation Holder in any country in the world. For a medicinal product Ior which the International
or scientiIic
name oI the Marketing Authorisation Holder Iollowed by the
ty and outcome are consistent with the
mpany core saIety inIormation.
be used in or administered to human
modiIying physiological Iunctions by
acological, immunological or metabolic action, or to making a medical
diagnosis (Art 1(2) oI Directive 2001/83/EC).
cientiIic name accompanied by a trade mark or the name oI the marketing authorisation
See also Invented name.
Non-interventional trial
in advance by a trial protocol but Ialls within the current practice and the prescription oI
International Birth Date (IBD)
The date oI the Iirst m
Birth Date is not known, the Marketing Authorisation Holder can designate an International Birth Date
to allow synchronisation oI submission oI Periodic SaIety Update Reports.
Invented name
The name oI a medicinal product as it appears in the Product InIormation, or the common
name together with a trademark or the
strength and the pharmaceutical Iorm oI the product.
See also Name of the medicinal product.
Listed adverse reaction
An adverse reaction whose nature, severity, speciIici
inIormation in the co
Medicinal product
Any substance or combination oI substances presented as having properties Ior treating or
preventing disease in human beings; or
Any substance or combination oI substances which may
beings either with a view to restoring, correcting or
exerting a pharm
Name of the medicinal product
The name, which may be either an invented name not liable to conIusion with the common name, or a
common or s
holder (Article 1(20) oI Directive 2001/83/EC).
The common name is the International Non-proprietary Name (INN) recommended by the World
Health Organization, or, iI one does not exist, the usual common name (Article 1(21) oI Directive
2001/83/EC).
A study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the
terms oI the marketing authorisation. The assignment oI the patient to a particular therapeutic strategy
is not decided
the medicine is clearly separated Irom the decision to include the patient in the study. No additional
diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall
be used Ior the analysis oI the collected data (Article 21 oI Directive 2001/20/EC).

66
In the context oI a clinical trial, an individual case is the inIormation provided by a primary source to describe
suspected unexpected serious adverse reactions related to the administration oI one or more investigational
medicinal products to an individual patient at a particular point oI time.
ANNEXES 198/229
Periodic Safety Update Report (PSUR)
Periodic saIety update reports mean the periodical reports containing the records reIerred to in Article
104 oI Directive 2001/83/EC and in Article 24(3) oI Regulation (EC) No 726/2004.
Post-authorisation study
Any study conducted within the conditions laid down in the Summary oI Product Characteristics and
other conditions laid down Ior the marketing oI the product or under normal conditions oI use. A post-
ty study
ard relating
83/EC).
See also under Clinical trial and Non-interventional trial
sks (any
as regards Patients` health or
See also unde
A risk rmacovigilance activities and interventions
des e to medicinal products, including
the s ctiveness oI those interventions (Article 34 oI Regulation (EC) No
190 0
ty, saIety or eIIicacy oI the medicinal product as regards Patients` health
k oI undesirable eIIects on the environment (Article 1(28) oI Directive
tening in this context reIers to a reaction in which the Patient was at risk oI death at the time
oI the reaction; it does not reIer to a reaction that hypothetically might have caused death iI more
severe.
Medical and scientiIic judgement should be exercised in deciding whether other situations should be

e
authorisation study Ialls either within the deIinitions oI a clinical trial or a non-interventional study
and may also Iall within the deIinition oI a post-authorisation saIety study.
See also under Clinical trial, Non-interventional trial and Post-authorisation safe
Post-authorisation safety study (PASS)
A pharmacoepidemiological study or a clinical trial carried out in accordance with the terms oI the
marketing authorisation, conducted with the aim oI identiIying or quantiIying a saIety haz
to an authorised medicinal product (Article 1,15. oI Directive 2001/
Risk-benefit balance
An evaluation oI the positive therapeutic eIIects oI the medicinal product in relation to the ri
risk relating to the quality, saIety or eIIicacy oI the medicinal product
public health) (Article 1,28a. oI Directive 2001/83/EC).
r Risks related to use of a medicinal product
Risk management system
management system shall comprise a set oI pha
ign d to identiIy, characterise, prevent or minimise risks relating
as essment oI the eIIe
1/2 06).
Risks related to use of a medicinal product
Any risk relating to the quali
or public health and any ris
2001/83/EC).
Serious adverse reaction
Serious adverse reaction means an adverse reaction which results in death, is liIe-threatening, requires
in-patient hospitalisation or prolongation oI existing hospitalisation, results in persistent or signiIicant
disability or incapacity, or is a congenital anomaly/birth deIect (Article 1(12) oI Directive
2001/83/EC).
LiIe threa
considered serious reactions, such as important medical events that might not be immediately liIe
threatening or result in death or hospitalisation but might jeopardise the Patient or might require
intervention to prevent one oI the other outcomes listed above. Examples oI such events are intensiv
ANNEXES 199/229
treatment in an emergency room or at home Ior allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalisation or development oI dependency or abuse.
Solicited sources of Individual Case Safety Reports
Organised data collection schemes which include clinical trials, registries, named-patients use
programmes, other patient support and disease management programmes, surveys oI patients or
healthcare providers or inIormation gathering on eIIicacy or patient compliance.
For the purpose oI saIety reporting, solicited reports should be classiIied as Individual Case SaIety
Reports Irom studies and thereIore should have an appropriate causality assessment by a Healthcare
ProIessional or the Marketing Authorisation Holder.
See also under Clinical trial, Non-interventional trial and Post-authorisation safety study
Spontaneous report, synonym: Spontaneous notification
An unsolicited communication by a Healthcare ProIessional or Consumer to a company, regulatory
authority or other organisation (e.g. WHO, a regional centre, a poison control centre) which IulIills the
Iollowing three conditions:
it describes one or more suspected adverse reactions in a patient
the patient was given one or more medicinal products
it does not derive Irom a study or any organised data collection scheme.
Healthcare ProIessionals or Consumers may be stimulated to report a suspected adverse reaction by
several situations including:
a Direct Healthcare ProIessional Communication
Early Post-Marketing Phase Vigilance (EPPV), e.g. in Japan
a report in the press
direct questioning oI Healthcare ProIessionals by company representatives.
In these circumstances, provided the report meets the three conditions above, it should be considered a
spontaneous report.
Unexpected adverse reaction
An adverse reaction, the nature, severity or outcome oI which is not consistent with the Summary oI
Product Characteristics (SPC) (Article 1(13) oI Directive 2001/83/EC)
67
. This includes class-related
reactions which are mentioned in the SPC but which are not speciIically described as occurring with
this product. For products authorised nationally, the relevant SPC is that approved by the Competent
Authority in the Member State to whom the reaction is being reported. For centrally authorised
products, the relevant SPC is the SPC authorised by the European Commission. During the time
period between a CHMP Opinion in Iavour oI granting a marketing authorisation and the Commission
Decision granting the marketing authorisation, the relevant SPC is the SPC annexed to the CHMP
Opinion.

