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VOLUME 9A 7

of the Rules Governing Medicinal Products in the European Union 8

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– Guidelines on Pharmacovigilance for Medicinal Products for Human Use – 10

Draft Volume 9A version dated 16 December 2006

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GENERAL OUTLINE OF CONTENTS 11

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INTRODUCTION 13

1. Legal Basis and Structure of Volume 9A 14

2. Legal Framework for Pharmacovigilance 15

3. The Roles of the Various Parties 16

PART I – Guidelines for Marketing Authorisation Holders 17

1. � General Principles 18

2. � Requirements for Pharmacovigilance Systems, Monitoring of Compliance and 19 Pharmacovigilance Inspections 20

3. � Requirements for Risk Management Systems 21

4. � Requirements for Expedited Reporting of Individual Case Safety Reports 22

5. � Requirements for Reporting in Special Situations 23

6. � Requirements for Periodic Safety Update Reports 24

7. � Requirements for Company-Sponsored Post-Authorisation Safety Studies 25

8. � Overall Pharmacovigilance Evaluation and Safety-Related Regulatory Action 26

PART II – Guidelines for Competent Authorities and the Agency 27

1. Undertaking of Pharmacovigilance Activities by Competent Authorities in Member States 28

2.A Conduct of Pharmacovigilance for Centrally Authorised Products 29

2.B Crisis Management Plan regarding Centrally Authorised Products 30

3. Conduct of Pharmacovigilance for Medicinal Products Authorised through the Mutual 31 Recognition or Decentralised Procedure 32

4. Rapid Alert and Non-Urgent Information System in Pharmacovigilance 33

5. Referrals in Case of Safety Concerns Related to Products Authorised in the EU and CHMP 34 Opinions Following Suspension or Revocation of a Medicinal Product by a Member State 35

6. Principles of Collaboration with the World Health Organization in Matters of International 36 Pharmacovigilance 37

PART III – Guidelines for Marketing Authorisation Holders, Competent Authorities 38 and the Agency on Electronic Exchange of Pharmacovigilance Information 39 in the EU 40

PART IV – Guidelines for Marketing Authorisation Holders and Competent Authorities 41 on Pharmacovigilance Communication 42

PART V – Guidelines for Marketing Authorisation Holders and Competent Authorities 43 on Product- or Population-Specific Pharmacovigilance 44

1. Guideline on Exposure to Medicinal Products During Pregnancy: Need for Post-Authorisation 45 Data 46

2. Guideline on the Conduct of Pharmacovigilance for Medicines Used by the Paediatric 47 Population 48

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ANNEXES 50

1. Glossary 51

2. Abbreviations 52

3. Terminology 53

4. ICH Guidelines 54

5. Templates 55

6. Distribution Requirements and Address Lists for Data Submission 56

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DETAILED TABLE OF CONTENTS 57

INTRODUCTION _________________________________________________________ 14 58

1. Legal Basis and Structure of Volume 9A (Human Pharmacovigilance) __________ 14 59

2. Legal Framework for Pharmacovigilance___________________________________ 15 60

3. The Roles of the Various Parties __________________________________________ 16 61 3.1 The Marketing Authorisation Holder ________________________________________ 16 62 3.2 The Competent Authorities ________________________________________________ 16 63 3.2.1 The Competent Authorities of the Member States ______________________________ 16 64 3.2.2 The European Commission ________________________________________________ 16 65 3.3 The EU Pharmacovigilance System _________________________________________ 16 66 3.3.1 The Role of Competent Authorities of the Member States for Products Authorised Through 67

National Procedures _____________________________________________________ 16 68 3.3.2 The Role of the Competent Authority of the Reference Member State for Products 69

Authorised Through the Mutual Recognition or Decentralised Procedure ____________ 16 70 3.3.3 The Role of the Rapporteur for Products Authorised Through the Centralised Procedure 17 71 3.3.4 The Role of the Agency___________________________________________________ 17 72 3.3.5 The Role of the CHMP Pharmacovigilance Working Party _______________________ 17 73

PART I – GUIDELINES FOR MARKETING AUTHORISATION HOLDERS – __________ 18 74

1. General Principles ______________________________________________________ 19 75 1.1 Legal Basis of the Marketing Authorisation Holder’s Obligations for Pharmacovigilance 19 76 1.2 Roles and Responsibilities of the Marketing Authorisation Holder and the Qualified Person 77

Responsible for Pharmacovigilance _________________________________________ 19 78 1.2.1 The Role and Responsibilities of the Qualified Person Responsible for Pharmacovigilance79

______________________________________________________________________ 20 80 1.2.2 Responsibilities of the Marketing Authorisation Holder in relation to the Qualified Person 81

Responsible for Pharmacovigilance _________________________________________ 21 82 1.3 Contractual Arrangements_________________________________________________ 21 83

2. Requirements for Pharmacovigilance Systems, Monitoring of Compliance and 84 Pharmacovigilance Inspections ___________________________________________ 23 85

3. Requirements for Risk Management Systems _______________________________ 24 86 3.1 Introduction ____________________________________________________________ 24 87 3.2 Description of the Risk Management System __________________________________ 26 88 3.3 EU Risk Management Plan (EU-RMP)_______________________________________ 26 89 3.4 Situations Requiring an EU-RMP ___________________________________________ 27 90 3.4.1 Marketing Authorisations via the Centralised Procedure _________________________ 27 91 3.4.2 Marketing Authorisations via the Mutual Recognition or Decentralised Procedures ____ 28 92 3.5 Location in the Application________________________________________________ 28 93 3.6 Safety Specification______________________________________________________ 28 94 3.6.1 Non-clinical Part of the Safety Specification __________________________________ 29 95 3.6.2 Clinical Part of the Safety Specification ______________________________________ 29 96 3.6.2.a) Limitations of the Human Safety Database____________________________________ 29 97 3.6.2.b) Populations not studied in the Pre-Authorisation Phase __________________________ 30 98 3.6.2.c) Adverse Events/Adverse Reactions__________________________________________ 30 99

Identified risks that require further evaluation_____________________________________________ 30 100 Potential risks that require further evaluation _____________________________________________ 30 101 Presentation of risk data______________________________________________________________ 31 102

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3.6.2.d) Identified and Potential Interactions including Food-Drug and Drug-Drug Interactions _ 31 103 3.6.2.e) Epidemiology __________________________________________________________ 32 104 3.6.2.f) Pharmacological Class Effects _____________________________________________ 32 105 3.6.2.g) Additional EU Requirements ______________________________________________ 32 106

Potential for overdose _______________________________________________________________ 32 107 Potential for transmission of infectious agents ____________________________________________ 32 108 Potential for misuse for illegal purposes _________________________________________________ 32 109 Potential for off-label use ____________________________________________________________ 33 110 Potential for off-label paediatric use ____________________________________________________ 33 111

3.6.3 Summary ______________________________________________________________ 33 112 3.7 Pharmacovigilance Plan __________________________________________________ 33 113 3.7.1 Routine Pharmacovigilance________________________________________________ 33 114 3.7.2 Additional Pharmacovigilance Activities and Action Plans _______________________ 33 115 3.7.3 Action Plan for Safety Concerns ____________________________________________ 34 116 3.8 Evaluation of the Need for Risk Minimisation Activities _________________________ 34 117 3.8.1 Potential for Medication Errors_____________________________________________ 35 118 3.9 The Risk Minimisation Plan _______________________________________________ 36 119 3.10 Risk Minimisation Activities_______________________________________________ 36 120 3.10.1 Risk Communication_____________________________________________________ 36 121 3.11 The Marketing Authorisation ______________________________________________ 36 122 3.12 Ensuring the Effectiveness of Risk Minimisation Activities_______________________ 37 123 3.12.1 Assessment of Risk Minimisation___________________________________________ 37 124 3.13 Summary of Activities in the EU-RMP_______________________________________ 37 125 3.14 Submission of Updated EU-RMP Documents _________________________________ 38 126 3. TABLE: METHODS FOR RISK MINIMISATION ___________________________________________________________ 40 127

1. Risk Minimisation ______________________________________________________________ 40 128 1.1 Provision of Information _________________________________________________________ 40 129 1.1.1 Additional Educational Material ___________________________________________________ 40 130 1.2 Legal Status of a Medicine _______________________________________________________ 41 131 1.3 Control at Pharmacy Level _______________________________________________________ 42 132 1.4 Control of Prescription Size or Validity _____________________________________________ 42 133 1.5 Informed Consent and other Patient Aspects__________________________________________ 42 134 1.6 Restricted Access Programmes ____________________________________________________ 42 135 1.7 Patient Registries_______________________________________________________________ 43 136

4. Requirements for Expedited Reporting of Individual Case Safety Reports _______ 44 137 4.1 Introduction ____________________________________________________________ 44 138 4.2 Reporting Time Frames___________________________________________________ 45 139 4.3 Requirements by Reporting Source__________________________________________ 46 140 4.3.1 Spontaneous Reports from Healthcare Professionals ____________________________ 46 141 4.3.2 Reports Published in the Worldwide Literature ________________________________ 47 142 4.3.3 Information on Adverse Reactions from the Internet ____________________________ 48 143 4.3.4 Reports from Post-Authorisation Studies _____________________________________ 48 144 4.3.5 Reports from Patients and Other Consumers __________________________________ 49 145 4.3.6 Reports from Other Non-Medical Sources ____________________________________ 49 146 4.3.7 Change in Nature, Severity or Outcome of an Expected Adverse Reaction ___________ 49 147 4.4 Data Elements for the Report ______________________________________________ 49 148 4.5 Method of Reporting _____________________________________________________ 50 149 4.6 Impact of Reported Suspected Adverse Reactions on the Overall Safety Profile of a 150

Product and its Summary of Product Characteristics ____________________________ 50 151

5. Requirements for Reporting in Special Situations ____________________________ 51 152 5.1 Introduction ____________________________________________________________ 51 153 5.2 Reporting in the Period between the Submission of the Marketing Authorisation 154

Application and the Granting of the Marketing Authorisation _____________________ 51 155 5.3 Reporting of Outcomes of Use of a Medicinal Product During Pregnancy ___________ 51 156

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5.4 Reporting of Adverse Reactions during Breastfeeding ___________________________ 52 157 5.5 Reporting of Data on Use of Medicinal Products in Children _____________________ 53 158 5.6 Reporting from Compassionate/Named-Patient Use_____________________________ 53 159 5.7 Reporting of Lack of Efficacy______________________________________________ 53 160 5.8 Reporting of Suspected Transmission of Infectious Agents _______________________ 53 161 5.9 Reporting in Relation to Overdose, Abuse and Misuse___________________________ 54 162 5.10 Reporting of Medication Errors ____________________________________________ 54 163

6. Requirements for Periodic Safety Update Reports ___________________________ 56 164 6.1 Introduction ____________________________________________________________ 56 165 6.2 General Principles _______________________________________________________ 56 166 6.2.1 General Scope of Information ______________________________________________ 56 167 6.2.2 One Periodic Safety Update Report for Products Containing an Active Substance 168

Authorised to One Marketing Authorisation Holder_____________________________ 57 169 6.2.3 Products Authorised to More Than One Marketing Authorisation Holder ____________ 57 170 6.2.4 Frequency of Review and Reporting_________________________________________ 57 171 6.2.4.a Regular and Ad Hoc Submission of Periodic Safety Update Reports________________ 57 172 6.2.4.b Submission of Periodic Safety Update Reports for Renewal of Marketing Authorisations 58 173 6.2.4.c Circumstances Where the Periodicity May Be Amended _________________________ 59 174 6.2.4.d Preparation of Periodic Safety Update Report according to the International Birth Dates 60 175 6.2.5 Reference Safety Information ______________________________________________ 61 176 6.2.6 Presentation of Data on Individual Cases _____________________________________ 62 177 6.2.6.a Sources of Information ___________________________________________________ 62 178 6.2.6.b Description of the Adverse Reaction_________________________________________ 62 179 6.2.6.c Line listings and/or Summary Tabulations ____________________________________ 63 180 6.3 Model for a Periodic Safety Update Report (PSUR)_____________________________ 63 181 6.3.1 PSUR section “Executive Summary” ________________________________________ 63 182 6.3.2 PSUR section “Introduction” ______________________________________________ 64 183 6.3.3 PSUR section “Worldwide Marketing Authorisation Status”______________________ 64 184 6.3.4 PSUR section “Update of Regulatory Authority or Marketing Authorisation Holder 185

Actions taken for Safety Reasons” __________________________________________ 65 186 6.3.5 PSUR section “Changes to Reference Safety Information” _______________________ 65 187 6.3.6 PSUR section “Patient Exposure”___________________________________________ 65 188 6.3.7 PSUR section “Presentation of Individual Case Histories”________________________ 66 189 6.3.7.a “Cases Presented as Line-Listings”__________________________________________ 67 190 6.3.7.b “Cases Presented as Summary Tabulations”___________________________________ 68 191 6.3.7.c “Marketing Authorisation Holder’s Analysis of Individual Case Histories” __________ 68 192 6.3.8 PSUR section “Studies” __________________________________________________ 69 193 6.3.8.a “Newly Analysed Studies” ________________________________________________ 69 194 6.3.8.b “Targeted New Safety Studies”_____________________________________________ 69 195 6.3.8.c “Published Studies”______________________________________________________ 69 196 6.3.8.d “Other” _______________________________________________________________ 69 197 6.3.9 PSUR section “Other information” __________________________________________ 69 198 6.3.9.a “Efficacy-related Information” _____________________________________________ 69 199 6.3.9.b “Late-breaking Information”_______________________________________________ 70 200 6.3.9.c “Risk Management Plan” _________________________________________________ 70 201 6.3.9.d “Benefit-Risk Analysis Report” ____________________________________________ 70 202 6.3.10 PSUR section “Overall Safety Evaluation”____________________________________ 70 203 6.3.11 PSUR section “Conclusion” _______________________________________________ 71 204 6.4 Contents of the PSUR Summary Bridging Report ______________________________ 71 205 6.5 Contents of the PSUR Addendum Report_____________________________________ 72 206

7. Requirements for Company-Sponsored Post-Authorisation Safety Studies _______ 73 207 7.1 Introduction ____________________________________________________________ 73 208 7.2 Extent and Objectives of Post-Authorisation Safety Studies ______________________ 74 209

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7.3 Conduct of Post-Authorisation Safety Studies _________________________________ 75 210 7.4 Liaison with Competent Authorities _________________________________________ 75 211 7.4.1 Evaluation of the Protocol_________________________________________________ 75 212 7.4.2 Reporting of Adverse Reactions ____________________________________________ 76 213 7.4.3 Progress and Final Study Reports ___________________________________________ 76 214 7.5 Promotion of Medicinal Products ___________________________________________ 77 215 7.6 Participation of Healthcare Professionals _____________________________________ 77 216 7.7 Ethical Issues___________________________________________________________ 77 217 7.8 Procedure for Complaints _________________________________________________ 78 218 7.9 Data Sources ___________________________________________________________ 78 219 7. TABLE: EPIDEMIOLOGICAL METHODS FOR POST-AUTHORISATION SAFETY STUDIES _____________________________ 79 220

1. Study Designs _________________________________________________________________ 79 221 1.1 Methods for Active Surveillance___________________________________________________ 79 222 1.1.1 Sentinel Sites__________________________________________________________________ 79 223 1.1.2 Intensive Monitoring Schemes ____________________________________________________ 80 224 1.1.2 Drug Event Monitoring __________________________________________________________ 80 225 1.1.3 Registries_____________________________________________________________________ 80 226 1.2 Comparative Observational Studies ________________________________________________ 81 227 1.2.1 Cross-sectional Study (Survey) ____________________________________________________ 81 228 1.2.2 Cohort Study __________________________________________________________________ 81 229 1.2.3 Case-control Study _____________________________________________________________ 81 230 1.2.4 Other Novel Designs ____________________________________________________________ 82 231 1.3 Clinical Trials _________________________________________________________________ 82 232 1.3.1 Large Simple Trials_____________________________________________________________ 83 233 1.4 Other Studies__________________________________________________________________ 83 234 1.4.1 Occurrence of Disease___________________________________________________________ 83 235 1.4.2 Drug Utilisation Study___________________________________________________________ 83 236 2. Data Sources __________________________________________________________________ 83 237

8. Overall Pharmacovigilance Evaluation and Safety-Related Regulatory Action ____ 85 238 8.1 Introduction ____________________________________________________________ 85 239 8.2 Principles of Benefit-Risk Assessment _______________________________________ 85 240 8.2.1 Assessment of Benefits ___________________________________________________ 86 241 8.2.2 Assessment of Risks _____________________________________________________ 86 242 8.2.3 Benefit-Risk Assessment__________________________________________________ 86 243 8.3 Improving the Risk-Benefit Balance_________________________________________ 87 244 8.4 Withdrawal of a Product from the Market on Risk-Benefit Grounds ________________ 88 245 8.5 Communication _________________________________________________________ 89 246

PART II – GUIDELINES FOR COMPETENT AUTHORITIES AND THE AGENCY –_____ 90 247

1. Undertaking of Pharmacovigilance Activities by Competent Authorities in Member 248 States_________________________________________________________________ 91 249

1.1 Introduction ____________________________________________________________ 91 250 1.2 Establishment of a Pharmacovigilance System_________________________________ 92 251 1.3 Management of Spontaneous Reporting Programmes ___________________________ 92 252 1.3.1 General Principles _______________________________________________________ 92 253 1.3.2 Collection and Validation of Individual Case Safety Reports (ICSRs)_______________ 93 254 1.3.3 Storage of Individual Case Safety Reports ____________________________________ 94 255 1.3.4 Processing of Individual Case Safety Reports__________________________________ 94 256 1.3.4.a Evaluation of Individual Case Data__________________________________________ 94 257 1.3.4.b Management of Duplicate Reports __________________________________________ 95 258 1.3.4.c Transmission of Individual Case Safety Reports _______________________________ 95 259 1.3.4.d Processing of Individual Case Safety Reports for Signal Identification ______________ 95 260 1.3.4.e Provision of Information to the World Health Organization and Other International Bodies261

______________________________________________________________________ 96 262

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1.3.5 Feedback Information to Reporting Healthcare Professionals _____________________ 96 263 1.3.6 Quality Management _____________________________________________________ 96 264 1.3.7 Confidentiality and Security _______________________________________________ 96 265 1.4 Company-Derived Pharmacovigilance Data ___________________________________ 96 266 1.4.1 Risk Management Plans __________________________________________________ 97 267 1.4.2 Individual Case Safety Reports _____________________________________________ 97 268 1.4.3 Periodic Safety Update Reports ____________________________________________ 97 269 1.4.4 Data from Company-Sponsored Post-Authorisation Safety Studies_________________ 98 270 1.4.5 Benefit-Risk Reviews ____________________________________________________ 98 271 1.4.6 Reports on Post-Authorisation Commitments__________________________________ 99 272 1.4.7 Other Data _____________________________________________________________ 99 273 1.5 Pharmacovigilance Data from Other Sources __________________________________ 99 274 1.5.1 Intensive Monitoring Schemes _____________________________________________ 99 275 1.5.2 Data on Medication Errors, Overdose, Misuse and Abuse ________________________ 99 276 1.5.3 Other Data Relevant for Pharmacovigilance__________________________________ 100 277 1.6 Procedures for Data Exchange and Evaluation of Safety Concerns ________________ 100 278 1.6.1 Transmission of Individual Case Safety Reports of Serious Adverse Reactions ______ 100 279 1.6.2 Transmission of Individual Case Safety Reports on Non-Serious Adverse Reactions __ 101 280 1.6.3 Procedures for Transmission and Management of Signals _______________________ 101 281 1.6.4 Technologies for Data Transmission to Facilitate Implementation of the Procedures 282

Conforming to the EU Pharmacovigilance System_____________________________ 101 283 1.7 Changes to Terms of Marketing Authorisations _______________________________ 101 284 1.8 Public Communication and Transparency____________________________________ 102 285 1. APPENDIX: MANDATE, OBJECTIVES AND RULES OF PROCEDURE OF THE CHMP PHARMACOVIGILANCE WORKING PARTY __ 103 286

2.A Conduct of Pharmacovigilance for Centrally Authorised Products_____________ 104 287 2.A.1 Introduction ___________________________________________________________ 104 288 2.A.2 Legal Framework ______________________________________________________ 104 289 2.A.3 Principles_____________________________________________________________ 105 290 2.A.4 Functions and Procedures ________________________________________________ 106 291 2.A.4.1 Reporting of Adverse Reactions and Other Safety-Related Information ____________ 106 292 2.A.4.1.a Pre-Authorisation Phase _________________________________________________ 106 293 2.A.4.1.b Post-Authorisation Phase ________________________________________________ 107 294 2.A.4.2 Monitoring of the Safety Profile ___________________________________________ 107 295 2.A.4.2.a Signal Identification ____________________________________________________ 107 296 2.A.4.2.b Signal Evaluation ______________________________________________________ 108 297 2.A.4.2.c Evaluation of Periodic Safety Update Reports ________________________________ 108 298 2.A.4.2.d Evaluation of Post-Authorisation Studies, Worldwide Literature and Other Information 109 299 2.A.4.2.e Evaluation of Post-Authorisation Commitments_______________________________ 109 300 2.A.4.3 Handling of Safety Concerns _____________________________________________ 110 301 2.A.4.3.a Safety Concerns in the Pre-Authorisation Phase_______________________________ 110 302 2.A.4.3.b Safety Concerns in the Post-Authorisation Phase ______________________________ 110 303 2.A.4.4 Information to Healthcare Professionals and the Public _________________________ 111 304 2.A.4.5 Advertising ___________________________________________________________ 112 305 2.A TABLE: SUMMARY OF THE ROLES AND THE RESPONSIBILITIES OF ALL PARTNERS INVOLVED IN THE CONDUCT OF 306

PHARMACOVIGILANCE FOR CENTRALLY AUTHORISED PRODUCTS ____________________________________ 113 307

2.B Crisis Management Plan regarding Centrally Authorised Products ____________ 115 308 2.B.1 Introduction ___________________________________________________________ 115 309 2.B.2 Principles of the Crisis Management Plan____________________________________ 115 310 2.B.3 Crisis Management Structures_____________________________________________ 116 311 2.B.3.1. European Crisis Group __________________________________________________ 116 312 2.B.3.2 Agency Crisis Team ____________________________________________________ 116 313 2.B.3.3 Advisory Network at the Level of the Member States __________________________ 118 314 2.B.4 Key Points of the Procedure ______________________________________________ 118 315

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2.B.5 Public Relations________________________________________________________ 118 316

3. Conduct of Pharmacovigilance for Medicinal Products Authorised through the 317 Mutual Recognition or Decentralised Procedure ____________________________ 119 318

3.1 Introduction ___________________________________________________________ 119 319 3.2 Principles_____________________________________________________________ 119 320 3.3 Roles and Responsibilities________________________________________________ 120 321 3.3.1 Reference Member State _________________________________________________ 120 322 3.3.2 Concerned Member States________________________________________________ 120 323 3.3.3 CHMP Pharmacovigilance Working Party (PhVWP)___________________________ 120 324 3.3.4 Coordination Group for Mutual Recognition and Decentralised Procedures _________ 120 325 3.3.5 Agency and the Committee for Medicinal Products for Human Use _______________ 120 326 3.3.6 European Commission __________________________________________________ 121 327 3.3.7 Marketing Authorisation Holders __________________________________________ 121 328 3.4 Functions and Procedures for the Conduct of Pharmacovigilance _________________ 121 329 3.4.1 Pre-Authorisation Phase _________________________________________________ 121 330 3.4.1.a Risk Management Plans _________________________________________________ 121 331 3.4.1.b Concerns during the ongoing Mutual Recognition or Decentralised Procedure _______ 121 332 3.4.2 Post-Authorisation Phase ________________________________________________ 122 333 3.4.2.a Expedited Reporting of Individual Case Safety Reports_________________________ 122 334 3.4.2.b Periodic Safety Update Reports and Other Relevant Post-Authorisation Information __ 122 335 3.4.2.c Risk Management Plans _________________________________________________ 122 336 3.4.2.d Signal Identification ____________________________________________________ 122 337 3.4.2.e Signal Evaluation ______________________________________________________ 123 338 3.4.2.f Proceedings in Case of Safety Concerns_____________________________________ 123 339

Non-Urgent Safety Concerns_________________________________________________________ 123 340 Urgent Safety Concerns_____________________________________________________________ 123 341 Actions consequential to Safety Concerns_______________________________________________ 124 342 a) Actions by the Marketing Authorisation Holder ________________________________________ 124 343 b) Actions by the Competent Authorities _______________________________________________ 124 344

3.4.2.g Communication to Healthcare Professionals and the Public______________________ 124 345

4. Rapid Alert and Non-Urgent Information System in Pharmacovigilance________ 126 346 4.1 Introduction ___________________________________________________________ 126 347 4.2 Criteria_______________________________________________________________ 127 348 4.2.1 Rapid Alert ___________________________________________________________ 127 349 4.2.2 Non-Urgent Information _________________________________________________ 127 350 4.3 Procedure_____________________________________________________________ 128 351 4.3.1 Sending a Rapid Alert or a Non-Urgent Information ___________________________ 128 352 4.3.2 Responses to a Rapid Alert or Non-Urgent Information_________________________ 130 353 4.3.3 Assessment of a Rapid Alert ______________________________________________ 130 354 4.3.4 Assessment of Non-Urgent Information _____________________________________ 131 355 4. TABLE: MINIMUM INFORMATION FOR TRANSMISSION OF A RAPID ALERT OR NON-URGENT INFORMATION ALWAYS TO BE 356

PROVIDED ______________________________________________________________________________ 132 357

5. Referrals in Case of Safety Concerns Related to Products Authorised in the EU and 358 Commission Decisions Following Suspension or Revocation of a Medicinal Product by 359 a Member State _______________________________________________________ 133 360

6. Principles of Collaboration with the World Health Organization in Matters of 361 International Pharmacovigilance_________________________________________ 134 362

6.1 Introduction ___________________________________________________________ 134 363 6.2 Provision of Individual Case Safety Reports__________________________________ 134 364 6.3 Review of Signals Raised by the WHO Collaborating Centre ____________________ 134 365 6.4 Provision of Information on Safety-Related Regulatory Action in the EU___________ 134 366 a) Centrally Authorised Products ____________________________________________ 134 367

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b) Nationally Authorised Products, including those Authorised through the Mutual 368 Recognition or the Decentralised Procedure __________________________________ 135 369

6.5 Participation in the Annual Meetings of the WHO Programme for International Drug 370 Monitoring____________________________________________________________ 135 371

6.6 Other Collaboration_____________________________________________________ 135 372

PART III – GUIDELINES FOR MARKETING AUTHORISATION HOLDERS, COMPETENT 373 AUTHORITIES AND THE AGENCY ON ELECTRONIC EXCHANGE OF 374 PHARMACOVIGILANCE INFORMATION IN THE EU – _________________________ 136 375

1. Introduction __________________________________________________________ 137 376

2. Applicable Electronic Reporting Standards ________________________________ 138 377

3. Message Format and Message Processing Rules ____________________________ 139 378

4. Definition of ‘Exceptional Circumstances’ _________________________________ 140 379

5. Preparation of Individual Case Safety Reports (ICSRs) ______________________ 140 380

6. Handling of Copies of Articles Published in the Worldwide Literature _________ 141 381

7. Compliance with Required Reporting Timeframes __________________________ 141 382

8. Electronic Re-transmission of Cases between Multiple Senders and Receivers ___ 141 383

9. Electronic Reporting through Company’s Headquarters _____________________ 142 384

10. Interim Electronic Reporting Measures by Regulatory and Industry Stakeholders 142 385

11. Specific Provisions for the Electronic Reporting to EudraVigilance ____________ 143 386 11.1 EudraVigilance Database Modules _________________________________________ 143 387 11.2 Data Collected in EudraVigilance__________________________________________ 143 388 11.2.1 Adverse Reaction Data Collected in EVPM __________________________________ 143 389 11.2.2 Adverse Reaction Data Collected in EVCTM_________________________________ 144 390 11.3 Data Quality of ICSRs Transmitted Electronically _____________________________ 144 391 11.4 Reporting of all Serious Cases from outside the EEA __________________________ 144 392 11.5 Retrospective Electronic Population of EudraVigilance_________________________ 145 393 11.6 Mapping of the CIOMS I Form to the Applicable ICH E2B(M) Data Elements and 394

Technical Specifications _________________________________________________ 146 395 11. TABLE 1: STANDARD FOR THE ELECTRONIC PROVISION OF RETROSPECTIVE ICSR DATA IN LINE WITH CIOMS I AND E2B(M) 396

DATA ELEMENTS _________________________________________________________________________ 146 397 11.7 Retrospective Electronic Population of EudraVigilance: Transmission Rules ________ 154 398 11.8 Handling of Community Languages ________________________________________ 154 399 11.9 Population of the EVMPD _______________________________________________ 155 400 11.10 Periodic Transmission of ICSRs in Electronic Format __________________________ 155 401 11.10.1 Electronic Transmission Rules for Periodic ICSRs_____________________________ 157 402 11. TABLE 2: ELECTRONIC TRANSMISSION OF PERIODIC ICSR DATA IN LINE WITH CIOMS II, ICH E2C AND E2B(M) DATA 403

ELEMENTS______________________________________________________________________________ 157 404

PART IV – GUIDELINES FOR MARKETING AUTHORISATION HOLDERS AND 405 COMPETENT AUTHORITIES ON PHARMACOVIGILANCE COMMUNICATION – ____ 162 406

<Space for future Guidelines to be developed, subject to separate consultation> __________ 163 407

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PART V – GUIDELINES FOR MARKETING AUTHORISATION HOLDERS AND 408 COMPETENT AUTHORITIES ON PRODUCT- OR POPULATION-SPECIFIC 409 PHARMACOVIGILANCE – ________________________________________________ 164 410

1. Guideline on Exposure to Medicinal Products During Pregnancy: Need for Post-411 Authorisation Data ____________________________________________________ 165 412

2. Guideline on Conduct of Pharmacovigilance for Medicines Used by the Paediatric 413 Population ___________________________________________________________ 166 414

ANNEXES _____________________________________________________________ 167 415

1. Glossary _____________________________________________________________ 168 416 1.1 General ______________________________________________________________ 168 417

Abuse of a medicinal product, synonym: Drug abuse ______________________________________ 168 418 Adverse event (AE), synonym: Adverse experience _______________________________________ 168 419 Adverse reaction, synonym: Adverse drug reaction (ADR), Suspected adverse (drug) reaction _____ 168 420 Clinical trial ______________________________________________________________________ 168 421 Consumer________________________________________________________________________ 169 422 Company Core Data Sheet (CCDS)____________________________________________________ 169 423 Company Core Safety Information (CCSI) ______________________________________________ 169 424 Data lock point____________________________________________________________________ 169 425 Drug abuse_______________________________________________________________________ 169 426 EU Birth Date (EBD)_______________________________________________________________ 169 427 Healthcare Professional _____________________________________________________________ 169 428 Individual Case Safety Report (ICSR), synonym: Safety report ______________________________ 169 429 International Birth Date (IBD)________________________________________________________ 170 430 Invented name ____________________________________________________________________ 170 431 Listed adverse reaction _____________________________________________________________ 170 432 Medicinal product _________________________________________________________________ 170 433 Non-interventional trial _____________________________________________________________ 170 434 Periodic Safety Update Report (PSUR)_________________________________________________ 170 435 Post-authorisation study_____________________________________________________________ 171 436 Post-authorisation safety study (PASS) _________________________________________________ 171 437 Risk-benefit balance _______________________________________________________________ 171 438 Risk management system____________________________________________________________ 171 439 Risks related to use of a medicinal product ______________________________________________ 171 440 Serious adverse reaction ____________________________________________________________ 171 441 Solicited sources of Individual Case Safety Reports _______________________________________ 172 442 Spontaneous report, synonym: Spontaneous notification ___________________________________ 172 443 Unexpected adverse reaction _________________________________________________________ 172 444 Unlisted adverse reaction____________________________________________________________ 173 445

1.2 Terms in Relation to Risk Management _____________________________________ 174 446 Additional risk minimisation activity __________________________________________________ 174 447 Competent Authority _______________________________________________________________ 174 448 Identified risk_____________________________________________________________________ 174 449 Important identified risk, important potential risk or important missing information ______________ 174 450 Missing information________________________________________________________________ 174 451 Potential risk _____________________________________________________________________ 174 452 Risk management system____________________________________________________________ 175 453 Risk minimisation _________________________________________________________________ 175 454 Routine pharmacovigilance __________________________________________________________ 175 455 Routine risk minimisation activities ___________________________________________________ 175 456 Safety concern ____________________________________________________________________ 175 457 Significant change in indication_______________________________________________________ 175 458 Similar biological medicinal product___________________________________________________ 175 459 Target Population__________________________________________________________________ 175 460

1.3 Terms in Relation to Electronic Exchange of Pharmacovigilance Information _______ 176 461

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Acknowledgement message (ICSRACK) _______________________________________________ 176 462 Acknowledgement message (MPRACK) _______________________________________________ 176 463 Acknowledgement of receipt _________________________________________________________ 176 464 Applicant ________________________________________________________________________ 176 465 Competent Authorities______________________________________________________________ 176 466 Electronic data interchange (EDI) _____________________________________________________ 176 467 EudraVigilance database management system (DBMS) ____________________________________ 176 468 EudraVigilance gateway ____________________________________________________________ 176 469 Extensible markup language (XML) ___________________________________________________ 176 470 Gateway_________________________________________________________________________ 177 471 Individual case____________________________________________________________________ 177 472 Individual Case Safety Report (ICSR), synonym: Safety Report _____________________________ 177 473 Investigational medicinal product (IMP) ________________________________________________ 177 474 Marketing Authorisation Holders (MAHs) ______________________________________________ 177 475 Medicinal product _________________________________________________________________ 177 476 Medicinal product file ______________________________________________________________ 177 477 Medicinal product report (MPR) ______________________________________________________ 177 478 Medicinal product report message (MPRM) _____________________________________________ 177 479 Medicinal product report transaction ___________________________________________________ 178 480 Message _________________________________________________________________________ 178 481 Message disposition notification (MDN)________________________________________________ 178 482 Message transaction________________________________________________________________ 178 483 Partner __________________________________________________________________________ 178 484 Receiver_________________________________________________________________________ 178 485 Receiver identifier _________________________________________________________________ 179 486 Report receiver____________________________________________________________________ 179 487 Report sender_____________________________________________________________________ 179 488 Report transaction _________________________________________________________________ 179 489 Safety file________________________________________________________________________ 179 490 Safety message____________________________________________________________________ 179 491 Sender __________________________________________________________________________ 180 492 Sender identifier___________________________________________________________________ 180 493 Sponsor _________________________________________________________________________ 180 494 Standard generalized markup language (SGML)__________________________________________ 180 495

2. Abbreviations_________________________________________________________ 181 496

3. Guidelines and Terminology Related to Part III ____________________________ 182 497 3.1 Guidelines ____________________________________________________________ 182 498 3.1.1 Note for Guidance on the Electronic Data Interchange (EDI) of Individual Case Safety 499

Reports (ICSRs) and Medicinal Product Reports (MPRs) in pharmacovigilance during the 500 pre- and post-authorisation phase in the European Economic Are (EEA) 501 (EMEA/115735/2004)___________________________________________________ 182 502

3.1.2 Technical Documentation – EudraVigilance Human Version 7.0 Processing of Safety 503 Messages and ICSRs) (EMEA/H/20665/04)__________________________________ 182 504

3.1.3 Detailed Guidance on the European database of Suspected Unexpected Serious Adverse 505 Reactions (EudraVigilance – Clinical Trial Module) (ENTR/CT4, Revision 1, April 2004)506 _____________________________________________________________________ 182 507

3.2 Terminology __________________________________________________________ 182 508

4. ICH Guidelines _______________________________________________________ 183 509

5. Templates ____________________________________________________________ 184 510 5.1 Template for EU Risk Management Plan ____________________________________ 184 511 5.2 Template for PSUR section "Worldwide Marketing Authorisation Status" __________ 185 512 5.3 Template for PSUR section "Line-listings of Individual Case Histories"____________ 186 513 5.4 Template for PSUR section "Summary Tabulations" ___________________________ 187 514 5.5 Template for Rapid Alert in Pharmacovigilance_______________________________ 188 515

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5.6 Template for Non-Urgent Information in Pharmacovigilance ____________________ 190 516 5.7 Template for Response to Rapid Alert/Non-Urgent Information in Pharmacovigilance 192 517

6. Distribution Requirements and Address Lists for Data Submission ____________ 194 518 6.1 Distribution Requirements and Address Lists for Periodic Safety Update Reports ____ 194 519

Introduction 14/198

INTRODUCTION 520

1. Legal Basis and Structure of Volume 9A (Human Pharmacovigilance) 521

Directive 2001/83/EC specifically requires the European Commission in consultation with the 522 European Medicines Agency (the Agency), Member States and interested parties to draw up guidance 523 on the collection, verification and presentation of adverse reaction reports in order to facilitate the 524 exchange of information about human pharmacovigilance within the Community. Directive 525 2004/27/EC includes the same requirement. 526

This guidance is required to include technical requirements for the electronic exchange of 527 pharmacovigilance information in accordance with internationally agreed formats. In addition, the 528 European Commission is also required to publish a reference to an internationally agreed medical 529 terminology. 530

This guidance shall be published in Volume 9A of The Rules governing Medicinal Products in the 531 European Union. 532

This present Volume has thus been prepared by the European Commission in close consultation with 533 the Agency, Member States and interested parties and is specifically related to human 534 pharmacovigilance. It brings together general guidance on the requirements, procedures, roles and 535 activities in this field, for both Marketing Authorisation Holders and Competent Authorities of 536 medicinal products for human use; it incorporates international agreements reached within the 537 framework of the International Conference on Harmonisation (ICH). 538

Volume 9A is presented in five parts: 539 Part I deals with Guidelines for Marketing Authorisation Holders; 540 Part II deals with Guidelines for Competent Authorities and the Agency; 541 Part III provides the Guidelines for the electronic exchange of pharmacovigilance in the EU; 542 Part IV provides Guidelines on pharmacovigilance communication; and 543 Part V provides Guidelines on product- or population-specific pharmacovigilance. 544

It should be noted, as with all guidance documents in rapidly evolving technical areas, that this 545 guidance is intended to be regularly reviewed and updated, with publication on the European 546 Commission’s website: 547

http://pharmacos.eudra.org/F2/eudralex/index.htm 548

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2. Legal Framework for Pharmacovigilance 549

The legal framework for pharmacovigilance of medicinal products for human use in the European 550 Union (EU) is given in Regulation (EC) No 726/20041 and Directive 2001/83/EC2 on the Community 551 code relating to medicinal products for human use, as last amended by Directive 2004/24/EC3 and by 552 Directive 2004/27/EC4 (hereinafter referred to simply as Directive 2001/83/EC). It should be noted 553 that although Chapter 3 of Regulation (EC) No 726/2004 and Title IX of Directive 2001/83/EC 554 contain the majority of pharmacovigilance provisions in the legislation, other measures directly 555 relevant to the conduct of pharmacovigilance are found in other chapters and titles of those legislative 556 texts. 557

The requirements explained in these guidelines are based on the ICH guidelines, where these exist, but 558 may be further specified or contain additional requests in line with the legislation of the EU. 559

It should be noted the pharmacovigilance obligations apply to all medicinal products authorised in the 560 EU, including those authorised before 1 January 1995 and whatever procedure was used for their 561 authorisation. For example, the obligations are the same for products authorised under Articles 10, 562 10a, 13 to 16 and 16a to 16i of Directive 2001/83/EC (‘generic’, ‘well-established use’ ‘homeopathic5’ 563 and ‘herbal’ products respectively) as for products authorised under Article 6 of the same Directive. 564

The legislation listed above describes the respective obligations of the Marketing Authorisation Holder 565 and of the Competent Authorities to set up a system for pharmacovigilance in order to collect, collate 566 and evaluate information about suspected adverse reactions. All relevant information should be shared 567 between the Competent Authorities and the Marketing Authorisation Holder, in order to allow all 568 parties involved in pharmacovigilance activities to assume their obligations and responsibilities. This 569 requires an intensive exchange of information between the Marketing Authorisation Holder, the 570 Competent Authorities of Member States and the Agency as well as procedures to avoid duplication, 571 maintain confidentiality and ensure the quality of the systems and data. 572

The EFTA States Iceland, Liechtenstein and Norway have through the Agreement of the European 573 Economic Area (EEA) adopted the complete Community acquis (i.e. the legislation at EU level, 574 guidelines and judgements) on medicinal products, and are consequently parties to the Community 575 procedures. Consequently, the following Guidelines do not only apply with regard to the Marketing 576 Authorisation Holder’s obligations towards Competent Authorities in Member States of the EU but 577 also to those towards the EFTA States Iceland, Liechtenstein and Norway. Likewise they apply to the 578 Competent Authorities in these EFTA States themselves. 579

The obligations concerned with the monitoring of adverse reactions occurring in clinical trials with 580 unauthorised products do not fall within the scope of pharmacovigilance activities, as described in 581 these Guidelines. The legal framework for such obligations is Directive 2001/20/EC on the 582 approximation of the laws, regulations and administrative provision of the Member States relating to 583 the implementation of good clinical practice in the conduct of clinical trials on medicinal products for 584 human use6. 585

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 of those registered through the special, simplified registration procedure of Article 14(1) of Directive 2001/83/EC. 6 OJ L 121 1.5.2001 p.34

Introduction 16/198

3. The Roles of the Various Parties 586

3.1 The Marketing Authorisation Holder 587

The Marketing Authorisation Holder must ensure that it has an appropriate system of 588 pharmacovigilance and risk management in place in order to assure responsibility and liability for its 589 products on the market and to ensure that appropriate action can be taken, when necessary (see Part I.). 590

3.2 The Competent Authorities 591

3.2.1 The Competent Authorities of the Member States 592

The authorities of the Member States are the Competent Authorities for medicinal products authorised 593 nationally through national procedures, including the mutual recognition or decentralised procedure. 594 The responsibilities for pharmacovigilance rest with the Competent Authorities of all the Member 595 States in which the marketing authorisations are held. In addition the Member States are the 596 supervisory authorities for centrally authorised products (see Chapter II.1). 597

3.2.2 The European Commission 598

In the case of centrally authorised medicinal products the European Commission is the Competent 599 Authority. The European Commission is responsible for the adoption of Decisions on the basis of 600 CHMP Opinions relating to centrally authorised products and those products subject to the procedure 601 of Articles 32, 33 and 34 of Directive 2001/83/EC. The European Commission also has 602 responsibilities for the overall Community system of pharmacovigilance and for the legal framework. 603 (see Chapter II.1). 604

3.3 The EU Pharmacovigilance System 605

3.3.1 The Role of Competent Authorities of the Member States for Products 606 Authorised Through National Procedures 607

In accordance with the legislation, each Member State has established a pharmacovigilance system for 608 the collection and evaluation of information relevant to the risk-benefit balance of medicinal products. 609 The Competent Authority continually monitors the safety profile of the products available on its 610 territory and takes appropriate action where necessary and monitors the compliance of Marketing 611 Authorisation Holders with their obligations with respect to pharmacovigilance. The Competent 612 Authority must ensure that Marketing Authorisation Holders implement, when appropriate, Risk 613 Management Plans to effectively monitor and manage risks associated with the safety of their 614 products. Furthermore the Competent Authority must ensure that pharmacovigilance data are shared 615 between Member States and the Agency via the data-processing network EudraVigilance and must 616 cooperate to continuously develop pharmacovigilance systems capable of achieving high standards of 617 public health protection for all medicinal products. 618

3.3.2 The Role of the Competent Authority of the Reference Member State for 619 Products Authorised Through the Mutual Recognition or Decentralised 620 Procedure 621

The responsibilities of pharmacovigilance rest with the Competent Authorities of all the Member 622 States in which the marketing authorisations are held. For practical reasons, the Member States agree 623 that the Reference Member State will normally take the lead for medicinal products authorised through 624 the mutual recognition or decentralised procedure and responsibility for evaluating and producing 625 Assessment Reports on safety concerns, in accordance with an agreed timetable. The Reference 626 Member State takes responsibility for the coordination of communication with the Marketing 627

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Authorisation Holder on such matters (see Chapter II.3) and for the monitoring of the compliance of 628 the Marketing Authorisation Holder with his obligations with respect to pharmacovigilance. These 629 arrangements do not replace the legal responsibilities of the Marketing Authorisation Holder with 630 respect to individual Competent Authorities. 631

3.3.3 The Role of the Rapporteur for Products Authorised Through the 632 Centralised Procedure 633

The Competent Authorities of the Member States are responsible for monitoring centrally authorised 634 medicinal products in their respective territories. However, the pre-authorisation Rapporteur takes the 635 lead in pharmacovigilance, unless otherwise decided by the CHMP. The Rapporteur is responsible for 636 evaluating and producing Assessment Reports on safety concerns related to a centrally authorised 637 product, in accordance with an agreed timetable (see Chapter II.2) and for the monitoring of the 638 compliance of the Marketing Authorisation Holder with its obligations with respect to 639 pharmacovigilance. 640

3.3.4 The Role of the Agency 641

The role of the secretariat of the European Medicines Agency (EMEA), hereinafter called the Agency, 642 is one of coordination of the supervision, under practical conditions of use, of medicinal products 643 which have been authorised within the EU and the provision of advice on the measures necessary to 644 ensure their safe and effective use, in particular by evaluation, coordination of the implementation of 645 pharmacovigilance obligations and the monitoring of such implementation. 646

The Agency’s scientific committee, the CHMP, aided by its Pharmacovigilance Working Party 647 (PhVWP), is responsible for evaluating evidence and formulating Opinions on emerging safety 648 concerns with centrally authorised products, based on the Rapporteur’s Assessment Report. The 649 Agency secretariat is responsible for communicating with the Marketing Authorisation Holders of 650 centrally authorised products on such concerns (see Chapter II.2) and for the coordination of issues 651 relating to the monitoring of the compliance of the Marketing Authorisation Holder with its 652 pharmacovigilance obligations. 653

The role of the Agency secretariat is one of coordination in the case of referrals made to the CHMP for 654 application of the procedures laid down in Articles 32, 33 and 34 of Directive 2001/83/EC. The 655 CHMP, aided by the PhVWP, is responsible for evaluating evidence and formulating Opinions on 656 matters referred to it (see Chapter II.5). 657

3.3.5 The Role of the CHMP Pharmacovigilance Working Party 658

The Mandate of the CHMP Pharmacovigilance Working Party (PhVWP) is to provide advice on the 659 safety of medicinal products and the investigation of adverse reactions, in order to enable effective risk 660 identification, assessment and management, in the pre- and post-authorisation phase, leading to 661 recommendations on harmonised and synchronised action at the request of the Competent Authorities 662 and for centrally authorised products and products referred under Article 32, 33 and 34 of Directive 663 2001/83/EC at the request of the CHMP. The Mandate is reproduced in full in Chapter II.1. 664

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665

666

667

668

669

670

PART I 671

– Guidelines for Marketing Authorisation Holders – 672

PART I 19/198

1. General Principles 673

1.1 Legal Basis of the Marketing Authorisation Holder’s Obligations for 674 Pharmacovigilance 675

The legal basis for the Marketing Authorisation Holder’s obligations for pharmacovigilance of 676 medicinal products for human use in the EU is given in Regulation (EC) No 726/2004 and Directive 677 2001/83/EC. 678

1.2 Roles and Responsibilities of the Marketing Authorisation Holder and the 679 Qualified Person Responsible for Pharmacovigilance 680

The Marketing Authorisation Holder must ensure that he has an appropriate system of 681 pharmacovigilance in place in order to assume responsibility and liability for his products on the 682 market and to ensure that appropriate action can be taken when necessary. The Marketing 683 Authorisation Holder should therefore ensure that all information relevant to the risk-benefit balance 684 of a medicinal product is reported to the Competent Authorities and the Agency fully and promptly in 685 accordance with the legislation. 686

When submitting an application for a marketing authorisation, the Applicant, in preparation of his role 687 and responsibilities as Marketing Authorisation Holder, needs to submit a description of his 688 pharmacovigilance system (Article 8(3)(ia) of Directive 2001/83/EC, see Chapter I.2) and submit 689 proof that he has the services of a Qualified Person Responsible for Pharmacovigilance, hereinafter 690 referred to as the Qualified Person (Article 8(3)(n) of Directive 2001/83/EC). 691

The Marketing Authorisation Holder should have permanently and continuously at his disposal a 692 Qualified Person, residing in the EU7. 693

The role of this Qualified Person is very important, and this Chapter therefore describes the role and 694 responsibilities of the Qualified Person but also provides guidance for the Marketing Authorisation 695 Holder on how to adequately support the Qualified Person. 696

Each company should appoint one Qualified Person for all medicinal products for which his company 697 holds marketing authorisations. 698

National regulations in some Member States require a nominated individual in that country who has 699 specific legal obligations in respect of pharmacovigilance at a national level. One such individual may 700 also act as the Qualified Person Responsible for Pharmacovigilance for the whole EU. Alternatively, 701 the Qualified Person for the EU may be a separate person, additional to requirements under the 702 relevant national regulations. 703

The Qualified Person should be appropriately qualified. This means that he should have documented 704 experience in all aspects of pharmacovigilance in order to fulfil his responsibilities and tasks. If he is 705 not medically qualified, access to a medically qualified person should be available. 706

The name and 24 hours contact details of the Qualified Person and, if applicable, a deputy need to be 707 notified to the Competent Authorities of the Member States, and for centrally authorised products to 708 the Agency as well. 709

7 As explained in the Introduction, the EFTA States having signed EEA Agreement adopted the complete Community acquis on medicinal products, and therefore the Qualified Person may also reside in the EFTA States having signed the EEA Agreement.