Any suspected transmission via a medicinal product oI an inIectious agent is also considered a serious
adverse reaction.
See also under Adverse reaction

67
Please note that Ior investigational medicinal products an unexpected adverse reaction is an adverse reaction,
the nature or severity oI which is not consistent with the applicable Product InIormation (e.g. the investigator`s
brochure Ior an unauthorised investigational product or the Summary oI Product Characteristics Ior an
authorised product) (Article 2(p) oI Directive 2001/20/EC).
ANNEXES 200/229
Unlisted adverse reaction
An adverse reaction that is not speciIically incl
Core SaIety InIormation (CCSI). Th
uded as a suspected adverse eIIect in the Company
is includes an adverse reaction whose nature, severity, speciIicity
or outcome is not consistent with the inIormation in the CCSI. It also includes class-related reactions
which are mentioned in the CCSI but which are not speciIically described as occurring with this
product.
ANNEXES 201/229
1.2 Terms in Relation to Risk Management
put in place to reduce the probability oI an adverse reaction occurring or
e risk minimisation activity e.g. additional
Additional risk minimisation activity
A risk minimisation activity
its severity should it occur which is not a routin
educational material or use oI one oI the other risk minimisation activities in Table I.3.A.
Identified risk
An untoward occurrence Ior which there is adequate evidence oI an association with the medicinal
erse reaction observed in well-designed clinical trials or epidemiological studies Ior
the magnitude oI the diIIerence, compared with the comparator group (placebo or
ests a causal
reaction suggested by a number oI well-documented spontaneous reports where
y supported by temporal relationship and biological plausibility, such as
information
An identiIied risk, potential risk or missing inIormation that could impact on the risk-beneIit balance
oI the product or have implications Ior public health.
Missing information
InIormation about the saIety oI a medicinal product which is not available at the time oI submission oI
the EU Risk Management Plan and which represents a limitation oI the saIety data with respect to
predicting the saIety oI the product in the marketplace.
Potential risk
An untoward occurrence Ior which there is some basis Ior suspicion oI an association with the
medicinal product oI interest but where this association has not been conIirmed. Examples oI potential
risks include:
Non-clinical saIety concerns that have not been observed or resolved in clinical studies
Adverse events observed in clinical trials or epidemiological studies Ior which the magnitude
oI the diIIerence, compared with the comparator group (placebo or active substance, or
unexposed group), on the parameter oI interest raises a suspicion oI, but is not large enough to
suggest, a causal relationship
A signal arising Irom a spontaneous adverse reaction reporting system
An event which is known to be associated with other products oI the same class or which
could be expected to occur based on the properties oI the medicinal product.
See also Adverse event
Risk management system
A risk management system shall comprise a set oI pharmacovigilance activities and interventions
designed to identiIy, characterise, prevent or minimise risks relating to medicinal products, including
the assessment oI the eIIectiveness oI those interventions (Article 34 oI Regulation (EC) No
1901/2006).
product oI interest. Examples oI identiIied risks include:
An adverse reaction adequately demonstrated in non-clinical studies and conIirmed by clinical
data
An adv
which
active substance, or unexposed group), on a parameter oI interest sugg
relationship
An adverse
causality is strongl
anaphylactic reactions or application site reactions.
Important identified risk, important potential risk or important missing
ANNEXES 202/229
Risk ation minimis
rse reaction occurring or its severity
on (EC) No 726/2004 and Directive 2001/83/EC
al products.
e Summary oI Product Characteristics and Patient
aging, which aim to reduce the probability oI an
its severity should it occur.
identiIied risk, important potential risk or important missing inIormation.
by the medicinal product according to the indication(s) and
y oI Product Characteristics.
This is a set oI activities used to reduce the probability oI an adve
should it occur.
Routine pharmacovigilance
Pharmacovigilance activities as speciIied in Regulati
that should be conducted Ior all medicin
Routine risk minimisation activities
The warnings and inIormation contained within th
LeaIlet, and the careIul use oI labelling and pack
adverse reaction occurring or
Safety concern
An important
Target Population
The Patients who might be treated
contraindication(s) in the Summar
ANNEXES 203/229
1.3 Terms in Relation to Electronic Exchange of Pharmacovigilance Information
ure to
essage and the SaIety Report(s) contained in the SaIety File.
ceipt
puter, oI commercial and administrative data using an
sage. EDI is based on the use oI structured and coded
system (DBMS)
Th t single point oI
con t
the EEA ing so, the EudraVigilance Gateway is considered a hub and all connections to the EDI
Par rs ent and Medicinal Product Report Messages are
rou t
th SGML.
col (SMTP)/Secure Multipurpose Internet Mail
Acknowledgement message (ICSRACK)
An EDI Message with the inIormation on the result oI the Acknowledgement oI Receipt proced
acknowledge the receipt oI one SaIety M
Acknowledgement message (MPRACK)
An EDI Message with the inIormation on the result oI the Acknowledgement oI Receipt procedure to
acknowledge the receipt oI one Medicinal Product Report Message and the Medicinal Product
Report(s) contained in the Medicinal Product File.
Acknowledgement of re
The procedure by which on receipt oI the SaIety Message/Medicinal Product Report Message the
syntax and semantics are checked.
Applicant
A pharmaceutical company applying Ior a marketing authorisation in the EEA.
Electronic data interchange (EDI)
Electronic transIer, Irom computer to com
agreed standard to structure an EDI mes
messages, the main characteristic oI which is their ability to be processed by computers and
transmitted automatically and without ambiguity. This makes EDI speciIic in comparison with other
data exchange such as electronic mail.
EudraVigilance database management
The pharmacovigilance database deIined in Community legislation.
EudraVigilance gateway
e da a-processing network as deIined in the Community legislation that provides a
tac between Marketing Authorisation Holders, Applicants, sponsors and Competent Authorities in
. By do
tne are known as spokes. SaIety, Acknowledgem
ted hrough the hub to the desired spoke.
Extensible markup language (XML)
A subset oI SGML that is completely compatible wi
Gateway
A data exchange service, which consists oI all core standards and Iunctionality required Ior supporting
the ICH standards (e.g. Simple Mail TransIer Proto
(SMIME)).
ANNEXES 204/229
Individual case
products/investigational medicinal products to an individual patient at a particular point oI time.
Investigational medicinal product (IMP)
ucts already with a marketing authorisation but used or assembled
(Iormulated or packaged) in a way diIIerent Irom the authorised Iorm, or when used Ior an
on, or when used to gain Iurther inIormation about the authorised Iorm (Art 1(d)
oI Directive 2001/20/EC).
The electronic Iile transmitted in one Message Transaction between one Sender and one Receiver
g one Medicinal Product Report Message.
nd update the EudraVigilance
Me in Medicinal Product Report may contain inIormation on an
aut is l product.
Me n ge (MPRM)
Message including the inIormation provided Ior one/more Medicinal Product Reports
in one Medicinal Product File exchanged between one Sender and one Receiver in one
ort transaction
edicinal Product Messages, which
oI a Medicinal Product Report Message
he MPR-MDN is received and stored by the Report Sender to document the success oI the
nal Product Report Message transmission
subjected to the Acknowledgement oI Receipt
This MDN is reIerred to as MPRACK-MDN
CK-MDN is received and stored by the Report Receiver to document the
The inIormation provided by a primary source to describe suspected adverse reaction(s)/suspected
unexpected serious adverse reactions related to the administration oI one or more medicinal
A pharmaceutical Iorm oI an active substance or placebo being tested or used as a reIerence in a
clinical trial, including prod
unauthorised indicati
Medicinal product file
containin
Medicinal product report (MPR)
An electronic report with a deIined set oI data elements to populate a
dic al Product Dictionary (EVMPD). A
hor ed medicinal product/investigational medicina
dici al product report messa
An EDI
contained
Message Transaction.
Medicinal product rep
The complete set oI actions in the electronic reporting oI M
routinely includes the Iollowing:
Creation
Transmission oI the Medicinal Product Report Message to the Report Receiver
On receipt oI the Medicinal Product Report Message by the Receiver`s Gateway return oI an
MDN
This MDN will be reIerred to as MPR-MDN
T
Medici
The Medicinal Product Report Message is
procedure by the Report Receiver
The Acknowledgement Message is created
The Acknowledgement Message is returned to the Report Sender (technically the Report
Receiver is a Message Sender Ior this part oI the transaction)
On receipt oI the Acknowledgement Message by the Report Sender`s Gateway return oI an
MDN
The MPRA
successIul transmission oI the Acknowledgement Message
The Acknowledgement Message is evaluated to document the success oI the Report
Transaction
ANNEXES 205/229
Me
An ctured using an agreed standard, prepared in a
com
Me e
A I turned by the Receiver`s Gateway to the Sender`s
Gatewa
to-G e
Me e
A
Ac w
the retu
sation exchanging EDI Messages in the area oI pharmacovigilance in the pre- or post-
Competent Authorities in the EEA
ng Authorisation Holders in the EEA
recipient oI the EDI Message.
ombined EDI qualiIier and ID oI the recipient.
recipient oI the transmission oI a SaIety Message, which Ior the purpose oI these Guidelines
er to submit a Medicinal Product Report, which Ior the purpose oI these
he complete set oI actions in the electronic reporting oI SaIety Messages to comply with regulatory
requirements which routinely includes the Iollowing:
ssage
EDI Message consists oI a set oI segments, stru
puter readable Iormat and capable oI being automatically and unambiguously processed.
ssag disposition notification (MDN)
noti ication on the receipt oI an EDI Message re
y. The MDN concludes a Message Transaction perIormed between two parties in a Gateway-
at way communication.
ssag transaction
set oI actions encompassing the electronic transmission oI an EDI Message (SaIety Message,
kno ledgement Message, Medicinal Product Message) between a Sender and a Receiver including
rn oI the Message Disposition NotiIication Ior that message.
Partner
An organi
authorisation phase with another organisation. For the purpose oI this guideline, EDI partners in the
pre- and post-authorisation phase in pharmacovigilance are as Iollows:
Marketi
Applicants
Sponsors in the EEA
Receiver
Intended
Receiver identifier
IdentiIication or c
Report receiver
Intended
is an EDI Partner. The Receiver is also the intended recipient oI the transmission oI a Medicinal
Product Report Message, which Ior the purpose oI these Guidelines is an EDI Partner being the
Agency.
Report sender
Person or entity creating a SaIety Message as EDI Message in order to submit a SaIety Report, which
Ior the purpose oI these Guidelines is an EDI Partner. In the Report Transaction the Report Sender will
always remain the same, whereas with the exchange oI messages the 'Sender and 'Receiver roles
will change. The same concepts apply to the organisation creating a Medicinal Product Message as
EDI Message in ord
Guidelines is an EDI Partner being an Applicant, a Marketing Authorisation Holder or a sponsor.
Report transaction
T
ANNEXES 206/229
ANNEXES 207/229
age to the Report Receiver
On receipt oI he Receiver`s Gateway return oI an MDN
This MDN will be reIerred to as ICSR-MDN
The ICSR-M document the success oI the
SaIety Messa
The SaIety M dgement oI Receipt procedure by the Report
Receiver
he Acknowl
The Acknow Message is returned to the Report Sender (technically the Report
Receiver is a I the transaction)
On receipt oI ge by the Report Sender`s Gateway return oI an
DN
is ACK-MDN
ICSRAC d stored by the Report Receiver to document the
successIul tra edgement Message
cknowledgeme ated to document the success oI the Report Transaction.
file
tronic Iile tr een one Sender and one Receiver
ining one SaIety
sage
I Message inc r one/more Individual Case SaIety Reports
ined in one Sa and one Receiver in one Message
on.
r
on or entity creati nsmission.
identifier
on (ID) or
dividual, comp isation, which takes responsibility Ior the initiation,
ement and/or Ii rt 2(e) oI Directive 2001/20/EC).
generalized m
al Standar Ior describing a document in terms oI its
(text, image) hs, etc.). It is a standard Ior how to
ment s itselI a document type
ition (DTD). SG itselI a document language, but a description oI how to speciIy one.
talanguage.
is based on th and other semantic elements that can be
ithout reIe
Creation oI a SaIety Message
Transmission oI the SaIety Mess
the SaIety Message by t
DN is received and stored by the Report Sender to