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1.2.1 The Role and Responsibilities of the Qualified Person Responsible for 710 Pharmacovigilance 711

The Qualified Person is responsible for 712

• establishing and maintaining the Marketing Authorisation Holder’s pharmacovigilance system 713 (noting that fulfilling the responsibility for maintenance requires full management of the 714 system); 715

• having an overview of the safety profiles and any emerging safety concerns in relation to the 716 medicinal products for which the Marketing Authorisation Holder holds authorisations; 717

• acting as a single contact point for the Competent Authorities on a 24-hour basis. 718

It is recognised that this important role of Qualified Person may impose extensive tasks on the 719 Qualified Person, depending on the number and type of medicinal products for which the company 720 holds authorisations. The Qualified Person may therefore assign specific tasks, under his supervision, 721 to appropriately qualified and trained individuals, e.g. acting as safety experts for certain products, 722 provided he maintains system oversight and overview over the safety profiles of all products. Such 723 assignment needs to be documented. 724

In case of absence, the Qualified Person should ensure that all responsibilities are taken over by an 725 adequately qualified deputy. The deputy should also reside in the EU (see Footnote 7 on page 19). 726

The Qualified Person should have a complete oversight of the pharmacovigilance system in terms of 727 structure and performance and be in a position to assure in particular the following system components 728 and processes, either directly or through supervision of personnel: 729

• the establishment and maintenance of a system which ensures that information about all 730 suspected adverse reactions which are reported to the personnel of the Marketing 731 Authorisation Holder, and to medical representatives, is collected and collated in order to be 732 accessible at least at one point within the EU; 733

• the preparation for Competent Authorities of the Member States, where the medicinal product 734 is authorised, of the reports referred to in Article 104 of Directive 2001/83/EC and in case of 735 centrally authorised products the preparation for the Agency and Competent Authorities of the 736 Member States of the reports referred to in Article 24 of Regulation (EC) No 726/2004. 737 Detailed guidance for the preparation of these reports are included in: 738 • Chapter I.4 on Individual Case Safety Reports (ICSRs) 739 • Chapter I.6 on Periodic Safety Update Reports (PSURs) and 740 • Chapter I.7 on reports on company sponsored post-authorisation safety studies; 741

• the conduct of on-going pharmacovigilance evaluation during the post-authorisation period 742 (see Chapter I.8); 743

• the ensuring that any request from the Competent Authorities for the provision of additional 744 information necessary for the evaluation of the benefits and the risks afforded by a medicinal 745 product is answered fully and promptly, including the provision of information about the 746 volume of sales or prescriptions of the medicinal product concerned; and 747

• the provision to the Competent Authorities of any other information relevant to the evaluation 748 of the benefits and risks afforded by a medicinal product, including appropriate information on 749 post-authorisation studies (including the information referred to in Chapter I.5). 750

The oversight referred to above should cover the functioning of the Marketing Authorisation Holder’s 751 pharmacovigilance system in all aspects, including quality control and assurance procedures, standard 752 operating procedures, database operations, compliance data (e.g. in relation to the quality, 753 completeness and timeliness for expedited reporting and submission of Periodic Safety Update 754 Reports), audit reports and training of personnel in relation to pharmacovigilance. 755

PART I 21/198

The Qualified Person will act as the Marketing Authorisation Holder’s contact point for 756 pharmacovigilance inspections. 757

1.2.2 Responsibilities of the Marketing Authorisation Holder in relation to the 758 Qualified Person Responsible for Pharmacovigilance 759

The Marketing Authorisation Holder should adequately support the Qualified Person to ensure that 760 there are appropriate processes, resources, communication mechanisms and access to all sources of 761 relevant information in place for the fulfilment of his responsibilities and tasks. 762

The Marketing Authorisation Holder should ensure that there is full documentation covering all 763 procedures and activities of the Qualified Person and all mechanisms in place that ensure that the 764 Qualified Person receives or seeks all relevant information. The Marketing Authorisation Holder 765 should implement mechanisms for the Qualified Person to be kept informed of emerging safety 766 concerns and any other information relating to the evaluation of the risk-benefit balance, including 767 information on ongoing or final clinical trials and other studies the Marketing Authorisation Holder is 768 aware of and which may be relevant to the safety of the medicinal product as well as information from 769 sources other than the specific Marketing Authorisation Holder, e.g. from partner companies. 770

The Marketing Authorisation Holder should ensure that the Qualified Person has sufficient authority 771 to implement changes to the Marketing Authorisation Holder’s pharmacovigilance system in order to 772 promote, maintain and improve compliance and sufficient authority to provide input into Risk 773 Management Plans (see Chapter I.3) and into the preparation of regulatory action in response to 774 emerging safety concerns (e.g. variations, urgent safety restrictions, and, as appropriate, 775 communication to Patients and Healthcare Professionals). 776

The Marketing Authorisation Holder has the responsibility to assess risks with potential impact on the 777 pharmacovigilance system and plan for business contingency, including back-up procedures (e.g. in 778 case of non-availability of personnel, adverse reaction database failure, failure of other hardware or 779 software with impact on electronic reporting and data analysis). 780

1.3 Contractual Arrangements 781

Detailed and clear contractual arrangements for meeting pharmacovigilance obligations should be 782 documented in the case where there are arrangements between the Marketing Authorisation Holder 783 and persons or organisations involved in the fulfilment of pharmacovigilance obligations. It is the 784 responsibility of the Marketing Authorisation Holder to ensure that these are in place and to notify the 785 Competent Authority of such arrangements as part of the description of the pharmacovigilance system 786 to be submitted with the application for marketing authorisation (see Chapter I.2). The Marketing 787 Authorisation Holder should also subsequently notify any proposed changes to the arrangements or 788 any new arrangements he plans to introduce in the post-authorisation phase. 789

When two or more separately authorised products, which are identical in all respects apart from their 790 invented name, are marketed in the same territory by separate Marketing Authorisation Holders, each 791 Marketing Authorisation Holder is obliged to meet the pharmacovigilance obligations in accordance 792 with the legislation. However in such cases, the Marketing Authorisation Holders may enter into 793 contractual arrangements in order to meet their obligations. They may even consider it appropriate in 794 such case to use the same pharmacovigilance system and to appoint the same individual as Qualified 795 Person. Any such contractual arrangements must be notified in writing to the Competent Authorities 796 as part of the description of the pharmacovigilance system to be submitted with the application for 797 marketing authorisation (see Chapter I.2), and subsequently when any changes to the arrangements are 798 proposed. Any new arrangements the Marketing Authorisation Holders plan to introduce in the post-799 authorisation phase need also to be notified. Such arrangements for joint pharmacovigilance data 800 collection and analyses are acceptable to the Competent Authorities and the EMEA, provided the 801

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Marketing Authorisation Holder confirms in writing to the Competent Authority that it understands 802 that legal responsibility in respect of pharmacovigilance rests with it. 803

Only one Marketing Authorisation Holder/Co-marketing Partner should report to EudraVigilance in 804 order to avoid the duplication of reports (e.g. literature reports). In cases where the Marketing 805 Authorisation Holders appoint the same individual as Qualified Person, this one Qualified Person must 806 have oversight and responsibility for the common pharmacovigilance system, with the formal 807 agreement of each Marketing Authorisation Holder that utilises the system. 808

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2. Requirements for Pharmacovigilance Systems, Monitoring of Compliance and 809 Pharmacovigilance Inspections 810

This Guideline is subject to separate consultation (see http://www.emea.eu.int) and will be 811 incorporated later. 812

813

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3. Requirements for Risk Management Systems 814

3.1 Introduction 815

It is recognised that at the time of authorisation, information on the safety of a medicinal product is 816 relatively limited. This is due to many factors including the small numbers of subjects in clinical trials, 817 restricted population in terms of age, gender and ethnicity, restricted co-morbidity, restricted 818 co-medication, restricted conditions of use, relatively short duration of exposure and follow up, and 819 the statistical problems associated with looking at multiple outcomes. 820

A medicinal product is authorised on the basis that in the specified indication(s), at the time of 821 authorisation, the benefit-risk is judged positive for the target population. However, not all actual or 822 potential risks will have been identified when an initial authorisation is sought. In addition, there may 823 be subsets of patients for whom the risk is greater than that for the target population as a whole. 824

Over the last few decades many important pharmacovigilance issues have been identified through 825 spontaneous reporting of adverse reactions. At the same time, consideration has been given to ways in 826 which the current reporting systems might be augmented and strengthened. A strong contender is that 827 planning of pharmacovigilance activities might be improved if it were more closely based on product-828 specific issues identified from pre- or post-authorisation data and from pharmacological principles. 829 Such planning would also guide the use of electronic data, which are routinely collected within health 830 services to provide rapid investigation of predicted or emerging safety concerns. This new proactive 831 approach has now been recognised in the European Pharmaceutical Legislation including a specific 832 reference to risk management. 833

The management of a single risk consists of four steps, risk detection, risk assessment, risk 834 minimisation and risk communication. However, a typical individual medicinal product will have 835 multiple risks attached to it and individual risks will vary in terms of severity, and individual patient 836 and public health impact. Therefore, the concept of risk management must also consider the 837 combination of information on multiple risks with the aim of ensuring that the benefits exceed the 838 risks by the greatest possible margin both for the individual patient and at the population level. 839

Recently introduced legislation discusses the use of a risk management system but it does not define it. 840 A risk management system is defined in this Guideline as a set of pharmacovigilance activities and 841 interventions designed to identify, characterise, prevent or minimise risks relating to medicinal 842 products, and the assessment of the effectiveness of those interventions. 843

This Guideline aims to provide guidance on how Marketing Authorisation Holders and Applicants 844 should meet the requirements for a description of a risk management system that they will introduce 845 for an individual medicinal product, or a series of medicinal products, in line with new Community 846 legislation. The Guideline also describes how such a risk management system can be presented to 847 Competent Authorities in the form of a Risk Management Plan. 848

Risk management is a continuing process throughout the lifetime of a medicinal product. However, the 849 activities used for risk management may be changed by technical, scientific and legislative 850 developments, as well as by the information available, the perceived risks and their estimated public 851 health impact and where a product is in its lifecycle. All these factors should be taken into account 852 when formulating Risk Management Plans in the EU. 853

EU legislation now requires Applicants/Marketing Authorisation Holders to provide Competent 854 Authorities with a description of pharmacovigilance and risk management systems. 855

The requirements and format for the description of a pharmacovigilance system are covered in Chapter 856 I.2, Requirements for Pharmacovigilance Systems, Monitoring of Compliance and Pharmacovigilance 857 Inspections, and should be submitted accordingly. 858

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The present Guideline provides guidance to Applicants and Marketing Authorisation Holders in the 859 European Union on how to meet the requirements for a ‘detailed description of the risk management 860 system’ (see Chapter I.3, Section 2) and the circumstances when it is appropriate (see Chapter I.3, 861 Sections 4 and 14) to provide it. The risks addressed in this Guideline are those related to non-clinical 862 and clinical safety. Where the disposal of the product might pose a particular risk because of 863 remaining active substance (e.g. patches) this should also be addressed. The Guideline is applicable to 864 products in both the pre-authorisation and post-authorisation phases of either the centralised, 865 decentralised or mutual recognition procedures. It incorporates the concepts of the International 866 Conference on Harmonisation ICH E2E Guideline. 867

Article 6 of Regulation (EC) No 726/2004 and Article 8 of Directive 2001/83/EC lay down the 868 particulars and documents to be included in an application for the authorisation of a medicinal product 869 for human use. More specifically and for the purpose of this Guideline it requires in accordance with 870 Article 8(3)(ia) of Directive 2001/83/EC the inclusion of “a detailed description of the 871 pharmacovigilance and, where appropriate, of the risk management system which the applicant will 872 introduce.” This provision forms the legal basis for this guideline. The EU Risk Management Plan 873 should be seen within the framework of the following provisions: 874

In the context of centrally authorised products Article 9(4) of Regulation (EC) No 726/2004 requires 875 for a favourable opinion that the following shall be attached to the Opinion: 876

“b) details of any conditions or restrictions which should be imposed on the supply or use of the 877 medicinal product concerned, including conditions under which the medicinal product may be made 878 available to the patients, in accordance with the criteria in Title VI of Directive 2001/83/EC”; 879

“c) details of any recommended conditions or restrictions with regard to the safe and effective use of 880 the medicinal product”. 881

In addition to Article 9(4)(c) above, Article 127a of Directive 2004/27/EC states that “When a 882 medicinal product is to be authorised in accordance with Regulation (EC) 726/2004 and the Scientific 883 Committee in its opinion refers to recommended conditions or restrictions with regard to the safe and 884 effective use of the medicinal product […], a decision addressed to the Member States shall be 885 adopted in accordance with the procedure provided for in Article 33 and 34 of the Directive, for the 886 implementation of those conditions or restrictions”. 887

The legislation provides for additional information to be requested from Marketing Authorisation 888 Holders. 889

Article 23 of Regulation (EC) No 726/2004 states “[…] That qualified person shall reside in the 890 Community and shall be responsible for the following:” 891

“c) ensuring that any request from the competent authorities for the provision of additional 892 information necessary for the evaluation of the risks and benefits of a medicinal product is answered 893 fully and promptly, including the provision of information regarding the volume of sales or 894 prescriptions for the medicinal product concerned […]”; 895

“d) providing the competent authorities with any other information relevant to the evaluation of the 896 risks and benefits of a medicinal product particularly information concerning post-authorisation 897 safety studies”. 898

Similarly, for nationally authorised products, Article 103 of Directive 2001/83/EC states “[…] That 899 qualified person shall reside in the Community and shall be responsible for the following:” 900

“c) ensuring that any request from the competent authorities for the provision of additional 901 information necessary for the evaluation of the benefits and risks afforded by a medicinal product is 902

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answered fully and promptly, including the provision of information about the volume of sales or 903 prescriptions of the medicinal product concerned”; 904

“d) the provision to the competent authorities, of any other information relevant to the evaluation of 905 the benefits and risks afforded by a medicinal product, including appropriate information on post-906 authorization safety studies”. 907

Article 26 of Regulation (EC) No 726/2004 states that “[…] for a period of five years following the 908 initial placing on the market in the Community, the Agency may request that the Marketing 909 Authorisation Holder arrange for specific pharmacovigilance data to be collected from targeted 910 groups of patients. […]” 911

The detailed description of a risk management system should be provided in the form of an EU Risk 912 Management Plan (EU-RMP) in the situations described in Chapter I.3, Section 4. It is strongly 913 recommended that discussions with the Competent Authorities on the need for, and content of, an EU-914 RMP should take place in advance of submission. 915

3.2 Description of the Risk Management System 916

A risk management system is a set of pharmacovigilance activities and interventions designed to 917 identify, characterise, prevent or minimise risks relating to medicinal products, including the 918 assessment of the effectiveness of those interventions. The legislation requires that a description of the 919 risk management system should be submitted when appropriate. This requirement can be met by the 920 submission of an EU-RMP in the circumstances detailed in Chapter I.3, Sections 4 and 14. 921

The aim of a risk management system is to ensure that the benefits of a particular medicine (or a series 922 of medicines) exceed the risks by the greatest achievable margin for the individual patient and for the 923 target population as a whole. This can be done either by increasing the benefits or by reducing the 924 risks but, by its definition, risk management focuses upon the risk reduction approach. Nevertheless, 925 whenever possible, increases in benefits should also be considered and the characteristics of patients 926 most likely to benefit from treatment better defined. 927

3.3 EU Risk Management Plan (EU-RMP) 928

The description of a risk management system should be submitted in the form of an EU-RMP. The 929 EU-RMP contains two parts: 930

Part I 931

• A Safety Specification 932 • A Pharmacovigilance Plan, and 933

Part II 934

• An evaluation of the need for risk minimisation activities 935

and if there is a need for additional (i.e. non-routine) risk minimisation activities 936

• A risk minimisation plan. 937

Part I of the EU-RMP incorporates the concepts of ICH E2E regarding the Safety Specification, which 938 summarises the safety profile of the medicinal product at the particular point in time of its life-cycle, 939 and the Pharmacovigilance Plan which is based on the Safety Specification. Chapter I.3, Sections 6 940 and 7 of this Guideline include relevant text from ICH E2E with additional commentary on 941 implementation within the EU. Chapter I.3, Section 6.2.f also details the additional EU requirements 942 for the Safety Specification. 943

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In Part II of the EU-RMP, on the basis of the Safety Specification, the Applicant/Marketing 944 Authorisation Holder should consider carefully the need for risk minimisation activities to be 945 introduced. Risk minimisation activities may be “routine” or “additional” (see Chapter I.3, Section 8, 946 and in Annex 1.2). Within the “evaluation of the need for risk minimisation activities”, the 947 Applicant/Marketing Authorisation Holder should discuss fully the use of routine risk minimisation 948 activities and whether there is a need for additional risk minimisation activities. If only routine risk 949 minimisation activities are required there is no need to submit a risk minimisation plan. If additional 950 risk minimisation activities are thought necessary, the Applicant/Marketing Authorisation Holder 951 should provide a risk minimisation plan within Part II of the EU-RMP. This risk minimisation plan 952 should contain both the routine and additional activities for each safety concern. Every time the EU-953 RMP is updated (see Chapter I.3, Section 14) the Applicant/Marketing Authorisation Holder should 954 reconsider its position vis-à-vis the need for risk minimisation activities and Part II should be updated 955 accordingly. 956

3.4 Situations Requiring an EU-RMP 957

An EU-RMP may need to be submitted at any time of a product’s life-cycle – i.e. during both the 958 pre-authorisation and post-authorisation phases. In particular an EU-RMP should be submitted: 959

• with the application for a new marketing authorisation for: 960

• any product containing a new active substance; 961 • a similar biological medicinal product; 962 • a generic/hybrid medicinal product where a safety concern requiring additional risk 963

minimisation activities has been identified with the reference medicinal product. 964

• with an application involving a significant change in a marketing authorisation (e.g. new 965 dosage form, new route of administration, new manufacturing process of a biotechnologically-966 derived product, significant change in indication) unless it has been agreed with the 967 Competent Authority that submission is not required; 968

• on request from a Competent Authority (both pre-and post-authorisation); 969

• on the initiative of an Applicant/Marketing Authorisation Holder when they identify a safety 970 concern with a medicinal product at any stage of its life cycle. 971

In some circumstances, products which are not in the above categories which are seeking a new 972 authorisation via the centralised procedure may require an EU-RMP: 973

• Known active substances 974

• Hybrid medicinal products where the changes compared with the reference medicinal product 975 suggest different risks 976

• Bibliographical applications 977

• Fixed combination applications. 978

For situations where the submission of an EU-RMP is not mandatory, the need for it should be 979 discussed with the Competent Authority well in advance of the submission. 980

3.4.1 Marketing Authorisations via the Centralised Procedure 981

At any stage, but in particular during the pre-authorisation phase, an Applicant/Marketing 982 Authorisation Holder may request advice on the need for, development or content of an EU-RMP 983 through the scientific advice procedure. 984

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Whether or not the scientific advice procedure has been used, discussion on the EU-RMP for a 985 medicinal product seeking a new authorisation through the centralised procedure should take place at 986 the pre-submission meeting. 987

For significant changes to an existing centralised marketing authorisation, the Marketing Authorisation 988 Holder should discuss the need for an EU-RMP with the EMEA at least two months in advance of the 989 submission. When it is not mandatory that an EU-RMP is submitted and the Applicant/Marketing 990 Authorisation Holder thinks it is unnecessary, the Applicant/Marketing Authorisation Holder should 991 submit a brief justification of this along with the application which will form part of the formal 992 assessment by the Rapporteur. However, it is strongly recommended that this is discussed with the 993 EMEA before submission of the application. 994

3.4.2 Marketing Authorisations via the Mutual Recognition or Decentralised 995 Procedures 996

The Competent Authority of the Member State should be contacted regarding the timings of 997 discussions on Risk Management Plans. Where there is a Reference Member State (RMS), the 998 Competent Authority of this country should be consulted. 999

3.5 Location in the Application 1000

An EU-RMP submitted at the time of an application for a Marketing Authorisation should be provided 1001 in Module 1.x (to be confirmed) of the Marketing Authorisation Application in a stand-alone format 1002 allowing circulation to, and evaluation by pharmacovigilance and risk management experts. It should 1003 be accompanied by other relevant documents such as study protocols, where applicable. 1004

Updates to the EU-RMP (see Chapter I.3, Section 14) should be presented preferably in a tab-1005 separated dossier and in accordance with the appropriate headings and numberings of the EU-CTD 1006 format. This should be accompanied by a cover letter, detailing which sections of the EU-RMP have 1007 been changed, and study reports (if appropriate). 1008

3.6 Safety Specification 1009

The Safety Specification should be a summary of the important identified risks of a medicinal product, 1010 important potential risks, and important missing information. It should also address the populations 1011 potentially at risk (where the product is likely to be used), and outstanding safety questions which 1012 warrant further investigation to refine understanding of the benefit-risk profile during the 1013 post-authorisation period. The Safety Specification is intended to help industry and regulators identify 1014 any need for specific data collection and also to facilitate the construction of the Pharmacovigilance 1015 Plan. 1016

In the EU-RMP the Safety Specification will also form the basis of the evaluation of the need for risk 1017 minimisation activities and, where appropriate, the risk minimisation plan. 1018

It is recommended that Applicants/Marketing Authorisation Holders follow the structure of elements 1019 provided below when compiling the Safety Specification. The elements of the Safety Specification 1020 that are included are only a guide. The Safety Specification can include additional elements, 1021 depending on the nature of the product and its development programme. Conversely, for products 1022 already on the market with emerging new safety concerns, only a subset of the elements might be 1023 relevant. 1024

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3.6.1 Non-clinical Part of the Safety Specification 1025

Within the Safety Specification, this section should present non-clinical safety findings that have not 1026 been adequately addressed by clinical data, for example: 1027

• Toxicity (including repeat-dose toxicity, reproductive/developmental toxicity, nephrotoxicity, 1028 hepatotoxicity, genotoxicity, carcinogenicity etc.) 1029

• General pharmacology (cardiovascular, including QT interval prolongation; nervous system; 1030 etc.) 1031

• Drug interactions 1032 • Other toxicity-related information or data. 1033

The relevance of the findings to the use in humans should be discussed. If the product is intended for 1034 use in special populations, consideration should be given to whether specific non-clinical data needs 1035 exist. 1036

3.6.2 Clinical Part of the Safety Specification 1037

3.6.2.a) Limitations of the Human Safety Database 1038

Limitations of the safety database (e.g. related to the size of the study population, study 1039 inclusion/exclusion criteria) should be considered, and the implications of such limitations with 1040 respect to predicting the safety of the product in the marketplace should be explicitly discussed. 1041 Particular reference should be made to populations likely to be exposed during the intended or 1042 expected use of the product in medical practice. 1043

In order to assess the limitation of the human safety database, the size of the study population should 1044 be detailed using both numbers of patients and patient time (patient-years, patient–months) exposed to 1045 the drug. This should be stratified, for relevant population categories such as age and gender, type of 1046 study (e.g. randomised controlled trial, open clinical trial, observational study) and any other relevant 1047 variable, such as dose, indication and duration of treatment. Limitations of the database should also be 1048 presented in terms of the frequencies of adverse drug reactions detectable given the size of the 1049 database. The limitations of the database should also be discussed with regard to suspected long-term 1050 adverse reactions (e.g. malignancies) when it is unlikely that exposure data is of sufficient duration 1051 and latency. 1052

Post-marketing (non-study) exposure: 1053

Where marketing of the medicine has occurred, the Marketing Authorisation Holder should provide 1054 data on patients exposed post-marketing. Exposure data based on the number of kilogrammes of 1055 medicinal product sold divided by the average dose is only valid if the medicinal product is always 1056 taken at one dose level for a fixed length of time – which is not the situation with most medicinal 1057 products. In paediatric populations or mixed populations of different indications or age groups, use of 1058 this measure alone is inappropriate and other measures should be used. 1059

A more accurate breakdown of drug exposure based on market research should be provided where 1060 possible. When deciding which measure to use for exposure data, it is important to consider the way a 1061 medicine is used. For example, for medicines used chronically, the appropriate measure may be 1062 patient years of use. However, when use is typically limited and utilisation is determined by pack size 1063 (e.g. a course of antibiotics), a simple count of packs sold may be more appropriate. The information 1064 should be stratified by relevant variables such as age, indication, dose and duration of treatment. 1065

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3.6.2.b) Populations not studied in the Pre-Authorisation Phase 1066

The Safety Specification should discuss which populations have not been studied or have only been 1067 studied to a limited degree in the pre-authorisation phase. The implications of this with respect to 1068 predicting the safety of the product in the marketplace should be explicitly discussed. 1069

Limitations of the database should also be presented in terms of the relevance of inclusion and 1070 exclusion criteria in relation to the target population, in particular when exclusion criteria are not 1071 proposed as contraindications for the drug. In discussing differences between target populations and 1072 those exposed in clinical trials it should be noted that some differences may arise through trial setting 1073 (e.g. hospital or general practice) rather than through explicit inclusion/exclusion criteria. 1074

Populations to be considered for discussion should include (but might not be limited to): 1075

• Children 1076 • The elderly 1077 • Pregnant or lactating women 1078 • Patients with relevant co-morbidity such as hepatic or renal disorders 1079 • Patients with disease severity different from that studied in clinical trials 1080 • Sub-populations carrying known and relevant genetic polymorphism 1081 • Patients of different racial and/or ethnic origins. 1082

Post Marketing Experience: 1083

For updates to the Safety Specification, specific reference should be made to how the realised pattern 1084 of exposure (including off-label use) has differed from that predicted and from the indication(s) and 1085 contraindications in the Summary of Product Characteristics. 1086

Newly identified safety concerns should be mentioned, in particular any issue found in relation to a 1087 population not studied in the pre-approval phase should be discussed along with the implications for 1088 the Summary of Product Characteristics. 1089

If regulatory action has been taken in relation to a safety concern, this should be mentioned. 1090

3.6.2.c) Adverse Events/Adverse Reactions 1091

This section should list the important identified and potential risks that require further characterisation 1092 or evaluation. 1093

Identified risks that require further evaluation 1094

More detailed information should be included on the most important identified adverse events/adverse 1095 reactions, which would include those that are serious or frequent and that also might have an impact 1096 on the balance of benefits and risks of the medicinal product. This information should include 1097 evidence bearing on a causal relationship, severity, seriousness, frequency, reversibility and at-risk 1098 groups, if available. Risk factors and potential mechanisms should be discussed. These adverse 1099 events/adverse reactions should usually call for further evaluation as part of the Pharmacovigilance 1100 Plan (e.g. frequency in normal conditions of use, severity, outcome, at-risk groups, etc.). 1101

Potential risks that require further evaluation 1102

Important potential risks should be described in this section. The evidence that led to the conclusion 1103 that there was a potential risk should be presented. It is anticipated that for any important potential 1104 risk, there should be further evaluation to characterise the association. 1105

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Presentation of risk data 1106

When the information is available, detailed risk data should be presented according to the following 1107 format: 1108

The frequency of important adverse reactions should be expressed taking into account the source of 1109 the data. For a product already on the market, the reporting rate based on the number of spontaneously 1110 reported adverse events/adverse reactions (in the numerator) and the sales data (in the denominator) is 1111 very likely to underestimate the rate of occurrence of an adverse reaction in an exposed population. 1112 When an accurate frequency is needed for an important adverse reaction, this should always be based 1113 on systematic studies (e.g. clinical trials or epidemiological studies) in which both the number of 1114 patients exposed to the medicinal product and the number of patients who experienced the respective 1115 adverse event/adverse reaction are known. 1116

The denominator should be expressed using the appropriate measure: e.g. number of patients or in 1117 patient-time or equivalent units (courses of treatment, prescriptions etc.) It should be stated clearly 1118 which frequency parameter is being used: e.g. incidence proportion (patient units in the denominator) 1119 or incidence rate (patient time units in the denominator). Confidence intervals should be provided. 1120 When using patient-time, the underlying assumption is that the hazard function must be nearly 1121 constant over the follow-up time. Otherwise it should be split into relevant categories where the 1122 assumption of constancy holds. Where appropriate, the period of major risk should be identified. 1123 Adverse event/adverse reaction incidence rates should be presented for the whole population and for 1124 relevant population categories. 1125

For important identified risks, the excess and relative incidence should be given. Excess incidence (in 1126 comparison to placebo and active comparator; if available) should be calculated based on the best 1127 available evidence (e.g. meta-analytic techniques) for each population (total controlled, total 1128 controlled plus open label extension, total study). Time to event data should be summarised using 1129 survival techniques which take appropriate account of informative censoring. Cumulative hazard 1130 functions may provide a simple visual comparison of the competing risks of different adverse 1131 reactions. These data can be stratified by substance (to investigate the difference in the adverse event 1132 profile between active and placebo), or by risk factors such as dose, gender or age. 1133

The potential impact of the most important identified and important potential risks should be 1134 addressed using for example: strength of evidence, supporting plausibility, nature of evidence and 1135 potential public health burden, morbidity and case fatality. Recording this in a structured form will 1136 facilitate assessment of the potential significance of a safety concern. Classification of the safety 1137 concern by dose, time and risk factors is encouraged. The identification of susceptible patients should 1138 receive specific attention, possibly from analysis of cases. It is likely that the adverse reactions will 1139 require further evaluation as part of the Pharmacovigilance Plan. 1140

3.6.2.d) Identified and Potential Interactions including Food-Drug and Drug-Drug 1141 Interactions 1142

Identified and potential pharmacokinetic and pharmacodynamic interactions should be discussed. For 1143 each, the evidence supporting the interaction and possible mechanism should be summarised, and the 1144 potential health risks posed for the different indications and in the different populations should be 1145 discussed. 1146

It should be stated which interactions require further investigation. 1147

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3.6.2.e) Epidemiology 1148

The epidemiology of the indication(s) should be discussed. This discussion should include incidence, 1149 prevalence, mortality and relevant co-morbidity, and should take into account whenever possible 1150 stratification by age, sex, and racial and/or ethnic origin. Differences in the epidemiology in the 1151 different regions should be discussed, where feasible, (because the epidemiology of the indication(s) 1152 may vary across regions), but the emphasis should be on the epidemiology in the EU. 1153

In addition, for important adverse events that may require further investigation, it is useful to review 1154 the incidence rate of these events among patients in whom the medicinal product is indicated (i.e. the 1155 background incidence rates). Information on risk factors for an adverse event would also be useful to 1156 include, if available. For example: if a medicinal product is intended for treating prostate cancer the 1157 target population is likely to be men over the age of 50 years. This population is also at increased risk 1158 of myocardial infarction. If it is suspected that the medicinal product might also cause myocardial 1159 infarction, it would be useful to know how many cases would be expected amongst prostate cancer 1160 patients (ideally) or men in the same age group, not on the medicinal product. 1161

3.6.2.f) Pharmacological Class Effects 1162

The Safety Specification should identify risks believed to be common to the pharmacological class. 1163

If a risk which is common to the pharmacological class is not thought to be a safety concern with the 1164 medicinal product, this should be justified. 1165

3.6.2.g) Additional EU Requirements 1166

The Applicant/Marketing Authorisation Holder is requested to discuss the topics below. If the 1167 potential is thought to be significant, the topic should be identified as an important potential risk and 1168 means for reducing or minimising it discussed in the “evaluation of the need for risk minimisation 1169 activities”. In this context, “significant” means that there is a reasonable likelihood that it will occur. 1170 Where a particular topic is not relevant to the individual medicinal product, this should be stated along 1171 with the reason. 1172

Potential for overdose 1173

Special attention should be given in particular cases, e.g. where there is a narrow therapeutic margin, a 1174 medicinal product with significant toxicity and/or there is an increased risk of overdose in the target 1175 population. 1176

Potential for transmission of infectious agents 1177

The Applicant/Marketing Authorisation Holder should discuss the potential for the transmission of an 1178 infectious agent in line with the “Guideline on reporting of suspected transmission of any infectious 1179 agent via a medicinal product”. 1180

Potential for misuse for illegal purposes 1181

The potential for misuse for illegal purposes should be considered. If appropriate, the means of 1182 limiting this, e.g. by the use of colorants and/or flavourings in the dosage form, limited pack size and 1183 controlled distribution should be discussed in the “evaluation of the need for risk minimisation 1184 activities.” 1185

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Potential for off-label use 1186

The potential for off-label use should be discussed. This is particularly relevant where a medicinal 1187 product has an indication restricted to a subset of the population within a disease area or there are 1188 situations where the medicinal product must not be given for safety reasons. The potential for use in 1189 other disease areas should also be considered where this is likely. 1190

Potential for off-label paediatric use 1191

If the disease or disorder which is being treated or prevented is found in the paediatric population, the 1192 potential for off-label paediatric use should be discussed. 1193

3.6.3 Summary 1194

At the end of the Safety Specification a summary should be provided of the: 1195

• Important identified risks 1196 • Important potential risks 1197 • Important missing information. 1198

Based on this summary the Applicant/Marketing Authorisation Holder will provide a 1199 Pharmacovigilance Plan and an evaluation of the need for risk minimisation activities (see Template in 1200 Annex 5.1). 1201

3.7 Pharmacovigilance Plan 1202

According to ICH E2E, the Pharmacovigilance Plan should be based on the Safety Specification and 1203 propose actions to address the safety concerns identified. Early discussions between Competent 1204 Authorities and the Applicant or Marketing Authorisation Holder are recommended to identify 1205 whether, and which, additional pharmacovigilance activities are needed. It is important to note that 1206 only a proportion of risks are likely to be foreseeable and the Pharmacovigilance Plan will not replace 1207 but rather complement the procedures currently used to detect safety signals. 1208

3.7.1 Routine Pharmacovigilance 1209

For medicinal products where no special concerns have arisen, routine pharmacovigilance should be 1210 sufficient for post-authorisation safety monitoring, without the need for additional actions (e.g. safety 1211 studies). 1212

A description of routine pharmacovigilance activities is covered elsewhere in Part I, which should be 1213 consulted in developing the Pharmacovigilance Plan. 1214

3.7.2 Additional Pharmacovigilance Activities and Action Plans 1215

For medicinal products with important identified risks, important potential risks, or important missing 1216 information, additional activities designed to address these safety concerns should be considered. 1217

Applicants/Marketing Authorisation Holders should also consider the situations when routine 1218 pharmacovigilance is likely to be inadequate. An example of this might be when a potential risk with 1219 an individual medicinal product has a significant background incidence in the target population(s), 1220 leading to difficulties in distinguishing between the effects of the medicinal product and the “normal” 1221 incidence. When any doubt exists about the need for additional pharmacovigilance activities, 1222 consultation with a Competent Authority should be considered. 1223

The objective(s) of additional pharmacovigilance activities will normally differ according to the safety 1224 concern to be addressed. For important identified and potential risks, objectives may be to measure the 1225

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incidence rate in a larger or a different population, to measure the rate ratio or rate difference in 1226 comparison to a reference medicinal product, to examine how the risk varies with different doses and 1227 durations of exposure, to identify risk factors or to assess a causal association. For important missing 1228 information, the objective may simply be to investigate the possibility of a risk or to provide 1229 reassurance about the absence of a risk. 1230

The threshold for investigating a safety concern further will depend upon the indication, the target 1231 population, and the likely impact on public health. For example, a safety concern with a vaccine might 1232 have a lower threshold for investigation than the same issue in a medicine used in the palliative 1233 treatment of metastatic cancer. 1234

The Table: Epidemiological Methods for Post-Authorisation Safety Studies, at the end of Chapter I.7 1235 lists some of the epidemiological activities which might be considered for inclusion in a 1236 Pharmacovigilance Plan. Additional pharmacovigilance activities included in the Pharmacovigilance 1237 Plan should be designed and conducted according to the recommendations in the Guidelines for Good 1238 Pharmacoepidemiology Practices (GPP)8. For studies involving children, the “Guideline on Conduct 1239 of Pharmacovigilance for Medicines Used by the Paediatric Population” (see Chapter V.2) should be 1240 consulted. The responsibility for the scientific value of study protocols remains with Applicants or 1241 Marketing Authorisation Holders, even if they have been previously discussed with Competent 1242 Authorities. 1243

3.7.3 Action Plan for Safety Concerns 1244

Within the Pharmacovigilance Plan the action plan for each safety concern should be presented and 1245 justified according to the following structure (see also Annex 5.1): 1246

• Safety concern 1247 • Objective of proposed action(s) 1248 • Action(s) proposed 1249 • Rationale for proposed action(s) 1250 • Monitoring by the Applicant/Marketing Authorisation Holder for safety concern and proposed 1251

action(s) 1252 • Milestones for evaluation and reporting. 1253

Protocols (draft or otherwise) for any formal studies should be provided. Details of the monitoring for 1254 the safety concern in a clinical trial could include: stopping rules, information on the drug safety 1255 monitoring board and when interim analyses will be carried out. 1256

Although not explicitly included in this structure, it is also necessary in the EU-RMP to explain the 1257 decision making processes which will depend on the outcomes of the proposed actions. The possible 1258 consequences of the study outcomes should be discussed. 1259

3.8 Evaluation of the Need for Risk Minimisation Activities 1260

On the basis of the Safety Specification, the Applicant/Marketing Authorisation Holder should provide 1261 an evaluation of the need for risk minimisation activities. 1262

For each safety concern, the Applicant/Marketing Authorisation Holder should assess whether any risk 1263 minimisation activities are needed. Some safety concerns may be adequately addressed by the 1264 proposed actions in the Pharmacovigilance Plan, but for others the risk may be of a particular nature 1265 8 Guidelines for Good Pharmacoepidemiology Practices (GPP), International Society for Pharmacoepidemiology, http://www.pharmacoepi.org/resources/guidelines_08027.cfm, August 2004. International Society for Pharmacoepidemiology. Guidelines for good pharmacoepidemiology practices (GPP) Pharmacoepidemiology and Drug Safety 2005; 14 (8): 589-595