ge transmission
essage is subjected to the Acknowle
T edgement Message is created
ledgement
Message Sender Ior this part o
the Acknowledgement Messa
M
This MDN
The
reIerred to as ICSR
K-MDN is received an
nsmission oI the Acknowl
The A nt Message is evalu
Safety
The elec ansmitted in one Message Transaction betw
conta Message.
Safety mes
An ED luding the inIormation provided Io
conta Iety File exchanged between one Sender
Transacti
Sende
Pers ng an EDI Message Ior tra
Sender
IdentiIicati combined EDI qualiIier and ID oI the Sender.
Sponsor
An in any, institution or organ
manag nancing oI a clinical trial (A
Standard arkup language (SGML)
Internation d (ISO 8879) computer language
content and logical structure (chapters, paragrap
speciIy a docu markup language or tag set. Such a speciIication i
deIin ML is not in
It is a me
SGML e idea that documents have structural
described w rence to how such elements should be displayed.

2. Abbreviations
ADR Adverse drug reaction
AE Adverse event
ATC Anatomical-Therapeutic-Chemical ClassiIication
CCDS Company Core Data Sheet
CCSI Company Core SaIety InIormation
CHMP Committee Ior Medicinal Products Ior Human Use
CMD(h) l Recognition and Decentralised Procedures Coordination Group Ior Mutua
(human)
CMS Concerned Member State(s)
CV(s) Curriculum (Curricula) Vitae
DHPC(s)
commonly called
Direct Healthcare ProIessional Communication(s)
commonly called
'DDL( 'Dear Doctor Letter(s) s)
DCP Decentralised procedure
DUS Drug utilisation studies
EBD EU Birth Date
EC European Commission
EDI Electronic data interchange
EEA European Economic Area
EMEA European Medicines Agency; 'the Agency
EU European Union
EVMPD al Product Dictionary EudraVigilance Medicin
EVPM EudraVigilance Post-Authorisation Module
FDA US Food and Drug Administration
IBD International Birth Date
ICH International ConIerence on Harmonisation
ICSR( Individual Case SaIety Report(s) s)
IMP edicinal product Investigational m
INN International Non-Proprietary Name
IT InIormation Technology
ISPE International Society Ior Pharmacoepidemiology
LLTs Lowest Level Terms (oI MedDRA)
MAH(s) Marketing Authorisation Holder(s)
MedDRA ctivities Medical Dictionary Ior Regulatory A
MPR Medicinal Product Report
MRP Mutual recognition procedure
NUI Non-Urgent InIormation
PAR Public Assessment Report
PASS Post-authorisation saIety study
PhVWP CHMP Pharmacovigilance Working Party
PL Package LeaIlet
PSUR(s) Periodic Update SaIety Report(s)
PUMA Paediatric Use Marketing Authorisation
QPPV QualiIied Person Responsible Ior Pharmacovigilance
RA Rapid Alert
RMS(s) Member State(s) ReIerence
SOCs System Organ Classes (oI MedDRA)
SPC Summary oI Product Characteristics
SUSAR(s) Suspected unexpected serious adverse reaction(s)
USR Urgent saIety restriction
WHO World Health Organization
ANNEXES 208/229
3. Other EU Guidelines and Relevant Terminology
3.1 Other EU Pharmacovigilance Guidelines
(EDI) of Individual
Safety Reports (ICSRs) and Medicinal Product Reports (MPRs) in
ring the Pre- and Post-Authorisation Phase in the
This Guideline is published under document reIerence number EMEA/115735/2004 on the
3.1.1 Note for Guidance on the Electronic Data Interchange
Case
Pharmacovigilance Du
European Economic Area (EEA)
Adopted at Community level in September 2004.
EudraVigilance website www.eudravigilance.emea.europa.eu.
3.1.2 Technical Documentation EudraVigilance Human Version 7.0 Processing
of Safety Messages and Individual Case Safety Reports (ICSRs)
This Guidel
EudraVigila udravigilance.emea.europa.eu
Adopted at Community level in July 2004.
ine is published under document reIerence number EMEA/H/20665/04 on the on the
nce website www.e .
Guid bsite
http://www.e
3.1.3 Guideline on the Exposure to Medicinal Products During Pregnancy: Need
for Post-Authorisation Data
This eline (EMEA/CHMP/313666/2005) is available on the EMEA we
mea.europa.eu.
Guideline on the Conduct of Pharmacovigilance for Medicines Used
Paediatric Popula
3.1.4 by the
tion
This Guideline (EMEA/CHMP/PhVWP/235910/2005) is available on the EMEA website
http://www.emea.europa.eu.
3.1.5 Guideline on the Use of Statistical Signal Detection Methods in the
EudraVigilance Data Analysis System
line (EMEA/106464/2006, latest version) is available on the EME
mea.europa.eu
This Guide A website
http://www.e .
3.2 Relevant Terminology
3.2.1 Medical Terms
See Annex 4
3.2.2 n
://www.pheur.org
.5 Ior Dictionary Ior Regulatory Activities (MedDRA).
Standard Terms on Pharmaceutical Dosage Forms, Routes of Administratio
and Containers
These Standard Terms are published by the Council oI Europe and are available on the website oI the
European Pharmacopoeia http .
ANNEXES 209/229
3.2.3 Controlled Vocabulary for Routes of Administration
See Annex 4
3.2.4
.7.1.
Controlled Vocabulary for Units and Measurements
See Annex 4.7.2.
3.3 Other Relevant Guidelines Specific to Similar Biological Medicinal Products
ing guidelines are not speciIic to pharmacovigilance but contain sp The Iollow eciIic
pharmacovigilance inIormation. They are not reIerenced elsewhere in Volume 9A.
This Guideline (CHMP/437/04, latest version) is available on the EMEA website
3.3.1 Guideline on Similar Biological Medicinal Products
3.3.2 Guideline on Similar Biological Medicinal Products Containing
Biotechnology-derived Products as Active Substance: Non-clinical and
This Guideli ion) is available on the EMEA website
http://www.emea.europa.eu
Clinical Issues
ne (EMEA/CHMP/BMWP/42832/2005, latest vers
.
eline on Similar Biological Medicinal Products Containing
edicinal Products Containing Recombinant
P/BMWP/94526/2005, latest version) is available on the EMEA website
3.3.3 Annex to Guid
Clinical Issues:
Guidance on Similar M
Erythropoietins
This guidance (EMEA/CHM
Annex to Guideline on Similar Biological Medicinal Products Containing
Biotechnology-derived Products as Active Substa
3.3.4
nce: Non-clinical and
olony Stimulating Factor
This guidance (EMEA/CHMP/BMWP/31329/2005, latest version) is available on the EMEA website
Clinical Issues:
Guidance on Similar Medicinal Products Containing Recombinant
Granulocyte-c
.
3.3.5 Annex to Guideline on Similar Biological Medicinal Products Containing
Clinical Issues:
Guidance on Similar Medicinal Products Containing Recombinant Human
Soluble Insulin
ANNEXES 210/229
ANNEXES 211/229
ilar Biological Medicinal Products Containing
3.3.6 Annex to Guideline on Sim
Clinical Issues:
Guidance on Similar Medicinal Products Containing Somatropin
3.3.7 Guideline on Comparability of Biotechnology-derived Medicinal Products
after a Change in the Manufacturing Process: Non-clinical and Clinical
This Guideline (EMEA/CHMP/BMWP/94528/2005, latest version) is available on the EMEA website
Issues
3.4 Other Relevant Guidelines
The Iollow ntain speciIic
pharmacovigilance inIormation. They are not reIerenced elsewhere in Volume 9A.
venous and/or Intramuscular Use
website
http://www.e
ing guidelines are not speciIic to pharmacovigilance but co
3.4.1 Guideline on the Clinical Investigation of Human Anti-D Immunoglobulin
for Intra
This Guideline (EMEA/CHMP/BPWG/575/99, latest version) is available on the EMEA
mea.europa.eu.
3.4.2 Guideline on Immunogenicity Assessment of Biotechnology-Derived
Therapeutic Proteins
ersion) is available on the EMEA website
This Guideline (EMEA/CHMP/BMWP/14327/2006, latest v
.
Clinical and Non-Clinical Evaluation During the
This Guideline (EMEA/CHMP/EWP/110540/2007, latest version) is available on the EMEA website
3.4.3 Guideline on the
Consultation Procedure on Medicinal Substances Contained in Drug-Eluting
(Medicinal Substance-Eluting) Coronary Stents
4. ICH Guidelines
4.1 ICH-E2B(R2) - Maintenance of the Clinical Safety Data Management
Including: Data Elements for Transmission of Individual Case Safety
Reports
This Guideline is published under document reIerence number CPMP/ICH/287/95 modiIication corr.
on the EMEA website www.emea.europa.eu. Please note that this Guideline was previously coded as
ICH-E2B(M).
4.1.1 ICH-E2B Q&As (R5): Questions and Answers Data Elements for
Transmission of Individual Case Safety Reports
This Guideline is published under document reIerence number CPMP/ICH/3943/03 on the EMEA
website www.emea.europa.eu.
4.2 ICH-E2C(R1): Clinical Safety Data Management - Periodic Safety Update
Reports for Marketed Drugs including Addendum to ICH-E2C
This Guideline is published under document reIerence number CPMP/ICH/288/95 Ior ICH-E2C and
CPMP/ICH/4679/02 Ior ICH-E2C Addendum on the EMEA website www.emea.europa.eu as a
combined document.
4.3 ICH-E2D: Post-Approval Safety Data Management - Definitions and
Standards for Expedited Reporting
4.4 ICH-E2E: Pharmacovigilance Planning
4.5 ICH-M1: Medical Terminology - Medical Dictionary for Regulatory
Activities (MedDRA)
ReIerence to the recommendations can be Iound on the EMEA website www.emea.europa.eu.
4.6 ICH-M2: Electronic Standards for Transmission of Regulatory Information
(ESTRI) - Individual Case Safety Report (ICSR)
ReIerence to the recommendations can be Iound on the EMEA website www.emea.europa.eu.
4.7 ICH-M5: Data Elements and Standards for Drug Dictionaries
4.7.1 Routes of Administration Controlled Vocabulary
This Guideline is published under document reIerence number CHMP/ICH/175860/05 on the EMEA
ANNEXES 212/229
ANNEXES 213/229
ents Controlled Vocabulary
uidel 175818/05 on the EMEA
e www
4.7.2 Units and Measurem
This G ine is published under document reIerence number CHMP/ICH/
websit .emea.europa.eu.
5. Templates
5.1.1 Template for EU Risk Managem t Plan (EU RMP) en
See document reIerence number te www.emea.europa.eu EMEA/192632/2006 on EMEA websi .
ANNEXES 214/229
ANNEXES 215/229
5.2.1 Template for Cover Page for PSUR Submission
Serial n er~ PER IC SAFE UPDATE REPORT
S CE INN~
(s)~
DI RO CTS COVERED:
Invented Name oI the
Medicinal Product(s)
Marketin
uthorisation
Number(s)
ate(s) oI
horisation
(Und e (Harmonised)
irth Date)
Marketing
Authorisation
Holder
umb
ME
A
IOD
SUB
CO
L P
g
TY
(S):
ode
D
Aut
erlin
EU B
Ior
TAN
(S)
DU
ACTIV
AT
CIN
E
C
A
DE : C
~ ~ ~ ~
~ ~ ~ ~