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and seriousness that risk minimisation activities are needed. It is possible that the risk minimisation 1266 activities may be limited to ensuring that suitable warnings are included in the product information or 1267 by the careful use of labelling and packaging, i.e. routine risk minimisation activities. If an 1268 Applicant/Marketing Authorisation Holder is of the opinion that no additional risk minimisation 1269 activities beyond these are warranted, this should be discussed and, where appropriate, supporting 1270 evidence provided. 1271

However, for some risks, routine risk minimisation activities will not be sufficient and additional risk 1272 minimisation activities will be necessary. If these are required they should be described in the risk 1273 minimisation plan (see section 4.8) which should be included in Part II of the EU-RMP. 1274

Within the evaluation of the need for risk minimisation activities, the Applicant/Marketing 1275 Authorisation Holder should also address the potential for medication errors (see Chapter I.3, Section 1276 8.1) and state how this has been reduced in the final design of the pharmaceutical form, product 1277 information, packaging and, where appropriate, device. 1278

As a rule, Applicants/Marketing Authorisation Holders should always consider the need for risk 1279 minimisation activities whenever the Safety Specification is updated in the light of new safety 1280 information on the medicinal product. In some circumstances, it may be appropriate to suggest that an 1281 additional risk minimisation activity be stopped because experience with the medicinal product 1282 suggests that it is no longer necessary for the safe and effective use. 1283

3.8.1 Potential for Medication Errors 1284

Applicants/Marketing Authorisation Holders are encouraged routinely to consider the likelihood of 1285 medication errors. In particular, they should assess prior to marketing, common sources of medication 1286 errors. During the development phase and during the design of the medicinal product for marketing, 1287 the applicant needs to take into account potential reasons for medication error. The naming (taking 1288 into account the “Guideline on the Acceptability of Invented Names for Human Medicinal Products 1289 Processed through the Centralised Procedure” (see CPMP/328/98 latest version on 1290 http://www.emea.eu.int)), presentation (e.g. size, shape and colouring of the pharmaceutical form and 1291 packaging), instructions for use (e.g. regarding reconstitution, parenteral routes of administration, dose 1292 calculation) and labelling are among the items to be considered. 1293

If a product has life-threatening potential when administered by an incorrect route, consideration 1294 should be given as to how such administration can be avoided. This is particularly important when it is 1295 common practice to administer the product at the same time as other medicinal products given by the 1296 hazardous route. 1297

The need for visual (or physical) differentiation between strengths of the same medicinal product and 1298 between other medicinal products commonly administered or taken at the same time should be 1299 discussed. When a medicinal product is likely to be used by a visually impaired population, special 1300 consideration should be given to the potential for medication error. 1301

Consideration should be given to the prevention of accidental ingestion or other unintended use by 1302 children. 1303

Medication errors identified during product development should be discussed and information on the 1304 errors, their potential cause(s) and possible remedies given. Where applicable an indication should be 1305 given of how these have been taken into account in the final product design. 1306

If post-marketing, it becomes apparent that adverse reactions are occurring as a result of medication 1307 errors, this topic should be discussed in the updated EU-RMP and ways of limiting the errors 1308 proposed. 1309

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3.9 The Risk Minimisation Plan 1310

The risk minimisation plan details the risk minimisation activities which will be taken to reduce the 1311 risks associated with an individual safety concern. When a risk minimisation plan is provided within 1312 an EU-RMP, the risk minimisation plan should include both routine and additional risk minimisation 1313 activities. A safety concern may have more than one risk minimisation activity attached to an 1314 objective. For example, a possible plan for a known teratogen could have the objective of avoiding any 1315 patient taking the drug becoming pregnant. A routine risk minimisation activity might be to emphasise 1316 the need for effective contraception in the Summary of Product Characteristics and a recommendation 1317 that patients should have a negative pregnancy test before each prescription. One additional risk 1318 minimisation activity might be to develop an educational pack to provide information to the patients 1319 on the risks of the medicine and the need for contraception. It might also be an activity to limit the 1320 pack sizes to one month’s supply of the medicine. 1321

The risk minimisation plan should list the safety concerns for which risk minimisation activities are 1322 proposed. The risk minimisation activities, i.e. both routine and additional, related to that safety 1323 concern should be discussed. For each safety concern the following headings in the plan will mirror 1324 those for safety concerns listed in Chapter I.3, Section 7.3. In addition, for each proposed additional 1325 risk minimisation activity, a section should be included detailing how the effectiveness of it as a 1326 measure to reduce risk will be assessed. (see Annex 5.1). 1327

3.10 Risk Minimisation Activities 1328

It is difficult to provide precise guidance on which risk minimisation activity should be used in a given 1329 situation as each safety concern needs to be considered on a case by case basis. Some of the risk 1330 minimisation activities are described in the Table: Methods for Risk Minimisation at the end of this 1331 Chapter, but it is essential that appropriate specialised experts should be consulted at all stages and 1332 marketing authorisation applicants and holders are also encouraged to discuss risk minimisation plans 1333 with the Competent Authorities early on. 1334

3.10.1 Risk Communication 1335

Accurate and timely communication of emerging data on risk is an essential part of 1336 pharmacovigilance. Risk communication is an important step in risk management as well as a risk 1337 minimisation activity. Patients and health care professionals need accurate and well communicated 1338 information about the risks associated with both the medicinal product, and the condition for which it 1339 is being used, so that an informed choice can be made about the most appropriate treatment. The 1340 product information in the form of the Summary of Product Characteristics and Patient Information 1341 Leaflets is an important means of informing prescribers and patients about the risks associated with a 1342 particular medicine but additional materials may be needed. A short list of established media for such 1343 communication is given in the Table: Methods for Risk Minimisation at the end of this Chapter (under 1344 additional educational material), but the target audience, levels of detail required to achieve effective 1345 results and the most appropriate forms of words will all vary with circumstances. Whereas Marketing 1346 Authorisation Holders may produce educational material to inform and educate Healthcare 1347 Professionals and Patients, the requirement to do this will only be included as a condition of the 1348 marketing authorisation when it is deemed necessary for the safe and effective use of the medicinal 1349 product. 1350

Because of the importance of risk communication it is recommended that appropriate experts are 1351 consulted. Further guidance is being developed on this topic. 1352

3.11 The Marketing Authorisation 1353

Restrictions and conditions within the marketing authorisation may be used as a risk minimisation 1354 activity (see Table: Methods for Risk Minimisation at the end of this Chapter). When a marketing 1355

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authorisation is granted, it must include details of any conditions or restrictions imposed on the supply 1356 or the use of the medicinal product, including the conditions under which the medicinal product may 1357 be made available to patients. These conditions may also be modified when the marketing 1358 authorisation is amended in the post-authorisation phase. This is commonly referred to as the “legal 1359 status” of a medicinal product. It may also restrict where the medicine can be administered (e.g. to a 1360 hospital) or by whom it can be prescribed (e.g. specialist). For medicines only available upon 1361 prescription, additional conditions may be imposed by classifying medicines into those available only 1362 upon either a restricted medical prescription or a special medical prescription. 1363

The CHMP or national Competent Authorities may also make recommendations on conditions or 1364 restrictions with regard to the safe and effective use of the medicinal product. In the case of the 1365 CHMP, these conditions or restrictions will usually only affect the Decision addressed to the 1366 Marketing Authorisation Applicant. However, in certain circumstances, the Commission may also 1367 decide to adopt a Decision addressed to the Member States. 1368

3.12 Ensuring the Effectiveness of Risk Minimisation Activities 1369

The definition of risk management requires assessment of the effectiveness of the interventions 1370 forming part of the process. It is clearly desirable that activities which may involve substantial 1371 investment of effort and resources should be shown to achieve the desired effects. In addition, as a 1372 public health measure it is imperative that alternative methods be adopted should a particular risk 1373 minimisation strategy prove ineffective. Assessment of effectiveness will also increase understanding 1374 of which activities are most appropriate in addressing specific types of safety concerns. 1375

3.12.1 Assessment of Risk Minimisation 1376

Direct measurement of risk minimisation should be employed whenever feasible. Surrogate measures 1377 should be considered when this is not feasible or to provide interim assessments whilst awaiting direct 1378 risk minimisation measurements. For example, for measures based on the provision of information to 1379 professionals, descriptive studies or surveys which assess whether the information is being effectively 1380 communicated might be appropriate. The use of medical databases might also allow direct measures of 1381 how uniformly such advice was being adhered to by reviewing, for example, concomitant medication 1382 or the results of laboratory tests. Since such studies are likely to be required with increasing frequency, 1383 the availability of such databases will be an ever more important factor in risk management. If the 1384 prescribing databases are further linked to patient clinical outcome, a study of the adequacy of the 1385 prescribing process could be designed to evolve over time into a full risk reduction study. 1386

It is clear that, even when risks are of a type which can be directly measured, ethical and practical 1387 considerations may prevent prospective comparison. It may be scientifically difficult to make direct 1388 comparison between a situation with and without the intervention to be assessed and may not be 1389 achievable in timescales which allow the lessons learned to be used to improve risk management. In 1390 particular this will occur when risks associated with long-term exposure or very rare events are to be 1391 reduced. For products where a risk minimisation plan has been introduced after some time on the 1392 market a comparison with historical data can be made. Not withstanding the above, 1393 Applicants/Marketing Authorisation Holders should investigate new methodologies for monitoring 1394 and assessment. 1395

3.13 Summary of Activities in the EU-RMP 1396

The EU-RMP should contain an overall summary of the activities detailed for the medicinal product. 1397 This should be in two parts: 1398

• Summary of activities for each important safety concern 1399 • Summary of all activities and their milestones. 1400

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The relationship between activities and safety concerns may be clarified by a cross-tabulation of the 1401 two categories showing which safety concerns are addressed by each activity (see Annex 5.1). 1402

Summary of activities for each safety concern: 1403

This should be a simple table listing each safety concern and summarising the activities (both 1404 pharmacovigilance and, where appropriate, risk minimisation) which will be taken. Where 1405 appropriate, it should provide a cross reference to the actions in the Pharmacovigilance Plan and the 1406 risk minimisation activities for the individual safety concern. 1407

Summary of all activities and their milestones: 1408

This section of the EU-RMP for the product should be organised in terms of the actions or activities to 1409 be undertaken and their milestones. The reason for this is that one proposed activity (e.g. a prospective 1410 safety cohort study) could address more than one of the safety concerns. Timelines and milestones 1411 should be included in the summary with a timetable for the submission of findings. In developing 1412 these milestones one should consider: 1413

• when it will be possible to detect an adverse reaction with a pre-defined frequency at a pre-1414 defined confidence level. This frequency should be chosen such as to reflect an acceptable 1415 level of risk for patients and public health; or 1416

• when it will be possible to assess with sufficient precision the effect of risk factors associated 1417 with the occurrence of an adverse reaction; 1418

• when the results of ongoing or proposed safety studies are expected to be available; 1419 • the seriousness and magnitude of the risk for which risk minimisation activities are being 1420

proposed. Evaluation of the effectiveness of the activities will need to be carried out earlier 1421 and more frequently if the risk is very serious. 1422

3.14 Submission of Updated EU-RMP Documents 1423

As additional information on the safety of a medicinal product becomes available, the Safety 1424 Specification and other sections of the EU-RMP should be updated accordingly. For example, 1425 spontaneous reports, clinical trials and pharmacoepidemiological studies may all give rise to safety 1426 signals which need to be investigated or the results from a study could provide new information to 1427 update the Safety Specification. It may be that, based on the new information, it can be concluded that 1428 the safety concern has been resolved and that no further actions are needed beyond routine 1429 pharmacovigilance. In other cases, additional activities may be proposed and new milestones should 1430 be developed. 1431

The update should include assessment of the effectiveness of the risk minimisation activities within 1432 the risk management plan. 1433

At each update, consideration should be given as to whether new risk minimisation activities are 1434 needed. This may be because of a new safety concern or with an existing safety concern because the 1435 data suggests that the current strategy is not effective. 1436

Updated EU-RMPs are only required for medicinal products where an EU-RMP (or similar document) 1437 has already been submitted under the conditions in Chapter I.3, Section 4 or required under the terms 1438 of the marketing authorisation. 1439

The updated EU-RMP should be submitted at the same time as the next Periodic Safety Update Report 1440 (PSUR) unless other requirements have been laid down as a condition of the marketing authorisation. 1441 In addition, an updated EU-RMP should be submitted: 1442

• when new information is received that may impact on the current Safety Specification, 1443 Pharmacovigilance Plan or risk minimisation activities. 1444

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• within 60 days of an important (Pharmacovigilance or risk minimisation) milestone being 1445 reached or the results of a study becoming available. 1446

• at the request of the Competent Authority. 1447

A cover letter should be submitted with the updated EU-RMP briefly summarising the changes from 1448 the previous EU-RMP. 1449

Where no changes to any part of the EU-RMP have occurred since the last submission, a letter stating 1450 this, and the date of the last EU-RMP submission should be sent. In this circumstance it is not 1451 necessary to re-submit the EU-RMP with the letter. 1452

Periodic Safety Update Reports 1453

A summary of any amendments made to the EU-RMP, prior to the data lock point of the Periodic 1454 Safety Update Report (PSUR), should be included in the PSUR (see Addendum to ICH E2C Clinical 1455 Safety Data Management. Periodic Safety Update Reports for Marketed Drugs, Section 2.8.3; 1456 CPMP/ICH/4679/02 latest version on http://www.emea.eu.int). 1457

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1458

3. TABLE: METHODS FOR RISK MINIMISATION

1. Risk Minimisation

Risk minimisation activities can be divided into those where a reduction in risk is achieved primarily through the provision of information and education and those which seek to control the use of the medicine. When it is obvious that a risk minimisation activity will be needed post authorisation, consideration should be given to piloting the activity during the development phase to see the effectiveness and suitability. When this is done, the outcome should be provided in the risk minimisation plan under the appropriate action.

1.1 Provision of Information

Provision of information to Healthcare Professionals and/or Patients on the specific risks of a product and the measures on how to reduce them is an essential activity of risk management. This provision of information may be confined to information contained within the Summary of Product Characteristics (SPC) and Package Leaflet (routine risk management) or may be through the use of additional educational material (additional risk management). The need for additional material beyond the Summary of Product Characteristics and Package Leaflet will depend upon the risk and should be considered on a case by case basis. Experts in risk communication should be consulted as appropriate.

1.1.1 Additional Educational Material

The need for additional educational material and the form in which it should be provided will depend upon the specific safety concern. The aim of a specialised educational programme for healthcare professionals and/or patients is to:

• Enhance understanding of the specific risk(s) • Enhance understanding of measures to reduce either the frequency or severity of adverse

reactions • Enhance early detection and treatment (if applicable) of an adverse reaction • Enhance patient information, awareness and provide information on the need and use of

additional precautions.

The educational programme may include but is not limited to the following materials:

• Direct Healthcare Professional Communications • Physician’s Guide to prescribing • Pharmacist’s Guide to dispensing • Checklists for assessing comprehension, knowledge, attitudes, and/or desired safety

behaviours about the risk(s). These should be tailored to the target audience (e.g. physicians, pharmacists or patients).

• Checklists for actions before prescribing or dispensing • Patient information Brochures • Specific training programmes.

The choice of media may also need to be considered (written, audio or video) as well as the use of drawing/symbols to improve understanding. For medicines where the target population may include a larger proportion of visually impaired patients, the use of Braille or audio media should be given special consideration. Pre-testing materials in the target audience(s) is highly desirable to help ensure good comprehension and acceptance of the communication method and contents. A variety of testing methods such as readability testing, focus groups or surveys could be used.

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Specific training programmes may be considered in certain circumstances. However, it is unlikely that prescription/dispensing of the medicine can be limited to people who have undertaken such a programme.

The above educational materials should be in strict compliance with the contents of the SPC and the Patient Information Leaflet and must be agreed with the Competent Authority.

1.2 Legal Status of a Medicine

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 of 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.

When a marketing authorisation is granted, it must include details of any conditions or restrictions imposed on the supply or the use of the medicinal product, including the conditions under which the medicinal product may be made available to patients. This is commonly referred to as the “legal status” of a medicinal product. Typically it includes information on whether or not the medicinal product is subject to medical prescription. It may also restrict where the medicine can be administered (e.g. to a hospital) or by whom it can be prescribed (e.g. specialist).

For medicines only available upon prescription, additional conditions may be imposed by classifying medicines into those available only upon either a restricted medical prescription or a special medical prescription. When considering classification as subject to restricted medical prescription the following factors shall be taken into account:

• the medicinal product, because of its pharmaceutical characteristics or novelty or in the interests of public health, is reserved for treatments which can only be followed in a hospital environment,

• the medicinal product is used for the treatment of conditions which must be diagnosed in a hospital environment or in institutions with adequate diagnostic facilities, although administration and follow up may be carried out elsewhere, or

• the medicinal product is intended for outpatients but its use may produce very serious adverse reactions requiring prescription drawn up as required by a specialist and special supervision throughout the treatment.

In the case of an application for a marketing authorisation submitted in accordance with the Centralised procedure, the CHMP is responsible for recommending the Legal Status to the Commission. Although the use of legal status is not a activity that can be used directly by an Applicant for the purposes of risk reduction, the Applicant could request the Competent Authority to consider a particular legal status.

However, the definition of what constitutes a specialist is not uniform throughout the Member States so, in practice the provisions of the last indent are usually phrased in section 4.2 of the Summary of Product Characteristics as: “treatment by a physician experienced in the treatment of <the disease>”. Although restriction to use in a hospital environment may in practice ensure that the medicine is always prescribed by a specialist, this needs to be balanced against the inconvenience to patients if they need to attend a hospital for every prescription. Care also needs to be taken when considering where a medicine can be safely administered. or example the term “clinic” has different connotations depending upon the country. For this reason, the type of equipment needed may be specified rather than a location, e.g. “use in a setting where resuscitation equipment is available.”

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For classification as subject to special medical prescription the following factors shall be taken into account:

• the medicinal product contains, in a non-exempt quantity, a substance classified as a narcotic or a psychotropic substance within he meaning of the international conventions in force, such as the United Nations Conventions of 1961 and 1971, or

• the medicinal product is likely, if incorrectly used, to present a substantial risk of medicinal abuse, to lead to addiction or be misused for illegal purposes, or

• the medicinal product contains a substance which, by reason of its novelty or properties, could be considered as belonging to the group envisaged in the previous indent as a precautionary measure.

There is possibility of implementing further sub-categories at Member State Level which permits the Member States to tailor the broad classifications described above to their national situation. The definitions and therefore also the implementation varies in those Member States where the sub-categories exist.

1.3 Control at Pharmacy Level

The control of dispensing is another potential activity for risk management. Pharmacists who are well informed about the risks of a medicine can help educate the patient and provide an additional level of protection.

1.4 Control of Prescription Size or Validity

Limiting the validity of a prescription is another activity for risk management in the situation where decision to prescribe depends upon the result of a test which is only valid for a specific time. In some Member Sates it is possible to limit the validity of a prescription but not in others.

Limiting the number of units prescribed is another risk management activity. This can be useful if regular testing or review is needed. By limiting the number of units, the patient will need to see a Healthcare Professional at defined intervals increasing the opportunity for testing and reducing the length of time a patient is without review. If 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 for review may be considered.

A small pack size can also be useful, especially if overdose is thought to be a major risk or if the potential for drugs to get into the general population needs to be controlled.

1.5 Informed Consent and other Patient Aspects

In a clinical trial, patients are given information about the possible benefits and risks of the trial medication and any procedures associated with the trial. The Patient signs a form to say that they have been given the information, they understand it and agree to take part in the trial. This is known as informed consent. It has potential as a risk management activity to ensure that patients have been provided with appropriate information regarding the risks of the medicine and appropriate measures to reduce the risks. Use of informed consent outside the clinical trial area may not be possible in some Member States.

1.6 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 specific surveillance programme.

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1.7 Patient Registries

Patient registries are often suggested as a means of risk management. They have been used (sometimes very successfully) in individual countries to record the results of tests, to ensure that the recommended conditions of use are being adhered to, and control access to a medicine. However, there are possible issues about who controls the registry and the confidentiality of medical data.

Whereas patient registries could be a very useful activity for pharmacovigilance studies to characterise risks, use as a means of controlling access is not currently possible in some Member States. It is strongly suggested that if a Marketing Authorisation Holder is contemplating the use of a patient registry, this should be discussed with the appropriate regulatory authority at a very early stage.

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4. Requirements for Expedited Reporting of Individual Case Safety Reports 1460

4.1 Introduction 1461

The obligations of the Marketing Authorisation Holder for recording and reporting suspected adverse 1462 reactions associated with a medicinal product for which he holds a marketing authorisation are defined 1463 in Directive 2001/83/EC and Regulation (EC) No 726/2004 and, for those reactions requiring 1464 expedited reporting, are further explained in this Chapter. Reporting requirements in special situations, 1465 including obligations of the Applicant in the pre-authorisation phase, are described in Chapter I.5. 1466

For authorised medicinal products, independent of the authorisation procedure, adverse reactions 1467 received from Healthcare Professionals, either spontaneously or through post-authorisation studies, 1468 should be reported, regardless of whether or not the medicinal product was used in accordance with 1469 the authorised Summary of Product Characteristics (SPC) and/or any other conditions laid down for 1470 the marketing of the product. Adverse reactions identified in the worldwide-published scientific 1471 literature should also be reported. Electronic reporting of adverse reactions is mandatory, save in 1472 exceptional circumstances (see Chapter III.4). 1473

The definitions of ‘suspected adverse reaction’, ‘serious adverse reaction’ and ‘expected/unexpected 1474 adverse reaction’ are provided in the Glossary (see Annex 1). In the context of pharmacovigilance, 1475 adverse reaction is considered as synonymous with suspected adverse reaction and adverse drug 1476 reaction. 1477

For reporting purposes, any suspected transmission via a medicinal product of an infectious agent is 1478 also considered a serious adverse reaction and therefore has to be reported in expedited manner (see 1479 Chapter I.5, Section 8). 1480

When the Marketing Authorisation Holder receives an Individual Case Safety Report (ICSR) where 1481 the invented name of the medicinal product is not specified but the active substance is included in any 1482 of the medicinal products he holds a marketing authorisation for, the Marketing Authorisation Holder 1483 should assume that the report may relate to his product. 1484

Spontaneous reports of adverse reactions received from Healthcare Professionals should be reported 1485 by the Marketing Authorisation Holder if: 1486

• the Healthcare Professional has made a statement that a causal relationship between the event 1487 and the medicinal product is considered to be at least a reasonable possibility, or if 1488

• the Healthcare Professional has not made any statement on the suspected causal relationship or 1489 has stated that the causal relationship is unknown, or if 1490

• the Marketing Authorisation Holder considers that a causal relationship is at least a reasonable 1491 possibility. 1492

If the Healthcare Professional has made an explicit statement that a causal relationship between the 1493 medicinal product and reaction has been excluded and the Marketing Authorisation Holder agrees with 1494 this, the event does not have to be reported. 1495

When the Marketing Authorisation Holder is aware that a Healthcare Professional may have reported a 1496 reaction to one of its products directly to the Competent Authority of a Member State, the Marketing 1497 Authorisation Holder should still report the reaction, informing the Competent Authority that the 1498 report is likely to be a duplicate of a previous report. In this situation it is essential for the Marketing 1499 Authorisation Holder to provide all the available details including all case identification numbers 1500 allocated to the case, in order to aid identification of the duplicate. For further guidance on reporting 1501 of potential duplicates, see also ICH E2B(M), A1.11 (http://www.ich.org (website of the International 1502 Conference on Harmonisation (ICH)) and Annex 4 in this Volume). 1503

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The Marketing Authorisation Holder is expected to attempt to validate all Individual Case Safety 1504 Reports (ICSRs) submitted to them to ensure, prior to reporting to the Competent Authorities, that the 1505 minimum information required is included in the report: 1506

• An identifiable Healthcare Professional reporter; 1507 • The reporter can be identified by either name or initials, or address or qualification (e.g. 1508

physician, dentist, pharmacist, nurse), taking into account EU regulation on data 1509 protection (Directive 95/46/EC, Regulation (EC) No 45/2001). 1510

• An identifiable Patient; 1511 • The Patient can be identified by initials or patient number, or date of birth or age or age 1512

category or sex. The information should be as complete as possible, taking into account 1513 EU regulation on data protection (Directive 95/46/EC, Regulation (EC) No 45/2001). 1514

• At least one suspected active substance/medicinal product; 1515

• At least one suspected adverse reaction. 1516

Reports should be followed-up to obtain additional information relevant to the case as necessary, and 1517 follow-up information should be reported to the Competent Authorities. All available clinical 1518 information relevant to the evaluation of the reaction should be provided. 1519

For reports on adverse reactions from Consumers, see Chapter I.4, Section 3.5. 1520

If Individual Case Safety Reports, which do not qualify for expedited reporting as outlined in this 1521 Chapter, provide information that could lead to a change in the known risk-benefit balance for the 1522 product, this possible change should be notified to the Competent Authorities without delay. 1523

4.2 Reporting Time Frames 1524

The Marketing Authorisation Holder should transmit all Individual Case Safety Reports requiring 1525 expedited reporting promptly and no later than 15 calendar days from receipt. This applies to initial 1526 and follow-up information. The clock for expedited reporting starts as soon as the minimum 1527 information (see Chapter I.4, Section 1), has been brought to the attention of: 1528

• any personnel of the Marketing Authorisation Holder or an organisation having a contractual 1529 arrangement with the Marketing Authorisation Holder, including medical representatives; or 1530

• the Qualified Person Responsible for Pharmacovigilance or persons working for this Person. 1531

In the case of relevant worldwide scientific literature, the clock starts with awareness of a publication 1532 containing the minimum information by any personnel of the Marketing Authorisation Holder (see 1533 Chapter I.4, Section 3.2). Contractual arrangements can be made with a second party to perform 1534 literature searches. If a second party is performing this task, explicit procedures and detailed 1535 agreements should exist between the Marketing Authorisation Holder and the second party to ensure 1536 that the Marketing Authorisation Holder is promptly made aware of any literature reports to ensure 1537 that the Marketing Authorisation Holder can comply with his reporting obligations. 1538

In general, where the Marketing Authorisation Holder has set up contractual arrangements with a 1539 person or organisation for e.g. the marketing of or research on the suspected product, the clock starts 1540 as soon as any personnel of the Marketing Authorisation Holder or the person/organisation receives 1541 the minimum information. Explicit procedures and detailed agreements should exist between the 1542 Marketing Authorisation Holder and the person/organisation to ensure that the Marketing 1543 Authorisation Holder can comply with his reporting obligations. 1544

The date the Marketing Authorisation Holder becomes aware of a report should be considered day 0. 1545 The reporting time clock begins again for the submission of the follow-up report from the day the 1546 Marketing Authorisation Holder receives the follow-up information. 1547

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4.3 Requirements by Reporting Source 1548

4.3.1 Spontaneous Reports from Healthcare Professionals 1549

a) Individual Case Safety Reports on adverse reactions occurring within the EU 1550

For all medicinal products, independently of the authorisation procedure, the Marketing Authorisation 1551 Holder should report, on an expedited basis, all serious adverse reactions occurring within the EU, and 1552 brought to its attention by a Healthcare Professional, to the Competent Authority of the Member State 1553 on whose territory the incident occurred. 1554

For products authorised through the mutual recognition or decentralised procedure and for products 1555 which have been the subject of a referral procedure, these should additionally be reported directly to 1556 the Reference Member State (RMS)/the Referral Rapporteur Member State or made accessible 1557 through EudraVigilance as agreed with national Competent Authorities. 1558

For reporting purposes, any suspected transmission via a medicinal product of an infectious agent is 1559 also considered a serious adverse reaction and therefore has to be reported in expedited manner (see 1560 Chapter I.5, Section 8). 1561

Reports on a serious adverse reaction transmitted to the Marketing Authorisation Holder by a 1562 Competent Authority within the EU should be included in the next Periodic Safety Update Report (see 1563 Chapter I.6). 1564

Non-serious adverse reactions occurring within the EU should only be reported in expedited manner 1565 on request and otherwise in accordance with Chapter I.6 on Periodic Safety Update Reports; for 1566 centrally authorised products and periodic transmission of such cases into EudraVigilance, see 1567 Chapter III.12, Section 10. 1568

b) Individual Case Safety Reports on adverse reactions occurring outside the EU 1569

For all medicinal products, independent of the authorisation procedure, the Marketing Authorisation 1570 Holder should report, on an expedited basis, all unexpected serious adverse reactions and any 1571 suspected transmission via a medicinal product of an infectious agent occurring in the territory of a 1572 non-EU country, and originally reported by a Healthcare Professional, to the Agency and to all 1573 Member States where the medicinal product is authorised. 1574

Serious unexpected adverse reactions and any suspected transmission via a medicinal product of an 1575 infectious agent originally reported by a Healthcare Professional transmitted to the Marketing 1576 Authorisation Holder by a regulatory authority outside the EU are also subject to expedited reporting 1577 to the Competent Authorities of the EU by the Marketing Authorisation Holder. 1578

Serious expected and non-serious adverse reactions occurring outside the EU should only be reported 1579 in expedited manner on request and otherwise in accordance with Chapter I.6 on Periodic Safety 1580 Update Reports; for centrally authorised products and periodic reporting of such cases into 1581 EudraVigilance, see Chapter III.12, Section 10. 1582

It is allowed to also report expected serious adverse reactions occurring outside the EU on expedited 1583 basis to Member States and the Agency, provided that reporting takes place electronically in 1584 accordance with ICH E2B(M) (see Part III). 1585

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Expedited Reporting Requirements 1586

Marketing Authorisation Type

Origin Adverse Reaction Type Destination Timeline

Centralised EU All serious adverse reactions, including any suspected transmission via a medicinal product of an infectious agent

To Member State where adverse reaction occurs

15 days

Mutual recognition or decentralised, or subject to referral

EU All serious adverse reactions, including any suspected transmission via a medicinal product of an infectious agent

To Member State where adverse reaction occurs and to Reference/Rapporteur Member State9

15 days

Purely national EU All serious adverse reactions, including any suspected transmission via a medicinal product of an infectious agent

To Member State where adverse reaction occurs

15 days

Centralised Non- EU

All serious unexpected adverse reactions and any suspected transmission via a medicinal product of an infectious agent

To all Member States and to the Agency

15 days

National, including mutual recognition, decentralised, or subject to referral

Non-EU

All serious unexpected adverse reactions and any suspected transmission via a medicinal product of an infectious agent

To all Member States where product is authorised and to the Agency

15 days

1587

4.3.2 Reports Published in the Worldwide Literature 1588

Individual case reports from the worldwide literature in accordance with the provisions of Chapter I.4, 1589 Section 1 are considered to be reports of which the Marketing Authorisation Holder can reasonably be 1590 expected to be aware and have knowledge of. 1591

The Marketing Authorisation Holder is therefore expected to maintain awareness of possible 1592 publications by accessing a widely used systematic literature review and reference database no less 1593 frequently than once a week and to ensure that relevant publications in each Member State are 1594 appropriately reviewed. In addition, all company offices are encouraged to be aware of publications in 1595 their local journals in the Member State and bring them to the attention of the Qualified Person 1596 Responsible for Pharmacovigilance as appropriate. 1597

Cases of adverse reactions from the scientific and medical literature, including relevant published 1598 abstracts from meetings and draft manuscripts, might qualify for expedited reporting. 1599

The Marketing Authorisation Holder should report promptly published serious adverse reactions 1600 associated with the use of the active substance(s) of his medicinal products, as relevant to the 1601 categories identified in Chapter I.4, Section 3.1 above. 1602

9 To avoid duplicates, the Reference/Rapporteur Member State should not forward the adverse reaction to EudraVigilance if 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.

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If the product source and/or the invented name is not specified, the Marketing Authorisation Holder 1603 should assume that it is his product containing the active substance the publication refers to, although 1604 the report should indicate that the specific product source and/or the invented name was not identified. 1605

If multiple products are mentioned in the publication, a report should be submitted only by the 1606 Marketing Authorisation Holder whose product is suspected. The suspect product is that identified as 1607 such by the publication’s author. 1608

A copy of the relevant publication should be provided in a language acceptable to the Member State. It 1609 is recommended that publications should be translated into English unless otherwise specified. The 1610 Marketing Authorisation Holder should arrange prompt translation, in order to meet the 15-day 1611 reporting timeline. 1612

4.3.3 Information on Adverse Reactions from the Internet 1613

The Marketing Authorisation Holder should regularly screen websites under his management or 1614 responsibility for potential reports on adverse reactions. The Marketing Authorisation Holder is not 1615 expected to screen external websites for information on adverse reactions. However, if a Marketing 1616 Authorisation Holder becomes aware of an adverse reaction on a website that he does not manage, the 1617 Marketing Authorisation Holder should review the case and determine whether it should be reported in 1618 expedited manner in accordance with Chapter I.4, Sections 3.1 and 3.5. 1619

The Marketing Authorisation Holder should consider utilising his websites to facilitate adverse 1620 reaction collection, e.g. by providing adverse reaction forms for reporting or by providing appropriate 1621 contact details for direct communication. In relation to such cases, identifiability of the reporter refers 1622 to the existence of a real person, i.e. it is possible to identify that the Patient and reporter exist. 1623

4.3.4 Reports from Post-Authorisation Studies 1624

Reports derived from organised data collection systems (which include clinical trials, post-1625 authorisation studies, registries, post-authorisation named-patient use programmes, other patient 1626 support and disease management programmes, surveys of Patients or Healthcare Providers, or 1627 information gathering on efficacy or patient compliance) are considered solicited reports. Reporting 1628 requirements for solicited reports differ depending on whether they are derived from interventional or 1629 non-interventional studies. 1630

a) Interventional Studies 1631

Interventional studies fall under the provisions of Directive 2001/20/EC on clinical trials and adverse 1632 reactions should be reported in line with that Directive and associated guidance, in particular the 1633 Detailed Guidance on the Collection, Verification and Presentation of Adverse Reaction Reports 1634 Arising from Clinical Trials on Medicinal Products for Human Use (ENTR/CT3), which includes 1635 guidance on unblinding, and the Detailed Guidance on the European Database of Suspected 1636 Unexpected Serious Adverse Reactions (EudraVigilance – Clinical Trial Module) (ENTR/CT4). (See 1637 EudraCT website http://eudract.eudra.org.) 1638

b) Non-interventional Studies 1639

Post-authorisation studies that are non-interventional are not covered by the provisions of Directive 1640 2001/20/EC but by Directive 2001/83/EC (see Annex 1 for the definition of a non-interventional trial). 1641 Reports of adverse reactions arising from such studies should be reported on an expedited basis 1642 according to the same criteria and timelines as adverse reactions reported spontaneously by Healthcare 1643 Professionals (see Chapter I.4, Section 3.1); this includes any suspected transmission via a medicinal 1644 product of an infectious agent. For further information on post-authorisation safety studies see 1645 Chapter I.7. 1646

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4.3.5 Reports from Patients and Other Consumers 1647

When information is received directly from a Patient or another Consumer suggesting that an adverse 1648 reaction may have occurred, the Marketing Authorisation Holder should attempt to obtain the Patient's 1649 consent to contact the Healthcare Professional involved for further information. When such a 1650 Consumer report has been confirmed by the Healthcare Professional, it should be considered as a 1651 spontaneous report from a Healthcare Professional and reported according to Chapter I.4, Sections 1 1652 and 3.1. When a Consumer submits medical documentation that supports the occurrence of the 1653 suspected adverse reaction, this should be considered sufficient to report the case if it provides the 1654 minimum information (see Chapter I.4, Section 1). Medically unconfirmed adverse reactions should 1655 not be reported to the Agency (EudraVigilance). For requirements to reflect Consumer reports in 1656 Periodic Safety Update Reports see Chapter I.6, Section 3.7. 1657

For requirements in relation to reporting of outcomes of use of medicinal products during pregnancy, 1658 originating from Consumers, see Chapter I.5, Section 3. 1659

When a possible signal for a safety concern arises from Consumer reports for which medical 1660 confirmation has not been obtained (e.g. several cases reporting the same or similar adverse 1661 experience), the Marketing Authorisation Holder should initiate further investigations and notify the 1662 Competent Authorities as appropriate. 1663

Member States may have additional requirements in place with regard to reports from Consumers, 1664 which need to be followed by the Marketing Authorisation Holder. 1665

4.3.6 Reports from Other Non-Medical Sources 1666

If a Marketing Authorisation Holder becomes aware of a case report from non-medical sources other 1667 than those mentioned in Chapter I.4, Section 3.5, e.g. the lay press or other media, every attempt 1668 should be made to obtain the minimum information (see Chapter I.4, Section 1) and to follow-up the 1669 case as for reports from a Patient or Consumer (see Chapter I.4, Section 5). 1670

4.3.7 Change in Nature, Severity or Outcome of an Expected Adverse Reaction 1671

An expected adverse reaction should be considered unexpected if Individual Case Safety Reports 1672 suggest a change in the nature (including frequency), severity or outcome of the adverse reaction. For 1673 example, if the Marketing Authorisation Holder identifies an increase in frequency of an expected 1674 serious adverse reaction he should notify the Competent Authority immediately. 1675

4.4 Data Elements for the Report 1676

The principles in the ICH E2D Guideline on good case management practices and ICH E2B(M) 1677 Guideline on data elements for transmission of Individual Case Safety Reports should be followed. 1678 The data elements for Individual Case Safety Reports are defined in Part III. 1679

For the minimum requirements for transmission of an Individual Case Safety Report see Chapter I.4, 1680 Section 1. 1681

It is essential for the Marketing Authorisation Holder to provide as many data elements as possible for 1682 cases of serious adverse reactions to facilitate assessment. The Marketing Authorisation Holder is 1683 expected to follow-up all reports of serious adverse reactions to his products to obtain comprehensive 1684 information where available. Additional information not available at the time of the initial report 1685 should be provided in the form of follow-up reports (see Chapter I.4, Section 1 and ICH E2D 1686 (http://www.ich.org and Annex 4 in this Volume)). 1687

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The active substance/invented name should be reported in accordance with ICH E2B(M) 1688 (http://www.ich.org and Annex 4 in this Volume), and the original words used by the reporter to 1689 describe the adverse reaction should be provided. Reports to the Competent Authority of the Member 1690 State where the adverse reaction occurred should be in the language of that Member State with an 1691 English translation. Reports to Competent Authorities other than the Competent Authority of the 1692 Member State where the reaction occurred and to the Agency should be in English. The appropriate 1693 Lowest Level Terms provided in the latest version of MedDRA (Medical Dictionary for Regulatory 1694 Activities) should be used. 1695

The Marketing Authorisation Holder may comment on whether he considers a causal relationship 1696 between the suspect product(s) and the reaction(s) reported is at least a reasonable possibility and 1697 should provide the criteria on which he has made the assessment. 1698

4.5 Method of Reporting 1699

Save in exceptional circumstances, all Individual Case Safety Reports should be reported 1700 electronically by the Marketing Authorisation Holder. The requirements for electronic transmission of 1701 Individual Case Safety Reports should be followed in accordance with Part III. 1702

4.6 Impact of Reported Suspected Adverse Reactions on the Overall Safety 1703 Profile of a Product and its Summary of Product Characteristics 1704

When a reported adverse reaction(s) (from any source) impacts significantly on the known risk-benefit 1705 balance of the product, the Marketing Authorisation Holder should notify this to the Competent 1706 Authority without delay and annex the Individual Case Safety Reports. Examples might be where the 1707 report is one of a series of similar or linked cases, which are being simultaneously reported. Other 1708 situations include a suggestion of a change in the nature, severity or frequency of expected adverse 1709 reaction or when new risk factors are identified. Rarely, even a single report of an unexpected adverse 1710 reaction may contain sufficient information to establish a causal association with the suspect medicinal 1711 product and impact on the risk-benefit balance. 1712

In situations where Individual Case Safety Reports impact on the known risk-benefit balance of a 1713 medicinal product, the Marketing Authorisation Holder should indicate what action he proposes in 1714 relation to the marketing authorisation, the Summary of Product Characteristics and Patient 1715 Information Leaflet. 1716

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5. Requirements for Reporting in Special Situations 1717

5.1 Introduction 1718

Adverse reactions should be reported according to the requirements outlined in Chapter I.4, regardless 1719 of whether or not the medicinal product was used in accordance with the authorised Summary of 1720 Product Characteristics (SPC) and/or any other conditions laid down for the marketing of the product. 1721

In addition to routine expedited and periodic reporting requirements as laid out in I.4 and I.6, the 1722 Marketing Authorisation Holder should be aware of the following additional reporting requirements 1723 relating to worldwide experience with the medicinal product: 1724

• Reporting in the period between the submission of the marketing authorisation application and 1725 the granting of the marketing authorisation 1726

• Reporting of outcomes of use of a medicinal product during pregnancy 1727 • Reporting of paediatric data 1728 • Reporting from compassionate/named-patient use 1729 • Reporting of lack of efficacy 1730 • Reporting of suspected transmission of infectious agents 1731 • Reporting in relation to overdose, abuse and misuse 1732 • Reporting of medication errors. 1733

5.2 Reporting in the Period between the Submission of the Marketing 1734 Authorisation Application and the Granting of the Marketing Authorisation 1735

In the period between submission of the marketing authorisation application and the authorisation, 1736 adverse reactions should be reported in accordance with Directive 2001/20/EC on clinical trials and 1737 associated guidance, in particular the Detailed Guidance on the Collection, Verification and 1738 Presentation of Adverse Reaction Reports Arising from Clinical Trials on Medicinal Products for 1739 Human Use (ENTR/CT3) and the Detailed Guidance on the European Database of Suspected 1740 Unexpected Serious Adverse Reactions (EudraVigilance – Clinical Trial Module) (ENTR/CT4). (See 1741 EudraCT website http://eudract.eudra.org.) Furthermore, spontaneous reports from countries where the 1742 product is authorised should be reported in accordance with this guidance. 1743

In addition, information that could impact on the risk-benefit balance may become available from the 1744 Applicant or from his experience in Member States where the product is already in use on a 1745 compassionate use basis, or from countries outside the EU where the product is marketed. It is the 1746 responsibility of the Qualified Person Responsible for Pharmacovigilance to ensure that this 1747 information is immediately submitted by the Applicant to the Competent Authorities of the Member 1748 States where the application is under assessment, and in the case of a centralised application to the 1749 Agency, the Rapporteur and Co-Rapporteur. 1750

5.3 Reporting of Outcomes of Use of a Medicinal Product During Pregnancy 1751

The Marketing Authorisation Holder should follow-up all reports from Healthcare Professionals 1752 relating to pregnancies where the foetus may have been exposed to one of his medicinal products 1753 (either through maternal exposure or transmission of a medicinal product via semen following parental 1754 exposure). Where reports originate from Consumers, reasonable attempts should be made at follow-up 1755 via the Patient’s Healthcare Professional. When a Consumer submits medical documentation that 1756 supports the occurrence of the suspected adverse reaction, this should be considered sufficient to 1757 report the case if it provides the minimum information (see Chapter I.4, Section 1). 1758

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When an active substance, or one of its metabolites, has a long half-life, this should be taken into 1759 account when considering whether a foetus may have been exposed (i.e. medicinal products taken 1760 before conception need to be considered). 1761

If a pregnancy results in an abnormal outcome which the reporting Healthcare Professional considers 1762 might be due to the medicinal product, this should be reported on an expedited basis, following the 1763 reporting requirements outlined in Chapter I.4 and in accordance with the Guideline on Exposure to 1764 Medicinal Products During Pregnancy: Need for Post-Authorisation Data (see Part V) and the ICH 1765 E2B(M) Guidelines (see ICH website http://www.ich.org and Annex 4 in this Volume). 1766

This refers especially to: 1767

• Reports of congenital anomalies in the foetus/child; 1768 • Reports of foetal death and spontaneous abortion; and 1769 • Reports of adverse reactions in the neonate that are classified as serious. 1770

Other cases, i.e. reports of termination of pregnancy without information on congenital malformation 1771 and reports of pregnancy exposure without outcome data, should not normally be reported on an 1772 expedited basis. 1773