AUTHOR the E
Centralise al tralis y N nal~
INTERNA L D):
PERIOD COVERED BY THIS REPORT:
ISA
d/M
TI
TION PR
utu
ONA
OC
gn
TH
EDU
ition
DA
RE
/De
TE
in
cen
(IB
U:
ed/P
Da
Reco
BIR
urel
te~
atio
from <Date> to <Date (i.e. data lock point)>
DATE OF THIS REPORT:
<Date>
VOLUME: Number~/Total ber oI volumes~
OTHER IN A
er ide m ry~
DATA LO IN D
M KET AUTHORISATION HOLDER'S NAME AND ADDRESS:
e~
Address~
NAME AND CONTACT DETAILS OF THE QPPV:
e~
Address~
phon
Fax numb
a
S A Signature~
LIST OF SERIAL NUMBERS
e umber~ Period covered~
num

FO
ntiI
CK
ING
RM
ying
PO
TIO
clar
T OF NEX
N:
iIyi Oth
AR
Nam
Nam
Tele
E-m
IGN
S
or ng inIor
T PSUR:
ation iI nec
ate
essa
~
e nu
er~
dre
RE:
mb

ss~
er~
il ad
TU
rial n

D R TION LIST
68

m nt Authority in the EU~ Number oI copies~
IST
Co
IBU
pete

6
For m al products authorised through the mutual recogn decentralised procedure the ReIerence
Member State and the Concerned Member States should be ind
8
edicin ition or
icated.
5.2.2 Template for PSUR section "Worldwide Marketing Authorisation Status"
his table is has been completed with Iictitious data.
ch Da vented
T
Country Action-Date Laun te In Name(s) Comments
Sweden 12/90
-
Bac
- -
A - 7/90
AR - 10/95
teroII -
Brazil A - 10/91 2/9
3/93
actoII
BactoII-IV
-
IV dosage Iorm
2 B
A - 1/93
United Kingd 6/92
7/94
Bacgone
Bacgone-C
(skin inIs)
) excluded
(PK)
Topical cream
AQ - 3/92
A - 4/94
Elderly (~ 65 om
Japan LA - 12/92 - - To be reIiled
France V - 9/92 - - Unrelated to saIety
Nigeria A - 5/93
A - 9/93
7/93
1/94
BactoII
BactoII
-
New indication
Etc.
Abbreviations: A authorised; AQ authorised with qualiIications; LA lack oI approval; V voluntary marketing application withdrawal by company;
AR authorisation renewal.
ANNEXES 216/229
5.2.3 Template for PSUR section "Line-listings of Individual Case Histories"
NO SEX

DOSE
DATE OF ONSET
OF REACTION
DATES OF
TREATMENT
treatment duration
REACTION
DESCRIPTION
OUTCOME COMMENT

MAH COUNTRY SOURCE AGE/ DAILY
mg/day or or
time to onset

ANNEXES 217/229
ANNEXES 218/229
5.2.4 PSUR section a u
This ta l ta h arke orisatio (e.g.: serious and
non-se ).
y s Diag s y I ud re C
s
e
Body s e reac
ontane
R latory
C u
T
s o
s in
mb
yste
e
nl
th
er
m
mp
y o
e s
oI
/A
lat
ne
am
Re
dv
e f
exa
e t
por
ers
or
mp
able
ts b
"S
e oI diIIerent possible data presen
bl
ym
um
es,
pt
m
etc.
om
ry

and
Sp
egu
Tab lati
tion
nose
on
s w
s)
All
ous
bod
s"
hi
Iro
Se
/
ies
ble i
riou
Nu
ch are
m Sp
rious
An * indicates an unlisted r

at
ont
Re
the di
aneou
action
screti
(Me
acti
lin
on
dic
on
ica
oI t
all
l st
e M
Con
dies
ting
ed)
A
, C
uth
lin
n Ho
y an
Literatur
lder
d Li
or a
Ter
s se
m
tion
pa
(Si
te
rat
gn
rm
e ta
s, S

irm ical St teratu
e
ases:
CNS
halluc
etc.
etc.
-------------
Sub-total

2
--------- --- -----
inations*
- --

0
---- -----

0
------
CV
etc.
etc.
-------------
Sub-total

--------- - ---

----- - --

----- -- ------
Etc.
TOTAL
In a Iootnote (or elsewhere), the num oI patient-cases that repres ta ted s uld be given (e.g.: x-spontaneous/regulatory clinic study,
and z-literature cases)
ber ent the bula

term sho , y- al
5.3.1 Template for Rapid Alert in Pharmacovigilance
oI the Member State/EMEA~
LERT IN PHARMACOVIGILANCE

Logo and name oI the Competent Authority

RAPID A
REFERENCE: doc.nr.~
N
o
oI pages: ~
N
o
oI attachments: ~
DATE: dd/month in
words/yy~
FROM: Member State/Agency~