In certain circumstances, the Marketing Authorisation Holder may be requested to treat any reports of 1774 pregnancy exposure as cases requiring expedited reporting, e.g. pregnancy exposure to products 1775 contraindicated in pregnancy because of a high teratogenic potential. 1776

Information on exposure to medicinal products during pregnancy should include dates of exposure 1777 and, as far as possible, details of the period of gestation at the time of exposure, specified by the 1778 method of assessment and expressed as weeks and/or days. This information is necessary to establish a 1779 possible causal relationship between the adverse event(s) reported and exposure to the product. 1780

It is also important to collect information on pregnancies, which have a normal outcome. Not 1781 infrequently, pregnant women or Healthcare Professionals will contact either the Marketing 1782 Authorisation Holder or Competent Authorities requesting information on the teratogenic potential of 1783 a medicinal product and/or experience of use during pregnancy (see Guideline on Exposure to 1784 Medicinal Products During Pregnancy: Need for Post-Authorisation Data in Part V). 1785

Expedited reports together with other reports on outcome of exposure during pregnancy should also be 1786 included in the Periodic Safety Update Report (PSUR) (see Chapter I.6) together with aggregated data 1787 on the overall exposure and details of normal/abnormal outcomes. Reports from prospective registries 1788 should also be included and evaluated in the PSUR. 1789

If, at any time, the Marketing Authorisation Holder identifies, or becomes aware of, a signal of a 1790 possible teratogenic effect (e.g. through a cluster of similar abnormal outcomes) all Competent 1791 Authorities where a marketing authorisation is held, and also the Agency in the case of centrally 1792 authorised medicinal products, should be informed immediately. This also applies to possible signals 1793 arising from Consumer reports for which medical confirmation has not (yet) been obtained. 1794

5.4 Reporting of Adverse Reactions during Breastfeeding 1795

Adverse reactions suspected in infants following exposure to a medicinal product from breastfeeding, 1796 should be reported in accordance with Chapter I.4. 1797

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5.5 Reporting of Data on Use of Medicinal Products in Children 1798

Collection and evaluation of data on exposure of children to medicinal products and associated risks is 1799 an important task and specific guidance is therefore included in the Guideline on Conduct of 1800 Pharmacovigilance for Medicines Used by the Paediatric Population (see Part V). Exposure of 1801 children should also be considered and addressed in the Risk Management Plan (see Chapter I.3). 1802

5.6 Reporting from Compassionate/Named-Patient Use 1803

Compassionate or named-patient use of a medicine should be strictly controlled by the company 1804 responsible for providing the medicine and should ideally be the subject of a protocol. 1805

Such a protocol should ensure that the Patient is registered and adequately informed about the nature 1806 of the medicine and that both the prescriber and the Patient are provided with the available information 1807 on the properties of the medicine with the aim of maximising the likelihood of safe use. The protocol 1808 should encourage the prescriber to report any adverse reactions to the company, and to the Competent 1809 Authority, where required nationally. 1810

Companies should continuously monitor the risk-benefit balance of medicines used on compassionate 1811 or named-patient basis (subject to protocol or not) and follow the requirements for reporting to the 1812 appropriate Competent Authorities. As a minimum, the requirements laid down in Chapter I.4, 1813 Section 1 apply. 1814

For inclusion of experience from compassionate or named-patient use in Periodic Safety Update 1815 Reports see Chapter I.6. 1816

5.7 Reporting of Lack of Efficacy 1817

Reports of lack of efficacy should not normally be reported on expedited basis, but should be 1818 discussed in the relevant Periodic Safety Update Report (see Chapter I.6). However, in certain 1819 circumstances reports of lack of efficacy should be treated as expedited cases for reporting purposes. 1820 Medicinal products used for the treatment of life-threatening diseases, vaccines and contraceptives are 1821 examples of classes of medicinal products where lack of efficacy should be considered as cases 1822 requiring expedited reporting. Judgement should be used in reporting, considering if other cases 1823 qualify for reporting. For example, antibiotics used in life-threatening situations where the medicinal 1824 product was not in fact appropriate for the infective agent should not be reported. However, a life-1825 threatening infection where the lack of efficacy seems to be due to the development of a newly 1826 resistant strain of a bacterium previously regarded as susceptible should be reported on an expedited 1827 basis. 1828

Lack of efficacy for anti-neoplastic agents should not be routinely reported as an expedited report 1829 unless the lack of efficacy indicates a change in the risk-benefit balance, e.g. a lower-than-expected 1830 efficacy or a higher than expected number or rate of deaths due to progressive disease. 1831

5.8 Reporting of Suspected Transmission of Infectious Agents 1832

For the purposes of reporting, any suspected transmission of an infectious agent via a medicinal 1833 product is also considered a serious adverse reaction and all such cases should be reported in expedited 1834 manner in accordance with the criteria outlined in Chapter I.4 and the Guideline on Reporting of 1835 Suspected Transmission of Any Infectious Agent Via a Medicinal Product (see <subject to later 1836 separate consultation> on http://www.emea.eu.int), whether they occur within or outside the EU. 1837

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For cases occurring outside the EU, the legislation mentions this reporting requirement specifically to 1838 ensure that such cases are appropriately reported and to avoid failure to report due to interpretation of 1839 such cases as expected (e.g. given the manufacturing process). For cases occurring within the EU, the 1840 legal requirement to report any such transmission in expedited manner is addressed by the reporting 1841 requirements for all (i.e. expected and unexpected) serious adverse reactions as Chapter I.4. 1842

Any organism, virus or infectious particle (e.g. prion protein transmitting Transmissible Spongiform 1843 Encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent. 1844

A transmission of an infectious agent may be suspected from clinical symptoms or laboratory findings 1845 indicating an infection in a patient exposed to a medicinal product. As in the case of suspected adverse 1846 reactions and adverse reactions, the terms suspected transmission and transmission are considered 1847 synonymous. Confirmation of contamination (including inadequate inactivation/attenuation of 1848 infectious agents as active substances) of the concerned medicinal product may increase the evidence 1849 for, or confirm, such a causal relationship. 1850

Signals arising from case reports on suspected transmission of an infectious agent should be 1851 investigated as for other adverse reactions. 1852

Where a quality defect is suspected or confirmed, the procedures laid down in the Compilation of 1853 Community Procedures on Inspections and Exchange of Information (see EMEA/INS/GMP/3351/03 1854 latest version on http://www.emea.eu.int) must also be followed. Any contamination of a medicinal 1855 product should be considered serious and is likely to be classified as a Class 1 or 2 product defect. 1856

The potential for transmission of an infectious agent via a medicinal product should also be addressed 1857 in the Risk Management Plan (see Chapter I.3). 1858

In the case of medicinal products derived from human blood or human plasma, haemovigilance 1859 procedures also apply, in accordance with Directive 2002/98/EC. 1860

Medicinal products must also comply with the Note for Guidance on Minimising the Risk of 1861 Transmitting Animal Spongiform Encephalopathy Agents Via Human and Veterinary Products 1862 (see EMEA/410/01 latest version on http://www.emea.eu.int). 1863

5.9 Reporting in Relation to Overdose, Abuse and Misuse 1864

The Marketing Authorisation Holder should collect any available information on overdose, abuse and 1865 misuse related to his products. Reports of overdose, abuse and misuse should be routinely followed up 1866 to ensure that information is as complete as possible with regard to early symptoms, treatment and 1867 outcome. The Marketing Authorisation Holder should report cases of overdose, abuse and misuse that 1868 lead to serious adverse reactions on an expedited basis in accordance with the requirements in 1869 Chapter I.4. This includes cases of intended suicide. The Marketing Authorisation Holder should 1870 continuously monitor and evaluate the potential impact of overdose, abuse and misuse on the overall 1871 risk-benefit balance of the medicinal product. The potential for overdose, abuse and misuse and the 1872 associated risks should also be addressed in the Periodic Safety Update Reports (see Chapter I.6) and 1873 the Risk Management Plan (see Chapter I.3). 1874

5.10 Reporting of Medication Errors 1875

The Marketing Authorisation Holder should report cases of medication errors that are associated with 1876 adverse reactions on an expedited basis in accordance with the requirements in Chapter I.4, and as 1877 required by national requirements. Cases not associated with adverse reactions and near misses should 1878 only be reported in accordance with national requirements. Cumulative information on medication 1879 errors, resulting in adverse reaction or not, should be discussed in the section of the Periodic Safety 1880

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Update Report on the overall safety evaluation (see Chapter I.6). The potential for medication errors 1881 and their prevention should be addressed in the Risk Management Plan (see Chapter I.3). 1882

For reporting of medication errors due to confusion of invented names in relation to centrally 1883 authorised products, see the Guideline on the Acceptability of Invented Names for Human Medicinal 1884 Products Processed through the Centralised Procedure (see EMEA/CPMP/328/98 latest version on 1885 http://www.emea.eu.int). 1886

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6. Requirements for Periodic Safety Update Reports 1887

6.1 Introduction 1888

Once a medicinal product is authorised in the EU, even if it is not marketed, the Marketing 1889 Authorisation Holder is required to submit Periodic Safety Update Reports (PSURs). PSURs are 1890 required to be prepared immediately upon request or normally at least every 6 months after 1891 authorisation. As long as the product is not yet marketed in the EU, a PSUR should state if the 1892 Marketing Authorisation Holder plans to market the product in the next PSUR reporting period. Once 1893 marketed, 6-monthly PSUR submissions should be continued until two years marketing experience in 1894 the EU has been gained and then once a year for the following two years and thereafter at 3-yearly 1895 intervals. 1896

There may, however, be exceptions where the submission of 6-monthly and subsequent yearly PSURs 1897 may be re-started, or where an exemption from the requirement for 6-monthly and yearly PSURs is 1898 granted. This is explained in Chapter I.6, Section 2.4.c and the review of the periodicity is also part of 1899 the Risk Management Plan and its assessment (see Chapter I.3). 1900

For the purpose of renewal application, the PSUR provides also the format for the submission of 1901 safety data. 1902

For medicinal products authorised under the centralised procedure PSURs, should be submitted to the 1903 Competent Authorities of all Member States and to the Agency in accordance with Regulation (EC) 1904 No 726/2004 Articles 23 and 24 and Commission Regulation (EC) 540/95 Articles 2 and 3 (see 1905 Distribution Requirements and Address Lists for PSURs in Annex 6.1). 1906

If a decision is taken to amend the SPC, the Marketing Authorisation Holder should submit the 1907 variation application at the same time as the PSUR, or where this is not possible, should state a 1908 timetable for submission. 1909

Marketing Authorisation Holders are reminded that amendments to the PSUR submission cycle should 1910 be agreed with the Competent Authorities via a type II variation. 1911

6.2 General Principles 1912

6.2.1 General Scope of Information 1913

The main focus of the report should be adverse reactions. Also reports of lack of efficacy, specifically 1914 for medicinal products used in the treatment of life-threatening conditions and for certain other 1915 medicinal products (see Chapter I.5, Section 7), e.g. contraceptives and vaccines, may represent a 1916 significant hazard and in that sense be a safety concern. These types of cases should be discussed 1917 within the PSUR (see Chapter I.6, Section 3.9.a). 1918

Moreover, data from pregnancy experience and outcome should also be discussed. 1919

An increase in the frequency of Individual Case Safety Reports (ICSRs) for known adverse reactions 1920 is considered as relevant new information. Although increased reporting should be discussed in the 1921 PSUR, it is not possible to provide specific guidance as to what constitutes increased reporting or what 1922 method should be used for quantifying this. The Marketing Authorisation Holder should provide 1923 details of the methods that have been used. Judgement should be used in such situations to determine 1924 whether the data reflect a meaningful change in occurrence of adverse reactions or in the safety profile 1925 and whether an explanation can be proposed for such a change (e.g. population exposed, duration of 1926 exposure). 1927

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6.2.2 One Periodic Safety Update Report for Products Containing an Active 1928 Substance Authorised to One Marketing Authorisation Holder 1929

It is strongly recommended that information on all indications, dosage forms and regimens for a given 1930 active substance for medicinal products authorised to one Marketing Authorisation Holder to be 1931 included in a single PSUR, with a single data lock point common for all aspects of product use. There 1932 is great advantage to having a consistent, broad-based examination of the safety information for the 1933 active substance(s) in a single document. 1934

When relevant and possible, data relating to a particular indication, dosage form, route of 1935 administration or dosing regimen should be presented in separate sections within the body of the 1936 PSUR and any safety concerns addressed accordingly without preparing a separate PSUR (e.g. a 1937 section dedicated on paediatric use summarising safety as well as exposure information). In 1938 exceptional cases, the Agency, the Competent Authorities or the Marketing Authorisation Holder 1939 might find it appropriate to have a separate PSUR. In this case, agreement should be obtained at the 1940 time of authorisation or during the PSUR assessment procedure. 1941

In the case of fixed combinations, options include either a separate PSUR for the combination with 1942 cross-reference to the single substance (s) PSUR(s) or inclusion of the fixed combination data within 1943 one of the single substance PSURs. 1944

If a subsequent marketing authorisation is granted to a Marketing Authorisation Holder for a product 1945 which contains the same active substance as one previously granted to the same Marketing 1946 Authorisation Holder, the data lock points used for the PSURs for the first product should normally be 1947 used for the following joint PSURs covering the first and all subsequent products. However the regular 1948 submission periodicity (see Chapter I.6, Section 2.4.a) will normally restart with the granting of a 1949 subsequent marketing authorisation unless other conditions are laid down within the terms of the 1950 granting of the marketing authorisation (see Chapter I.6, Section 2.4.c). 1951

In addition, in order to put in place measures facilitating worksharing of PSUR assessment among 1952 Competent Authorities, a harmonisation of the birth dates, the renewal dates and/or the PSUR 1953 submission schedules of medicinal products containing the same active substances may be proposed 1954 by the Marketing Authorisation Holder or the Competent Authorities. 1955

6.2.3 Products Authorised to More Than One Marketing Authorisation Holder 1956

Where a product is authorised to more than one Marketing Authorisation Holder, in the case of 1957 multiple applications, the submission of joint PSURs is acceptable provided that the products remain 1958 identical in all respects apart from their invented name and provided that the PSURs are submitted 1959 independently by or on behalf of the respective Marketing Authorisation Holder for his product. The 1960 data lock point should be based on the birth date used for the first authorised product. 1961

When data received from a person or organisation with whom the Marketing Authorisation Holder 1962 holds a contractual arrangement might contribute meaningfully to the safety analysis and influence 1963 any proposed or effected changes in the Product Information of the medicinal product authorised to 1964 the reporting Marketing Authorisation Holder, these data should be included, with the source 1965 indicated, and discussed in the PSUR, even if it is known that they are included in another Marketing 1966 Authorisation Holder’s PSUR. 1967

6.2.4 Frequency of Review and Reporting 1968

6.2.4.a Regular and Ad Hoc Submission of Periodic Safety Update Reports 1969

Before the initial placing on the EU market, PSURs are required to be prepared and submitted: 1970

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• immediately upon request from a Competent Authority or the Agency; and 1971 • at least every 6 months after authorisation. 1972

After the initial placing on the EU market, in accordance with the regular periodicity, 1973

• 6-monthly PSUR submissions should be continued until two years marketing experience 1974 in the EU has been gained; 1975

• then yearly PSURs should be submitted for the following two years; and 1976 • thereafter PSURs should be submitted at 3-yearly intervals. 1977 • In addition, PSURs should be submitted immediately upon request from a Competent 1978

Authority or the Agency. 1979

The first PSUR should be submitted within 6 months after the granting of the marketing authorisation. 1980

The date of the initial placing on the EU market is the date of launch, for the first time, in any Member 1981 State. 1982

Because the renewal is an independent process, it does not change the regular submission periodicity 1983 of the PSURs. 1984

When yearly or 3-yearly PSURs should be submitted, multiples of 6-monthly or yearly PSURs are 1985 acceptable, provided that the Marketing Authorisation Holder submits a PSUR Summary Bridging 1986 Report, the content of which is described in Chapter I.6, Section 4. 1987

If a time gap occurs between the data lock point of a regular PSUR and a data request from a 1988 Competent Authority (e.g. renewal, Benefit-Risk Review, ad hoc PSUR request), a PSUR Addendum 1989 Report should also be submitted (see Chapter I.6, Section 5). For a PSUR that spans longer time 1990 intervals, e.g. 3 years, an Addendum Report would only be considered appropriate if the time since 1991 preparation of the 3-year PSUR and the locally required report is greater than 6 months. 1992

Each PSUR should cover the period of time since the last PSUR and should be submitted within 60 1993 days after the data lock point. 1994

However, in rare circumstances, a Marketing Authorisation Holder may make a special request to the 1995 Competent Authority for 30 additional calendar days to submit a PSUR. Ideally, this request should be 1996 made before the data lock point. The Competent Authority shall commit to respond as rapidly as 1997 possible. The basis of such a request should be justified and could include: 1998

• a large number of case reports for the reporting period, provided that there is no new 1999 significant safety concern; 2000

• safety concerns raised by Competent Authorities in the previous PSUR for which the 2001 Marketing Authorisation Holder is preparing additional or further analysis in the next PSUR; 2002 and/or 2003

• safety concerns identified by the Marketing Authorisation Holder that might require additional 2004 or further analysis. 2005

The Marketing Authorisation Holder should make such a request only for the single PSUR in question 2006 and not for subsequent PSURs. Subsequent PSURs will generally be expected to be submitted on the 2007 appropriate date in line with their original periodicity. 2008

6.2.4.b Submission of Periodic Safety Update Reports for Renewal of Marketing 2009 Authorisations 2010

The Marketing Authorisation Holder should submit safety data with the renewal application at least 6 2011 months before the expiry date of the marketing authorisation in the EU. For the submission of safety 2012

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data as part of the application for renewal of the marketing authorisation, the PSUR concept should be 2013 used. The Marketing Authorisation Holder should lock the data no more than 60 days before 2014 submitting the PSUR. 2015

For the purpose of the renewal application of the marketing authorisation, the Marketing Authorisation 2016 Holder should submit: 2017

• the PSUR, or the PSUR plus a PSUR Addendum Report (see Chapter I.6, Section 5), or line-2018 listings and/or summary tabulations, or only a PSUR Addendum Report, or only line-listings 2019 and/or summary tabulations, covering the period since the data lock point of the last PSUR 2020 (e.g. for the first renewal, the safety data of this PSUR or Addendum Report together with the 2021 PSURs previously submitted should cover a period of 4 years and 4 months since the 2022 marketing authorisation); and 2023

• a PSUR Summary Bridging Report, bridging all PSURs (even those already submitted) 2024 covering the period of 4 years and 4 months, or the information of the PSUR Summary 2025 Bridging Report included in the Clinical Overview to be submitted with the renewal 2026 application. 2027

It is accepted that previously submitted PSURs are not re-submitted provided that a listing of original 2028 submission dates is appended to the Summary Bridging Report. 2029

If the Marketing Authorisation Holder should also submit a subsequent renewal application, the 2030 periodicity of the PSURs may be revised requesting 6-monthly or yearly PSURs. In any case the 2031 safety data included in PSURs for the subsequent renewal should cover the period of five years since 2032 the data lock point of the first renewal. 2033

Because the renewal is an independent process, it does not change the periodicity and submission 2034 dates of the PSURs due under the pharmacovigilance reporting requirements. 2035

6.2.4.c Circumstances Where the Periodicity May Be Amended 2036

The submission of PSURs are part of the normal conditions of marketing authorisations and 2037 pharmacovigilance obligations of the Marketing Authorisation Holder. More frequent submissions 2038 than outlined in Chapter I.6, Section 2.4.a may be required as a condition of authorisation. The 2039 periodicity of PSUR submission may be amended (see below in this Section and above in Chapter I.6, 2040 Section 2.2). In certain circumstances less frequent submissions may be appropriate. 2041

Where an amendment is proposed, the Applicant should submit, as part of the application for a 2042 marketing authorisation, a reasoned request for the amendment, which, if granted, becomes part of the 2043 conditions of authorisation. If an amendment is applied for after authorisation, such an application 2044 should follow the procedures for a type II variation. If the request for an amendment is granted, the 2045 Competent Authority will specify the amendments. 2046

Submission of PSURs at a lower frequency than once every 3 years is not possible. 2047

There may be circumstances where Competent Authorities require an amendment of the periodicity of 2048 PSUR submission. 2049

The PSUR submission periodicity following a line extension should be identical to the one already in 2050 place for the authorised product containing the same active substance. However, there may be valid 2051 reasons for amending the periodicity, at least initially; for example, approval of a new route of 2052 administration or new indication may require that 6-monthly or yearly PSURs are submitted for a 2053 period after authorisation, with subsequent phasing-in of the PSUR submission periodicity with that 2054 for other products. This will have to be decided on a case-by-case basis. 2055

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The addition of a paediatric indication for an existing medicinal product requires submission of 6-2056 monthly PSURs for two years and yearly PSURs for the following two years. Thereafter, the 2057 periodicity of the PSUR submission should be phased in with the PSUR submission schedule already 2058 in place (see Guideline on the Conduct of Pharmacovigilance for Medicines Used by the Paediatric 2059 Population in Part V). 2060

Generics should preferably have the same birth date as the corresponding innovator product. For 2061 newly authorised generics an immediate move to the submission of a 3-yearly PSUR (and thereafter 3-2062 yearly PSURs to be continued) can be made as part of the authorisation application. However, in the 2063 case of specific safety concerns, it may not be appropriate to amend the regular PSUR periodicity but 2064 this should be decided on a case-by-case basis, for example in circumstances of: 2065

• an active substance which is a different salt/ester derivative (with the same therapeutic 2066 moiety); 2067

• the presence of an excipient without an established safety profile; or 2068

• a Risk Management Plan in place for the corresponding innovator product requiring specific 2069 monitoring of a safety concern. 2070

Therefore, the first PSUR of a new generic could cover a period of up to 3 years or shorter, depending 2071 on the harmonised birth date of the innovator product. The second PSUR would then cover a period of 2072 3 years. 2073

6.2.4.d Preparation of Periodic Safety Update Report according to the International 2074 Birth Dates 2075

Medicinal products, which are also authorised outside the EU, will have an International Birth Date 2076 (IBD). This is the date of the first marketing authorisation for the product granted to the Marketing 2077 Authorisation Holder in any country in the world. For medicinal products first authorised in the EU, 2078 the EU Birth Date (EBD) is the date of the first marketing authorisation for a medicinal product 2079 granted in the EU. If desired by the Marketing Authorisation Holder, the IBD may be designated as 2080 the last day of the same month. 2081

In order to harmonise PSURs internationally, the Marketing Authorisation Holder may use the IBD to 2082 determine the data lock points in the EU rather than the EBD. If the IBD is used, the first data lock 2083 point must be within 6 months after the EU marketing authorisation date, unless other requirements 2084 have been laid down at the time of granting the authorisation. 2085

After the initial placing of the product on the EU market, the Marketing Authorisation Holder has to 2086 submit at least four PSURs covering 6 months each, in order to cover, by 6-monthly PSURs, full two 2087 years of experience with the product on the EU market, while keeping the data lock point according to 2088 the IBD or EBD. 2089

For purely nationally authorised medicinal products that are on the market in Member States, the 2090 Marketing Authorisation Holder might wish to synchronise national birth dates with the IBD. 2091 Although such a process can be difficult (e.g. multiple applications for variations might be required), 2092 such a step might be feasible and should be discussed with the Competent Authorities. 2093

For a nationally authorised product where the IBD is not known, the Marketing Authorisation Holder, 2094 in liaison with the Competent Authorities, can designate the IBD. Once the IBD is designated, the 2095 Marketing Authorisation Holder should notify and get approval from the Competent Authorities, and 2096 the IBD should be adhered to thereafter. Such harmonisation of national birth dates allows 2097 synchronisation of submission of the same PSURs to all Competent Authorities and sharing of PSUR 2098 assessment by Competent Authorities. 2099

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If, in the transition period to a harmonised birth date for that product, the use of a local authorisation 2100 date is applicable, the Marketing Authorisation Holder can submit his already prepared IBD-based 2101 PSUR, plus: 2102

• line-listings and/or summary tabulations covering the additional period (i.e. when the 2103 additional period is less than 3 months for a 6-monthly PSUR or 6 months or more (see 2104 Chapter I.6, Section 5) for a longer-duration PSUR without further comment unless, of course, 2105 the data reveal a new and important risk); 2106

or 2107

• a PSUR Addendum Report when the additional period is greater than 3 months for a 6-2108 monthly PSUR or 6 months for a PSUR covering a period of more than 6 months (see Chapter 2109 I.6, Section 5). The purpose of an Addendum is to supplement, not to replace, a PSUR, whilst 2110 maintaining the regular PSUR submission dates. The next scheduled PSUR will be prepared 2111 according the IBD or EBD. 2112

Regardless of whether the IBD or EBD is used, the PSUR must always be submitted within the 60 2113 days following the data lock point. Additional time for submission may be requested in exceptional 2114 circumstances (see Chapter I.6, Section 2.4.a). 2115

6.2.5 Reference Safety Information 2116

An objective of a PSUR is to establish whether information recorded during the reporting period is in 2117 accordance with previous knowledge on the medicinal product’s safety, and to indicate whether 2118 changes should be made to the Product Information or the Risk Management Plan. Reference 2119 information is needed to perform this comparison. 2120

Having one reference safety document will facilitate a practical, efficient and consistent approach to 2121 the safety evaluation and make the PSUR a unique report also accepted in other regions of the world. 2122

It is common practice for Marketing Authorisation Holders to prepare their own Company Core Data 2123 Sheet (CCDS), which covers material relating to safety, indications, dosing, pharmacology, and other 2124 information concerning the product. A practical option for the purpose of the PSUR is for each 2125 Marketing Authorisation Holder to use, as a reference, the safety information contained within his 2126 CCDS, which is referred to as Company Core Safety Information (CCSI). 2127

For the purposes of PSURs, the CCSI forms the basis for determining whether an adverse reaction is 2128 already listed or is still unlisted (listed and unlisted are terms that are introduced to distinguish them 2129 from the usual terminology of expectedness, which is used in association with the authorised Product 2130 Information). The EU Summary of Product Characteristics (SPC) or national SPC authorised by a 2131 Member State continues to be the reference document upon which expectedness is based for the 2132 purpose of expedited post-authorisation safety reporting in the EU. 2133

Differences between the CCSI and the EU or national SPC have to be highlighted in the cover letter 2134 accompanying the submission of the PSUR. The EU or national SPC should also be provided. 2135

For 6-monthly and yearly PSURs the version of the CCSI in effect at the beginning of the period 2136 covered by the PSUR should be used as the reference. 2137

When producing a PSUR covering a period of more than one year, or a PSUR Summary Bridging 2138 Report, it is often impractical to base the analysis of listedness on the CCSI that was in effect at the 2139 beginning of the period. There can be considerable variation in listedness over the reporting period. 2140 Therefore, the latest CCSI in effect at the end of the period can be used for PSURs of longer duration. 2141 The Marketing Authorisation Holder should ensure that all changes to the CCSI made over the period 2142

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covered are described in the relevant section of the PSUR entitled “Changes to the Reference Safety 2143 Information” (see Chapter I.6, Section 3.5). 2144

For PSURs covering a period of more than one year, when listedness is assessed at the time of PSUR 2145 preparation after the data lock point, it is generally considered appropriate to use the version of the 2146 CCSI in place at the end of the reporting period as the reference document, as long as that choice is 2147 made clear in the PSUR. Marketing Authorisation Holders assessing listedness at case entry or on an 2148 ongoing basis throughout the reporting period should include the current version of the CCSI and 2149 comment on the reasons for any change in listedness assessment over time. In both cases, changes 2150 added since the previous PSUR should be explained in the PSUR sections “Changes to Reference 2151 Safety Information” (see Chapter I.6, Section 3.5) and/or “Overall Safety Evaluation” (see Chapter I.6, 2152 Section 3.10). 2153

6.2.6 Presentation of Data on Individual Cases 2154

6.2.6.a Sources of Information 2155

Generally, data from the following sources of adverse reaction case information are potentially 2156 available to the Marketing Authorisation Holder and should be included in the PSUR: 2157

• Direct reports to the Marketing Authorisation Holder (or under his control): 2158

• Spontaneous reports from Healthcare Professionals 2159 • Marketing Authorisation Holder-sponsored studies or named-patient/compassionate use 2160

• Literature 2161

• Adverse reaction reporting systems of regulatory authorities worldwide: 2162

• Spontaneous and non-spontaneous reports from Healthcare Professionals 2163

Other sources of data include: 2164

• Reports on adverse reactions exchanged in the framework of contractual arrangements (e.g. 2165 licensors-licensees agreements) 2166

• Data in special registries, such as maintained in organ toxicity monitoring centres 2167 • Reports from poison control centres 2168 • Epidemiological databases 2169 • Reports from Patients and other Consumers. 2170

6.2.6.b Description of the Adverse Reaction 2171

The reaction terms used in the PSUR should be in accordance with the MedDRA terminology (see 2172 Annex 3). 2173

Whenever possible, the original reporter’s reaction terms should be used to describe the adverse 2174 reaction. 2175

However, when the original reporter’s terms are not medically appropriate or meaningful, the 2176 Marketing Authorisation Holder should use the best alternative compatible reaction terms from 2177 MedDRA to ensure the most accurate representation possible of the original terms. Under such 2178 circumstances, the following should be borne in mind: 2179

• In order to be able to make it available on request, the “verbatim” information supplied by the 2180 original reporter should be kept on file (in the original language and/or as a medically sound 2181 English translation, if applicable). 2182

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• In the absence of a diagnosis by the original reporter, a suggested diagnosis for a symptom 2183 complex may be made by the Marketing Authorisation Holder and used to describe the case, 2184 in addition to presenting the reported individual signs, symptoms and laboratory data. 2185

• If the Marketing Authorisation Holder disagrees with a diagnosis that is provided by the 2186 original reporter, he may indicate such disagreement within the line-listing of cases (see 2187 Chapter I.6, Section 2.6.c). 2188

• The Marketing Authorisation Holder should report and try to understand all information 2189 provided within a case report. An example is a laboratory abnormality not addressed/evaluated 2190 by the original reporter. 2191

Therefore, when necessary and relevant, two descriptions of the signs, symptoms or diagnosis could 2192 be presented in the line-listing: first, the reaction as originally reported; second, when it differs, the 2193 Marketing Authorisation Holder’s medical interpretation (identified by asterisk or other means). 2194

6.2.6.c Line listings and/or Summary Tabulations 2195

Depending on their type or source, available adverse reaction cases should be presented as line-listings 2196 and/or as summary tabulations (see Annex 5.3 and 5.4). 2197

A line-listing provides key information but not necessarily all the details customarily collected on 2198 individual cases; however, it does serve to help Competent Authorities identify cases which they 2199 might wish to examine more completely by requesting full case reports. 2200

The Marketing Authorisation Holder should prepare line-listings of consistent structure and content 2201 for cases directly reported to him (or under his control), including those from persons and 2202 organisations with whom the Marketing Authorisation Holder has set up contractual arrangements, as 2203 well as those received from worldwide regulatory authorities (see Chapter I.6, Section 2.6.a). They 2204 should usually do the same for published cases (usually well documented; if not, follow-up with the 2205 author may be possible). However, inclusion of individual cases from second- or third-hand sources, 2206 such as persons or organisations the Marketing Authorisation Holder has contractual arrangements 2207 with, and special registries (see Chapter I.6, Section 2.6.a) might not be (1) possible without 2208 standardisation of data elements, or (2) appropriate due to the paucity of information, and might 2209 represent unnecessary re-entry/reprocessing of such information by the Marketing Authorisation 2210 Holder. Therefore, summary tabulations or possibly a narrative review of these data are considered 2211 acceptable under these circumstances. 2212

In addition to individual case line-listings, summary tabulations of adverse reaction terms for signs, 2213 symptoms and diagnoses across all patients should usually be presented to provide an overview. Such 2214 tabulations should be based on the data in line-listings (e.g. all serious adverse reaction and all non-2215 serious unlisted adverse reaction), but also on other cases for which line-listings are not requested (e.g. 2216 non-serious listed adverse reactions). Details are found in sections Chapter I.6, Sections 3.7.a and 2217 3.7.b. 2218

6.3 Model for a Periodic Safety Update Report (PSUR) 2219

The following subchapters are organised as a model PSUR. In each of these subchapters, guidance is 2220 provided on what should be included. 2221

6.3.1 PSUR section “Executive Summary” 2222

The Marketing Authorisation Holder should prepare a brief overview of each PSUR in the form of an 2223 Executive Summary to provide the reader with a description of the most important information. The 2224 Executive Summary should be placed at the beginning of the PSUR immediately after the title page 2225 and should include the following: 2226

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• A summary of the marketing authorisation status worldwide 2227 • Exposure data 2228 • Number of case reports covered by the PSUR 2229 • Overall findings of the PSUR 2230 • Conclusions. 2231

When the Marketing Authorisation Holder has performed a review of one or several specific safety 2232 concern(s), this should be stated in this Executive Summary (as well as the nature of safety concerns 2233 that have been reviewed). 2234

6.3.2 PSUR section “Introduction” 2235

The Marketing Authorisation Holder should briefly introduce the product so that the PSUR “stands 2236 alone” but is also placed in perspective relative to previous PSURs and circumstances. 2237

Reference should be made not only to product(s) covered by the PSUR but also those excluded. 2238

Exclusions should be explained; for example, they may be covered in a separate PSUR (e.g. for a 2239 combination product). 2240

If it is known that a PSUR on the same product(s) will be submitted by another Marketing 2241 Authorisation Holder and some of whose data are included in the report (see Chapter I.6, Section 2.3), 2242 the possibility of data duplication should be noted. 2243

6.3.3 PSUR section “Worldwide Marketing Authorisation Status” 2244

This section of the PSUR provides cumulative information. 2245

The following information should be provided, usually as a table, for all countries where a regulatory 2246 decision about marketing has been made related to the following: 2247

• Dates of marketing authorisation and subsequent renewal 2248 • Any qualifications surrounding the authorisation, such as limits on indications if relevant to 2249

safety 2250 • Treatment indications and special populations covered by the market authorisation, when 2251

relevant 2252 • Lack of approval, including explanation, by worldwide regulatory authorities 2253 • Withdrawal by the company of an application for authorisation submission if related to safety 2254

or efficacy 2255 • Dates of launch 2256 • Trade name(s). 2257

Typically, indications for use, populations treated (e.g. children vs. adults) and dosage forms will be 2258 the same in many or even most countries where the product is authorised. However, when there are 2259 important differences, which would reflect different types of patient exposure, such information 2260 should be noted. This is especially true if there are meaningful differences in the newly reported safety 2261 information that are related to such different exposures. 2262

If more convenient and useful, separate regulatory status tables for different product uses or forms can 2263 be utilised. 2264

Country entries should be listed in chronological order of regulatory authorisations. 2265

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Annex 5.2 provides an example, with fictitious data for an antibiotic, of how such a table might be 2266 organised. The product was initially developed as a solid oral dosage form for out-patient treatment of 2267 various infections. 2268

6.3.4 PSUR section “Update of Regulatory Authority or Marketing Authorisation 2269 Holder Actions taken for Safety Reasons” 2270

This subchapter should include details on the following types of worldwide actions relating to safety 2271 that were taken during the period covered by the PSUR and between data lock point and PSUR 2272 submission: 2273

• Marketing authorisation withdrawal, revocation or suspension 2274 • Failure to obtain a marketing authorisation renewal 2275 • Restrictions on distribution 2276 • Clinical trial suspension 2277 • Dosage modification 2278 • Changes in target population or indications 2279 • Formulation changes 2280 • Urgent safety restrictions. 2281

The safety related reasons that led to these actions should be described and documentation appended 2282 when appropriate; any communication with the Healthcare Professionals (e.g. Direct Healthcare 2283 Professional Communications (DHPC), commonly called “Dear Doctor Letter” (DDL)) as a result of 2284 such action should also be described with copies appended. 2285

6.3.5 PSUR section “Changes to Reference Safety Information” 2286

For 6-monthly and yearly PSURs, the version of the CCDS with its CCSI coming into effect at the 2287 beginning of the period covered by the report should be used as reference. For a PSUR covering a 2288 period of over one year, the latest CCSI in effect at the end of the period can be used (see Chapter I.6, 2289 Section 2.5). 2290

The CCSI used as reference should be numbered, dated and appended to the PSUR and include the 2291 date of the last revision. Changes to the CCSI, such as new contraindications, precautions, warnings, 2292 adverse reactions or interactions, already made during the period covered by the PSUR, should be 2293 clearly described, with presentation of the modified sections. The revised CCSI should be used as the 2294 reference for the next PSUR and the next period (see also Chapter I.6, Section 2.5). 2295

With the exception of emergency situations, it may take some time before intended modifications are 2296 introduced in the Product Information. Therefore, during that period the amended reference document 2297 (CCDS) may contain more “listed” information than the existing Product Information in many 2298 countries. 2299

When differences exist between the CCSI and the EU/Member State’s Summary of Product 2300 Characteristics (SPC) (or the official data sheets/Product Information documents approved in a 2301 country), a brief comment should be prepared by the Marketing Authorisation Holder, describing the 2302 local differences and their consequences on the overall safety evaluation and on the actions proposed 2303 or initiated. This commentary may be provided in the cover letter accompanying the local submission 2304 of the PSUR. 2305

6.3.6 PSUR section “Patient Exposure” 2306

Estimating patient exposure data for marketed medicinal products often relies on gross approximations 2307 of in-house or purchased sales data or volume to determine patient exposure. This is not always 2308 reliable or available for all products. For example, hospital-based (in-patient exposure) statistics from 2309

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the major use-monitoring sources are frequently unavailable. It is also difficult to obtain accurate data 2310 for medicinal products of which generic presentations are in use. For non-prescription products, use is 2311 often on an as-required basis, and individual packages are frequently used by multiple family members 2312 of different ages and weights. 2313

Where possible, an estimate of patient exposure should cover the same period as the interim safety 2314 data. While it is recognised that it is usually difficult to obtain and validate accurate exposure data, an 2315 estimate of the number of patients exposed should be provided along with the method used to derive 2316 the estimate. An explanation and justification should be presented if the number of patients is 2317 impossible to estimate. In its place, other measures of exposure, such as patient-days, number of 2318 prescriptions or number of dosage units are considered appropriate; the method used should be 2319 explained. Given the difficulty of estimating cases, patients' exposure should be preferably given in 2320 number of person-time of exposure (days, months, years). The Marketing Authorisation Holder should 2321 be consistent in its method of calculation across PSURs for the same product. If a change in the 2322 method is appropriate, then both methods and calculations should be shown in the PSUR introducing 2323 the change. If these or other more precise measures are not available, bulk sales (tonnage) may be 2324 used. The concept of a Defined Daily Dose may be used in arriving at patient exposure estimates. 2325 When possible and relevant, data broken down by sex and age (especially paediatric vs. adult) should 2326 be provided. Paediatric population exposure should be broken down according to age groups. An 2327 estimate of use outside the terms of the marketing authorisation should be provided along with the 2328 method use to provide the estimate. Pregnancy exposure should also be estimated specially in the case 2329 of pregnancy registries using the same data lock point as the PSUR. 2330

When a pattern of case reports indicates a potential problem, details by country (with locally 2331 recommended daily dose) or other breakdowns (e.g. indication, dosage form) should be presented if 2332 available. 2333

When adverse reaction data from clinical studies are included in the PSUR, the relevant 2334 denominator(s) should be provided. For ongoing and/or blinded studies, an estimation of patient 2335 exposure may be made. 2336

When the exposure data are based on information from a period that does not fully cover the period of 2337 the PSUR, the Marketing Authorisation Holder can make extrapolations using the available data. If 2338 this is done it should be clearly indicated what data were used and why it is valid to extrapolate for the 2339 PSUR period in question (e.g. stable sales over a long period of time, seasonality of use of the 2340 product). 2341

In a PSUR Summary Bridging Report, every effort should be made to avoid patient exposure data and 2342 calculations that involve overlapping time periods. 2343

6.3.7 PSUR section “Presentation of Individual Case Histories” 2344

This section should contain a description and analysis of selected cases containing new or relevant 2345 safety information and grouped by medically relevant headings/System Organ Classes (SOCs). 2346

A description of the criteria used to select cases (if necessary, e.g. due to a large number of cases) for 2347 presentation should be given. 2348

Follow-up data on individual cases may be obtained subsequent to their inclusion in a PSUR. If such 2349 information is relevant to the interpretation of the case (e.g. significant impact on the case description 2350 or analysis), the new information should be presented in the next PSUR, and the correction or 2351 clarification noted relative to the earlier case description. 2352

With regard to the literature, Marketing Authorisation Holders should monitor standard, recognised 2353 medical and scientific journals for safety information relevant to their products and/or make use of one 2354

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or more literature search/summary services for that purpose. Published cases may also have been 2355 received as spontaneously reported cases, be derived from a sponsored clinical study, or arise from 2356 other sources. Care should be taken to include such cases only once. Also, no matter what “primary 2357 source” is given for case, if there is a publication, it should be noted and the literature citation given. 2358

Medically unconfirmed spontaneous reports that originate from Patients/Consumers or other non-2359 Healthcare Professionals should be presented in a separate line-listing (see Chapter I.6, Section 3.7.a) 2360 and or summary tabulation (see Chapter I.6, Section 3.7.b). When included in the analysis of safety 2361 concerns in the PSUR section “Overall Safety Evaluation” (see Chapter I.6, Section 3.10), such reports 2362 should clearly be identified by their source. 2363

6.3.7.a “Cases Presented as Line-Listings” 2364

The types of cases listed below should be included in the line-listings (see Annex 5.3). Attempts 2365 should be made to avoid duplicate reporting of cases from literature and regulatory sources. 2366

• All serious adverse reactions and non-serious unlisted adverse reactions from spontaneous 2367 reporting and post-authorisation safety studies (PASS) 2368

• All serious adverse reactions (attributable to the medicinal product by either investigator or 2369 sponsor) available from studies (including those which are part of the Risk Management Plan) 2370 or named-patient/compassionate use 2371

• All serious adverse reactions, and non-serious unlisted adverse reactions from the literature 2372 • All serious adverse reactions and non-serious unlisted adverse reactions transmitted to the 2373

Marketing Authorisation Holder by worldwide regulatory authorities 2374

Collection and reporting of non-serious, listed adverse reactions may not be required in all Member 2375 States. 2376

Therefore, a line-listing of spontaneously reported non-serious listed reactions that have been collected 2377 should be submitted as an addendum to the PSUR only when requested by a Competent Authority. 2378

If appropriate, all Patient/Consumer and other non-Healthcare Professional reports should be 2379 submitted in a separate line-listing. 2380

The line-listing(s) (see Annex 5.3) should include each Patient only once regardless of how many 2381 adverse reaction terms are reported for the case. If there is more than one reaction, they should all be 2382 mentioned but the case should be listed under the most serious adverse reactions (sign, symptom or 2383 diagnosis), as judged by the Marketing Authorisation Holder. 2384

It is possible that the same Patient may experience different adverse reactions on different occasions 2385 (e.g. weeks apart during a clinical trial). Such experiences would probably be treated as separate 2386 reports. Under such circumstances, the same Patient might then be included in a line-listing more than 2387 once, and the line-listings should be cross-referenced when possible. Cases should be organised 2388 (tabulated) by body system (standard organ system classification scheme (SOC)). 2389

Where joint PSURs are submitted, the line-listings should still reflect the name of the active 2390 substance/medicinal product as reported by the original reporter. 2391

The following headings should usually be included in the line-listing (see Annex 5.3): 2392

• Marketing Authorisation Holder case reference number 2393 • Country in which the case occurred 2394 • Source (e.g. clinical trial, literature, spontaneous, regulatory authority) 2395 • Age and sex of the Patient 2396 • Daily dose of suspected medicinal product (and, when relevant, dosage form or route) 2397

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• Date of onset of the adverse reaction(s). If not available, best estimate of time to onset from 2398 therapy initiation. For an adverse reactions known to occur after cessation of therapy, estimate 2399 of time lag if possible (may go in comments section) 2400

• Dates of treatment. If not available, best estimate of treatment duration 2401 • Description of adverse reaction(s) as reported, and when necessary as interpreted by the 2402

Marketing Authorisation Holder (English translation when necessary) (see Chapter I.6, 2403 Section 2.6.b) 2404

• Patient outcome (at case level) (e.g. resolved, fatal, improved, sequelae, unknown). This 2405 should indicate the consequences of the adverse reaction(s) for the Patient, using the worst of 2406 the different outcomes for multiple reactions 2407

• Comments, if relevant (e.g. causality assessment if the manufacturer disagrees with the 2408 reporter; concomitant medications suspected to play a role in the reactions directly or by 2409 interaction; indication treated with suspect medicinal product(s); dechallenge/rechallenge 2410 results if available). It should be used only for information that helps to clarify individual 2411 cases. 2412

Depending on the product or circumstances, it may be useful or practical to have more than one line-2413 listing, such as for different dosage forms or indications, if such differentiation facilitates presentation 2414 and interpretation of the data. 2415

6.3.7.b “Cases Presented as Summary Tabulations” 2416

An aggregate summary for each of the line-listings should usually be presented. These tabulations 2417 usually contain more terms than patients. It would be useful to have separate tabulations (or columns) 2418 for serious reactions and for non-serious reactions, for listed and unlisted reactions; other breakdowns 2419 might also be appropriate (e.g. by source of report). See Annex 5.4 for a sample data presentation on 2420 serious reactions. 2421

A summary tabulation should be provided when necessary for the non-serious, listed, spontaneously 2422 reported reactions (see also Chapter I.6, Section 3.7.a). 2423

The terms used in these tables should ordinarily be those used by the Marketing Authorisation Holder 2424 to describe the case (see Chapter I.6, Section 2.6.b). 2425

Except for cases obtained from regulatory authorities, the data on serious reactions from other sources 2426 (see Chapter I.6, Section 2.6.a) should normally be presented only as a summary tabulation. If useful, 2427 the tabulations may, for example, be sorted by source of information or country. 2428

When the number of cases is very small, or the information inadequate for any of the tabulations, a 2429 narrative description rather than a formal table is considered suitable. 2430

As previously described, the data in summary tabulations should be interval data, as should the line-2431 listings from which they are derived. However, for adverse reactions that are both serious and unlisted, 2432 a cumulative figure (i.e. all cases reported to date) should be provided in the table(s) or as a narrative. 2433

6.3.7.c “Marketing Authorisation Holder’s Analysis of Individual Case Histories” 2434

This section may be used for brief comments on the data concerning individual cases. For example, 2435 discussion can be presented on particular serious or unanticipated findings (their nature, medical 2436 significance, mechanism, reporting frequency, etc.). The focus here should be on individual case 2437 discussion and should not be confused with the global assessment in the PSUR section “Overall Safety 2438 Evaluation” (see Chapter I.6, Section 3.10). 2439

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6.3.8 PSUR section “Studies” 2440

All studies (non-clinical, clinical and epidemiological) yielding safety information with potential 2441 impact on Product Information, studies specifically planned or in progress, and published that address 2442 safety concerns should be included with a discussion of any final or interim results. The Marketing 2443 Authorisation Holder should not routinely catalogue or describe all the studies. Studies that are part of 2444 the Risk Management Plan should be mentioned (see Chapter I.6, Section 3.9.c). 2445

6.3.8.a “Newly Analysed Studies” 2446

All relevant studies containing important safety information and newly analysed during the reporting 2447 period should be described, including those from epidemiological, toxicological or laboratory 2448 investigations. Reference should be made to the Risk Management Plan, where applicable. The study 2449 design and results should be clearly and concisely presented with attention to the usual standards of 2450 data analysis and description that are applied to non-clinical and clinical Study Reports. Copies of full 2451 study reports should be appended, e.g. in case of post-authorisation safety studies and for other studies 2452 with a significant safety finding only if deemed appropriate. 2453

6.3.8.b “Targeted New Safety Studies” 2454

New studies specifically planned or conducted to examine a safety concern (actual or hypothetical) 2455 should be described (e.g. objective, starting date, projected completion date, number of subjects, 2456 protocol abstract). 2457

When possible and relevant, if an interim analysis was part of the study plan, the interim results of 2458 ongoing studies may be presented. When the study is completed and analysed, the final results should 2459 be presented in a subsequent PSUR as described in Chapter I.6, Section 3.8.a. 2460

Copies of full reports should be appended in case of post-authorisation safety studies and for other 2461 studies with a significant safety finding. 2462

Planned studies should also be discussed in the Risk Management Plan (see Chapter I.3) and if 2463 relevant in the related PSUR section (see Chapter I.6, Section 3.9.c). 2464

6.3.8.c “Published Studies” 2465

Reports in the scientific and medical literature, including relevant published abstracts from meetings, 2466 containing important safety findings (positive or negative) should be summarised and publication 2467 reference(s) given. 2468

6.3.8.d “Other” 2469

The Marketing Authorisation Holder should provide any relevant information of the data collected by 2470 pregnancy exposure registries and a copy of the last interim reports from these registries. 2471

6.3.9 PSUR section “Other information” 2472

6.3.9.a “Efficacy-related Information” 2473

For a product used in prevention (e.g. vaccines) or in treatment of serious or life-threatening diseases 2474 (e.g. antibiotics and antiviral products) or products used in healthy Consumers (e.g. contraceptives), 2475 medically relevant lack of efficacy reporting, which might represent a significant hazard to the treated 2476 population, should be described and explained. 2477

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6.3.9.b “Late-breaking Information” 2478

Any important, new information received after the database was frozen for review and report 2479 preparation may be presented in this section. Examples include significant new cases or important 2480 follow-up data. These new data should be taken into account in the PSUR section “Overall Safety 2481 Evaluation (see Chapter I.6, Section 3.10). 2482

6.3.9.c “Risk Management Plan” 2483

When a specific Risk Management Plan (see Chapter I.3) is in place, it should be discussed. In this 2484 case, the status of the Risk Management Plan should be presented including a summary of the 2485 amendments made and available results. 2486

Risk management actions should be presented with an impact analysis (see Chapter I.3). 2487

6.3.9.d “Benefit-Risk Analysis Report” 2488

When a more comprehensive safety or benefit-risk analysis (e.g. all indications reviewed) has been 2489 conducted separately, a summary of the analysis should be included in this section. 2490

6.3.10 PSUR section “Overall Safety Evaluation” 2491

The Marketing Authorisation Holder should provide a concise analysis of the data presented, taking 2492 into account any late-breaking information (see Chapter I.6, Section 3.9.b), and followed by the 2493 Marketing Authorisation Holder’s assessment of the significance of the data collected during the 2494 period. Discussion and analysis for the “Overall Safety Evaluation” should be organised by SOC 2495 rather than by listedness or seriousness; the latter properties should, of course, still be covered under 2496 each SOC. Although related terms might be found in different SOCs, they should be reviewed together 2497 for clinical relevance. 2498

The Marketing Authorisation Holder should also review the cumulative experience and highlight any 2499 new information on: 2500

• A change in characteristics of listed reactions, e.g. severity, outcome, target population 2501 • Serious unlisted adverse reactions, placing into perspective the cumulative reports 2502 • Non-serious unlisted adverse reactions 2503 • An increased reporting frequency of listed adverse reactions, including comments on whether 2504

it is believed the data reflect a meaningful change in adverse reactions occurrence. 2505

This section should also explicitly address any new safety concern on the following (lack of 2506 significant new information should be mentioned for each): 2507

• Interactions 2508 • Experience with overdose, deliberate or accidental, and its treatment 2509 • Abuse or misuse 2510 • Positive or negative experiences during pregnancy or lactation 2511 • Experience in special patient groups (e.g. children. elderly, organ impaired, a qualitative 2512

description of off-label use should be given) 2513 • Effects of long-term treatment 2514 • Consumer and other non-Healthcare Professional reports (see Chapter I.6, Section 3.7) 2515 • Prescription errors/medication errors, including those due to the invented names or to the 2516

presentation of the medicinal products, that have safety implications. 2517

A subsection of the PSUR should deal with the use of the medicinal product in children if the product 2518 has a paediatric indication, if there is evidence of significant off-label use in children or if there are 2519

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adverse reactions reported in the paediatric population. Data from completed or ongoing clinical trials 2520 should be presented separately from spontaneous reports. (see Guideline on the Conduct of 2521 Pharmacovigilance for Medicines Used by the Paediatric Population in Part V). 2522

6.3.11 PSUR section “Conclusion” 2523

The “Conclusion” should: 2524

• indicate which safety data do not remain in accord with the previous cumulative experience 2525 and with the reference safety information (CCSI); 2526

• specify and justify any action recommended or initiated. 2527

Having made the decision to amend the SPC, the Marketing Authorisation Holder should submit the 2528 Variation application at the same time as the PSUR, or where this is not possible, should state a 2529 timetable for submission. 2530

6.4 Contents of the PSUR Summary Bridging Report 2531

The PSUR Summary Bridging Report should not contain any new data but should provide a brief 2532 summary bridging two or more PSURs (e.g. two consecutive 6-monthly PSURs for a yearly PSUR or 2533 six consecutive 6-monthly PSURs to make a 3-year PSUR). It is intended to assist Competent 2534 Authorities with a helpful overview of the appended PSURs. The PSUR data should not be repeated 2535 but should be cross-referenced to individual PSURs. The format of the Summary Bridging Report 2536 should be identical to that of the usual PSUR, but the content should consist of summary highlights 2537 and an overview of data from the attached PSURs to which it refers. 2538

A Summary Bridging Report should contain the following: 2539

• Introduction (a brief description of the purpose of the document specifying the time periods 2540 covered and cross-referencing the appended PSURs) 2541

• Worldwide marketing authorisation status (number of countries which have approved the 2542 product) 2543

• Update on regulatory authority- or Marketing Authorisation Holder-initiated actions for safety 2544 reasons (an integrated summary of actions taken if appropriate) 2545

• Changes to CCSI (significant changes over the entire period) 2546 • Exposure data (estimation of the total number of patients exposed in the time period) 2547 • Individual case histories (brief statement giving the total number of cases as cumulative 2548

summary tabulations ordered by SOC, seriousness when there is an important specific safety 2549 concern that has not been adequately discussed in one or more of the PSURs, then it would be 2550 appropriate to include a cumulative line-listing or summary tabulation for the types of cases of 2551 concern, pointing out any differences from prior listings or tabulations. In this case, there 2552 should be a clear understanding that the tables will be generated from live databases, which 2553 change over time as cases are updated. These tables will then reflect the most up-to-date data 2554 available at the time they are generated. It is recognised that the case counts in these summary 2555 tables can differ somewhat from the contents of the individual tables in the appended PSURs. 2556 A general statement describing the differences should be provided) 2557

• Studies (a brief summary of important targeted clinical safety studies) 2558 • Other information (only highly significant safety information received after the data lock 2559

point) 2560 • Overview of the safety concerns and Conclusion (unresolved key issues). 2561

In addition, the Summary Bridging Report should also contain information on differences between the 2562 approved SPC and the current CCSI. 2563

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6.5 Contents of the PSUR Addendum Report 2564

A PSUR Addendum Report is an update to the most recently completed PSUR when a Competent 2565 Authority requests or requires a safety update outside the usual IBD-based PSUR submission 2566 schedule. An Addendum Report should be used when more than 3 months for a 6-monthly or yearly 2567 PSUR, and more than 6 months for a PSUR covering a longer period have elapsed since the data lock 2568 point of the most recent PSUR (otherwise line-listing(s) and/or summary tabulations might be 2569 sufficient). It might also be appropriate to provide an Addendum Report to the PSUR Summary 2570 Bridging Report (see Chapter I.6, Section 4). 2571

The Addendum Report should summarise the safety data received between the data lock point of the 2572 most recent PSUR and the Competent Authority’s requested cut-off date. It is not intended that the 2573 Addendum Report provide an in-depth analysis of the additional cases, as these can be included in the 2574 next regularly scheduled PSUR. Depending on circumstances and the volume of additional data since 2575 the last scheduled report, an Addendum Report can follow the PSUR format or a simplified 2576 presentation. 2577

The proposed simplified presentation should include the following sections, containing any new 2578 information or changes beyond the most recent PSUR to which the Addendum Report refers: 2579

• Introduction (purpose; cross reference to most recent PSUR) 2580 • Changes to the CCSI (including a copy of the most recent CCSI document if it differs from the 2581

one in the PSUR) 2582 • Significant worldwide regulatory authorities’ actions bearing on safety 2583 • Line-listing(s) and/or summary tabulations 2584 • Conclusions (brief overview of new information and any impact on the known safety profile). 2585

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7. Requirements for Company-Sponsored Post-Authorisation Safety Studies 2586

7.1 Introduction 2587

There is a continuous need to monitor the safety of medicinal products as they are used in clinical 2588 practice. Spontaneous reporting schemes provide important early warning signals of safety concerns 2589 and also provide a means of continuous surveillance. Formal studies to evaluate safety may also be 2590 necessary, particularly in the confirmation, characterisation and quantification of safety concerns 2591 identified at an earlier stage of product development or during post-authorisation use (see Chapter I.8). 2592 Such studies may also be useful in identifying previously unsuspected adverse reactions or in 2593 confirming the safety profile of a medicinal product under normal conditions of use. In accordance 2594 with legislation, post-authorisation safety studies (PASS) may be required by competent authorities 2595 either as a commitment at the time of authorisation or in the post-authorisation phase to further assess 2596 a signal. In both cases, the study will be referred to as a relevant part of risk management (see Chapter 2597 I.1, Section 3). 2598

This Section of Volume 9A applies to the conduct of studies sponsored by the pharmaceutical 2599 industry, which evaluate the safety of products with a marketing authorisation for human use. They 2600 encompass all studies carried out to evaluate the safety of authorised medicinal products and for which 2601 a Marketing Authorisation Holder takes responsibility for their initiation, management and/or 2602 financing. This includes studies where the medicine is provided by the sponsoring company and those 2603 where it is prescribed in the normal way, both in general practice and in the hospital setting. 2604

The present guidance provides a framework whereby a variety of data collection methods can be used 2605 to evaluate the safety of authorised medicinal products. Whilst it is recognised that the study design 2606 used needs to be tailored to particular products and safety concerns, the guidance in this section 2607 defines the essential principles to be applied in a variety of situations. The study methods in this field 2608 continue to develop and therefore there will be a need to regularly review the guidance to ensure that it 2609 reflects advances made in the assessment of product safety (see Table "Epidemiological Methods for 2610 Post-Authorisation Safety Studies" at the end of this chapter). 2611

The definition of a post-authorisation safety study is provided in Directive 2001/83/EC (see Glossary, 2612 Annex 1). According to the definition of non-interventional trials provided in Directive 2001/20/EC 2613 (see Glossary, Annex 1), a fundamental distinction can be made between non-interventional 2614 (observational) and interventional post-authorisation safety studies. The latter are considered clinical 2615 trials and come under the scope of the Directive 2001/20/EC. 2616

For a study to be considered non-interventional, patients must not be allocated to one of several 2617 treatments by either a randomisation scheme or any other procedure established in a protocol. 2618 Otherwise, it should be considered as a clinical trial. A study consisting in an organised collection of 2619 data related to the diagnosis or the monitoring of a medical condition in accordance with the terms of 2620 authorisation of a product may be considered non-interventional if the diagnostic or monitoring 2621 procedure(s) do(es) not go beyond what is done in normal clinical practice (e.g. interviews, 2622 questionnaires, blood samples). When a procedure required by the study does not clearly fall within 2623 normal clinical practice the risk to which patients are exposed should be assessed. When there is no 2624 discernible risk to patients, the study may still be considered as non-interventional. Otherwise, the 2625 study should be submitted as a clinical trial. 2626

The guidance on Good Clinical Practice does not apply to observational pharmacoepidemiological 2627 studies. 2628

The guidance below relates principally to those non-interventional post-authorisation safety studies 2629 where there is a known safety issue under investigation and/or when the numbers of patients to be 2630 included in the study will add significantly to the existing safety data for the product(s). A safety 2631 concern may be unexpectedly identified in the course of performing a study on an authorised 2632 medicinal product that would normally fall outside the scope of this guidance. In that case, the 2633

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Marketing Authorisation Holder and specifically the Qualified Person responsible for 2634 pharmacovigilance is expected to inform the relevant Competent Authorities immediately and to 2635 provide a brief report on progress at intervals and at study end as requested by the Authorities. 2636

After a product has been placed on the market, clinical trials exploring e.g. new indications, new 2637 methods of administration or new combinations, are not covered by the guidance below. In such cases 2638 Directive 2001/20/EC and the related guidance needs to be followed. 2639

In cases of doubt as to whether or not a study comes under the jurisdiction of the guidance below the 2640 company should discuss the intended protocol with the relevant Competent Authorities of the Member 2641 State(s) in which the study is to be conducted. 2642

In addition to the guidance below, Marketing Authorisation Holders should adhere to the Guidelines 2643 for Good Pharmacoepidemiology Practices issued by the International Society for 2644 Pharmacoepidemiology (ISPE) (see http://www.pharmacoepi.org/index.cfm). 2645

7.2 Extent and Objectives of Post-Authorisation Safety Studies 2646

Post-authorisation studies may be conducted for the purpose of identifying previously unrecognised 2647 safety concerns (hypothesis-generation), investigating potential and identified risks (hypothesis-testing 2648 in order to substantiate a causal association) or confirming the known safety profile of a medicinal 2649 product under normal conditions of use. They may also be conducted to quantify established adverse 2650 reactions and to identify risk factors. 2651

Situations where studies may be appropriate include: 2652

• A medicinal product with a novel chemical structure or novel mode of action 2653 • Where there is uncertainty as to the clinical relevance of a toxic effect in animals 2654 • Where there is uncertainty as to the safety profile 2655 • Where there is a need to better quantify adverse events identified in clinical trials and 2656

elucidate risk factors 2657 • Where there is a need to confirm or refute safety signals suggested by other sources 2658

(e.g. spontaneous reporting) 2659 • Where there is a highly specific use requiring specialist monitoring 2660 • Where there is a concern regarding the use of the medicinal product (e.g. to quantify the off-2661

label use). 2662

A variety of designs may be appropriate including observational cohort studies, or case-control studies 2663 and registries (see Table "Epidemiological Methods for Post-Authorisation Safety Studies" at the end 2664 of this chapter). Clinical trials involving systematic allocation of treatment (e.g. randomisation) may 2665 also be used to evaluate the safety of authorised products. Such clinical trials should comply with 2666 Directive 2001/20/EC. 2667

The design to be used will depend on the objectives of the study, which must be clearly defined in the 2668 study protocol. Any specific safety concerns to be investigated should be identified in the protocol and 2669 explicitly addressed by the proposed methods. 2670

The protocol should include the elements described in the Guidelines for Good 2671 Pharmacoepidemiology Practices issued by the International Society for Pharmacoepidemiology 2672 (ISPE) (http://www.pharmacoepi.org/index.cfm). 2673

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7.3 Conduct of Post-Authorisation Safety Studies 2674

Responsibility for the conduct of the study shall be vested in the sponsor, usually the Marketing 2675 Authorisation Holder’s medical department. It shall be supervised by a designated monitor(s) sited in 2676 the Member State(s) in which the study is to be conducted, and whose names shall be recorded in the 2677 study documents. 2678

The EU Qualified Person responsible for pharmacovigilance and, where applicable, the national 2679 Qualified Person for pharmacovigilance should be involved in the protocol review of all post-2680 authorisation safety as well as other studies developed within the company, in order to ensure 2681 compliance with pharmacovigilance requirements. 2682

7.4 Liaison with Competent Authorities 2683

7.4.1 Evaluation of the Protocol 2684

Marketing Authorisation Holders proposing to perform a post-authorisation safety study should send 2685 the protocol to the Competent Authority of the Member State(s) in whose territory the study is to be 2686 performed. In case of products authorised through the mutual recognition or decentralised procedure, 2687 the protocol should also be sent to the Reference Member State and, in case of centrally authorised 2688 products, to the Agency, the Rapporteur and Co-Rapporteur. Marketing Authorisation Holders should 2689 discuss the draft protocol at an early stage with the relevant Competent Authorities and independent 2690 experts. Competent Authorities should agree upon the final protocol (see Chapter II.1). National legal 2691 requirements or guidelines should be taken into account in those Member States where these exist. 2692

Two different situations can be envisaged depending on whether the study has been requested or not 2693 by Competent Authorities: 2694

a) Studies requested by Competent Authorities 2695

The contact point will depend on the procedure by which the product has been authorised in the EU: 2696

• For centrally authorised products, the Agency will normally be the contact point. The 2697 Rapporteur will initially review the draft protocol for approval by the Committee for 2698 Medicinal Products for Human Use (CHMP). The draft protocol may also be discussed at 2699 PhVWP level at CHMP request. 2700

• For products authorised through the mutual recognition or decentralised procedure, the 2701 Reference Member State will normally be the contact point and the initial reviewer of the draft 2702 protocol. A further discussion will normally take place at PhVWP level. 2703

• For purely nationally authorised medicinal products, the Competent Authority of the Member 2704 State requesting the study and the Competent Authority of each Member State where the study 2705 is to be conducted will be the contact points. However, when the need of the study has been 2706 discussed at PhVWP level, a Lead Rapporteur Member State may be nominated acting as the 2707 contact point and initial reviewer for the draft protocol. A further discussion will normally 2708 take place at PhVWP level when the study is to be conducted in several Member States or the 2709 product is used in several Member States. 2710

Specific meetings will be held between the designated Rapporteur or Reference Member State and the 2711 Marketing Authorisation Holder in order to agree upon a protocol and a timetable. When the 2712 Marketing Authorisation Holder considers that the protocol requires an amendment, this should be 2713 reported to the Rapporteur or Reference Member State who will consider its appropriateness and the 2714 need for a further evaluation at CHMP and/or PhVWP level. 2715

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When the same or similar study is also requested by other Competent Authorities, e.g. countries 2716 outside the EU for centrally authorised or other Member States for nationally authorised product, an 2717 effort should be made to reach an agreement on the protocol. 2718

b) Post-authorisation safety studies performed at the initiative of the Marketing Authorisation 2719 Holders 2720

The responsibility for the conduct of the study will rest with the sponsoring company, though it may 2721 be shared with other organisations as stated in the protocol. The Marketing Authorisation Holder 2722 should inform the relevant Competent Authorities when the study has commenced. Any amendment to 2723 the protocol should be immediately reported to the relevant authorities accompanied by a justification 2724 for it. Authorities may comment as necessary within a 30-day time period following receipt. 2725

The Marketing Authorisation Holder should submit the protocol plus any proposed communications to 2726 Healthcare Professionals to the relevant Competent Authorities of each Member State where the study 2727 is to be performed, in accordance with a timetable agreed with Competent Authorities. 2728

7.4.2 Reporting of Adverse Reactions 2729

The usual regulatory requirements for reporting of adverse reactions must be fulfilled: Marketing 2730 Authorisation Holders should ensure that they are notified of serious adverse reactions and should 2731 report these to the relevant Competent Authorities immediately and no later than 15 calendar days of 2732 receipt (see Chapter I.4). Non-serious adverse reactions and serious or non-serious events, which are 2733 not suspected by the investigator or the sponsor to be adverse reactions, should not be reported as 2734 Individual Case Safety Report (ICSR), but they should be summarised in the final Study Report in 2735 separate frequency tables. Reports of serious adverse reactions occurring in post-authorisation safety 2736 studies should also be included in the Periodic Safety Update Report (see Chapter I.6). The Qualified 2737 Person responsible for pharmacovigilance should provide to the Competent Authorities any other 2738 information relevant to the evaluation of the benefits and risks afforded by the medicinal product, 2739 including appropriate information on post authorisation safety studies. 2740

The expedited reporting of individual cases may not be appropriate for certain study designs, such as 2741 case-control or retrospective cohort studies, in particular when automated databases are used. In these 2742 cases, the sponsor could request to the Competent Authorities for an exemption providing adequate 2743 reasons. 2744

For post-authorisation safety studies that come under the consideration of clinical trials, the reporting 2745 criteria laid down in Directive 2001/20/EC and related guidance (see Volume 10 of the Rules 2746 Governing Medicinal Products in the EU on http://pharmacos.eudra.org/F2/eudralex/index.htm) 2747 should be followed. 2748

7.4.3 Progress and Final Study Reports 2749

Marketing Authorisation Holders will provide a Study Report on its progress annually, or more 2750 frequently as requested by the Competent Authorities or on its own initiative. If the study is 2751 discontinued, a final report should also be submitted, which will include the reasons that led to 2752 stopping the study. 2753

The content of the progress report should follow a logical sequence and will include all the available 2754 data which is judged relevant for the progress of the study; e.g. number of patients who have entered 2755 the study according to their status (exposure, outcome etc.), problems and difficulties found and 2756 deviations from the expected plan. After review of the report, Competent Authorities may request 2757 additional information. 2758

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A final report on the study should be submitted according to an agreed timetable. The content of the 2759 final report should follow the recommendations laid down in the Guidelines for Good 2760 Pharmacoepidemiology Practices issued by the International Society for Pharmacoepidemiology 2761 (ISPE) (see http://www.pharmacoepi.org/index.cfm). The findings of the study should be submitted 2762 for publication. 2763

Both progress and final reports should be sent to the Competent Authorities of the Member States in 2764 which the study is being conducted and to the Competent Authority that requested the study. In case of 2765 products authorised through the mutual recognition or decentralised procedures, these reports should 2766 also be sent to the Reference Member State and, in case of centrally authorised products, to the 2767 Agency, the Rapporteur and Co-Rapporteur. For evaluation of such reports, the same procedure as for 2768 evaluation of the protocol should be followed (see Chapter I.7, Section 4.1). 2769

7.5 Promotion of Medicinal Products 2770

Post-authorisation studies should not be planned or conducted for the purposes of promoting the use of 2771 medicinal products. 2772

Company representatives should not be involved in studies in such a way that it could be seen as a 2773 promotional exercise, such as in the recruitment of patients and physicians. 2774

7.6 Participation of Healthcare Professionals 2775

Subject to the Healthcare Professional’s terms of service, payment may be offered to the participating 2776 Healthcare Professional in recompense for any additional time and expenses incurred according to a 2777 scale of fees agreed nationally. 2778

No inducement for a Healthcare Professional to participate in a post-authorisation study should be 2779 offered, requested or given. 2780

7.7 Ethical Issues 2781

Post-authorisation safety studies that come under the consideration of clinical trials are covered by 2782 Directive 2001/20/EC. For non-interventional post-authorisation safety studies the sponsors and 2783 investigators should follow the relevant national legislation in those Member States where this exists, 2784 in addition to the guidance given here. 2785

The highest possible standards of professional conduct and confidentiality must always be maintained 2786 and legislation on data protection followed (see Directive 95/46/EC). The Patient’s right to 2787 confidentiality is paramount. The Patient’s identity in the study documents should be codified, and 2788 only authorised persons should have access to identifiable personal details if data verification 2789 procedures demand inspection of such details. Identifiable personal details must always be kept in 2790 confidence. (See also Guidelines for Good Pharmacoepidemiology Practices issued by the 2791 International Society for Pharmacoepidemiology (ISPE) (see http://www.pharmacoepi.org/index.cfm). 2792 Responsibility for the retrieval of information from personal medical records lies with the medical 2793 practitioner(s) responsible for the Patient’s care. Such information should be directed to the medical 2794 practitioner nominated by the sponsor, who is thereafter responsible for the handling of such 2795 information. 2796

Observational post-authorisation studies should be referred to an Ethics Committee. Studies conducted 2797 entirely using automated databases or records not containing any personal identifier (e.g. anonymised 2798 records) may not require an ethical review or only an abridged one. However, national guidelines 2799 should be followed. 2800

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According to European data protection legislation, an explicit consent is required when the study plans 2801 to collect data containing personal identifiers, though some exceptions are envisaged. The use of 2802 anonymised records is outside the scope of this legislation and an individual informed consent may not 2803 be required. 2804

7.8 Procedure for Complaints 2805

A post-authorisation study, which gives cause for concern, should be referred to the relevant 2806 Competent Authorities, or, if appropriate, to other bodies within Member States which are deemed to 2807 have the matter within their remit. 2808

7.9 Data Sources 2809

Marketing Authorisation Holders should select the best data source according to validity (e.g. 2810 completeness of relevant information, possibility of outcome validation) and efficiency criteria (e.g. 2811 time span to provide results) (see Table "Epidemiological Methods for Post-Authorisation Safety 2812 Studies" at the end of this chapter)). External validity should also be taken into account: as far as 2813 feasible the data source chosen to perform the study should include the population in which the safety 2814 concern has been raised. In case another population is involved, the Marketing Authorisation Holder 2815 should evaluate the differences that may exist in the relevant variables (e.g. sex, age, pattern of use of 2816 the medicinal product) and the potential impact on the results. In the statistical analysis, the potential 2817 effect of modification of such variables should be investigated. 2818

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2819

7. TABLE: EPIDEMIOLOGICAL METHODS FOR POST-AUTHORISATION SAFETY STUDIES

Spontaneous reporting schemes are valuable tools for providing safety signals in a continuous manner. In many situations, however, such passive surveillance should be complemented with more formal approaches in order to increase the sensitivity for risk identification or to confirm, characterise or quantify possible safety concerns. These more formal approaches are included under the term ‘post-authorisation safety studies’ and may adopt a variety of designs.

1. Study Designs

Post-authorisation safety studies may adopt different designs depending on their objectives. A brief description of the fundamental types of studies, as well as the types of data resources available, is provided hereinafter. However, this table does not have the intention to be exhaustive and must be complemented with other widely available information sources10. The ICH E2E Guideline has been followed 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 of adverse events in a given population via a continuous organised process. An example of active surveillance is the follow-up of patients treated with a particular medicinal product through a risk management system. Patients who fill a prescription for this product may be asked to complete a brief survey form and give permission for later contact. In general, it is more feasible 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 can be achieved by reviewing medical records or interviewing patients and/or physicians/pharmacists in a sample of sentinel sites to ensure complete and accurate data on reported adverse events. The selected sites can provide information, such as data from specific patient subgroups that would not be available in a passive spontaneous reporting system. Further, collection of information on the use of a medicinal product, such as the potential for abuse, can be targeted at selected sentinel sites. Some of the major weaknesses of sentinel sites are problems with selection bias, small numbers of patients, and increased costs. Active surveillance with sentinel sites is most efficient for those medicinal products used mainly in institutional settings such as hospitals, nursing homes, and haemodialysis centres. Institutional settings can have a greater frequency of use for certain products and can provide an infrastructure for dedicated reporting. In addition, automatic detection of abnormal laboratory values from computerised laboratory reports in certain clinical settings can provide an efficient active surveillance system. Intensive monitoring of sentinel sites can also be helpful in identifying risks among patients taking orphan drugs.

10 1. Mann RD and Andrews EB (eds.) Pharmacovigilance. West Sussex: John Wiley and Sons, Ltd; 2002. 2. Strom BL (ed). Pharmacoepidemiology. 4th ed. New York: John Wiley and Sons, Ltd; 2005. 3. Hartzema AG, Porta M, Tilson H (eds). Pharmacoepidemiology: An introduction. 3rd ed. Cincinnati: Harvey

Whitney Books; 1998. 4. Rothman KJ, Greenland S (eds.). Modern Epidemiology. 2nd ed. Philadelphia: Lippincott-Raven Publishers;

1998.

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1.1.2 Intensive Monitoring Schemes

Intensive monitoring is a system of record collation in designated areas, e.g. hospital units or by specific physicians in community practice. The Competent Authority may be involved in the drawing-up of the protocol to undertake this collection of data or will be informed that such monitoring is taking place. Furthermore, it may be considered appropriate in the authorisation of certain medicinal products to impose specific requirements in respect of reporting serious or unexpected reactions on the prescribing physician and to make these requirements a condition of use of the product under the terms of the marketing authorisation. The relevant pharmacovigilance centre should ensure that data and reports are collected at agreed intervals and in an appropriate format.

1.1.2 Drug Event Monitoring

Prescription event monitoring is a method of active pharmacovigilance surveillance. In prescription event monitoring, patients might be identified from electronic prescription data or automated health insurance claims. A follow-up questionnaire can then be sent to each prescribing physician or patient at pre-specified intervals to obtain outcome information. Information on patient demographics, indication for treatment, duration of therapy (including start dates), dosage, clinical events, and reasons for discontinuation can be included in the questionnaire11. Limitations of prescription event monitoring include incomplete physician response and limited scope to study products which are used exclusively in hospitals. More detailed information on adverse events from a large number of physicians and/or patients might be collected.

1.1.3 Registries

A registry is a list of patients presenting with the same characteristic(s). This characteristic can be a disease (disease registry) or a specific exposure (exposure or drug registry). Both types of registries, which only differ by the type of patient data of interest, can collect a battery of information using standardised questionnaires in a prospective fashion.

Disease registries, such as registries for blood dyscrasias, severe cutaneous reactions, or congenital malformations can help collect data on drug exposure and other factors associated with a clinical condition. A disease registry might also be used as a base for a case-control study comparing the drug exposure of cases identified from the registry and controls selected from either patients within the registry with another condition, or from outside the registry.

Exposure registries address populations exposed to medicinal products of interest (e.g. registry of rheumatoid arthritis patients exposed to biological therapies) to determine if a medicinal product has a special impact on this group of patients. Some exposure registries address exposures to medicinal products in specific populations, such as pregnant women. Patients can be followed over time and included in a cohort study to collect data on adverse events using standardised questionnaires. Single cohort studies can measure incidence, but, without a comparison group, cannot provide proof of association. However, they can be useful for signal amplification particularly for rare outcomes. This type of registry can be very valuable when examining the safety of an orphan drug indicated for a specific condition.

11 1. Mann RD and Andrews EB (eds.) Pharmacovigilance. West Sussex: John Wiley and Sons, Ltd; 2002. 2. Strom BL (ed). Pharmacoepidemiology. 4th ed. New York: John Wiley and Sons, Ltd; 2005. 3. Mann RD. Prescription-event monitoring: recent progress and future horizons. Brit Journal of Clin

Pharmacol 1998; 46(3): 195-201. 4. Shakir SAW. Prescription Event Monitoring. In: Strom BL (ed). Pharmacoepidemiology. 4th ed. New York:

John Wiley and Sons, Ltd; 2005.

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1.2 Comparative Observational Studies

Traditional epidemiological methods are a key component in the evaluation of adverse events. There are a number of observational study designs that are useful in validating signals from spontaneous reports or case series. Major types of 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 of patients at a single point in time (or interval of time) regardless of exposure or disease status constitute a cross-sectional study. These types of studies are primarily used to gather data for surveys or for ecological analyses. The major drawback of cross-sectional studies is that the temporal relationship between exposure and outcome cannot be directly addressed. These studies are best used to examine the prevalence of a disease at one time point or to examine trends over time, when data for serial time points can be captured. These studies can also be used to examine the crude association between exposure and outcome in ecologic analyses. Cross-sectional studies are best utilised when exposures do not change over time.

1.2.2 Cohort Study

In a cohort study, a population-at-risk for the disease (or event) is followed over time for the occurrence of the disease (or event). Information on exposure status is known throughout the follow-up period for each patient. A patient might be exposed to a medicinal product at one time during follow-up, but non-exposed at another time point. Since the population exposure during follow-up is known, incidence rates can be calculated. In many cohort studies involving exposure to medicinal product(s), comparison cohorts of interest are selected on the basis of medication use and followed over time. Cohort studies are useful when there is a need to know the incidence rates of adverse events in addition to the relative risks of adverse events. Multiple adverse events can also be investigated using the same data source in a cohort study. However, it can be difficult to recruit sufficient numbers of patients who are exposed to a product of interest (such as an orphan drug) or to study very rare outcomes. Like case-control studies, the identification of patients for cohort studies can come from large automated databases or from data collected specifically for the study at hand. In addition, cohort studies can be used to examine safety concerns in special populations (the elderly, children, patients with co-morbid conditions, pregnant women) through over-sampling of these patients or by stratifying the cohort if sufficient numbers of patients exist.

1.2.3 Case-control Study

In a case-control study, cases of disease (or events) are identified. Controls, or patients without the disease or event of interest, are then selected from the source population that gave rise to the cases. The controls should be selected in such a way that the prevalence of exposure to the medicinal product among the controls represents the prevalence of exposure in the source population. The exposure status of the two groups is then compared using the odds ratio, which is an estimate of the relative risk of disease among the exposed as compared to the non-exposed. Patients can be identified from an existing database or using data collected specifically for the purpose of the study of interest. If safety information is sought for special populations, the cases and controls can be stratified according to the population of interest (the elderly, children, pregnant women, etc.). For rare adverse events, existing large population-based databases are a useful and efficient means of providing needed exposure and medical outcome data in a relatively short period of time. Case-control studies are particularly useful when the goal is to investigate whether there is an association between a medicinal product (or products) and one specific rare adverse event, as well as to identify risk factors for adverse events (or actually, effect-modifiers). Risk factors can include conditions such as renal and hepatic dysfunction, which might modify the relationship between the drug exposure and the adverse event. Under specific conditions, a case-control study can provide the absolute incidence rate of the event. If all cases of interest (or a well-defined fraction of cases) in the

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catchment area are captured and the fraction of controls from the source population is known, an incidence rate can be calculated.

When the source population within which the case-control study is conducted is a well-defined cohort, it is then possible to select a random sample from it to form the control series. The name “nested case-control study” has been coined to designate those studies in which the control sampling is density-based (e.g. the control series represents the person-time distribution of exposure in the source population). The case-cohort is also a variant in which the control sampling is performed on the persons integrating the source population regardless the time they may have contributed.

A case-control approach could also be set up as a permanent scheme to identify and quantify risks (case-control surveillance). This strategy has been followed for rare diseases with a relevant aetiology fraction attributed to medicinal products, including blood dyscrasias or serious skin disorders.

1.2.4 Other Novel Designs

Some novel designs using only a sample of the cases have been described to assess the association between intermittent exposures and short-term events, including the case-series, the case-crossover and the case-time-control studies. In these designs the control information is obtained from past person-time experience of the cases themselves. One of the important strengths of these designs is that those confounding variables that do not change within individuals are automatically matched.

1.3 Clinical Trials

When significant risks are identified from pre-approval clinical trials, further clinical studies might be called for to evaluate the mechanism of action for 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 of adverse events. Genetic testing can also provide clues about which group of patients might be at an increased risk of adverse reactions. Furthermore, based on the pharmacological properties and the expected use of the medicinal product in general practice, conducting specific studies to investigate potential drug-drug interactions and food-drug interactions might be called for. These studies can include population pharmacokinetic studies and drug concentration monitoring in patients and normal volunteers.

Sometimes, potential risks or unforeseen benefits in special populations might be identified from pre-approval clinical trials, but cannot be fully quantified due to small sample sizes or the exclusion of subpopulations of patients from these clinical studies. These populations might include the elderly, children, or patients with renal or hepatic disorder. Children, the elderly, and patients with co-morbid conditions might metabolise medicinal products differently than patients typically enrolled in clinical trials. Further clinical trials might be used to determine and to quantify the magnitude of the risk (or benefit) in such populations.

To elucidate the risk-benefit profile of a medicinal product outside of the formal/traditional clinical trial setting and/or to fully quantify the risk of a critical but relatively rare adverse event, a large simplified trial might be conducted.

In performing clinical trials Directive 2001/20/EC and related guidance on Good Clinical Practice should be followed.

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1.3.1 Large Simple Trials

Yusuf, Collins and Peto in Stat Med 1984 and subsequently Strom, in Pharmacoepidemiology used the phrase “Large Simple Trial” in relation to a specific form of clinical trial where large numbers of patients are randomised to treatment but data collection and monitoring is kept to the absolute minimum consistent with the aims of the study.12

1.4 Other Studies

Descriptive studies are an important component of pharmacovigilance, although not for the detection or verification of adverse events associated with exposures to medicinal products. These studies are primarily used to obtain the background rate of outcome events and/or establish the prevalence of the use of drugs in specified populations.

1.4.1 Occurrence of Disease

The science of epidemiology originally focused on the natural history of disease, including the characteristics of diseased patients and the distribution of disease in selected populations, as well as estimating the incidence and prevalence of potential outcomes of interest. These outcomes of interest now include a description of disease treatment patterns and adverse events. Studies that examine specific aspects of adverse events, such as the background incidence rate of or risk factors for the adverse event of interest, can be used to assist in putting spontaneous reports into perspective13. For example, an epidemiologic study can be conducted using a disease registry to understand the frequency at which the event of interest might occur in specific subgroups, such as patients with concomitant illnesses.

1.4.2 Drug Utilisation Study

Drug utilisation studies (DUS) describe how a medicinal product is marketed, prescribed, and used in a population, and how these factors influence outcomes, including clinical, social, and economic outcomes. These studies provide data on specific populations, such as the elderly, children, or patients with hepatic or renal dysfunction, often stratified by age, gender, concomitant medication, and other characteristics. DUS can be used to determine if a product is being used in these populations. From these studies denominator data can be derived for use in determining rates of adverse reactions. DUS have been used to describe the effect of regulatory actions and media attention on the use of medicinal products, as well as to develop estimates of the economic burden of ADRs. DUS can be used to examine the relationship between recommended and actual clinical practice. These studies can help to determine whether a medicinal product has the potential for abuse by examining whether patients are taking escalating dose regimens or whether there is evidence of inappropriate repeat prescribing. Important limitations of these studies may include a lack of clinical outcome data or information of the indication for use of a product.

2. Data Sources

Pharmacoepidemiological studies can be performed using a variety of data sources. Traditionally, field studies were require for retrieving the necessary data on exposure, outcomes, potential confounders and other variables, through interview to appropriate subjects (e.g. patients, relatives) or by consulting the paper-based medical records. However, the advent of automated healthcare

12 1. Strom BL (ed). Pharmacoepidemiology. 4th ed. New York: John Wiley and Sons, Ltd; 2005. 2. Yusuf S, Collins R, Peto R. Why do we need some large simple randomized trials. Stat Med 1984; Oct – De

3(4): 409-422 13 Mann RD and Andrews EB (eds.) Pharmacovigilance. West Sussex: John Wiley and Sons, Ltd; 2002

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databases has remarkably increased the efficiency of pharmacoepidemiologic research. There are two main types of automated databases, those that contain comprehensive medical information, including prescriptions, diagnosis, referral letters and discharge reports, and those mainly created for administrative purposes, which require a record-linkage between pharmacy claims, and medical claims databases. These datasets may include millions of patients and allow for large studies. They may not have the detailed and accurate information needed for some research, such as validated diagnostic information or laboratory data, and paper-based medical records should be consulted to ascertain and validate test results and medical diagnoses. Depending on the outcome of interest, the validation may require either a case-by-case approach or just the review of a random sample of cases. There are many databases in place for potential use on pharmacoepidemiological studies, or in their validation phase for future use.

With any data source used the privacy and confidentiality regulations that apply to personal data should be followed. The anonymisation of medical records when feasible is the best option.