TO: ALL EU MEMBER STATES
EFTA COUNTRIES CONCERNED
EMEA
EUROPEAN COMMISSION
CHMP CHAIRPERSON
RAPPORTEUR (iI applicable)
TYPE OF RAPID ALERT:

<select/delete below> Concern about a change in the risk-beneIit balance based on:
prod
Repo esting greater severity than known, new long-term
sequ
A sig s adverse reaction
Evid unexpected risk or a
h similar eIIicacy
A series oI report(s) oI unexpected serious adverse reactions
Occu or human blood- and plasma derived medicinal rrence oI vCJD in a donor oI blood used I
ucts;
rts oI an expected adverse reaction sugg
rs elae or identiIying new risk Iacto
niIicant increase in the reporting rate oI expected seriou
or epidemiological studies) indicative oI ence Irom studies (clinical trials
change in Irequency or severity oI a known risk
e eIIicacy oI a medicinal product is not established as assumed to date Knowledge that th
Evidence that the risks oI a particular product are greater than alternatives wit
Other reason: specify~
SUBJECT:
mplete as appropriate, using key words/short description of safety concern~
ternational Non-proprietary Name (INN) or Class: ~
nted name(s): ~
Procedure(s) oI marketing authorisation: <select/delete below>
Product(s) authorised through mutual recognition or decentralised procedure
Product(s) which has (have) been subject to a reIerral procedure
Other: specify~
tomical-Therapeutic-Chemical ClassiIication (ATC code): ~
Holder(s): ~
ManuIacturer(s): complete/delete if not relevant~
Indication(s): ~
Co

In
Inve
Centrally authorised (or applied Ior) product(s)
Purely nationally authorised product(s)

Strength(s): ~
Pharmaceutical Form(s) and Dosage(s): ~
oute oI Administration(s): ~ R
Ana
ANNEXES 219/229
ANNEXES 220/229
ON F REAS OR RAPID ALERT:
summarise relevant evidence for the safety concern~
SOURCE OF INFORMATION: <select/delete b ow>

Spontaneous reports
el
Clinical trial
Pre-clinical study
Other: specify~
PLANNED ACTIONS/ACTIONS TAKEN delete ACTIONS TAKEN, if not applicable. If both
ategories are applicable, identify which actions have been taken and which are planned~:
oI the marketing authorisation
as applicable~
Action Ior hum nal products Iollowing occurrence oI vCJD in
s well as expired batches~
Urgent saIety restriction/variation <delete as applicable>
y oI Product Characteristics (SPC) <select/delete below>
estriction in the availability oI a medicinal product
ealthcare ProIessionals or Patients about an identiIied risk
c
<select/delete below>

al <delete as applicable> Suspension/withdraw
Suspension oI use oI a product
e market at Recall oI the medicinal product Irom th
Hold e er/Pharmacy/Patient level delet
an blood- and plasma derived medici
a blood donor specify action and concerned batches on the market a
Changes in the Summar

Introduction oI new contraindications
Introduction oI new warnings
Reduction in the recommended dose
Restriction in the indications
R
Other: specify~
Urgent need to inIorm H
Other: <specify>
DETAILS ON PROPOSED ACTION AND/OR ACTION TAKEN:
licable~ complete/delete if not app

~
ADDITIONAL INFORMATION: complete/delete if not applicable~

~
The iss ES NO ue could aIIect (an)other Member State(s): Y
INFORMATION REQUESTED: complete/delete if not applicable~

~
PLEASE RESPOND BY: dd/month in words/yy~
NAME OF PERSON RESPONSIBLE FOR SENDING THIS MESSAGE:

~
5.3.2 Template for Non-Urgent Information in Pharmacovigilance

y oI the Member State/EMEA~
ENT INFORMATION IN PHARMACOVIGILANCE

Logo and name oI the Competent Authorit

NON-URG
REFERENCE: doc.nr.~
N
o
oI pages: ~
N
o
oI attachments: ~
DATE: dd/month in
words/yy~
FROM: Member State/Agency~

TO: ALL EU MEMBER STATES
EUROPEAN COMMISSION
CHMP CHAIRPERSON
EFTA COUNTRIES CONCERNED
EMEA

RAPPORTEUR (iI applicable)
TYPE OF NON-URGENT INFORMATION: select/delete below~

Pre-signal inIormation
ory action
ber States, but does not require a response
e of discussions from
national safety committees, when to expect an Assessment Report on certain items, current media

Request Ior inIormation
Organisational matters
Interaction with external party
Planned communication at national level
Other reason: specify~
InIormation on status oI implementation oI regulat
InIormation which might be oI interest to other Mem
e.g. withdrawal of a product for reasons other than safety, the outcom
activity
SUBJECT:
Complete as appropriate, using key words/short description of safety concern~

International Non-proprietary Name (INN) or Class: ~
Invented name(s): ~
Procedure(s) oI marketing authorisation: <select/delete below>
Centrally authorised (or applied Ior) product(s)
Mutual recognition or decentralised procedure
Purely nationally authorised product(s)
Product(s) which has (have) been subject to a reIerral procedure
Other: specify~

Strength(s): ~
Pharmaceutical Form(s) and Dosage(s): ~
Route oI Administration(s): ~
Anatomical-Therapeutic-Chemical ClassiIication (ATC code): ~
Marketing Authorisation Holder(s):
ManuIacturer(s) (iI essential):
Indication(s):
ANNEXES 221/229
ANNEXES 222/229
ONS REAS FOR NON-URGENT INFORMATION:
summarise relevant evidence for safety concern~
SOURCE OF INFORMATION: <select/delete below>

Spontaneous reports
study
Clinical trial
Pre-clinical
Other: specify~
PROPOSED ACTION AND/OR ACTION TAKEN:

~
ADDITIONAL INFORMATION: complete/delete if not applicable~

~
The issue could aIIect (an)other Member State(s): YES NO
INFORMATION REQUESTED: complete/delete if not applicable~

~
PLEASE RESPOND BY dd/month in words/yy~
NAME OF PERSON RESPONSIBLE FOR SENDING MESSAGE:

~
5.4.1 Template for Direct Healthcare Professional Communications
Date~
Document reIerence number~
Direct Healthcare Professional Communication on the association of <INN and Invented Name(s)>
with <safety concern>