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8. Overall Pharmacovigilance Evaluation and Safety-Related Regulatory Action 2820

8.1 Introduction 2821

The granting of a marketing authorisation for a medicinal product indicates that it is considered to 2822 have a satisfactory risk-benefit balance under the conditions defined in the Summary of Product 2823 Characteristics (SPC), on the basis of the information available at that time. 2824

During the post-authorisation period the product will be used in a setting different from clinical trials 2825 and larger populations are likely to be exposed. New information on the benefit or risk of the product 2826 will be generated, and evaluation of this information needs to be an on-going process, both within the 2827 Marketing Authorisation Holder and the Competent Authorities. 2828

Both the Marketing Authorisation Holder and the Competent Authorities must keep abreast of all 2829 relevant information in order to fulfil the following responsibilities: 2830

• Ensuring that appropriate action is taken in response to new evidence which impacts on the 2831 known risk-benefit balance, 2832

• Keeping Healthcare Professionals and Patients informed through changes to authorised 2833 Product Information and by direct communication. 2834

The responsibilities of the Marketing Authorisation Holder, and in particular of the Qualified Person 2835 Responsible for Pharmacovigilance, are provided in Chapter I.1, Section 2. It is the responsibility of 2836 the Qualified Person Responsible for Pharmacovigilance to provide to the Competent Authority any 2837 information relevant to the evaluation of benefits and risks afforded by a medicinal product, including 2838 appropriate information on post-authorisation safety studies. 2839

In the event of any new or changing information becoming available which may influence the overall 2840 benefit-risk assessment of a medicinal product, the Marketing Authorisation Holder should 2841 immediately inform all Competent Authorities in Member States where the product is authorised, and 2842 additionally, for centrally authorised products, the Agency. Where the Competent Authority identifies 2843 new or changing information, which may influence the overall benefit-risk assessment, it is usually 2844 appropriate that they communicate this concern to the Marketing Authorisation Holder at the time that 2845 such information is shared with other Competent Authorities. A comprehensive Assessment Report 2846 evaluating the issue and the risks in the context of the benefits should be submitted at the earliest 2847 opportunity and no later than the agreed date specified in the written communications between the 2848 Competent Authority and the Marketing Authorisation Holder. It should be sent to all Competent 2849 Authorities in Member States where the medicinal product is authorised, and additionally to the 2850 Agency for centrally authorised products. 2851

The Competent Authorities are responsible for providing Individual Case Safety Reports of serious 2852 adverse reactions occurring in Member States to the relevant Marketing Authorisation Holder within 2853 15 calendar days of receipt. 2854

This Chapter: 2855

• provides the principle on which an assessment of the risk-benefit balance should be based; and 2856 • outline the steps that Marketing Authorisation Holders and Competent Authorities can take in 2857

order to address a change in the risk-benefit balance. 2858

8.2 Principles of Benefit-Risk Assessment 2859

Overall benefit-risk assessment should take into account and balance all the benefits and risks referred 2860 to below. Benefit-risk assessment should be conducted separately in the context of each indication and 2861 population, which may impact on the conclusions and actions. 2862

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8.2.1 Assessment of Benefits 2863

When a new or changing risk is identified, it is important to re-evaluate the benefit of the medicinal 2864 product using all available data. The benefit of a medicinal product can be seen as the decrease in 2865 disease burden associated with its use. Benefit is composed of three parameters: (1) the extent to 2866 which the medicinal product cures or improves the disease, or relieves the symptoms, (2) the 2867 responder rate, (3) the duration of response. In the case of prophylactic medicinal products the benefit 2868 may be considered as the reduction of the expected severity or incidence of the disease. With 2869 diagnostics, the benefit will be defined in terms of sensitivity and specificity or, in other words, false 2870 negative and false positive rates. Any available information on misuse of the product and on the level 2871 of compliance in clinical practice, which may have an impact on the evaluation of its benefits, should 2872 also be considered. The quality and degree of the evidence of benefit should be taken into account. 2873 Efficacy and benefit should, as far as possible, be expressed in quantitative terms in a way that makes 2874 them comparable to the expression of risks. 2875

8.2.2 Assessment of Risks 2876

Assessment of risk involves a stepwise process requiring identification, confirmation, characterisation 2877 (including identification of the determinants of risk), and quantification of the risk in the exposed 2878 population. Overall assessment of risk should consider all available sources of information, including: 2879

• National and international spontaneous adverse reaction reports 2880 • Adverse reaction data from studies which may or may not be company-sponsored 2881 • In vitro and in vivo laboratory experiments 2882 • Registries of congenital anomaly/birth defects 2883 • Data published in the worldwide scientific literature or presented as abstracts, posters or 2884

communications 2885 • Investigations on pharmaceutical quality 2886 • Data on sales and product usage. 2887

Important issues, which should be addressed in the assessment of adverse reactions, include evidence 2888 for causal association, seriousness, absolute and relative frequency, and presence of risk determinants, 2889 which may allow preventive measures. The quality and degree of evidence of risk should be taken into 2890 account. 2891

When possible, but not sufficiently established, risks are identified, which, if conformed, would have 2892 an impact on the overall risk-benefit balance of a medicinal product, the Marketing Authorisation 2893 Holder should propose appropriate studies to further investigate the nature and frequency of the 2894 adverse reactions. Such studies should comply with the guidance provided in Chapter I.7. 2895

When a new safety concern arises in the post-authorisation period, a Risk Management Plan may be 2896 requested by the Competent Authorities. These should be prepared and submitted by the Marketing 2897 Authorisation Holder in line with the format and timelines recommended in Chapter I.3. 2898

8.2.3 Benefit-Risk Assessment 2899

Whenever possible, both benefits and risks should be considered in absolute terms and in comparison 2900 to alternative treatments. The degree of risk that may be considered acceptable is dependent on the 2901 seriousness of disease being treated and on the efficacy of the medicinal product. For example: 2902

• In the treatment of a disease with high mortality, a high risk of serious adverse reactions may 2903 be acceptable providing the benefits associated with treatment have been shown to be greater. 2904

• For medicines used in chronic diseases or in prevention of disabling diseases, some level of 2905 risk may be acceptable if there is a substantial improvement in the prognosis or quality of life. 2906

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• In situations where the main benefit is symptom relief for minor illnesses in otherwise healthy 2907 individuals or where individuals are treated not only for their own benefit but also or the 2908 benefit of the community (e. g. vaccination), risk levels must be exceptionally low. 2909

• In cases where convincing evidence demonstrating therapeutic benefit is lacking, even a few 2910 cases of a serious adverse reaction may suffice to render the risk-benefit balance as 2911 unfavourable. 2912

• If, for two medicinal products with essentially similar efficacy and types of adverse reactions, 2913 one or more serious adverse reactions were shown to differ in frequency, the risk-benefit 2914 balance of the product with the higher adverse reaction frequency may no longer be 2915 acceptable. 2916

The populations being treated must also be taken into account, including off-label use. 2917

8.3 Improving the Risk-Benefit Balance 2918

The Marketing Authorisation Holder should aim to optimise the safe use and the risk-benefit balance 2919 of an individual product and ensure that the adverse consequences of a medicinal product do not 2920 exceed the benefits within the population treated. The risk-benefit balance of a medicinal product 2921 cannot be considered in isolation but should be compared with those of other treatments for the same 2922 disease. 2923

The risk-benefit balance can be improved either by increasing the benefits, e.g. by restricting the use 2924 to identified responders, or by reducing the risks by minimising risk determinants (e.g. by contra-2925 indicating the use in patients particularly at risk, lowering dosage, introducing pre-treatment tests to 2926 identify patients at risk, monitoring during treatment for early diagnosis of adverse reactions). When 2927 proposing measures to improve the risk-benefit balance of a product their feasibility in normal 2928 conditions of use should be taken into account. 2929

The following types of action may be necessary and can be undertaken on the initiative of and by the 2930 Marketing Authorisation Holder or compulsorily by Competent Authorities in accordance with 2931 legislation: 2932

• Variation of marketing authorisation in respect of the indication, dosage recommendations, 2933 warnings or information about adverse reactions and subsequent modification of the SPC and 2934 the Package Leaflet (PL); 2935

• Risk communication, i.e. direct provision of important safety information to Healthcare 2936 Professionals and Patients/the public (e.g. through letters and/or bulletins or via electronic 2937 media). 2938

If there are important new safety concerns requiring urgent action, the Marketing Authorisation Holder 2939 himself, or on the request of the Competent Authorities, should undertake an urgent safety restriction 2940 (USR) in accordance with Commission Regulations (EC) No 1084/2003 and (EC) No 1085/2003 2941 followed by a Type II variation. These measures must be immediately communicated to the relevant 2942 Competent Authorities and in addition to the Agency in case of a centrally authorised product. If no 2943 objections are raised within 24 hours of a valid application, the USR may be introduced and the 2944 corresponding application for the variation submitted without delay to the Competent Authorities and, 2945 with respect to centrally authorised medicinal products, the Agency (see Chapter II.1, Section 7). 2946

If any significant alteration to the safety information in the SPC is made, the appropriate Healthcare 2947 Professionals must be informed promptly and provided with the new SPC. 2948

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8.4 Withdrawal of a Product from the Market on Risk-Benefit Grounds 2949

In the event that the overall risk-benefit balance is judged to be unfavourable and other risk 2950 minimisation measures are considered inadequate, the medicinal product should be withdrawn from 2951 the market and Healthcare Professionals and Patients/the public informed as appropriate (see 2952 Chapter I.8, Section 5). Such action may be taken voluntarily by Marketing Authorisation Holders. It 2953 is recommended that any such intended measure be discussed at an early stage with all Competent 2954 Authorities concerned. All concerned Competent Authorities and the Agency must be informed 2955 immediately of any definite action. Marketing Authorisation Holders are reminded of their legal 2956 obligations under Article 104(9) of Directive 2001/83/EC to not communicate information relating to 2957 pharmacovigilance concerns to the public without notification to the Competent Authorities (see 2958 Part IV). 2959

For medicinal products authorised through national procedures, the Competent Authorities may 2960 suspend or revoke an authorisation where the product proves to be harmful under normal conditions of 2961 use, in order to protect the Patients’ health (see Article 116 of Directive 2001/83/EC). 2962

In addition, Article 107 of Directive 2001/83/EC states that where a Member State considers that a 2963 marketing authorisation should be withdrawn as a result of the evaluation of pharmacovigilance data, 2964 it is required to forthwith inform the Agency, the other Member States and the Marketing 2965 Authorisation Holder. In case of urgency, it may suspend the marketing authorisation of the medicinal 2966 product provided the Agency, the European Commission and the other Member States are informed at 2967 the latest on the following working day and the procedures mentioned in Chapter II.5 should be 2968 followed. 2969

If the interests of the Community are involved, a Member State, the European Commission, the 2970 Applicant or the Marketing Authorisation Holder may refer the matter to the CHMP for an Opinion 2971 according to Article 31 of Directive 2001/83/EC. 2972

For medicinal products authorised through the mutual recognition, decentralised and ex-concertation 2973 procedure, where a Member State considers the suspension or withdrawal of a product is necessary to 2974 protect the Patients’ health, the matter will be referred to the CHMP for an Opinion (Article 36 and 37 2975 of Directive 2001/83/EC respectively). In exceptional cases, where urgent action is essential to protect 2976 public health, a Member State may suspend the marketing and use of the medicinal products on its 2977 territory until a definitive position is adopted. The Member State is required to inform the European 2978 Commission and the other Member States no later than the following working day of the reasons for 2979 its action. 2980

In the case of centrally authorised products Article 20 of Regulation (EC) No 726/2004 states that 2981 where urgent action is essential to protect human or animal health or the environment, a Member State 2982 may suspend the use of the medicinal product on its territory. It shall inform the European 2983 Commission, the Agency and the other Member States immediately, or no later than the following 2984 working day, of the reasons for its action. The European Commission shall immediately consider the 2985 reason given by the Member State and shall request the Opinion of the CHMP within a time limit, 2986 which it shall determine having regard to the urgency of the matter. 2987

In the event that withdrawal of a product from the market seems likely, the Marketing Authorisation 2988 Holder should be informed at an early stage of any possible intended action. In the case of medicinal 2989 products authorised through national procedures, it is the responsibility of the Competent Authorities 2990 in the Member States concerned to inform the Marketing Authorisation Holder. For mutually 2991 recognised products, this task is normally undertaken by the Reference Member State. Where a 2992 product is authorised centrally, the Agency, in consultation with the Rapporteur, should inform and 2993 liaise with the Marketing Authorisation Holder. 2994

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8.5 Communication 2995

In the event of an urgent safety restriction or an important variation the content of Public Statements, 2996 Direct Healthcare Professional Communication (DHPC) and other communication from the Marketing 2997 Authorisation Holder to Healthcare Professionals, Patients and the general public, including the time 2998 frame for the distribution of such communication, should be agreed with the relevant Competent 2999 Authorities. For further guidance see Part IV. 3000

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3001

3002

3003

3004

3005

3006

3007

PART II 3008

– Guidelines for Competent Authorities and the Agency – 3009

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1. Undertaking of Pharmacovigilance Activities by Competent Authorities in 3010 Member States 3011

1.1 Introduction 3012

As described in Regulation (EC) No 726/2004 (particularly Articles 21-29), Directive 2001/83/EC 3013 (mainly Title IX) and national legislation, each Member State must establish a national 3014 pharmacovigilance system for the collection and evaluation of information on medicinal products with 3015 particular reference to adverse reactions. Member States should undertake all appropriate activities, 3016 including the following: 3017

• To encourage physicians and other Healthcare Professionals to report suspected adverse 3018 reactions to the national Competent Authorities; 3019

• To facilitate reporting of adverse reactions by Patients either directly to national Competent 3020 Authorities, or via patient organisations, or via Healthcare Professionals, as appropriate in 3021 accordance with the national system; 3022

• To oblige Marketing Authorisation Holders to systematically collect information on risks 3023 related to their medicinal products and to transmit this information to the Competent 3024 Authorities and the Agency as appropriate in accordance with Part I; 3025

• To ensure that Marketing Authorisation Holders implement appropriate Risk Management 3026 Plans to effectively monitor and manage risks associated with the safety of their products; 3027

• To monitor the impact and effectiveness of such Risk Management Plans and regulatory 3028 action taken to enhance safe use of medicinal products; 3029

• To monitor the compliance of Marketing Authorisation Holders in relation to their 3030 pharmacovigilance activities; 3031

• To implement conditions and restrictions with regard to the safe and effective use of centrally 3032 authorised products on the basis of Commission Decisions; 3033

• To interact with relevant international organisations, particularly the World Health 3034 Organization (WHO), in accordance with agreed guidance and procedures (see Chapter II.6); 3035

• To communicate the evaluation of safety issues as appropriate to Healthcare Professionals and 3036 as necessary to the public, through timely and appropriate methods of communication and to 3037 audit the impact of such communications. 3038

• Case reports must be made accessible to the Agency, to the Competent Authorities of other 3039 Member States, and to the concerned Marketing Authorisation Holders according to the 3040 criteria laid down in legislation, and described in Chapters II.2.A and II.3, and in Part III on 3041 the Electronic Exchange of Pharmacovigilance Information. 3042

• Electronic data and paper-based case reports should be recorded in a database by the national 3043 Competent Authority. Data storage should ensure on-line accessibility of data. 3044 Recommendations cover individual data entry, audit trail, and correct use of terminologies. 3045

The requirements and procedures involved in such a system are described in this Chapter, which 3046 relates to medicinal products authorised in the EU (using either centralised, mutual recognition, 3047 decentralised or purely national procedures) and covers collection and evaluation of all information 3048 useful in the surveillance of medicinal products. This Chapter should be read in association with the 3049 other relevant Chapters included in this Volume, in particular as described in Chapter II.2.A on the 3050 conduct of pharmacovigilance for centrally authorised products and Chapter II.3 on the conduct of 3051 pharmacovigilance for medicinal products authorised through the mutual recognition or decentralised 3052 procedure, Part III on electronic reporting, Chapter II.2.B on the Crisis Management Plan for centrally 3053 authorised products, Chapter II.4 on the Rapid Alert/Non-Urgent Information System, Chapter I.3 on 3054 Risk Management Systems and Part IV on communication to the public. 3055

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1.2 Establishment of a Pharmacovigilance System 3056

Each Member State should have in place a system for surveillance of medicinal products, for receipt 3057 and evaluation of all pharmacovigilance data within that Member State. Furthermore this centre must 3058 be in a position to handle these pharmacovigilance data in a way that is compatible with the 3059 procedures undertaken in the other Member States and the Agency in order that pertinent data may be 3060 transferred between the Member States and the Agency. 3061

Each Member State should develop collaborative procedures between pre-authorisation and post-3062 authorisation functions to ensure the availability of comprehensive and integrated pharmacovigilance 3063 systems at national and EU level. 3064

Each Member State should monitor Marketing Authorisation Holder compliance with 3065 pharmacovigilance obligations (e.g. timely reporting of expedited adverse reaction reports, timely 3066 submission of Periodic Safety Update Reports in accordance with agreed formats and content, 3067 appropriate and comprehensive responses to ad hoc queries from Competent Authorities) and should 3068 undertake pharmacovigilance inspections in accordance with Chapter I.2 on monitoring of compliance 3069 and pharmacovigilance inspections. 3070

The CHMP’s Pharmacovigilance Working Party (PhVWP) has been given a Mandate, Objectives and 3071 Rules of Procedure (see Appendix) to provide advice on the safety of medicinal products authorised in 3072 the EU and on the investigation of adverse reactions to enable effective identification, assessment and 3073 management and communication of risk at any phase in the product life, and to provide 3074 recommendations for regulatory action to the CHMP and the national Competent Authorities. This 3075 requires interaction with the CHMP and specialised experts as appropriate, as well as consensus 3076 development and coordination of pharmacovigilance issues at EU level. Each Member State should 3077 ensure that it actively participates in and cooperates with the PhVWP in order to fulfil its 3078 pharmacovigilance requirements at EU level. 3079

All Member States should cooperate with international bodies, in particular the World Health 3080 Organization (WHO) and the WHO Collaborating Centre for International Drug Monitoring through 3081 their national pharmacovigilance centres, in keeping with the guidance provided in Chapter II.6 on 3082 principles of collaborating with WHO. 3083

1.3 Management of Spontaneous Reporting Programmes 3084

1.3.1 General Principles 3085

Each Member State should have in place a system for the collection of spontaneous suspected adverse 3086 reaction reports (e.g. free postal, telephone and/or web-based systems) from Healthcare Professionals, 3087 Marketing Authorisation Holders (see also Chapter I.4) and, where appropriate, from 3088 Patients/Consumers. Each Member States’ pharmacovigilance centre must liaise with Healthcare 3089 Professionals in their territory, to increase awareness of the reporting system, stressing its importance 3090 and encouraging reporting (e.g. by the provision of a user-friendly system of reporting and provision 3091 of feedback after each report, as appropriate). 3092

Member States should interact with Healthcare Professionals to ensure adequate reporting of suspected 3093 adverse reactions to the national Competent Authorities. To this end, it is desirable that each Member 3094 State should ensure the following: 3095

• That reporting of adverse reactions is straightforward and accessible to Healthcare 3096 Professionals; 3097

• That all adverse reaction reports are acknowledged where appropriate and further information 3098 is forwarded as requested; and 3099

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• That regular contact is maintained between the pharmacovigilance centre and Healthcare 3100 Professionals, for example by: 3101 • Publication of regular pharmacovigilance bulletins; 3102 • Circulation of Direct Healthcare Professional Communications, where appropriate, (either 3103

by the Competent Authority and/or the Marketing Authorisation Holder); 3104 • Provision of information in response to specific requests from the Healthcare 3105

Professional, pharmaceutical companies or others; 3106 • Lectures and talks given to Healthcare Professionals during scientific meetings and 3107

conferences; and 3108 • Comprehensive websites that facilitate and encourage reporting of adverse reactions. 3109

The following recommendations concern the spontaneous reporting system procedure: 3110

• A Healthcare Professional or Marketing Authorisation Holder reports a suspected adverse 3111 reaction, related to one or more medicinal products, to the Competent Authority in the 3112 Member State where the reaction occurred. Reports are made in writing (e.g. using report 3113 forms), by telephone, electronically, or by any other approved way. 3114

• Reports are collected and validated by the national Competent Authority and are usually 3115 entered into a database. Serious reactions should be handled with the highest priority. The 3116 database is used to identify potential signals and analyse data in order to e.g. clarify risk 3117 factors and apparent changes in reporting profiles. 3118

• Case reports must be made accessible to the Agency, to the Competent Authorities of other 3119 Member States, and to the concerned Marketing Authorisation Holders according to the 3120 criteria laid down in legislation, and described in Chapters II.2.A and II.3, and in Part III on 3121 the electronic exchange of pharmacovigilance information. 3122

The following procedures relate to the Competent Authorities of Member States and are independent 3123 of the structure of the national pharmacovigilance systems (centralised or regionalised). The 3124 procedures are divided into: 3125

• Collection and validation of Individual Case Safety Reports 3126 • Storage of Individual Case Safety Reports 3127 • Processing of Individual Case Safety Reports 3128 • Feedback information to reporting Healthcare Professionals 3129 • Quality management 3130 • Confidentiality and security 3131

1.3.2 Collection and Validation of Individual Case Safety Reports (ICSRs) 3132

This concerns the collection and validation of primary data i.e. the data transmitted from the original 3133 reporter (i.e. Healthcare Professional or Marketing Authorisation Holder) to the Competent Authority. 3134 For validation and management of electronically transmitted reports, the specific operational 3135 procedure should be followed (see Part III). 3136

Collection of ICSRs 3137

A single case report concerns one Patient, one identifiable reporter, one or more suspected adverse 3138 reaction(s), and one or more suspected medicinal product(s). Cases that meet the criteria for expedited 3139 reporting should be submitted in accordance with the requirements specified in Chapter I.4. 3140

Validation of ICSRs 3141

The national Competent Authorities are expected to attempt to validate all Individual Case Safety 3142 Reports submitted to them to ensure, prior to reporting to the Marketing Authorisation Holders and the 3143 Agency, that the minimum information required (see Chapter I.4, Section 1) is included in the ICSR. 3144

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This minimum information allows the case to be entered onto a database and become available for 3145 signal identification. Every effort should be made to obtain complete information where appropriate. 3146

Reports should be followed-up to obtain additional information relevant to the case as necessary, and 3147 follow-up information should be reported to the Marketing Authorisation Holder and the Agency. All 3148 available clinical information relevant to the evaluation of the reaction should be provided. 3149

With regard to interpretation of the term suspected, see Chapter I.4. 3150

1.3.3 Storage of Individual Case Safety Reports 3151

Paper-based data must be stored and treated in the same way as other medical documents, with 3152 appropriate respect for confidentiality and in accordance with the requirements specified by 3153 Directive 95/46/EC on protection of personal data. 3154

Electronic data and paper-based case reports should be recorded in a database by the national 3155 Competent Authority, taking account of the above Directive requirements. Data storage should ensure 3156 on-line accessibility of data. Recommendations cover individual data entry, audit trail, and correct use 3157 of terminologies. 3158

Data Entry 3159

Conformity of stored data with initial and follow-up reports should be ensured by a quality control 3160 procedure, which provides for validation against the original data or images thereof. 3161

Audit Trail 3162

Storage should ensure traceability (audit trail) of all data entered or modified, including dates and 3163 sources of received data, dates and destinations of transmitted data. 3164

Terminologies 3165

The internationally agreed medical terminology (MedDRA) should be used. All coding used in 3166 national pharmacovigilance databases should be compatible with or automatically transferable to the 3167 format of the ICH E2B(M) standard (see Annexes 3 and 4). 3168

Reaction terms should be entered as the closest term available in the terminology using the appropriate 3169 MedDRA Lowest Level Terms (LLTs), and, if possible, also in the original reporter's words. Use of 3170 terminologies should be monitored and validated, either systematically or by regular random 3171 evaluation. Data entry staff should be instructed in the use of the terminologies, and their proficiency 3172 verified. 3173

1.3.4 Processing of Individual Case Safety Reports 3174

Case report processing concerns evaluation of data in individual cases, identification of individual 3175 cases requiring specific handling, signal identification and processing and any other data processing of 3176 aggregate cases. 3177

1.3.4.a Evaluation of Individual Case Data 3178

Following validation, evaluation of the case report includes determination of seriousness and 3179 expectedness of the adverse reaction. These terms (seriousness and expectedness) have specific 3180 meanings in the context of adverse reaction report evaluation (see Annex 1). Evaluation of the 3181 probability of the causal relationship between medicinal products and the reaction(s) is undertaken 3182

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when considered appropriate. All methods used to evaluate these parameters should be documented. 3183 Evaluators should be trained in the methods used and their training verified. 3184

If the original notification of a case is made orally or made by telephone to the national Competent 3185 Authority, it should be confirmed in writing by a Healthcare Professional. When several suspected 3186 adverse reactions to one or more suspected medicinal products occur in one Patient, but are considered 3187 to be independent reactions, they should be treated as separate cases. If considered appropriate, 3188 especially in the case of serious or unexpected adverse reactions, data in the report concerning the 3189 Patient, the medicinal products taken, the adverse reactions experienced, including signs and 3190 symptoms and laboratory reports, and the dates should be confirmed by copies of the most important 3191 and relevant original documents (e.g. hospital discharge forms, specialist reports, laboratory tests, 3192 prescriptions and post mortem reports). 3193

1.3.4.b Management of Duplicate Reports 3194

Some cases, especially those which are serious, may be reported to Competent Authorities from more 3195 than one source, or from a single source through more than one channel. The Competent Authority 3196 should make every effort to ensure that case reports contain sufficient information to identify such 3197 duplicates, e.g. from Patient/reporter initials (or names if allowed), addresses, date of birth, other 3198 dates. Databases should be reviewed regularly to identify duplicates in accordance with national 3199 Competent Authority and Agency procedures. After identification, duplicates should be flagged as 3200 such. 3201

1.3.4.c Transmission of Individual Case Safety Reports 3202

Individual Case Safety Reports (ICSRs) that meet the criteria for expedited reporting to other 3203 Competent Authorities, the Agency or Marketing Authorisation Holders should be transmitted in 3204 accordance with approved formats and timelines, as defined in Chapter I.4. 3205

National Competent Authorities should ensure that ICSRs are transmitted electronically to the 3206 Agency, as required (see Part III). 3207

1.3.4.d Processing of Individual Case Safety Reports for Signal Identification 3208

Database management should enable users to identify cumulative data and trends indicating a signal. 3209 Once a signal has been identified, the possibility of a causal relationship should be considered. In this 3210 instance, all adverse reaction reports should be classified according to national preferences or 3211 requirements, using nationally or internationally accepted methodologies. All ICSRs fulfilling the 3212 minimum information requirement (see Chapter I.4, Section 1) should be included in the overall 3213 analysis. Certain analyses (for example those concerning the role of risk factors) may be confined to 3214 cases where sufficient information is available, but it should be made clear that this is a subset of the 3215 data. 3216

Competent Authorities in Member States and Marketing Authorisation Holders should inform each 3217 other of identified signals, which may impact on the known risk-benefit balance of nationally 3218 authorised medicinal products. In accordance with the PhVWP Mandate, initial review and evaluation 3219 of such signals should be undertaken at national level, prior to discussion and finalisation of regulatory 3220 proposals by the PhVWP upon request of a Member State. The Rapid Alert-Non-Urgent Information 3221 System should be used by Competent Authorities when applicable (see Chapter II.4). 3222

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1.3.4.e Provision of Information to the World Health Organization and Other 3223 International Bodies 3224

Competent Authorities should ensure that appropriate and timely information is provided to 3225 international bodies, in particular the World Health Organization (WHO), in accordance with the 3226 guidance provided in Chapter II.6. 3227

1.3.5 Feedback Information to Reporting Healthcare Professionals 3228

National Competent Authorities should ensure that the original reporter(s) of a case is (are) informed 3229 of its receipt and is provided with the allocated reference number and if appropriate, additional 3230 information requested. 3231

1.3.6 Quality Management 3232

Quality management concerns every step in the processes described above. Quality control and quality 3233 assurance should be ensured by national Competent Authorities, who should devise, document and 3234 implement appropriate procedures. 3235

1.3.7 Confidentiality and Security 3236

Confidentiality of Patients' records including personal identifiers, if provided, should always be 3237 maintained. Identifiable personal details of reporting Healthcare Professionals should be kept in 3238 confidence, as appropriate and in keeping with national and EU legislation. 3239

At each stage of storage and processing of pharmacovigilance data, all care must be taken to ensure 3240 data security and confidentiality. This involves strict control of access to documents and to databases 3241 to authorised personnel sharing the medical and administrative confidentiality of the data. This 3242 security extends to the complete data path. Case report information should only be transmitted, or 3243 otherwise provided by Competent Authorities in an anonymous form. 3244

In addition, procedures should be taken to ensure security and non-corruption of data during data 3245 transfer. 3246

1.4 Company-Derived Pharmacovigilance Data 3247

The Marketing Authorisation Holder must ensure that an appropriate system of pharmacovigilance is 3248 in place in order to ensure responsibility and liability for his products marketed and to ensure that 3249 appropriate action can be taken, when necessary. Guidance for Marketing Authorisation Holders on 3250 the implementation and practical procedures involved in complying with the legislation is laid out in 3251 Part I. 3252

Company-derived pharmacovigilance data includes the following: 3253

• Risk Management Plans 3254 • Individual Case Safety Reports (ICSRs) 3255 • Periodic Safety Update Reports (PSURs) 3256 • Data from company sponsored post-authorisation safety studies 3257 • Benefit-Risk Reviews 3258 • Reports on post-authorisation commitments 3259 • Other relevant data, e.g. proposed communication texts. 3260

This subchapter deals with the procedures, to be undertaken for handling company-derived 3261 pharmacovigilance data. 3262

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1.4.1 Risk Management Plans 3263

Applicants and the Marketing Authorisation Holders should submit product-specific Risk 3264 Management Plans in accordance with the requirements specified in Chapter I.3. 3265

Risk Management Plans should be thoroughly assessed by the Competent Authorities in terms of 3266 complexity, content and adequacy. Feedback and comments should be provided to Applicants and 3267 Marketing Authorisation Holders, as appropriate. 3268

Risk Management Plans serve as a basis for post-marketing pharmacovigilance activities; therefore 3269 they should be stored in a way that allows rapid and complete access to the documentation. 3270

An Assessment Report on a Risk Management Plan should be prepared by the national Competent 3271 Authority for purely nationally authorised products, or by the Reference Member State or the 3272 Rapporteur for products authorised via the mutual recognition, decentralised or centralised procedures 3273 respectively. 3274

1.4.2 Individual Case Safety Reports 3275

Each national Competent Authority should ensure that all Individual Case Safety Reports (ICSRs) 3276 submitted by Marketing Authorisation Holders conform to the requirements as laid out in Chapter I.4, 3277 in order to ensure conformity of reporting of adverse reactions by Marketing Authorisation Holders in 3278 each Member State. Furthermore, national Competent Authority must ensure validation and 3279 verification of all data included in these ICSRs as far as possible. Finally, each national Competent 3280 Authority should ensure that these reports are followed up by the Marketing Authorisation Holders 3281 where appropriate, in order to improve the quality of data available and to facilitate causality 3282 assessment. National Competent Authorities should ensure that they have the capability to send and 3283 receive ICSRs electronically and should ensure that Marketing Authorisation Holders do so in 3284 accordance with agreed procedures and guidance (see Part III). 3285

1.4.3 Periodic Safety Update Reports 3286

A Periodic Safety Update Report (PSUR) is intended to provide an update of the worldwide safety 3287 experience of a medicinal product to Competent Authorities at defined times post-authorisation. 3288

It is the responsibility of each national Competent Authority to evaluate these reports for nationally 3289 authorised products as well as products authorised via the mutual recognition or decentralised 3290 procedure, as appropriate. 3291

PSURs for products authorised via the mutual recognition or decentralised procedure are evaluated by 3292 the Reference Member State. An Assessment Report is circulated by the Reference Member State to 3293 all Concerned Member States within 6 weeks of receipt of the PSUR (see Chapter II.3). 3294

In the case of nationally authorised products, any major action (e.g. variation, suspension, revocation 3295 or withdrawal of a marketing authorisation) considered necessary as a result of such evaluation should 3296 be notified to the Agency and the other Member States according to established procedures (see 3297 Chapter II.4). 3298

In order to reduce duplication of effort and maximise use of available resources, Competent 3299 Authorities are encouraged to participate in the PSUR work-sharing project on assessment of PSURs 3300 for nationally authorised products and to follow relevant internal guidelines. In this case the project 3301 rules apply. 3302

PSURs for centrally authorised products are evaluated by the Rapporteur according to a timetable 3303 agreed by the CHMP (see Chapter II.2.A). 3304

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PSUR Assessment Reports should be provided to the Marketing Authorisation Holder. 3305

1.4.4 Data from Company-Sponsored Post-Authorisation Safety Studies 3306

Marketing Authorisation Holders proposing to perform post-authorisation safety studies (PASS) are 3307 advised to discuss the draft protocol with the relevant Competent Authorities (see Chapters I.6 and 3308 I.7). 3309

It is recommended that Competent Authorities in Member States maintain a register of PASS 3310 conducted on their territory, to improve compliance monitoring and to limit inappropriate use of PASS 3311 for marketing purposes. 3312

Where a PASS falls under the provisions of Directive 2001/20/EC on clinical trials, national 3313 Competent Authorities have to follow the related provisions accordingly. 3314

The Competent Authorities in Member States should review PASS taking place within their 3315 jurisdiction on a regular basis. 3316

Individual Case Safety Reports occurring in non-interventional PASS should be processed by the 3317 national pharmacovigilance system. 3318

On completion of each PASS, the final Study Report from the Marketing Authorisation Holders (see 3319 Chapter I.7, Section 4.3) should be evaluated by the Competent Authority and any impact of the 3320 findings on the Product Information should be assessed. All relevant data (showing e.g. a significant 3321 change in the frequency of a known adverse reaction, an unexpected adverse reaction, or a new 3322 interaction) should be incorporated into the Product Information (Summary of Product Characteristics 3323 and Package Leaflet) and notified, as appropriate, in accordance with the criteria described in 3324 Chapter II.4. 3325

All data from the study should be evaluated and an Assessment Report will be elaborated as a result. 3326

In the case of studies conducted for purely nationally authorised medicinal products, the relevant 3327 Member State(s) will be responsible for evaluation of the final Study Report. 3328

In the case of medicinal products authorised through the mutual recognition or decentralised 3329 procedure, evaluation of the final Study Report will normally be carried out by the Reference Member 3330 State. 3331

In the case of medicinal products authorised through the centralised procedure, the Rapporteur will 3332 normally assess the final Study Report (see Chapter II.2.A). 3333

The Assessment Report should be distributed to the Marketing Authorisation Holder, Member States, 3334 the CHMP and the Agency, as appropriate, within three months of receipt of the final report from the 3335 Marketing Authorisation Holder. 3336

If any pharmacovigilance issue, which requires regulatory action, is identified during any phase of the 3337 evaluation, this should be communicated using the appropriate procedure (see Chapter II.4). 3338

1.4.5 Benefit-Risk Reviews 3339

Benefit-Risk Reviews requested by Competent Authorities should always be thoroughly evaluated by 3340 the Competent Authorities and an Assessment Report prepared. As such reviews are prepared and 3341 submitted to the Authorities for important reasons, they should be prioritised for assessment. 3342

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The Assessment Reports should be provided to the Marketing Authorisation Holder and as 3343 appropriate, to other Competent Authorities and the Agency. 3344

1.4.6 Reports on Post-Authorisation Commitments 3345

Competent Authorities should have a tracking system in place to monitor the progress of post-3346 authorisation commitments. The system should ensure that any commitment specified at the time of 3347 granting of the marketing authorisation is fulfilled. For centrally authorised products, the EMEA 3348 maintains such a tracking system. 3349

Reports submitted by the Marketing Authorisation Holder should be assessed and the Assessment 3350 Reports provided to the Marketing Authorisation Holder and, as appropriate, to other Competent 3351 Authorities and the Agency. 3352

When a product is authorised via the mutual recognition or decentralised procedure, the Concerned 3353 Member States should be informed by the Reference Member State. 3354

When a product is centrally authorised, the Agency and all Member States should be informed by the 3355 Rapporteur. 3356

1.4.7 Other Data 3357

Competent Authorities should also consider all other pharmacovigilance-related data submitted by or 3358 requested from Marketing Authorisation Holders, such as data on volume of sales and prescription of 3359 medicinal products. 3360

1.5 Pharmacovigilance Data from Other Sources 3361

1.5.1 Intensive Monitoring Schemes 3362

Intensive Monitoring is a system of record collation in designated areas, e.g. hospital units or by 3363 specific physicians in community practice. The Competent Authority may be involved in the drawing 3364 up of the protocol to undertake this collection of data or will be informed that such monitoring is 3365 taking place. 3366

Furthermore, it may be considered appropriate in the authorisation of certain medicinal products to 3367 impose specific requirements in respect of reporting serious or unexpected reactions on the prescribing 3368 physician and to make these requirements a condition of use of the product under the terms of the 3369 marketing authorisation. 3370

The relevant national Competent Authority should ensure that data and reports are collected at agreed 3371 intervals and in an appropriate format. 3372

1.5.2 Data on Medication Errors, Overdose, Misuse and Abuse 3373

Reports of suspected adverse reactions due to medication errors, overdose, misuse and abuse of 3374 medicinal products, which are received by the national Competent Authorities (e.g. directly from 3375 Healthcare Professionals or via Marketing Authorisation Holders or poison centres) should be handled 3376 in the same way as other Individual Case Safety Reports (see Chapter II.1, Section 3). 3377

The Competent Authorities in Member States should ensure cooperation with other national agencies 3378 responsible for collation of data associated with medication errors, overdose, misuse and abuse, as 3379 appropriate (see also Chapter I.5). 3380

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1.5.3 Other Data Relevant for Pharmacovigilance 3381

These data include the following: 3382

• Drug usage figures; 3383 • Published adverse reaction reports; 3384 • Data from pharmacoepidemiology studies conducted by organisations other than the 3385

Marketing Authorisation Holder; 3386 • Data from pre-clinical studies; 3387 • Significant quality data; and 3388 • Reports on products not currently marketed in Member States. 3389

Such information is important for determining for example frequency, occurrence of unexpected 3390 adverse reactions, new interactions and the overall risk-benefit balance. In cases where significant data 3391 are received from these sources, these findings may be transmitted to other Member States and the 3392 Agency (see Chapter II.1, Section 6 and Chapter II.4). 3393

1.6 Procedures for Data Exchange and Evaluation of Safety Concerns 3394

This section describes the procedures that should be implemented in order to improve the 3395 communication of pharmacovigilance information between Competent Authorities in Member States 3396 and between Competent Authorities and the Agency, and to optimise human resources for identifying 3397 and evaluating pharmacovigilance signals. 3398

Where the national Competent Authority identifies new information which may influence the overall 3399 benefit-risk assessment it is usually appropriate that they communicate this concern to the Marketing 3400 Authorisation Holder at the time that such information is shared with other Competent Authorities and 3401 the Agency. A comprehensive Assessment Report evaluating the issue and the risks in the context of 3402 the benefits should be submitted by the Competent Authority at the earliest opportunity and no later 3403 than the agreed date specified in the written communications between the Competent Authority and 3404 the Marketing Authorisation Holder. It should be sent to all Competent Authorities in Member States 3405 where the medicinal product is authorised, and usually in addition to the Agency. 3406

The following areas will be discussed: 3407

• Transmission of Individual Case Safety Reports of serious adverse reactions; 3408 • Transmission of Individual Case Safety Reports of non-serious adverse reactions; 3409 • Procedures for data transmission and management of signals; and 3410 • Technologies for data transmission to facilitate implementation of the procedures conforming 3411

to the EU pharmacovigilance system. 3412

1.6.1 Transmission of Individual Case Safety Reports of Serious Adverse 3413 Reactions 3414

All serious adverse reactions, occurring within the Member State and notified to the national 3415 Competent Authority should be transmitted to the Marketing Authorisation Holder and to the Agency 3416 within 15 calendar days of their receipt by the centre. 3417

In the case of centrally authorised medicinal products, it is the responsibility of the Agency to inform 3418 each Member State of serious reports received from other Member States via EudraVigilance. 3419 Information should be transmitted within the timeframe outlined in Chapter II.2.A. 3420

The data transmitted should be as complete as possible in order to facilitate assessment, but it is not 3421 obligatory for national Competent Authorities to have made a formal evaluation before this 3422 transmission (see also Chapter II.4 and Part III). 3423

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1.6.2 Transmission of Individual Case Safety Reports on Non-Serious Adverse 3424 Reactions 3425

These include non-serious expected or unexpected adverse reaction reports that are received from all 3426 sources. Whenever appropriate, these data should be available for transmission to all relevant parties 3427 (Marketing Authorisation Holder, Member States and the Agency), as outlined below (see Chapter II.4 3428 and Part III). 3429

1.6.3 Procedures for Transmission and Management of Signals 3430

Once a potential safety concern (e.g. a series of unexpected or serious adverse reactions or an increase 3431 in the reporting rate of a known adverse reaction) for a specific medicinal product or a class of 3432 medicines has been identified by a national Competent Authority, it should be transmitted in 3433 accordance with Chapter II.4. 3434

It is essential that there is communication of the concern at an early stage, before a national decision is 3435 taken. 3436

1.6.4 Technologies for Data Transmission to Facilitate Implementation of the 3437 Procedures Conforming to the EU Pharmacovigilance System 3438

For data exchange and communication between Competent Authorities in Member States, the Agency 3439 and Marketing Authorisation Holders, only appropriate secure communication systems (e.g. EudraNet 3440 and EudraVigilance) should be used. EudraLink should only be used when transmission via EudraNet 3441 is not possible. 3442

Competent Authorities should ensure that their pharmacovigilance personnel are familiar with the 3443 rules and procedures involved in the use of these systems and with the requirements for electronic 3444 reporting of adverse reactions (see Part III). 3445

1.7 Changes to Terms of Marketing Authorisations 3446

The Competent Authority in each Member State, as part of its obligation to undertake ongoing 3447 evaluation of the risk-benefit balance of medicinal products, must ensure that all pharmacovigilance 3448 data received and evaluated, as outlined above, are taken into account on an ongoing basis. 3449

In the case of centrally authorised medicinal products, changes to the marketing authorisation status or 3450 Summary of Product Characteristics are undertaken according to Commission Regulation (EC) 3451 No 1085/2003 and as outlined in the Chapter II.2.A. 3452

The procedure to be followed for changes to the marketing authorisation status or the Summary of 3453 Product Characteristics of medicinal products authorised via the mutual recognition or decentralised 3454 procedure is laid out in Commission Regulation (EC) No 1084/2003 and in Chapter II.3. It is the 3455 responsibility of the Reference Member State to coordinate the procedure. The changes are 3456 implemented simultaneously in all Concerned Member States. The national decisions shall take effect 3457 on the day agreed after discussion between the Reference Member State and the Marketing 3458 Authorisation Holder in consultation with the Concerned Member States. Every effort should be made 3459 to implement these changes as soon as possible. 3460

In the case of purely nationally authorised medicinal products, where updated pharmacovigilance data 3461 are seen to adversely affect the risk-benefit profile of the medicinal product, the Competent Authority 3462 in the Member State may request a variation, or suspend or revoke the marketing authorisation or not 3463 renew it, as appropriate. 3464

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Any significant change to the marketing authorisation status or Summary of Product Characteristics, 3465 undertaken nationally as a result of these pharmacovigilance data should be notified to the other 3466 Member States and the Agency (see Chapter II.4). For CHMP Opinions following suspension or 3467 revocation of a medicinal product by a Member State see Chapter II.5. 3468

As provided for in Commission Regulations (EC) No 1084/2003 and 1085/2003, provisional urgent 3469 safety restrictions may be taken in the event of a risk to public health. An urgent safety restriction may 3470 be taken by the Marketing Authorisation Holder if the Competent Authority in the Member State or, 3471 for centrally authorised products, the Agency does not raise any objection within 24 hours after the 3472 Marketing Authorisation Holder’s notification. The Competent Authority may also impose an urgent 3473 safety restriction. In case of a centrally authorised product, the Agency will act in accordance with 3474 Chapter II.2.A and notify all Member States, circulating a Rapid Alert (see Chapter II.4). In case of a 3475 non-centrally authorised product, the national Competent Authority will notify any urgent safety 3476 restriction to the other Member States and the Agency circulating a Rapid Alert (see Chapter II.4). 3477 Should this concern a product authorised via the mutual recognition or decentralised procedure, the 3478 agreed guidance in Chapter II.3 will be followed. An urgent safety restriction must be followed by 3479 submission by the Marketing Authorisation Holder of a variation application immediately and in no 3480 case later than 15 days after the initiation of the urgent safety restriction. 3481

Under the terms of Article 31, 36 and 37 of Directive 2001/83/EC, a Member State, the European 3482 Commission or the Marketing Authorisation Holder may refer a pharmacovigilance matter to the 3483 CHMP whenever the interests of the Community are involved. These matters may be referred by the 3484 CHMP to the PhVWP for consideration. The Commission Decision issued on the basis of the CHMP 3485 Opinion is binding on all Member States (see Chapter II.5 for reference to further guidance). 3486

1.8 Public Communication and Transparency 3487

Competent Authorities should ensure that Healthcare Professionals, Patients/Consumers and the 3488 general public are informed, where appropriate, of any significant changes in the Product Information 3489 (Summary of Product Characteristics and Package Leaflet) and of any suspected safety concerns 3490 requiring vigilance. Competent Authorities should ensure their compliance with requirements for 3491 transparency and public communication (see Part IV). 3492

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1. APPENDIX: MANDATE, OBJECTIVES AND RULES OF PROCEDURE OF THE CHMP PHARMACOVIGILANCE 3493 WORKING PARTY 3494

<to be inserted later> 3495

http://www.emea.eu.int/pdfs/human/phvwp/8878604en.pdf 3496

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2.A Conduct of Pharmacovigilance for Centrally Authorised Products 3497

Note: Procedures for the conduct of pharmacovigilance for centrally authorised products are currently 3498 under review and an updated version of this chapter will be subject of separate public consultation in 3499 2006. 3500

2.A.1 Introduction 3501

The objective of this Chapter is to describe a framework whereby all centrally authorised products are 3502 closely monitored to allow timely evaluation of new information relevant to the risks and benefits of 3503 these products, so that appropriate action may be taken, when necessary, to protect public health. 3504

The conduct of pharmacovigilance for centrally authorised products is based on obligations and 3505 activities placed, through legislation, on a number of parties, i.e. the Member States, the European 3506 Commission, the Agency and the Marketing Authorisation Holders. In order to ensure that the 3507 obligations are met, it is necessary to clarify the respective roles and responsibilities of the various 3508 parties. 3509

This Chapter presents: 3510

• Principles relevant to the conduct of pharmacovigilance for centrally authorised products; 3511 • The functions and procedures for conducting pharmacovigilance for these products; 3512 • The specific roles of the Member States, the CHMP, the Pharmacovigilance Working Party 3513

(PhVWP), the (Co)-Rapporteur(s), the Agency, the Marketing Authorisation Holders and the 3514 European Commission, in carrying out functions and procedures for the conduct of 3515 pharmacovigilance for centrally authorised products. 3516

2.A.2 Legal Framework 3517

The legal provisions regarding the conduct of pharmacovigilance for centrally authorised products are 3518 set out in Chapter 3 of Title II (Articles 21-29) as well as in Articles 13, 55, 57 and 67 of Regulation 3519 (EC) No 726/2004 (ex 2309/93) and Council Regulation (EC) No 540/95. The examination of 3520 variations to the terms of marketing authorisation and urgent safety restrictions is the subject of 3521 Commission Regulation (EC) No 1085/2003 (ex 542/95). 3522

Obligations of the Marketing Authorisation Holders: 3523

The obligations in relation to risk management are addressed in Article 9 of Regulation (EC) No 3524 726/2004 and Article 8 of Directive 2001/83/EC (see Chapter I.3). 3525

Marketing Authorisation Holders are obliged to report within 15 calendar days all suspected serious 3526 adverse reactions occurring within the EU to the Member States in whose territory the incident 3527 occurred. 3528

Furthermore, Marketing Authorisation Holders have to report all suspected serious unexpected adverse 3529 reactions from outside the EU to the Agency and the Member States within 15 calendar days14 (for 3530 details see Chapters I.4 and I.5). 3531

Marketing Authorisation Holders have to submit Periodic Safety Update Reports (PSURs) to the 3532 Agency and the Member States as detailed in Chapter I.6. 3533

14 This relates to adverse reactions falling outside the scope of Directive 2001/20/EC of the European Parliament and the Council where legal provisions regarding safety reporting from clinical trials are set out (Articles 16-18).

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Legal provisions regarding information of Healthcare Professionals and Patients/the public about 3534 safety concerns and related regulatory action for centrally authorised products are included in Article 3535 24 of Regulation (EC) No 726/2004. 3536

Obligations of the Member States: 3537

Members States have to report all suspected serious adverse reactions occurring within their territory 3538 to the Agency within 15 calendar days. Save in exceptional circumstances, these adverse reactions 3539 shall be transmitted electronically in the form of a report and in accordance with the guide referred to 3540 in Article 26 of Regulation (EC) No 726/2004 (see Part III). 3541

Legal provisions regarding information to Healthcare Professionals and the public about safety 3542 concerns and related regulatory action for centrally authorised products are included in Articles 20 and 3543 24 of Regulation (EC) No 726/2004. 3544

Obligations of the Agency: 3545

The Agency should receive all relevant information about suspected adverse reactions for centrally 3546 authorised products. The Agency shall forward the information to the national pharmacovigilance 3547 systems set up in accordance with Article 102 of Directive 2001/83/EC as outlined in Article 25(2) of 3548 Regulation (EC) No 726/2004. 3549

The legal provisions regarding supervision and sanctions for centrally authorised products are set out 3550 in Chapter 2 of Title II (Articles 16-20) and Article 57 of Regulation (EC) No 726/2004. In particular 3551 Article 20 provides the basis and the procedures for adoption of Commission Decisions following 3552 Opinions by the CHMP on the measures necessary to ensure the safe and effective use of centrally 3553 authorised products as well as procedures for urgent protection of human health or the environment. 3554

Legal provisions regarding information to Healthcare Professionals and the public about safety 3555 concerns and related regulatory action for centrally authorised products are included in Articles 22, 26 3556 and 57 of Regulation (EC) No 726/2004. 3557

2.A.3 Principles 3558

The responsibilities and functions of the various partners involved in the centralised procedure have 3559 been well defined for the coordination and evaluation of centralised marketing authorisation 3560 applications and subsequent variation applications. This framework should also be applied to the 3561 conduct of pharmacovigilance for centrally authorised products. As a matter of principle, the handling 3562 and analysis of pharmacovigilance data should always be done in close cooperation between the (Co)-3563 Rapporteur(s), the Agency and any Member State(s) who has identified a possible issue. 3564

The pre-authorisation Rapporteur should take the lead in pharmacovigilance, acting to evaluate all 3565 issues relevant to the centrally authorised product. However, there may be situations where the 3566 original Rapporteur is not able to fulfil the functions of such evaluation. In such cases the Co-3567 Rapporteur could take this responsibility. If this is not possible, the CPHMP would need to appoint 3568 another Rapporteur who could take on these responsibilities. In the particular case that one would be 3569 confronted with a class-related effect and different Rapporteurs were involved in the pre-authorisation 3570 assessment of the various centrally authorised products, the CHMP would need to appoint a “leading” 3571 Rapporteur. 3572

In view of the large number of issues to be handled in the post-authorisation period for centrally 3573 authorised products, the Rapporteur will have the responsibility for evaluating and reaching 3574 conclusions on these issues in accordance with an agreed timetable, and for determining the issues 3575 which need to be considered by PhVWP and CHMP, in close cooperation with the Agency. 3576

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Information relevant to the risks and benefits of centrally authorised products need to be continuously 3577 collected in all Member States. Therefore, each Member State plays an important role in collecting 3578 information on adverse reactions and in identifying and evaluating possible safety concerns for 3579 centrally authorised products. The scientific expertise of the Member States will be utilised by the 3580 Rapporteurs in carrying out pharmacovigilance evaluations. The Rapporteur will generally use the 3581 expertise of the Member State from which he originates. However, if considered more appropriate, the 3582 Rapporteur may work with another Member State, e.g. the Member State that identified the issue 3583 under investigation. 3584

In accordance with current legislation the Agency should collect all information about serious 3585 suspected adverse reactions and distribute this information to the Member States. The role of the 3586 Agency, therefore, is one of continuous coordination of the pharmacovigilance system for centrally 3587 authorised products. The Agency will ensure that Marketing Authorisation Holders for centrally 3588 authorised products adhere to the requirements for safety reporting in accordance with current 3589 legislation. Meetings for Marketing Authorisation Holders will be organised at the Agency at regular 3590 intervals in order to provide guidance on adverse reaction reporting to the Agency. The PhVWP will 3591 be informed of such meetings in advance and will be given the opportunity to participate. 3592

The Agency, in close cooperation with the Rapporteur, will inform the CHMP/PhVWP of any safety 3593 concern wherever there is a need for discussion and subsequent action to be taken. It will, in 3594 agreement with the Rapporteur, participate in the identification of signals of possible unexpected 3595 hazards or changes in severity, characteristics or frequency of expected adverse reactions. 3596

The PhVWP evaluates potential signals, investigates adverse reactions and provides advice on the 3597 safety of medicinal products, enabling effective risk identification, assessment and management in the 3598 pre-and post-authorisation phase. Following a CHMP request, their recommendations on centrally 3599 authorised products are transmitted to the CHMP for consideration. A Drug Monitor, including 3600 centrally authorised products, is in place to track safety issues and is reviewed at each meeting of the 3601 PhVWP. In addition specific issues relating to Periodic Safety Update Reports, specific obligations, 3602 follow-up measures or the need for safety variations may be discussed by the PhVWP at the request of 3603 the Rapporteur. 3604

The primary responsibility of the Marketing Authorisation Holders is to assure the safety of their 3605 product. Therefore, the Marketing Authorisation Holder is obliged to adhere to the legal provisions as 3606 to the spontaneous reporting of adverse reactions as well as to the submission of PSURs and other 3607 information. Furthermore, issues requiring clarification, further information or specific actions by the 3608 Marketing Authorisation Holder need to be clearly presented to the Marketing Authorisation Holder in 3609 writing. Such requirements of the Marketing Authorisation Holder should be prepared in collaboration 3610 between the Rapporteur, the Agency and any Member State requesting further information, and 3611 endorsed where necessary by the CHMP. Meetings with the Marketing Authorisation Holder should 3612 involve the Rapporteur, the Agency and others as considered necessary. Minutes of such meetings 3613 should be taken and distributed to attendees. 3614

A summary of the role and responsibilities of each of the parties involved in the pharmacovigilance 3615 system for centrally authorised products is provided in the Table at the end of this Chapter. 3616

2.A.4 Functions and Procedures 3617

2.A.4.1 Reporting of Adverse Reactions and Other Safety-Related Information 3618

2.A.4.1.a Pre-Authorisation Phase 3619

Once an application for a marketing authorisation is submitted to the Agency, in the pre-authorisation 3620 phase, information relevant to the benefit-risk evaluation may become available from the Applicant, or 3621 Member States where the product is already in use on a compassionate basis, or from third countries 3622

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where the product is already marketed. Since it is essential for this information to be included in the 3623 assessment carried out by the (Co)-Rapporteur(s) assessment teams, the Applicant is responsible for 3624 informing immediately the Agency and the (Co)-Rapporteur(s). 3625

In the period between the CHMP reaching a final Opinion and the Commission Decision there need to 3626 be procedures in place to deal with information relevant to the risk-benefit balance of centrally 3627 authorised products, which were not known at the time of the Opinion. It is essential for this 3628 information to be sent to the Agency and (Co)-Rapporteur(s) so that it can be rapidly evaluated to an 3629 agreed timetable and considered by the CHMP to assess what impact, if any, it may have on the 3630 Opinion. The Opinion may need to be amended as a consequence. 3631

2.A.4.1.b Post-Authorisation Phase 3632

Suspected adverse reactions related to centrally authorised products are reported directly by 3633 Healthcare Professionals, to each Member State. Marketing Authorisation Holders report serious 3634 suspected adverse reactions to the Member State in which the reactions occurred, within 15 calendar 3635 days of receipt. Each Member State is responsible for following up the Individual Case Safety Reports 3636 it receives to obtain further information as necessary. 3637

The Member States should forward to the Agency serious suspected adverse reactions occurring 3638 within their territories. 3639

The Agency and all Member States should receive directly from the Marketing Authorisation Holders 3640 suspected serious and unexpected adverse reactions that occur in a country outside of the EU. 3641

The Agency should ensure that all relevant information about suspected serious unexpected adverse 3642 reactions from outside the EU are entered into the EudraVigilance database, and Member States 3643 should ensure that data on suspected serious adverse reactions occurring in their territory are uploaded 3644 into the EudraVigilance database. For details see Chapter I.4 and Part III. 3645

2.A.4.2 Monitoring of the Safety Profile 3646

2.A.4.2.a Signal Identification 3647

It is likely that many potential signals will emerge in the early stages of marketing and it will be 3648 important for these to be effectively evaluated. 3649

A signal of possible unexpected hazards or changes in severity, characteristics or frequency of 3650 expected adverse effects may be identified by: 3651

• the Marketing Authorisation Holders, 3652 • the Rapporteur, 3653 • the Member States, 3654 • the Agency in agreement with the Rapporteur. 3655

It is the responsibility of each Member State to identify signals from information arising in their 3656 territory. However, it will be important for the Rapporteur and the Agency to have the totality of 3657 information on serious adverse reactions occurring inside and outside the EU in order to have an 3658 overall view of the experience gathered with the concerned centrally authorised product. 3659

As a matter of routine, the Rapporteur should continually evaluate the adverse reactions included in 3660 the EudraVigilance system and all other information relevant to risk-benefit balance in the context of 3661 information already available on the product, to determine the emerging adverse reactions profile. 3662 Additional information should be requested from the Marketing Authorisation Holder and Member 3663 States as necessary, in liaison with the Agency. 3664

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When a Member State other than the Rapporteur wishes to request information from the Marketing 3665 Authorisation Holder (apart from routine follow-up of cases occurring on their own territory) for the 3666 purposes of signal identification, the request should be made in agreement with the Rapporteur and the 3667 Agency. 3668

Member States will inform the Rapporteur(s) and the Agency when performing class-reviews of safety 3669 issues which include centrally authorised products. 3670

The PhVWP should regularly review emerging safety issues which will be tracked through the Drug 3671 Monitor. 3672

2.A.4.2.b Signal Evaluation 3673

As signals of possible unexpected hazards or changes in the severity, characteristics or frequency of 3674 expected adverse reactions may emerge from many different sources of data (see above), the relevant 3675 information needs to be brought together for effective evaluation, over a time scale appropriate to the 3676 importance and likely impact of the signal. 3677

Irrespective of who identified the signal, a signal evaluation should be carried out by: 3678

• the Rapporteur, or 3679 • the Member State where a signal originated. 3680

The Rapporteur should work closely with the identifier of the signal to evaluate the issue. Agreement 3681 needs to be reached in each case on the responsibility for the Assessment Report on the risk-benefit 3682 balance, by the Rapporteur or the Member State where the signal originated from, or jointly. 3683

A Member State other than that of the Rapporteur should not start a full evaluation prior to having 3684 contacted the Agency and the Rapporteur, in order to prevent any unnecessary duplication of effort. 3685

At request of the CHMP, the PhVWP evaluates signals arising from any source and keeps any 3686 potential safety issues under close monitoring. 3687

2.A.4.2.c Evaluation of Periodic Safety Update Reports 3688

The Marketing Authorisation Holder is required to provide Periodic Safety Update Reports (PSURs) 3689 to all the Member States and the Agency, as detailed in Chapter I.6. It is the responsibility of the 3690 Agency to ensure that the Marketing Authorisation Holder meets the deadlines. 3691

The Marketing Authorisation Holder should submit any consequential variations simultaneously with 3692 the PSUR at the time of its submission, in order to prevent any unnecessary duplication of effort. 3693 Variations may, however, also be requested subsequently by the Rapporteur, after agreement by the 3694 CHMP. 3695

It is the responsibility of the Rapporteur to evaluate and provide a report in accordance with the agreed 3696 timetable and to determine what issues if any need to be referred to the PhVWP and CHMP. 3697

Actions required following the evaluation of a PSUR will be determined by the Rapporteur and the 3698 Marketing Authorisation Holder will be informed by the Agency, after agreement by the CHMP. 3699

Where changes to the marketing authorisation are required, the CHMP will adopt an Opinion which 3700 will be forwarded to the European Commission for preparation of a Decision. 3701

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2.A.4.2.d Evaluation of Post-Authorisation Studies, Worldwide Literature and Other 3702 Information 3703

Final and interim reports of Marketing Authorisation Holder sponsored post-authorisation studies and 3704 any other studies, and other relevant information, may emerge from the Marketing Authorisation 3705 Holder, the Member States or other countries at times in between PSURs. 3706

The Rapporteur should receive and assess any relevant information and provide an Assessment Report 3707 where necessary. 3708

As above, the Rapporteur should determine what issues if any need to be referred to the PhVWP and 3709 CHMP. 3710

The actions required following an evaluation will be determined by the Rapporteur and the Marketing 3711 Authorisation Holder will be informed by the Agency, after agreement by the CHMP. 3712

Where changes to the marketing authorisation are required, the CHMP will adopt an Opinion which 3713 will be forwarded to the European Commission for preparation of a Decision. 3714

The Marketing Authorisation Holder should submit any consequential variations simultaneously with 3715 the data, in order to prevent any unnecessary duplication of effort. Variations may, however, also be 3716 requested subsequently by the Rapporteur, after agreement by the CHMP. 3717

2.A.4.2.e Evaluation of Post-Authorisation Commitments 3718

It is the responsibility of the Agency to ensure that the Marketing Authorisation Holder meets the 3719 deadlines for the fulfilment of specific obligations and follow-up measures, and that the information 3720 provided is available to the Rapporteur and the CHMP. 3721

The Marketing Authorisation Holder should submit any consequential variations simultaneously with 3722 the requested information for the fulfilment of specific obligations/follow-up measures, in order to 3723 prevent any unnecessary duplication of effort. Variations may, however, also be requested 3724 subsequently by the Rapporteur, after agreement by the CHMP. 3725

For marketing authorisations granted under exceptional circumstances, specific obligations will be set 3726 out in Annex II.C of the CHMP Opinion. Specific obligations should be reviewed by the Rapporteur, 3727 at the interval indicated in the Marketing Authorisation and at the longest annually, and should be 3728 subsequently agreed by the CHMP. As above, the Rapporteur should determine what issues if any 3729 need to be referred to the PhVWP and CHMP. 3730

For marketing authorisations granted under exceptional circumstances, the annual review will include 3731 a re-assessment of the risk-benefit balance. The annual review will in all cases lead to the adoption of 3732 an Opinion which will be forwarded to the European Commission for preparation of a Decision. 3733

For all marketing authorisations (whether or not the authorisation is granted under exceptional 3734 circumstances) follow-up measures may be established, which are annexed to the CHMP Assessment 3735 Report. These will be reviewed by the Rapporteur, and will be considered by PhVWP and CHMP at 3736 the Rapporteur’s request. 3737

Where changes to the marketing authorisation are required, the CHMP will adopt an Opinion which 3738 will be forwarded to the European Commission for preparation of a Decision. 3739

In the case of non-fulfilment of specific obligations or follow-up measures, the CHMP will have to 3740 consider the possibility of recommending a variation, suspension, or withdrawal of the marketing 3741 authorisation. 3742

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2.A.4.3 Handling of Safety Concerns 3743

2.A.4.3.a Safety Concerns in the Pre-Authorisation Phase 3744

Following the receipt of Individual Case Safety Reports or other information relevant to the risk-3745 benefit balance of a product by the Agency and the (Co)-Rapporteur(s), the latter should assess these 3746 pharmacovigilance data. The outcome of the evaluation should be discussed at the CHMP for 3747 consideration in the Opinion. 3748

If pharmacovigilance findings emerge following an Opinion but prior to the Decision, a revised 3749 Opinion, if appropriate, should be immediately forwarded to the European Commission to be taken 3750 into account before preparation of a Decision. 3751

2.A.4.3.b Safety Concerns in the Post-Authorisation Phase 3752

A Drug Monitor, including centrally authorised products, is in place as a tracking system for safety 3753 concerns and is reviewed on a regular basis by the PhVWP at its meetings. This summary document 3754 also records relevant actions that have emerged from PSURs, specific obligations, follow-up measures 3755 and safety variations. 3756

Following the identification of a signal the relevant information needs to be brought together for 3757 effective evaluation, over a time scale appropriate to the importance and likely impact of the signal: 3758

i) Non-urgent safety concerns 3759

Potential concerns that do not fulfil the criteria for a Rapid Alert should be brought to the attention of 3760 the Rapporteur and the Agency only in the first instance. 3761

Further information may be requested from: 3762

• other Member States by the originator of the concern, issuing a Non-Urgent Information (see 3763 Chapter II.4); 3764

• the Marketing Authorisation Holder by the Agency, in agreement with the originator of the 3765 concern and the Rapporteur. 3766

The Rapporteur should work closely with the originator of the concern to evaluate it. 3767

Following evaluation, the need for further discussion at the PhVWP and CHMP will be determined by 3768 the Rapporteur, and any necessary actions will be agreed by CHMP. 3769

The Agency is responsible for transmitting the outcome of the evaluation to the Marketing 3770 Authorisation Holder. 3771

However, if deemed necessary, the CHMP should formulate an Opinion on the pharmacovigilance 3772 data and forward it to the European Commission accordingly in order to take a Decision. 3773

These issues will be included in the Drug Monitor by the Agency if a Non-Urgent Information has 3774 been issued. 3775

ii) Urgent safety concerns 3776

A Rapid Alert (see Chapter II.4) should be issued by the Rapporteur, the Member States or the Agency 3777 when a signal is identified which leads to concern about the risk-benefit balance of a centrally 3778 authorised product and which could lead to major changes for the status of the authorisation. If it is the 3779 Marketing Authorisation Holder who first identifies a potentially urgent and serious issue, he needs to 3780 inform the Agency without delay. 3781

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The Rapid Alert should be transmitted to the contact points of the Member States, the Agency and the 3782 European Commission, and to the Rapporteur of the centrally authorised product which is the subject 3783 of the Rapid Alert. 3784

The Agency, in agreement with the Rapporteur, should promptly start an inquiry and information 3785 exchange with the Marketing Authorisation Holder(s). 3786

The Agency will coordinate the process. 3787

The Rapporteur should work closely with the originator of the concern to evaluate the issue. 3788 Agreement needs to be reached in each case on the responsibility for the Assessment Report on the 3789 risk-benefit balance, by the Rapporteur, the Member State where the signal originated from, or jointly. 3790

Following risk evaluation a discussion should be held at the PhVWP and subsequently at the CHMP 3791 within a defined timeframe. 3792

Any resulting CHMP Opinion on the measures to ensure the safe and effective use of the centrally 3793 authorised product will be transmitted by the Agency to the European Commission, in order to take a 3794 Decision. 3795

In some cases immediate action is essential to protect public health. In such cases the basic steps 3796 outlined above need to be followed, but within a much shorter time frame, with the involvement of 3797 PhVWP and CHMP at a much earlier stage, and with particular mechanisms in place to provide a 3798 CHPMP Opinion and Commission Decision rapidly. Rapid actions will need to be coordinated across 3799 all Member States, however in some situations one or a number of Member States may consider it 3800 necessary to take immediate suspensive action before such coordinated action occurs. 3801

Crisis Management: 3802

• Following detection of an urgent safety concern, which could have a serious impact on public 3803 health, immediate action needs to be taken to evaluate and consider the options and timescale 3804 for action. An urgent safety restriction to be completed within 24 hours may be initiated by the 3805 Marketing Authorisation Holder or the European Commission if necessary. A Crisis 3806 Management Plan, agreed with the CHMP, has been implemented by the Agency in close 3807 consultation with the European Commission (see Chapter II.2.B). 3808

Action taken by a Member State: 3809

• Upon detection of a safety concern where urgent action is deemed essential to protect human 3810 health, a Member State may suspend the use of a medicinal product on its territory. 3811

• The Member State must inform the Agency, the European Commission and other Member 3812 States no later than the following working day of the reasons for its action. A Rapid Alert 3813 should be issued for this purpose (see Chapter II.4). 3814

• The European Commission will request the Opinion of the Agency within a time frame which 3815 it shall determine depending on the urgency of the matter. In that respect two possible 3816 procedures can be envisaged for implementation by the Agency depending on the time frame: 3817 • the first procedure is described in the Crisis Management Plan (see Chapter II.2.B); 3818 • the second is the convening of an extraordinary CHMP by the Executive Director of the 3819

Agency, after consultation with the CHMP Chairperson, in order to provide the European 3820 Commission with a recommendation on the measures. 3821

2.A.4.4 Information to Healthcare Professionals and the Public 3822

Healthcare professionals and, if considered appropriate, the public need to be informed about safety 3823 issues relevant to centrally authorised products, in addition to the information provided in Product 3824 Information. It is important that consistent information is provided in all Member States. If there is 3825

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such a requirement the Rapporteur or the Marketing Authorisation Holder in cooperation with the 3826 Rapporteur should propose the content of information for consideration by the PhVWP and 3827 subsequent discussion and adoption by the CHMP. The agreed information may be distributed in 3828 Member States, for example, by Direct Healthcare Professional Communication from the Marketing 3829 Authorisation Holder, or by Competent Authorities in Member States or through Member States’ drug 3830 bulletins. In some cases coordinated press releases, in addition to the CHMP Public Statements, may 3831 be necessary. The text and timing for release of such information should be agreed by all parties prior 3832 to their despatch. The Marketing Authorisation Holder should notify, at his own initiative, the Agency 3833 at an early stage of any information he intends to make public, in order to facilitate consideration by 3834 the PhVWP and adoption by the CHMP as well as agreement about timing for release, in accordance 3835 with the degree of urgency. Marketing Authorisation Holders are reminded of their legal obligations 3836 under Article 24(5) of Regulation (EC) No 726/2004 to not communicate information relating to 3837 pharmacovigilance concerns to the public without notification to the Competent Authorities/Agency 3838 (see Part IV). 3839

2.A.4.5 Advertising 3840

Title VIII of Directive 2001/83/EC lays down the legal base for the control of advertising medicinal 3841 products. Because company marketing strategies for centrally authorised products may be similar 3842 across the EU, consideration should be given to what interactions should take place between Member 3843 States in the event of an important advertising concern with potential public health implications 3844 occurring with a centrally authorised product. The Agency and the Rapporteur should be informed by 3845 the Member States of such concerns. The PhVWP may be an appropriate forum to discuss such issues 3846 in order to ensure that when it is considered that a company is making misleading claims with safety 3847 implications in several Member States, consistent action is taken whenever possible. The CHMP 3848 should be informed subsequently. 3849

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3850

2.A TABLE: SUMMARY OF THE ROLES AND THE RESPONSIBILITIES OF ALL PARTNERS INVOLVED IN THE CONDUCT OF PHARMACOVIGILANCE FOR CENTRALLY AUTHORISED PRODUCTS

Marketing Authorisation Holder

• Establish and maintain a system, accessible at a single point in the EU, to collect, collate, and evaluate pharmacovigilance data

• Meet legal obligations for reporting of suspected adverse reactions

• Meet legal obligations regarding the preparation and the submission of Periodic Safety Update Reports

• Respond fully to requests from authorities for additional information necessary for the evaluation of the benefits and risks of a medicinal product

• Ensure the marketing authorisation is maintained and reflects the latest information

Member States • Have in place national pharmacovigilance systems • Inform the European Commission, the CHMP, the

Agency, the Member States and the Marketing Authorisation Holders of any relevant actions

• Collect and collate data on the risk-benefit 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 of receipt

• Identify and evaluate safety concerns and conduct benefit-risk evaluations

• Provide representation on CHMP, PhVWP and Rapporteurs/Co-Rapporteurs

• Implement Commission Decisions • In case of urgent action to protect public health, suspend

the use of the product in the Member State’s territory and inform, in accordance with the legislation, the Agency and the European Commission of the basis for action

Agency • Coordination of the pharmacovigilance system for centrally authorised products

• Monitor the legal obligations of the Marketing Authorisation Holders

• Receipt of serious adverse reaction reports and provision to the Member States and the Rapporteur

• In agreement with the Rapporteur, identify signals of unexpected potential risks or changes in expected adverse reactions

• In agreement with the Rapporteur, inform all involved parties of any safety concern

• Coordination of the evaluation of data by the Rapporteurs and consideration by the CHMP to reach Opinions

• Communication of Opinions to the European Commission

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• Communication with the Marketing Authorisation Holder on all relevant issues in consultation with the Rapporteur

• Maintenance of the crisis management system for centrally authorised products

Rapporteur • Responsible for evaluating all safety concerns and benefit-risk issues for centrally authorised products

• Regularly evaluate adverse reactions and other risk-benefit data on receipt, Periodic Safety Update Reports, company reports and variation applications to agreed timetables, obtaining additional information from the Marketing Authorisation Holder and Member States as necessary

• Provide Assessment Reports to agreed timetables for consideration by the PhVWP and CHMP as necessary, with proposals on appropriate action

CHMP Pharmacovigilance Working Party

• Evaluation of potential signals arising from spontaneous reporting, including those identified from EudraVigilance, and all other sources

• Investigation of adverse reactions • Regularly review Drug Monitor of safety concerns • Discussion of emerging safety concerns at the request of

the Rapporteur • Discussion of PSURs at the request of the Rapporteur • Providing advice to the CHMP on safety, enabling

effective risk identification, assessment and management in the pre- and post-authorisation phase

• Recommendations to the CHMP on benefit-risk evaluations and actions necessary to minimise risk and maximise benefit

CHMP • Discussion of the risk-benefit balance on the basis of the Rapporteur’s Assessment Report

• Formulation of Opinions European Commission • Competent Authority for centrally authorised products

• Formulation of Decisions • Enforcement of legal requirements and enforcement of the

implementation of Decisions by Member States and Marketing Authorisation Holders

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2.B Crisis Management Plan regarding Centrally Authorised Products 3851

Note for public consultation: Procedures for crisis management for centrally authorised products are 3852 currently under review and an updated version of this Chapter will be subject of separate public 3853 consultation in 2006. 3854

2.B.1 Introduction 3855

This Chapter outlines the principles underlying a Crisis Management Plan which allows rapid and 3856 efficient handling of crisis situations involving a centrally authorised product. In order to achieve this 3857 objective, it is necessary to plan and agree in advance with all the involved parties, how the crisis will 3858 be managed. 3859

The Crisis Management Plan outlines the procedures to be followed in order to deal with the crisis and 3860 also highlights the management structures and systems to be set up. These procedures will be followed 3861 in response to new information in the context of pharmacovigilance while the procedures on how to 3862 deal with new quality-related information with potential adverse effects are included in the 3863 Compilation of Community Procedures on Inspections and Exchange of Information 3864 (EMEA/INS/GMP/3351/03/Rev 3 corr), published on the EMEA website (see 3865 http://www.emea.eu.int) on behalf of the European Commission. 3866

2.B.2 Principles of the Crisis Management Plan 3867

The objective of the Crisis Management Plan is to define and implement a strategy for the rapid and 3868 efficient handling of crisis situations by the Agency in liaison with the CHMP, the Rapporteur, the 3869 Competent Authorities of the Member States, the European Commission and the Marketing 3870 Authorisation Holder(s). 3871

A crisis is defined in the present document as an event which occurs when new information, which 3872 could have a serious impact on public health, is received for a centrally authorised product, and which 3873 requires immediate action. 3874

In some cases the new information can be related to both quality and safety concerns (for instance 3875 problems of viral contamination with biological products). 3876

Crises may be subdivided into those where, at the time the crisis is identified, the information has not 3877 become public, and those where it has. In the latter case, the handling of communications becomes 3878 crucial especially when public confidence is at risk. 3879

Sometimes a crisis may be triggered when there is no new information but media exposure leads to 3880 serious public concerns about a product. In this case implementation of the Crisis Management Plan 3881 may be appropriate. 3882

There are two possible outcomes to the crisis: 3883

• Urgent regulatory action is needed; in this case, a recommendation on the action to be taken 3884 and, if needed, on the public communication has to be provided; 3885

• Urgent regulatory action is not required; in this case, a recommendation on the follow-up and, 3886 if needed, public communication has to be provided. 3887

In both cases the basis of the conclusion should be documented. 3888

As a matter of principle, the handling of crises should always involve a close cooperation between all 3889 parties concerned, i.e. the Competent Authorities of the Member States, the European Commission, 3890 the Agency, the CHMP, the Rapporteur and the Marketing Authorisation Holder(s). In accordance 3891

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with the principles laid down in Chapter II.2.A on the conduct of pharmacovigilance for centrally 3892 authorised products, the Rapporteur should have a key role when there is a safety issue, in close 3893 cooperation with the Agency. 3894

The timeframe, during which a crisis should be dealt with, will depend upon the urgency of the matter. 3895 The proposed procedure should, however, be flexible enough to allow for immediate action to be 3896 taken (e.g. an urgent product recall), if considered necessary by the European Commission and/or the 3897 Member States. However, in the case of urgent action required to protect public health, Member States 3898 may need to take pre-emptive action in accordance with the legislation. 3899

2.B.3 Crisis Management Structures 3900

Three different management structures are foreseen, i.e.: 3901

• A European Crisis Group; 3902 • An Agency Crisis Team; 3903 • An advisory network at the level of the Member States. 3904

2.B.3.1. European Crisis Group 3905

In order to deal successfully with a crisis, a European Crisis Group needs to be created. For logistical 3906 reasons and rapid and efficient issue management, the core members of the European Crisis Group 3907 must be kept to a minimum. Due to logistical and time constraints, some meetings may need to take 3908 place without all members being present. Of course additional members and expertise may be co-3909 opted into the European Crisis Group as need arises. 3910

The core European Crisis Group comprises: 3911

• The Chairperson of the CHMP; 3912 • The Chairperson of the CHMP Pharmacovigilance Working Party (PhVWP); 3913 • The Rapporteur of the product concerned, supported by his/her scientific assessment team; 3914 • If appropriate, a representative of the Member State where the signal originated; 3915 • The Executive Director of the Agency, as well as the other members of the Agency Crisis 3916

Team (for further details, see Chapter II.2.B, Section 3.2). 3917

The primary role of the European Crisis Group is to deal with containing and controlling the situation. 3918 This will be achieved by: 3919

• Confirming the crisis; 3920 • Managing the crisis situation by: 3921

• Defining a strategy to handle the crisis; 3922 • Convening an extraordinary CHMP meeting, if necessary, or referring the matter to the 3923

next regular CHMP meeting, in order to define what possible action should be taken 3924 considering the seriousness of the crisis; 3925

• Ensuring that all Competent Authorities and relevant Marketing Authorisation Holders 3926 are rapidly and fully informed; 3927

• Developing the appropriate communication strategy towards the public, including 3928 patients and healthcare professionals. 3929

The decision to convene the European Crisis Group will be taken by the Executive Director, in 3930 consultation with the CHMP Chairperson. 3931

2.B.3.2 Agency Crisis Team 3932

The availability of an internal Agency crisis management structure involves the creation of an Agency 3933 Crisis Team, which should become operational within the shortest possible timeframe. It should be set 3934

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up in such a way that it is also able to deal with crises arising during weekends or public holidays. The 3935 Agency Crisis Team should consist of an identified group of individuals. 3936

The Agency Crisis Team is normally chaired by the Executive Director, or, in his absence, a 3937 designated deputy. 3938

It has a core membership with optional/additional participants. The core members, in addition to the 3939 Executive Director, are: 3940

• The Head of Unit Post-authorisation Evaluation of Medicines for Human Use 3941 • The Head of Sector Pharmacovigilance and Post-authorisation Safety & Efficacy of Medicines 3942 • The Product Team Leader concerned 3943 • The EMEA Press Officer. 3944

Optional/additional participants may be co-opted as necessary; for example a legal administrator, other 3945 Product Team Members or Product Team Leaders, as well as support personnel (technical, secretarial 3946 and linguistic support) will be needed. 3947

The role of the Agency Crisis Team consists of: 3948

• coordinating all activities; 3949 • acting at all stages in cooperation with the other participants of the European Crisis Group. 3950

The following Members have the following specific tasks: 3951

The Executive Director (or, in his absence, a designated deputy): 3952

• deciding, together with the CHMP Chairperson, to convene a European Crisis Group; 3953 • chairing the Agency Crisis Team; 3954 • deciding upon the communication plan; 3955 • liaising with the European Commission. 3956

The Head of Unit Post-authorisation Evaluation of Medicines for Human Use: 3957

• liaising with the Executive Director, the Chairperson of the CHMP and the EMEA Press 3958 Officer; 3959

• providing all necessary scientific resources. 3960

The Head of Sector Pharmacovigilance and Post-authorisation Safety & Efficacy Medicines: 3961

• acting as overall coordinator, responsible for: 3962 • organising and coordinating the actions of the Agency Crisis Team Members; 3963 • centralising all updated information related to the crisis; 3964 • preparing all documents for public communication; 3965 • informing the Executive Director and the Head of Unit Post-authorisation Evaluation of 3966

Medicines for Human Use of all developments. 3967

The Product Team Leader: 3968

• collecting internal and external information on an ongoing basis; 3969 • writing file notes on meetings and ensure that key action points and recommendations are 3970

documented and filed. 3971

A list of all crisis contact points within the Agency is available. 3972

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2.B.3.3 Advisory Network at the Level of the Member States 3973

A prerequisite in this respect is the availability of designated contact points within the Member States. 3974 This network should also foresee the involvement of the national pharmacovigilance systems in case 3975 of safety concerns. 3976

A consolidated list of all contact points at the level of the Member States has been prepared. This list 3977 shall continuously be updated. It is the responsibility of the Member States to inform the Agency of 3978 any changes to be implemented. 3979

2.B.4 Key Points of the Procedure 3980

In addition to the management structures, management systems are put in place at the level of the 3981 Agency and the Competent Authorities of the Member States. They aim to meet the following 3982 objectives: 3983

• To activate all available networks and to coordinate the different activities between the 3984 interested parties; 3985

• To arrive at a common conclusion and, where regulatory action is considered necessary, an 3986 Opinion, and to implement the regulatory action at the same moment in the whole EU; this 3987 implies the availability of efficient immediate links with the Heads of Medicines Agencies; 3988

• To convey a unified message to the public, including Patients and Healthcare Professionals; 3989 this requires efficient contacts with the European Commission and with the press officers 3990 available in Member States. 3991

In order to achieve these objectives, a close cooperation between all the different parties involved and 3992 the following steps should be ensured: 3993

1. Confirmation of the crisis; 3994 2. Initiation, if considered necessary, of the crisis procedure; 3995 3. Rapid scientific re-appraisal of the risk-benefit balance of the product concerned; 3996 4. Definition of strategy; 3997 5. Recommendation on action or no action with documentation of the reasons for the 3998

recommendation; 3999 6. In case of regulatory action, monitoring of the implementation in all Member States; 4000 7. Development of an action plan to monitor the sequelae. 4001

2.B.5 Public Relations 4002

In all cases it is essential that public relations are handled sensitively and in a timely fashion. Failure 4003 to do so may mean that, however well the crisis is managed from a safety and regulatory perspective, 4004 public confidence will be lost and the image of the Competent Authorities will be damaged. 4005

For this reason, the responsibility for press briefing and the preparation of Public Statements is at the 4006 highest levels. A communication plan will be decided by the EMEA Director on the basis of the 4007 communication strategy proposed by the European Crisis Group, with the Head of Sector 4008 Pharmacovigilance and Post-authorisation Safety & Efficacy of Human Medicines being responsible 4009 for drafting the communication documents, and the EMEA Press Officer acting as the public 4010 spokesperson. The ideal is that press releases should be coordinated between the Member States, the 4011 Agency and the Marketing Authorisation Holder(s). However in some situations, this ideal may not be 4012 met. In such cases, close cooperation between the Agency and the Member States should ensure that 4013 the messages coming from them are consistent. 4014

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3. Conduct of Pharmacovigilance for Medicinal Products Authorised through the 4015 Mutual Recognition or Decentralised Procedure 4016

3.1 Introduction 4017

The objective of this guidance is to develop a framework whereby all medicinal products for human 4018 use which fall under the mutual recognition procedure (MRP) or the decentralised procedure (DP) are 4019 closely monitored to allow timely evaluation of new information relevant to the risks and benefits of 4020 these products, so that appropriate action may be taken, when necessary, to protect public health. 4021 Products covered by these procedures include those authorised through MRP, DP or ex-concertation 4022 procedure and those previously referred under Articles 30 and 31 of Directive 2001/83/EC. The 4023 revised Community legislation allows for marketing authorisations of medicinal products referred to 4024 under Article 31(2) to remain as given by the Competent Authority. 4025

The responsibility for the conduct of pharmacovigilance of any MRP or DP product rests with the 4026 Competent Authorities of all individual Member States who have granted the authorisation. 4027

The smooth running of MRP and DP is facilitated by the Coordination Group for the Mutual 4028 Recognition and Decentralised Procedures (CMD) in accordance with Article 27 of Directive 4029 2001/83/EC. The CMD acts to support the development of consensus where differences of view arise 4030 so as to minimise the need for arbitration at the level of the Committee for Medicinal Products for 4031 Human Use (CHMP). The Member States have agreed that for pharmacovigilance of MRP and DP 4032 products the CHMP Pharmacovigilance Working Party (PhVWP) is the platform for exchange of 4033 information, evaluation and views and that the PhVWP advises the CMD on actions to be taken (see 4034 Appendix to Chapter II.1 for Mandate). 4035

Because of the need to coordinate the process of pharmacovigilance and any consequential regulatory 4036 action across all relevant Member States, best practice guidance has been made available on the 4037 cooperation between the CMD and the PhVWP (see Heads of Agencies website 4038 http://heads.medagencies.com). This will facilitate harmonised actions in the Member States. 4039

This Chapter presents: 4040

• Principles relevant to the conduct of pharmacovigilance for MRP and DP products; and 4041 • The specific roles of the different parties involved in carrying out these functions. 4042

Directive 2001/83/EC sets the basis for the authorisation of medicinal products through the MRP and 4043 DP and for pharmacovigilance thereafter. Pharmacovigilance procedures and obligations of Marketing 4044 Authorisation Holders, Competent Authorities and the Agency, which includes the CHMP and the 4045 Secretariat. Commission Regulation (EC) No 1084/2003 provides the legislative basis for variation of 4046 MRP and DP marketing authorisations including urgent safety restrictions. 4047

3.2 Principles 4048

The responsibilities and functions of the various parties involved in the handling of marketing 4049 authorisation and subsequent variation applications in the MRP and DP are defined in the legislation. 4050 Member States have accordingly agreed principles that should be applied for the conduct of 4051 pharmacovigilance for MRP and DP products, with the Reference Member State (RMS) taking the 4052 lead in pharmacovigilance in close cooperation with Concerned Member States (CMS). Any reference 4053 to Member States below should be taken to mean both the RMS and CMS. The roles of the relevant 4054 parties are presented below. 4055

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3.3 Roles and Responsibilities 4056

3.3.1 Reference Member State 4057

Article 104(5) of Directive 2001/83/EC stipulates that the Marketing Authorisation Holder should 4058 ensure that all serious adverse reactions occurring in the EU are reported in such a way as to be 4059 accessible to the RMS and that the RMS shall assume the responsibility of analysing and monitoring 4060 such serious adverse reactions. For practical reasons, Member States have agreed that the RMS should 4061 be assigned responsibility for evaluating all safety concerns relevant to a MRP or DP product, for 4062 providing Assessment Reports to the CMS to an agreed timetable and presenting the safety concerns 4063 which need to be considered by the PhVWP. The RMS will be responsible for liaising with the 4064 Marketing Authorisation Holder on all such matters. In cases where the RMS is unable to carry out 4065 these functions, another Member State may be assigned to act as RMS. In situations where a class-4066 related effect is identified for products with different RMSs, a Lead-RMS may be appointed by 4067 agreement between the relevant RMSs to take forward evaluation of the class-related effect. 4068