Summary
A brieI description oI the saIety concern, recommendations Ior risk
minimisation (e.g. contraindications, warnings, precautions oI use) and, iI
applicable, switch to alternative treatment, preIerably in bullet points~
Recall inIormation, iI applicable (e.g. pharmacy or patient level, date oI
recall)~
A statement indicating that the inIormation has been endorsed by a national
Competent Authority/the Agency/the Marketing Authorisation Holder, iI
applicable~
Style guide: The Summary section should be in larger font size than the other
sections of the DHPC.
Further information on the safety concern
Important details about the saIety concern (adverse reaction, seriousness, statement on the suspected
causal relationship, e.g. the pharmacodynamic mechanism, temporal relationship, positive re-challenge
or de-challenge, risk Iactors), also indicating the reason Ior disseminating the DHPC at this point in
time~
Placing oI the risk in the context oI the beneIit~
Revised Product InIormation text or, preIerably, reIerence to revised Product InIormation in Annex~
An estimation oI the Irequency oI the adverse reaction or reporting rates with estimated patient
exposure~
A statement indicating any association between the adverse reaction and oII-label use, iI applicable~
A statement indicating the context in which the assessment has been conducted (national
procedure/CHMP procedure/European consensus~
A schedule Ior Iollow-up action(s) by the Marketing Authorisation Holder/Competent Authority, iI
applicable~
Further information on recommendations to healthcare professionals
II needed, details on the recommendations Ior risk minimisation ~
II needed, additional detailed instructions on how to use the new saIety or therapeutic eIIectiveness
inIormation~
Call for reporting
A reminder oI the need to report adverse reactions in accordance with the national spontaneous
reporting system~
Details (name, postal address, Iax number, website address) on how to access the national
spontaneous reporting system/Details on how to report to the Marketing Authorisation Holder~
Communication information
Date and key messages oI communication to the public~
Content and dissemination mechanism oI inIormation to the general public or Patients, iI applicable~
Contact point details Ior access to Iurther inIormation, including relevant website address(es),
telephone numbers and a postal address~
ANNEXES 223/229
ANNEXES 224/229
nexes:
ailed sc
An
Text oI the revised Product InIormation (with changes made visible), iI applicable~
Det ientiIic inIormation, iI necessary~
List oI literature reIerences, iI applicable~

6. s n equirements and dress Lists for D Submission
6 Requirements for Expedited Reporting in Member States
Abbreviations:
AU: Austria, Bund Gesundheitswesen / Agentur Ir Gesundheit und
E hrungssicherh
BE: Belgium, Directorate-General Public Health tec n: dicinal u
BG: Bulgaria, Bulgarian Drug Agency
CY: Cyprus, Pharm ervices
CZ: Czech Republic, State Institute Ior Drug Control
DE-BIArM: Germa deral Institute Ior Drugs and Medical Devices
DE-PEI: Germany, hrlich-Institut
DK: Denmark, Danish Medicines Agency
EE: Estonia, Estonian State Agency edicine
ES: Spain, Agencia Espaola de Medicamentos roductos Sanitarios
EV: EudraVigilance
FI: Finland, National Agency Ior Me ines
FR: France, AFSSAPS
GR: Greec ational Or isation I edicin
H lth
HU: Hungary, National Institute oI Pharmacy
IE: Ireland, Irish Medicines Board
IS: Iceland, LyIjastoInun Icelan edici ntrol cy)
I , A z alian arma
L te in o o e Ir imitte
L ua State d Con ency
L em rg, D i la Ph ie et d dicam
LV: Latvia, State Agency e i c L
M mber State
MT: Malta, Medicines Authority
NCA: National Com hority
Non-HP: Non-medically ed s as de in th ment
NL: Netherlands, Colleg eoord van ge idde
NO: Norway, Norwegian cines cy
PL: Poland, The OIIice F egistra OI Medicinal Products, Medical Devices Biocid
Products
PT: Portugal, Instituto Nacional da Farmacia e do Medicam o
R ania, National Medicines Agency
S den, Medical Pro ts Agen
SI: Slovenia, Agency Ior dicinal ucts an edical Devices oI the Republic oI Sloveni
SK: Slovak Republic, State Institute Ior Drug Control
UK: United Kingdom, Medicines and Healthcare Products Regulatory Agency

Di tributio R Ad ata
.1
rnae
P: Hea
T: Italy
I: Liech
T: Lith
U: Lux
S: Me
O: Rom
E: Swe
esamt Ir Sicherheit im
eit
aceuti
ny, Fe
Paul-E
Pro tio Me Prod cts

cal S
oI M
dic
or M
dic M
co
Arzne
trol Ag
armac
nes oI

report
eling
Agen
tion
cy
Prod
s
y P
es
nes Co
l

es Me
epubli
Iined
neesm
d M
e, N
care ProIessional
gen
nste
nia,
bou
gan
(The
a del F
llstell
icines
on de
oI M
nt Aut
conIirm
e ter b
Medi
or R
duc
Me
Agen
ents
atvia
is docu
len
ent
ia It
, K ntr
Me
ivis
pete
dic the R oI
.
And al
a
ANNEXES 225/229
6.1.1 Specific Expedited (15-days) Reporting Requirements in Member States for ICSRs from Spontaneous Reporting and Non-
Interventional Studies Occurring in the Territory of a given Member State
Seriousness All suspected serious ICSRs
All suspected non-
serious ICSRs
15 days reporting Periodic
A
u
t
h
o
r
i
s
a
t
i
o
n

r
o
c
e
d
u
r
e

P
Time frame and reporting
ICSRs to be sent to NCA
ICSRs to be sent to EV EMEA
post-authorisation module only
ICSRs to be sent to
NCA
AU, CZ, DE-BIArM, DE-PEI, DK, EE, E *, HU, IE, IS
1
, IT, LT, LU, LV, MT,
NL, NO, PL*, PT K, UK
PL
1
, RO
1

BE, BG, S, FI, FR, GR
, RO, SE, SI, S HP
CY, IS
1
,LI
s
t

DK, HU LI
Spontaneou
repor
Non HP

AU, CZ, DE-BIArM, DE-PEI, DK, EE, E *, HU, IE, IS
1
NL, NO, PL*, PT K, UK
PL
1

HP
BE, BG, S, FI, FR, GR
, RO, SE, SI, S
IS
1

C
e
n
t
r
a
l
l
y

a
p
p
r
o
v
e
d

n

s
DK, HU
Reports from
no
interventional
studie
Non HP

AU, CZ, DE-BIArM, DE-PEI, DK, EE, ES, FI, FR, GR*, HU, IE, IS
1
NL, NO, PL*, PT, RO, S SI, SK, UK
PL
1
, RO
1

BE, BG,
E, HP
CY, IS
1
,LI
s
DE-BIArM, DK, HU LI
Spontaneou
report

Non HP

AU, BE, BG, CZ, DE-BIArM, DE-PEI, DK, EE, ES, FI, FR, GR*, HU, IE, IS
1
NL, NO, PL*, PT, RO, S SI, SK, UK
PL
1

HP E,
IS
1

P
u
r
e
l
y

N
a
t
i
o
n
a
l

DE-BIArM, DK, HU
Reports from
non
interventional
studies
Non HP

P
AU, BE, BG, CZ, DE-BI U, LV, MT,
PL
1
, RO
1

ArM, DE-PEI, DK, EE, ES, FI, FR, GR*, HU, IE, IS
1
, IT, LT, L
NL, NO, PL*, PT, RO, SE, SI, SK, UK
CY, IS
1
,LI
H s
P DE-BIArM, DK, HU LI
Spontaneou
report

Non H

P
AU, BE, BG, CZ, DE-BI
1
U, LV, MT,
PL
1

H
ArM, DE-PEI, DK, EE, ES, FI, FR, GR*, HU, IE, IS , IT, LT, L
NL, NO, PL*, PT, RO, SE, SI, SK, UK
IS
1

M
R
P
,

D
e
c
e
n
t
r
a
l
i
s
e
d
,

E
x
-
R
e
f
e
r
r
a
l

al
P DE-BIArM, DK, HU
Reports from
non
intervention
studies
Non H
*: Cases should be submitted to NCA both electronically and in hard copy (CIOMS I Iorm). IS
1
: Cases to be sent electronically to both the Icelandic Medicines Control Agency and to EV EMEA p
authorisation module. PL
1
: Cases recommended to be reported to Polish NCA in a timeIrame convenient Ior MAH. RO
1
: Cases to be reported to Romanian NCA on a monthly basis.
ost-
ANNEXES 226/229
6.1.2 Specific Expedited (15-days) Reporting Requirements in Member States for ICSRs from Spontaneous Reporting and Non-
Interventional Studies Occurring in the Territory of Another Member State
Seriousness All suspected serious ICSRs
15 days reporting
A
u
t
h
o
r
i
s
a
t
i
o
n

P
r
o
c
e
d
u
r
e

Time frame and reporting
ICSRs to be sent to
NCA
ICSRs to be sent to NCA when RMS or Rapporteur MS ICSRs to be sent to EV EMEA post-authorisation module only *

CZ, IE, UK BG, CY, EE, IS, IT, LT, SK
HP
UK
1

Spont neous a
report

Non HP

HP
UK
1
CZ, IE, UK BG, EE, IS, IT, LT, SK
C
e
n
t
r
a
l
l
y

a
p
p
r
o
v
e
d

in tional

Reports from
non
terven
studies
Non HP

HP
U
1
K BG, CY, EE, IE, IS, LT, SK
Spontaneous
report

Non HP

HP
UK
1
BG, EE, IE, IS, LT, SK
P
u
r
e
l
y

N
a
t
i
o
n
a
l

Reports from
non
interventional
studies
Non HP
U
1 AU
1
, BE
1 1
HU, IE, IS
, BG , CZ, DE-BIArM, DE-PEI, EE , ES, FI, FR, GR,
1
, LU, LV, MT, NL, PL, PT, RO, SE, SI, SK
1
, UK HP
K AU
1
, BG
1
,CY, EE
1
, IS
1
, IT, LT, SK
1

Spontaneous
report

Non HP

HP
UK
AU
1
, BE
HU, IE, IS
1
, LU, LV, MT , SK
1
, UK
1

, BG
1
, CZ, DE-BIArM, DE-PEI, EE
1
, ES, FI, FR, GR,
, NL, PL, PT, RO, SE, SI
AU
1
, BG
1
, EE
1
, IS
1
, IT, LT, SK
1

M
R
P
,

D
e
c
e
n
t
r
a
l
i
s
e
d
,

E
x
-
R
e
f
e
r
r
a
l

Reports from
non
interventional
studies
Non HP
*: ICSRs should not be sent to EV EMEA post-authorisation module by the MAH as they are made available by the NCA where the reaction occurred. AU
1
, BG
1
, EE1, IS
1
, SK
1
: Cases to be sent
electronically to EV EMEA post-authorisation module and in addition to the NCA iI country is RMS. UK
1
: For Black Triangle products in United Kingdom (new products under intensive monitoring).

ANNEXES 227/229
ANNEXES 228/229
6.1.3 Specific Expedited (15-days) Reporting Requirements in Member States for ICSRs from Spontaneous Reportin Non
Interventional Studies Occurring Outside the EU
g and -
Seriousness / Expectedness
All suspected serious ICSRs Suspected unexpected serious ICSRs only
15 days reporting 15 days reporting
A
u
t
h
o
r
i
s
a
t
i
o
n

P
r
o
c
e
d
u
r
e

Time frame and reporting ICSRs to be sent to EV
EMEA post-authorisation
module only *
ICSRs to be sent to NCA
ICSRs to be sent to EV EMEA i odule post-author sation m
only *

HP
CY
BE, CZ
1
, DE-BIArM, DE-PEI, DK, FR, IE, LU, MT
1
, PL
2
,
RO
2
, SE, UK
AU, BG, CZ
1
, EE, ES, FI, GR, HU, IS, I, LT MT
1
,
NL
1
, NO, PT, SI, S
IT, L
K
, LV,
Spontaneous
report

Non HP DK

HP

BE, CZ
1
, DE-BIArM, DE-PEI, DK, FR, IE, LU, MT
1
, PL
2
,
RO
2
, SE, UK
AU, BG, CZ
1
, EE, ES, FI, GR, HU, IS, I T, LV , NL
1
,
NO, PT, SI, SK
T, L , MT
1
C
e
n
t
r
a
l
l
y

a
p
p
r
o
v
e
d

Reports from
non
interventional
studies
Non HP DK

HP
CY, IT BE, DE-BIArM, DE-PEI, DK, FR, IE, LU, PL
2
, RO
2
, SE, UK
AU, BG, CZ, EE, ES, FI, GR, HU, IS, T, LV NL
1
,
NO, PT, SI, SK
LI, L , MT,
Spontaneous
report

Non HP DK

HP
IT BE, DE-BIArM, DE-PEI, DK, FR, IE, LU, PL
2
, RO
2
, SE, UK
AU, BG, CZ, EE, ES, FI, GR, HU, IS, L V, M
1
, NO,
PT, SI, SK
T, L T, NL
P
u
r
e
l
y

N
a
t
i
o
n
a
l

Reports from
non
interventional
studies
Non HP DK

HP
CY, IT
BE, CZ
1
, DE-BIArM, DE-PEI, DK, EE
2
,

FR, IE, LU, MT
1
,
NL
2
, PL
2
, RO
2
, SE, UK
AU, BG, CZ
1
, EE
2
, ES, FI, GR, HU, IS, T, LV
1
,NL
1
,
NO, PT, SI, SK
LI, L , MT
Spontaneous
report

Non HP DK

HP
IT
BE, CZ
1
, DE-BIArM, DE-PEI, DK, EE
2
, FR, IE, LU, MT
1
,
NL
2
, PL
2
, RO
2
, SE, UK
AU, BG, CZ
1
, EE
2
, ES, FI, GR, HU, I , LV, ,NL
1
,
NO, PT, SI, SK
S, LT MT
1
M
R
P
,

D
e
c
e
n
t
r
a
l
i
s
e
d
,

E
x
-
R
e
f
e
r
r
a
l

Reports from
non
interventional
studies
Non HP DK
*: Reporting obligations are already IulIilled when submitting to EV EMEA post-authorisation module. CZ
1
, MT
1
: Cases to be sent to EV EMEA post-authorisation module and in addition CA iI
country is Rapporteur-MS or RMS. EE
2
: Cases to be sent to EV EMEA post-authorisation module and in addition to NCA iI EE is RMS. NL
1
: Provided that a waiver has been obtained not port t
NCA; all serious ICSRs allowed. NL
2
: ICSRs to be sent to NCA when NL are RMS; all serious ICSRs allowed. PL
2
and RO
2
: Cases to be submitted to NCAs electronically until access to ata
System is available.
to N
to re
EV D
o the
Analysis
ANNEXES 229/229
"#$%6.2 Distribution Requirements and Address Lists for Periodic Safety Update
Reports
A table reIlecting the requirements will be kept up-to-date on the EMEA website
&'www.emea.europa.eu'&.

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Final September 2008

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