3.3.2 Concerned Member States 4069

The Competent Authorities of all CMS have a responsibility to continuously collect information on 4070 adverse reactions and play an important role in identifying and evaluating possible signals of safety 4071 concerns for MRP and DP products. The CMS will work closely with the RMS on such concerns, and 4072 will respond to proposals from the RMS within the agreed timetable. 4073

All Competent Authorities are responsible for ensuring implementation of regulatory action in their 4074 Member State. 4075

3.3.3 CHMP Pharmacovigilance Working Party (PhVWP) 4076

The PhVWP facilitates coordination of pharmacovigilance of MRP and DP products across Member 4077 States and the development of consensus on conclusions and proposed actions where differences arise 4078 between Member States. 4079

The PhVWP is the forum for discussing all safety concerns relevant to MRP and DP products. Items 4080 for discussion may be raised by the RMS or CMS. The present Mandate of the PhVWP (see 4081 Chapter II.1, Appendix) encompasses consideration of items at the request of the CHMP or a Member 4082 State. These items are handled as clearly defined in separated parts of the PhVWP agenda. 4083

3.3.4 Coordination Group for Mutual Recognition and Decentralised Procedures 4084

The Coordination Group for Mutual Recognition and Decentralised Procedures (CMD) will be kept 4085 closely informed on issues relevant to it, e.g. variations for safety reasons by provision of the agendas 4086 and minutes of the PhVWP or otherwise as appropriate. 4087

3.3.5 Agency and the Committee for Medicinal Products for Human Use 4088

The Agency will be kept informed about safety data and (proposed) regulatory actions by the Member 4089 States according to Directive 2001/83/EC, Articles 105 and 107. 4090

The CHMP becomes involved in the discussion on safety concerns relevant to MRP or DP products 4091 whenever there is a procedure according to Directive 2001/83/EC, Articles 29(4), 31 or 36(1). 4092 The Agency coordinates all activities in the event of referral to the CHMP (see Chapter II.5). 4093

For CHMP Opinions following suspension or revocation of a medicinal product by a Member State 4094 according to Article 107(2) of Directive 2001/83/EC, see also Chapter II.5. 4095

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3.3.6 European Commission 4096

The European Commission takes the final decision relating to medicinal products on any CHMP 4097 Opinion adopted as a result of referrals according to the procedures laid down in Articles 32, 33 and 4098 34 of Directive 2001/83/EC and of CHMP Opinions according to Article 107(2) of Directive 4099 2001/83/EC. 4100

3.3.7 Marketing Authorisation Holders 4101

According to Article 104(5), the Marketing Authorisation Holder should report all serious adverse 4102 reactions of MRP and DP products occurring in the EU in such a way as to be accessible to the RMS. 4103 The Marketing Authorisation Holder is further obliged to adhere to the other legal requirements of 4104 pharmacovigilance (e.g. reporting of adverse reactions occurring outside the EU, submission of 4105 Periodic Safety Update Reports and other information including post-authorisation safety studies) for 4106 MRP and DP products as for any other nationally authorised products. This information should be 4107 provided to all Member States at the same time. Member States have agreed that the RMS will 4108 normally act as the primary liaison with the Marketing Authorisation Holder, specifying issues 4109 requiring clarification, further information or specific actions by the Marketing Authorisation Holder. 4110 This will be clearly presented in writing to the Marketing Authorisation Holder by the RMS working 4111 closely with CMS. Meetings with the Marketing Authorisation Holder should involve the RMS, and 4112 any other CMS by request. The conclusions of such meetings should be distributed to the PhVWP and 4113 the CMD. The RMS may also ask the Marketing Authorisation Holder to present further clarification 4114 to the plenary meeting of the PhVWP. In the case of bilateral contact between a CMS and the 4115 Marketing Authorisation Holder, the relevant CMS should keep the RMS informed. 4116

3.4 Functions and Procedures for the Conduct of Pharmacovigilance 4117

3.4.1 Pre-Authorisation Phase 4118

In the interim time between an application for a marketing authorisation through the DP or MRP and 4119 granting of the marketing authorisation, information relevant to the safety of the product may become 4120 available from the Applicant, Member States or third countries where the product is already marketed. 4121 Since it is essential for this information to be included in the risk-benefit balance, the Applicant is 4122 responsible for immediately informing the RMS and the other CMS. The RMS will assess whether this 4123 new information alters the overall assessment, circulating an amended Assessment Report as 4124 necessary. For reporting requirements see Chapter I.5, Section 2. 4125

3.4.1.a Risk Management Plans 4126

If the Marketing Authorisation Holder has submitted a Risk Management Plan, the RMS will 4127 distribute an Assessment Report and collect comments from the CMS. Thereafter the RMS will 4128 distribute the final Assessment Report, which will also be sent to the Marketing Authorisation Holder. 4129 The Marketing Authorisation Holder should give an appropriate follow-up to the Assessment Report. 4130 The Assessment Report will usually be discussed at a PhVWP meeting. Results of post-authorisation 4131 studies performed in the frame of the Pharmacovigilance Plan should be processed in a similar way by 4132 the RMS (see Chapter I.3). 4133

3.4.1.b Concerns during the ongoing Mutual Recognition or Decentralised 4134 Procedure 4135

If, in the course of a MRP or DP and following the assessment of all information relevant to the safety 4136 of a product, the RMS considers that a significant risk has emerged to change the risk-benefit balance, 4137 the outcome of the evaluation should be discussed at the PhVWP. The PhVWP will report the 4138 outcome of the discussion to the CMD. 4139

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3.4.2 Post-Authorisation Phase 4140

3.4.2.a Expedited Reporting of Individual Case Safety Reports 4141

All Competent Authorities have spontaneous adverse reaction reporting schemes in place whereby 4142 Healthcare Professionals and Marketing Authorisation Holders report adverse reactions to medicinal 4143 products. Directive 2001/83/EC lays down specific obligations on national Competent Authorities and 4144 Marketing Authorisation Holder on the expedited reporting of serious adverse reactions. Member 4145 States are responsible for collecting, collating and evaluating reports occurring in their respective 4146 territory. In accordance with Article 104(5) of Directive 2001/83/EC as amended, for products which 4147 have been the subject of a MRP or DP, the Marketing Authorisation Holder should additionally make 4148 these reports accessible to the RMS (see also Chapter II.3, Section 3.1 and Chapter I.4). 4149

The responsibility to collate and evaluate these reports has been assigned to the RMS by the Member 4150 States. 4151

3.4.2.b Periodic Safety Update Reports and Other Relevant Post-Authorisation 4152 Information 4153

The Marketing Authorisation Holder is required to provide all Competent Authorities with Periodic 4154 Safety Update Reports (PSURs) and relevant safety information from post-authorisation 4155 commitments, post-authorisation studies, worldwide literature, or other sources as outlined in the 4156 Directive 2001/83/EC and guidance documents for Marketing Authorisation Holders. Any 4157 consequential variation should be submitted by the Marketing Authorisation Holders to the RMS and 4158 all CMS at the same time. The RMS will evaluate the information and circulate an Assessment Report 4159 to the CMS within 6 weeks of receipt. CMS should respond within 3 weeks of receipt of the RMS 4160 Assessment Report. This Assessment Report will, if requested by the RMS or a CMS, be discussed at 4161 a PhVWP meeting. The PSUR submission schedule to be followed is the one in place in the RMS, 4162 unless otherwise agreed during the MRP or DP. This has to be decided on a case-by-case basis. 4163

3.4.2.c Risk Management Plans 4164

If the Marketing Authorisation Holder has submitted a new or updated Risk Management Plan in the 4165 post-authorisation phase, the RMS will distribute an Assessment Report and collect comments from 4166 the CMS. Thereafter the RMS will distribute the final Assessment Report, which will also be sent to 4167 the Marketing Authorisation Holder. The Marketing Authorisation Holder may be requested to revise 4168 the Risk Management Plan. The Risk Management Plan and the Assessment Report will, if requested 4169 by the RMS or CMS, be discussed at a PhVWP meeting. Results of post-authorisation studies 4170 performed in the frame of the Pharmacovigilance Plan should be processed in a similar way by the 4171 RMS (see Chapter I.3). 4172

3.4.2.d Signal Identification 4173

It is possible that potential signals will emerge in the early stages of the marketing of a MRP or DP 4174 product especially for a new active substance. It will be important for these signals to be evaluated 4175 effectively. A signal of possible unexpected adverse reactions or changes in severity, characteristics or 4176 frequency of expected adverse reactions may be identified from many different sources of information 4177 held by the Marketing Authorisation Holders, the RMS, or any CMS or the Agency. 4178

It is the responsibility of each Member State to transmit reports of serious adverse reactions to the 4179 EudraVigilance database in an expedited way and to identify signals from information arising in its 4180 territory. It is important for the RMS to have the totality of information in order to have an overall 4181 view of the experience gathered in relation to the concerned MRP or DP product. Additional 4182 information requested from the Marketing Authorisation Holder should be provided to the RMS and 4183 all CMS simultaneously. The EudraVigilance database services are a very important source of 4184

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information, since all reports of serious adverse reactions are included in the database in accordance 4185 with the revised Community legislation. 4186

As a matter of routine, the RMS should continually evaluate all newly submitted information in the 4187 context of information already available on the product, to determine the emerging adverse reaction 4188 profile. Signals of a possible safety concern will, if requested by the RMS or a CMS, be discussed at 4189 the meeting of the PhVWP. 4190

3.4.2.e Signal Evaluation 4191

As signals of unexpected potential risks or changes in the severity, characteristics or frequency of 4192 adverse reactions emerge, the relevant information needs to be brought together for effective 4193 evaluation over a timescale appropriate to the importance and likely impact of the signal. 4194

Any risk evaluation prompted by a signal should normally be carried out by the RMS unless other 4195 arrangements are agreed with another Member State, this could be for example the CMS where the 4196 original signal was identified. The RMS should in any case work closely with the originator of the 4197 alert. Agreement needs to be reached in each case on the responsibility for the benefit-risk Assessment 4198 Report, by the RMS or the originating Member State, or jointly. Assessment Reports may be discussed 4199 at the PhVWP as necessary on request of the RMS or CMS. According to Article 23, 8th subparagraph, 4200 of Directive 2001/83/EC the Marketing Authorisation Holder may be asked to provide data 4201 demonstrating that the risk-benefit balance remains favourable. All data provided by the Marketing 4202 Authorisation Holder to the RMS should simultaneously be provided to all CMS. 4203

A Member State other than the RMS should not start a full evaluation prior to having contacted the 4204 RMS, in order to prevent any unnecessary duplication of effort. 4205

3.4.2.f Proceedings in Case of Safety Concerns 4206

Non-Urgent Safety Concerns 4207

Potential concerns that do not fulfil the criteria for a Rapid Alert (see Chapter II.4) should be brought 4208 to the attention of the RMS. The RMS may request further information from the CMS or the 4209 Marketing Authorisation Holder. The RMS should work closely with the Member State who identified 4210 the issue to evaluate the matter. Agreement needs to be reached in each case on the responsibility for 4211 the benefit-risk Assessment Report, by the RMS or the originator Member State, or jointly. The RMS 4212 should consider sending a Non-Urgent Information request (see Chapter II.4). Following evaluation, 4213 the need for further discussion at the PhVWP will be at the request of the RMS or CMS. The CMD 4214 should be informed by the RMS. 4215

Urgent Safety Concerns 4216

The Rapid Alert System should be used by the RMS or CMS when a signal is detected which leads to 4217 concern about the risk-benefit balance of a MRP or DP product and which could lead to major changes 4218 in the status of that authorisation. The Rapid Alert should be transmitted to the contact points of the 4219 RMS, the CMS, the European Commission and the Agency (see Chapter II.4). The Marketing 4220 Authorisation Holder should also be informed. The RMS should work closely with the initiator (if not 4221 the RMS itself) of the Rapid Alert to evaluate the matter. Responsibilities for management and 4222 assessment of the safety concern should be agreed between RMS and the initiating Member State. 4223 They should also decide what additional information should be requested from the Marketing 4224 Authorisation Holder and CMS. Following risk evaluation a discussion should be held at the PhVWP 4225 aimed at reaching agreement between RMS and all CMS. In cases of particular urgency a special 4226 meeting of the PhVWP may need to be set up. The RMS should keep the CMD informed. Any 4227 Member State may initiate immediate suspension of the marketing and use of the medicinal product 4228 concerned if considered necessary (see below "Actions by the Competent Authorities"). 4229

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Actions consequential to Safety Concerns 4230

Safety concerns are likely to emerge from the many sources of information considered above which 4231 warrant amendment to the conditions of the marketing authorisation, through a short Type II variation 4232 procedure, or urgent safety restriction procedure. In the case of serious risk, which is considered to 4233 outweigh the benefit of a product, there may be a need to withdraw the product from the market or 4234 revoke the marketing authorisation. Such actions may be taken either by Marketing Authorisation 4235 Holder or by Competent Authorities as described below. 4236

a) Actions by the Marketing Authorisation Holder 4237

Variations of the marketing authorisation submitted by the Marketing Authorisation Holder because of 4238 safety concerns should be handled through the 30 day-Type II variation procedures for MRP and DP 4239 products with the RMS evaluating the variation and circulating an Assessment Report to the CMS 4240 within the standardised time table. For urgent safety concerns, the Marketing Authorisation Holder 4241 may submit an urgent safety restriction. 4242

In the case of a Marketing Authorisation Holder wishing to withdraw its product from the market, 4243 action needs to be coordinated across the CMS by the RMS. To this end the RMS and CMS should be 4244 informed of the situation as early as possible (see Chapter I.8, Section 4). It is important that the same 4245 action is followed in all Member States including communication to Healthcare Professionals. It is 4246 recommended that any such intended action be discussed at an early stage with all Competent 4247 Authorities concerned. In addition, all concerned Competent Authorities must be informed well in 4248 advance of any action taken. 4249

b) Actions by the Competent Authorities 4250

If following risk evaluation by the RMS it is considered that action is necessary to vary the terms of, 4251 or to suspend, revoke or withdraw, the marketing authorisation of a medicinal product, the RMS 4252 should inform the CMS, the Agency and the Marketing Authorisation Holder. The RMS should also 4253 keep the CMD informed. 4254

Where possible, in order to ensure a coordinated approach, efforts should be made to reach a 4255 consensus on the proposed action to be taken, through discussion within the PhVWP. 4256

Where appropriate, the RMS should communicate with the Marketing Authorisation Holder on the 4257 reasons for the conclusions reached by the Member State and the action that should be taken by the 4258 Marketing Authorisation Holder. If the Marketing Authorisation Holder does not voluntarily vary, 4259 withdraw or suspend the marketing authorisation, an urgent safety restriction procedure should be 4260 started by the RMS, or a referral according to Directive 2001/83/EC Article 36 to the CHMP should be 4261 initiated (see Chapter II.5). The resulting CHMP Opinion will be followed by a single Decision of the 4262 European Commission binding on all Member States and the Marketing Authorisation Holder. 4263

In urgent cases, any Member State may initiate immediate suspension of the marketing and use of a 4264 medicinal product on its territory, informing all Member States, the European Commission and the 4265 Agency within 24 hours. Such action should preferably be taken in all Member States in a coordinated 4266 manner facilitated by a proposal from the PhVWP to the Competent Authorities of Member States. 4267

For CHMP Opinions according to Article 107(2) of Directive 2001/83/EC, see Chapter II.5. 4268

3.4.2.g Communication to Healthcare Professionals and the Public 4269

When a marketing authorisation is issued, according to Article 21(4) of Directive 2001/83/EC, the 4270 Competent Authorities should make publicly accessible without delay the Assessment Report, together 4271 with the reasons for their opinion, after deletion of any information of a commercially confidential 4272

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nature. In other words the RMS is obliged to prepare a Public Assessment Report (PAR). This PAR 4273 needs to be endorsed by the CMS before release to the public. 4274

Such a PAR needs updating, without delay, once regulatory action in response to a safety concern has 4275 been taken. 4276

In case of a referral to the CHMP, the CHMP Opinion should be made publicly accessible. 4277

In addition it may be appropriate to inform Healthcare Professionals and the public about safety 4278 concerns related to MRP and DP products in other ways (e.g. Direct Healthcare Professional 4279 Communication (DHPC), Public Statements). It is important that consistent information is provided in 4280 all Member States. 4281

In such cases, the RMS should propose the content of the information to be provided, and whenever 4282 possible, this should be agreed by the CMS and, if necessary considered by the PhVWP. There should 4283 be agreement whenever possible, on the method and timing of distribution of the information e.g. by 4284 letters from Marketing Authorisation Holder or Member States’ Competent Authorities, or through 4285 Competent Authorities' bulletins. Agreement should also be reached on the need and timing of Public 4286 Statements and the reaction to press enquiries. 4287

For guidance on pharmacovigilance communication, see Part IV. 4288

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4. Rapid Alert and Non-Urgent Information System in Pharmacovigilance 4289

4.1 Introduction 4290

During the marketing period of a medicinal product, urgent measures to safeguard public health may 4291 be necessary. Within the EU pharmacovigilance system it is essential that information concerning 4292 safety concerns, particularly that which may result in major changes to the marketing authorisation 4293 status or the revocation or withdrawal of a product, is exchanged between the Member States, the 4294 Agency and the European Commission with the appropriate degree of urgency. 4295

Early exchange of information will enable the Competent Authorities of Member States to initiate data 4296 research and seek specialist expertise so that appropriate action may be taken in a coordinated manner 4297 as soon as possible. 4298

To support rapid notification of safety concerns and exchange of information required to take 4299 appropriate action, the Competent Authorities of Member States, the Agency and the European 4300 Commission operate the Rapid Alert/Non-Urgent Information System in accordance with the 4301 procedure laid down in this Chapter. In order to avoid multiplication of effort and to ensure more 4302 efficient resource utilisation of national systems, information during the phase of signal identification 4303 could also be exchanged in order to support informal communication between Member States (pre-4304 signal information exchange). 4305

The purpose of a Rapid Alert (RA) is to alert, with the appropriate degree of urgency, the Competent 4306 Authorities, the Agency and the European Commission about pharmacovigilance data related to 4307 medicinal products, which indicate that action may be needed urgently to protect public health. It is 4308 essential that the communication of such problems occur at an early stage, normally before a decision 4309 is taken in a Member State. 4310

A Non-Urgent Information (NUI) supports the collection and exchange of pharmacovigilance 4311 information between the Competent Authorities and the Agency while it does not fulfil the criteria for 4312 a RA. 4313

In both situations, the safety concern may then be reviewed as follows: 4314

• at the PhVWP on the basis of the Drug Monitor and an Assessment Report if applicable; or 4315 • at the CHMP; or 4316 • within procedures laid down in Article 31, 36 and 37 of Directive 2001/83/EC or Article 20 of 4317

Regulation (EC) No 726/2004. 4318

A RA/NUI should primarily be used to highlight concerns relating to the risk-benefit balance of a 4319 medicinal product authorised according to Directive 2001/83/EC or Regulation (EC) No 726/2004. 4320

It may be also used for sharing information on major findings from pharmacovigilance inspections. 4321

In case of other safety concerns for products not authorised as medicinal products, e.g. herbal 4322 products, chemical products, the system may also be used. 4323

Occasionally, a NUI may be circulated to solicit information on national policies or views on draft 4324 guidance documents or certain organisational matters, in order to prepare discussions of such matters 4325 at the level of the PhVWP. 4326

RAs should not be circulated for the exchange of less urgent information. For this purpose, a NUI 4327 should be used. 4328

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Rapid Alerts regarding quality problems of a medicinal product or specific batches of a medicinal 4329 product are not considered in this Chapter, but guidance for this is available in the Compilation of 4330 Community Procedures on Inspections and Exchange of Information (EMEA/INS/GMP/3351/03/Rev 4331 3 corr) (see http://www.emea.eu.int). However, in cases of an adverse reaction, lack of efficacy, or 4332 suspicion thereof, which are associated with quality issues, liaison with Inspectorate colleagues should 4333 be initiated to assess the safety implications of the quality problem. 4334

4.2 Criteria 4335

4.2.1 Rapid Alert 4336

A RA should be used when a Member State has a safety concern which potentially has as a major 4337 impact on the known risk-benefit balance of a medicinal product and which could warrant prompt 4338 regulatory action and communication to Healthcare Professionals/general public, such as: 4339

• Urgent safety restriction, suspension, revocation or withdrawal of the marketing authorisation 4340 and/or recall of the medicinal product from the market; 4341

• Suspension of use of an unauthorised product; 4342 • Changes in the Summary of Product Characteristics (SPC), e.g.: 4343

• Introduction of new contraindications 4344 • Introduction of new warnings 4345 • Reduction in the recommended dose 4346 • Restriction of the indications 4347 • Restriction in the availability of a medicinal product 4348 • Need to inform Healthcare Professionals or Patients about an identified risk without 4349

delay. 4350

A RA may also be used when there are concerns about a change in the risk-benefit balance of a 4351 medicinal product or an active ingredient, following: 4352

• a series of report(s) of an unexpected and serious adverse reaction; 4353 • reports of an expected adverse reaction which suggest greater severity or long-term sequelae 4354

than previously known, or which identify new risk factors; 4355 • a significant increase in the reporting rate of an expected serious adverse reaction; 4356 • evidence from studies (clinical trials or non-interventional studies) indicative of an unexpected 4357

risk, or a change in frequency or severity of a known risk; 4358 • knowledge that the efficacy of a medicinal product is not established as assumed to date; or 4359 • evidence that the risks of a particular product are greater than alternatives with similar 4360

efficacy. 4361

4.2.2 Non-Urgent Information 4362

A NUI should be used for information exchange in relation to safety concerns not fulfilling the criteria 4363 for a RA as defined above. For example, a NUI should be used to communicate pharmacovigilance 4364 data which do not require immediate or urgent action and/or where additional information is required 4365 from other Member States to support the evaluation of the concern. 4366

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In each case the reason for sending a NUI should be provided, such as: 4367

• Provision of emerging pharmacovigilance information at an early stage; 4368 • Information on a potential new safety signal; 4369 • Information on implementation status; 4370 • Information which might be of interest to other Member States, but does not require a 4371

response (e.g. the withdrawal of a product, the outcome of discussions from national safety 4372 committees, when to expect an Assessment Report on certain items, Public Statements (press 4373 releases), Direct Healthcare Professional Communication, current media activity); 4374

• Request for information; 4375 • Organisational matters; 4376 • Interaction with the US Food and Drug Administration (FDA). 4377

4.3 Procedure 4378

Normally the safety concern identified by one Member State after evaluation of the data available in 4379 that Member State or the receipt of any other relevant important information should be shared with 4380 other Member States, the Agency and the European Commission. This should also include any action 4381 initiated by the Marketing Authorisation Holder(s). 4382

4.3.1 Sending a Rapid Alert or a Non-Urgent Information 4383

In accordance with Article 26 of Regulation (EC) No 726/2004, the Agency, in consultation with 4384 Member States and the European Commission, has set up a data-processing network for the rapid 4385 transmission of data between the EU competent authorities in the event of an alert relating to faulty 4386 manufacture, serious adverse reactions and other pharmacovigilance data regarding medicinal 4387 products marketed in the Community. RAs and NUIs fall under other pharmacovigilance data and use 4388 EudraNet as the data-processing network. 4389

To send a RA or NUI, the established EudraNet RA mailbox (address list "All Human RA") should be 4390 used, which refers to the contact points of the Competent Authorities of Member States, the Agency 4391 and the European Commission. The EudraNet E-mail policy IT-SOP 9724 applies accordingly. 4392

Following successful implementation between the Agency, the Member States and the European 4393 Commission, electronic submission has replaced the telefax system used in the past to exchange this 4394 kind of information. However, in case of emergency, e.g. EudraNet access is not available or there is a 4395 network failure, the former telefax system needs to be maintained and should be used as an alternative. 4396 Changes related to the fax numbers should be notified immediately to the Agency, the European 4397 Commission and the contact points in Member States. The Agency and all Competent Authorities 4398 should dedicate a fax machine to the Rapid Alert/Non-Urgent Information System which allows 4399 storage of the fax numbers and process group dialling. 4400

The electronic communication with partners that are not connected via EudraNet, i.e. the Marketing 4401 Authorisation Holder and WHO, has to be performed in a way that guarantees security and 4402 confidentiality of the data exchanged, e.g. via EudraLink (see https://eudralink.emea.eu.int). 4403

Templates for RAs and NUIs are annexed (see Annexes 5.5, 5.6 and 5.7). These templates are also 4404 available on the EudraNet website (http://www.eudra.org/eudraportal/) and may be accessed via the 4405 established pharmacovigilance domain. 4406

When preparing a RA or NUI, the following rules apply: 4407

• The template (see Annexes 5.5 and 5.6) chosen must comply with the criteria either for a RA 4408 or for a NUI. 4409

• Clear and concise information on the safety concern and reasons for sending the RA or NUI 4410 should be provided so that there is no need for clarification in the first instance. 4411

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a) The product(s) concerned should be identified by the International Non-Proprietary Name (INN). 4412

b) The authorisation status of the product should be specified, i.e. if the product is centrally authorised, 4413 purely nationally authorised, subject to mutual recognition or decentralised or simplified registration 4414 or referral procedure or the nature of the product if not authorised. 4415

c) The Competent Authority generating the RA/NUI should transmit at least the minimum information 4416 listed in Table 1 at the end of this Chapter and use the templates (see Annexes 5.5 and 5.6). 4417

d) Any information required from recipients should be clearly specified, together with the timeframe 4418 for response. 4419

e) Annexes to the RA/NUI, where necessary, should also be transmitted electronically, if available. 4420 The format to be used is the one specified in the EudraNet E-mail policy IT-SOP 9724. In case the 4421 annexes are not available electronically, the form should be completed including a reference that the 4422 referred annexes would be submitted separately via telefax; the form should be sent via the defined 4423 address list to the dedicated mailboxes. A hardcopy of this completed form should be attached to the 4424 faxed annexes. 4425

f) The Rapid Alert and the Non-Urgent Information should be transmitted to the nominated contact 4426 points of the Member States, the Agency, the CHMP Chairperson and the European Commission. In 4427 case of a centrally authorised product, the RA/NUI also needs to be sent to the Rapporteur. In cases 4428 where telefax transmission is used, the fax should be transmitted to the established contact points as 4429 indicated above. 4430

g) The title line in the e-mail message which contains the completed template should: 4431

• first, identify the product(s) concerned by INN, name of the product class or another 4432 appropriate name; 4433

• second, provide a key word identifying the safety concern or other reason for sending the RA 4434 or NUI, using commonly understandable abbreviations (e.g. “GI tox” for gastrointestinal 4435 toxicity); 4436

• third, identify if the message is a RA or NUI; 4437 • fourth, provide the deadline for response if requested. 4438

Title lines would therefore look for example like “INN-GI tox-RA” or “INN-Eye disorder-NUI - by 4439 ddmmyy”. 4440

h) In case of urgency, when the Concerned Member State has suspended the marketing authorisation 4441 of a medicinal product or has withdrawn the medicinal product from the market in order to protect 4442 public health, the Agency, the European Commission and all Competent Authorities in the Members 4443 States should be informed on the following working day at the latest. 4444

i) When a Rapid Alert is circulated 4445

• related to a nationally authorised product, the initiating Member State should inform the 4446 Marketing Authorisation Holder(s) concerned in his country adequately and promptly. 4447 Receiving Member States are responsible for informing Marketing Authorisation Holder(s) in 4448 their own country. Information on the Marketing Authorisation Holder(s) may be given via 4449 Marketing Authorisation Holders associations both in the sending and receiving Member 4450 State. In case of products authorised through the mutual recognition or decentralised 4451 procedure, the Reference Member State should inform the Marketing Authorisation Holder 4452 adequately and promptly. 4453

• related to a centrally authorised product, the Agency in agreement with the Rapporteur will 4454 promptly start an inquiry and information exchange with the Marketing Authorisation 4455 Holder(s). 4456

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• the initiator should consider if it qualifies for informing the World Health Organization 4457 (WHO) in accordance with Chapter II.6. 4458

j) A RA may be used for the preparation and conduct of an urgent safety restriction in line with the 4459 relevant guidance on post-authorisation procedures (for centrally authorised products this is the EMEA 4460 Post-Authorisation Guidance Human Medicinal Products (http://www.emea.eu.int) and for mutually 4461 recognised products this is the Standard Operating Procedure on urgent safety restrictions 4462 (http://heads.medagencies.com). 4463

4.3.2 Responses to a Rapid Alert or Non-Urgent Information 4464

Responses to a RA should be sent to all Member States, the Agency and the European Commission no 4465 later than one week after the receipt of the RA, unless otherwise specified. The initiator of a RA 4466 requesting information has to compile and circulate the compiled RA Responses as quickly as 4467 possible. 4468

In case of a NUI, requested NUI Responses should only be provided to the initiating Competent 4469 Authority and the Agency within the time frame indicated by the initiator, unless otherwise specified. 4470

The title line in the e-mail message which contains the completed response template should identify if 4471 the message is a RA or NUI Response (e.g. “INN-GI tox-RA Response; analogous to Chapter II.4, 4472 Section 3.1, paragraph g). 4473

The template to be used is the "Response to Rapid Alert/Non-Urgent Information" (see Annex 5.7). 4474 The information requested by the initiator of the RA/NUI should be provided. 4475

The Agency will summarise the issues raised in the RAs and NUIs in the Drug Monitor, which will be 4476 discussed and updated at each meeting of the PhVWP. 4477

4.3.3 Assessment of a Rapid Alert 4478

After transmission of the initial RA, an interim Assessment Report should be prepared for the next 4479 meeting of the PhVWP: 4480

• for a purely nationally authorised medicinal product, the initiating Member State, taking into 4481 account all information, including that received and collated from other Member States, 4482 prepares the Assessment Report on the risk-benefit balance; 4483

• for a product authorised through the mutual recognition or decentralised procedure, any risk 4484 evaluation should normally be carried out by the Reference Member State unless other 4485 arrangements are agreed between Member States. In each case agreement needs to be reached 4486 on the responsibility for the management of the RA and the Assessment Report on the risk-4487 benefit balance by the Reference Member State, or initiating Concerned Member State, or 4488 jointly, 4489

• for a centrally authorised product, the Rapporteur should work closely with the initiator of the 4490 RA to provide an assessment in relation to the safety concern. Agreement needs to be reached 4491 in each case on the responsibility for the Assessment Report on the risk-benefit balance, by the 4492 Rapporteur or the initiating Member State, or jointly. 4493

When the collated information provides evidence of a serious safety concern, a full Assessment Report 4494 on the risk-benefit balance should be prepared, for consideration by the PhVWP. 4495

The Assessment Report should be sent to all Competent Authorities in Member States, the Agency and 4496 the European Commission and should be discussed at the next meeting of the PhVWP. 4497

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The Assessment Report should be distributed electronically using the established EudraNet 4498 Pharmacovigilance mailbox (address list "All Human Pharmacovigilance") as indicated in the 4499 EudraNet E-mail policy in the latest version. 4500

Consideration will need to be given to whether the matter is of Community interest and should be 4501 referred under Article 31, 36 and 37 of Directive 2001/83/EC as amended. 4502

4.3.4 Assessment of Non-Urgent Information 4503

On the basis of the Drug Monitor the PhVWP will discuss all topics on which information was 4504 exchanged as a NUI and will agree on a case-by-case basis how to process the safety concern. In the 4505 event that preparation of an Assessment Report is considered necessary, the same assessment 4506 procedure applies as indicated for a RA (see Chapter II.4, Section 3.3). 4507

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4508

4. TABLE: MINIMUM INFORMATION FOR TRANSMISSION OF A RAPID ALERT OR NON-URGENT INFORMATION ALWAYS TO BE PROVIDED

1. Identification

- Type of message <select Rapid Alert/Non-Urgent Information> - Document reference - Initiator - Recipients - Date of message

2. Medicinal Product

- Active substance(s) by INN (and name of class if applicable) - Invented name(s) - Status of the medicinal product <select> � Centrally Authorised Product � Mutual Recognition � Decentralised Product � Simplified Registration Product � Purely Nationally Authorised Product � Product which has been subject to a referral process - Pharmaceutical form and dosage if appropriate - Marketing Authorisation Holder(s) - Manufacturer if essential

3. Reason for the Rapid Alert/Non-Urgent Information

- <select from template>

4. Action(s)

- Action(s) proposed - Action(s) taken (steps taken to collect more information at national level and temporary

measure taken to protect public health)

5. Information Exchange

- Information requested

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5. Referrals in Case of Safety Concerns Related to Products Authorised in the EU 4509 and Commission Decisions Following Suspension or Revocation of a Medicinal 4510 Product by a Member State 4511

Guidance on Community Referrals is provided in Chapter 3 of the Notice to Applicants, Volume 2A 4512 of the Rules Governing Medicinal Products in the EU (http://pharmacos.eudra.org/F2/eudralex/vol-4513 2/home.htm). 4514

Guidance on Opinions issued by the Committee for Medicinal Products for Human Use (CHMP) in 4515 accordance with Article 107(2) of Directive 2001/83/EC following suspension or revocation of a 4516 medicinal product by a Member State and on subsequent Commission Decisions in accordance with 4517 Article 121(3) is provided in <reference to Guideline, subject to separate consultation>. 4518

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6. Principles of Collaboration with the World Health Organization in Matters of 4519 International Pharmacovigilance 4520

6.1 Introduction 4521

As laid down in Article 27 of Regulation (EC) No 726/2004, the Agency shall collaborate with the 4522 World Health Organization (WHO) in matters of international pharmacovigilance and shall submit 4523 promptly to WHO appropriate and adequate information regarding the measures taken in the EU 4524 which may have a bearing on public health protection in countries outside the EU. 4525

In addition, it should be noted that the Agency, in accordance with Article 58 of Regulation (EC) No 4526 726/2004, may give a scientific opinion, in the context of cooperation with WHO, for the evaluation of 4527 certain medicinal products for human use intended exclusively for markets outside the EU. 4528 A guideline on the related procedural aspects is available on the EMEA Website (see 4529 EMEA/CHMP/5579/04 latest version on http://www.emea.eu.int) and addresses the conduct of 4530 pharmacovigilance for such products. 4531

This Chapter describes the principles for providing WHO with pharmacovigilance information on 4532 measures taken for medicinal products in the EU and other collaboration with WHO in the field of 4533 pharmacovigilance15. The Competent Authorities of the EU Member States are members of the WHO 4534 Programme for International Drug Monitoring and should fulfil their membership obligations 4535 accordingly (see also Chapter II.1). The principles below have been agreed between the Competent 4536 Authorities and the Agency at the level of the PhVWP, reflecting their respective roles and 4537 responsibilities as part of the EU pharmacovigilance system for the medicinal products authorised in 4538 the EU. 4539

6.2 Provision of Individual Case Safety Reports 4540

Cases of adverse reactions occurring in the EU should be reported to the WHO Collaborating Centre 4541 by the Competent Authority of the Member State in whose territory the reaction occurred, in 4542 accordance with the agreements between the WHO Collaborating Centre and countries participating in 4543 the WHO Programme for International Drug Monitoring. This applies to adverse reaction case reports 4544 for centrally and non-centrally authorised medicinal products submitted to the Competent Authorities 4545 either by Healthcare Professionals or by the Marketing Authorisation Holders16. 4546

6.3 Review of Signals Raised by the WHO Collaborating Centre 4547

The Competent Authorities in Member States and additionally, for centrally authorised products, the 4548 Agency, should consider the summary document of signals provided by the WHO Collaborating 4549 Centre as feedback information from their case report database Vigibase. This database may be 4550 consulted by all countries participating in the WHO Programme for International Drug Monitoring. 4551

6.4 Provision of Information on Safety-Related Regulatory Action in the EU 4552

a) Centrally Authorised Products 4553

The Agency transmits to WHO EMEA Public Statements on safety-related regulatory action for 4554 centrally authorised products prior to embargo date. The Agency will also transmit any other EMEA 4555 Public Statements concerning centrally authorised products prior to embargo date. 4556 15 Unless otherwise specified below, any information is provided to the WHO Headquarters in Geneva and the WHO Collaborating Centre for International Drug Monitoring in Uppsala, thereafter referred to as WHO Collaborating Centre. 16 Adverse reactions occurring in Luxembourg will be transmitted to the WHO Collaborating Centre by the French Competent Authority.

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The Agency should provide responses to Vigimed17 queries in relation to centrally authorised products 4557 as appropriate. 4558

b) Nationally Authorised Products, including those Authorised through the 4559 Mutual Recognition or the Decentralised Procedure 4560

Information on safety-related regulatory action for purely nationally authorised products will be 4561 transmitted to WHO by the Competent Authority of the Member State if measures related to such 4562 marketing authorisations (restrictive measures, variations, suspension, revocation, withdrawal) are 4563 implemented or a Public Statement or a Direct Healthcare Professional Communication is issued by, 4564 or in agreement, with the Competent Authority. 4565

For products authorised through mutual recognition or the decentralised procedure, the Reference 4566 Member State is responsible for provision of such information on behalf of the Concerned Member 4567 States. 4568

Member States or the Reference Member State respectively should provide responses to Vigimed 4569 queries as appropriate. 4570

In addition, Member States should provide any additional information to WHO for nationally 4571 authorised products according to requirements specified by national legislation and agreements. 4572

Occasionally, the Agency issues EMEA Public Statements on safety-related matters for nationally 4573 authorised products which have been discussed at the level of the CHMP in the context of legal 4574 proceedings as per Community legislation. Such information will also be sent to WHO by the Agency 4575 prior to embargo date. 4576

6.5 Participation in the Annual Meetings of the WHO Programme for 4577 International Drug Monitoring 4578

Member States and the Agency should participate regularly at the Annual Meetings of the WHO 4579 Programme for International Drug Monitoring, contributing appropriately to issues of common 4580 concern and of interest to international pharmacovigilance. 4581

6.6 Other Collaboration 4582

Other collaboration with WHO and their Collaborating Centres will be considered, as need arises, by 4583 the Agency or the Competent Authorities of Member States. 4584

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

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4585

4586

4587

4588

4589

4590

4591

PART III 4592

– Guidelines for Marketing Authorisation Holders, 4593

Competent Authorities and the Agency on 4594

Electronic Exchange of Pharmacovigilance Information in the EU – 4595

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1. Introduction 4596

The revision of Volume 9, Chapter III reflects the requirements for mandatory electronic reporting of 4597 adverse reactions, save in exceptional circumstances, as defined in Regulation (EC) No. 726/2004 and 4598 Directive 2001/83/EC. 4599

Volume 9A, Part III has been updated to incorporate: 4600

• All applicable ICH Guidelines and standards for electronic reporting of Individual Case Safety 4601 Reports (i.e. ICH E2A, E2B(M), E2C, E2D, M1, M2; see Annex 4). 4602

• The ‘Note for Guidance on the Electronic Data Interchange (EDI) of Individual Case Safety 4603 Reports (ICSRs) and Medicinal Product Reports (MPRs) in pharmacovigilance during the pre- 4604 and post- authorisation phase in the European Economic Area (EEA)’ (EMEA/115735/2004) 4605 (adopted at Community level in September 2004). 4606

• The EMEA Guidance ‘Technical Documentation – EudraVigilance Human Version 7.0 4607 Processing of Safety Messages and ICSRs’ (EMEA/H/20665/04) (adopted at Community 4608 level in July 2004). 4609

• ‘Detailed guidance on the European database of Suspected Unexpected Serious Adverse 4610 Reactions (EudraVigilance – Clinical Trial Module), (ENTR/CT4, Revision 1, adopted at 4611 Community level in April 2004). 4612

• The recommendations of the EudraVigilance Ad Hoc Group and EMEA proposal as endorsed 4613 by the Heads of Medicines Agencies in February 2005 and the EMEA Management Board in 4614 March 2005. 4615

Volume 9A, Part III replaces: 4616

• Note for Guidance on Electronic Exchange of Pharmacovigilance Information for Human and 4617 Veterinary Medicinal Products in the European Union (CXMP/PhVWP/2056/99). 4618

• Note for Guidance on Regulatory Electronic Transmission of Individual Case Safety Reports 4619 (ICSRs) in Pharmacovigilance (EMEA/H/31387/01). 4620

The mandatory electronic reporting of adverse reactions, save in exceptional circumstances, is defined 4621 in Regulation (EC) No. 726/2004 and Directive 2001/83/EC and applies to all medicinal products 4622 authorised in the European Economic Area (EEA), independent of the authorisation procedure. 4623

Part III of Volume 9A refers to the electronic exchange of pharmacovigilance information and 4624 provides a reference to the preparation and electronic transmission of Individual Case Safety Reports 4625 (ICSRs). It applies to national Competent Authorities , the European Medicines Agency (hereafter 4626 referred to as the Agency) and Marketing Authorisation Holders in the EEA. 4627

The standards to support the electronic transmission of ICSRs on an expedited and periodic basis are 4628 defined in the frame of the International Conference of Harmonisation of Technical Requirements for 4629 Registration of Pharmaceuticals for Human Use (referred to as ICH). 4630

Taking into account the international dimension of adverse reaction reporting and the need to achieve 4631 uniformity and high quality with regard to content and format of ICSRs between all involved parties it 4632 is of utmost importance that all parties follow the applicable ICH and Community guidelines. This 4633 applies in particular to electronic reporting, which requires strict adherence to uniform standards. 4634

The electronic reporting obligations of ICSRs on an expedited and periodic basis are defined in 4635 Community legislation and refer to the following electronic data interchange (EDI) partners: 4636 Competent Authorities in Member States as well as Iceland, Liechtenstein and Norway, Marketing 4637 Authorisation Holders and the Agency. 4638

PART III 138/198

To support the fulfilment of these electronic reporting obligations, the European Commission, in 4639 collaboration with the Agency established EudraVigilance, the European pharmacovigilance database 4640 and data-processing network as defined in Regulation (EC) No. 726/2004, Article 26 and Article 57, 4641 paragraph d with the following main objectives: 4642

• Assist the rapid and secure transmission of ICSRs between all EDI partners, 4643 • Fully comply with the respective ICH and Community guidelines and standards as outlined in 4644

chapter 0, 4645 • Facilitate the electronic reporting by providing the necessary technical tools to the EDI 4646

partners, 4647 • Assist the administration and management of ICSRs, 4648 • Provide signal detection functionalities and support scientific evaluation of ICSRs, 4649 • Establish a central repository of highest quality data on electronically reported adverse 4650

reactions occurring within and outside the Community. 4651

2. Applicable Electronic Reporting Standards 4652

The electronic transmission and management of ICSRs will be carried out by all EDI parties according 4653 to the following guidelines and specifications: 4654

• The ICH E2A guideline ‘Clinical Data Management: Definition and the Standards for 4655 Expedited Reporting’, which presents the standard definitions and terminology for key aspects 4656 of clinical safety reporting and provides guidance on the appropriate mechanism for handling 4657 expedited reporting in the investigational phase. 4658

• The ICH E2B(M) guideline ‘Maintenance of the ICH guideline on clinical safety data 4659 management: data elements for transmission of Individual Case Safety Reports E2B(M). 4660 Recommended for Adoption at Step 4 of the ICH Process on 17 July 1997 and amended for 4661 Maintenance on 10 November 2000 by the ICH Steering Committee (Including the Post Step 4 4662 corrections agreed by the Steering Committee on 5 February 2001) CPMP/ICH/287/95 4663 modification corr.’, which extends the above guideline to standardise the data elements for the 4664 transmission of all types of ICSRs, regardless of their source and destination. 4665

• The ICH E2B(M) ‘Implementation Working Group Questions & Answers’, Version 1.1, 3 4666 March 2005. 4667

• The ICH E2C guideline ‘Clinical Safety Data Management: Periodic Safety Update Reports 4668 for Marketed Drugs’, CPMP/ICH/288/95 and addendum CPMP/ICH/4679/02, which provides 4669 guidance on the format and content of safety updates, which need to be provided to regulatory 4670 authorities, at defined intervals, after the medicinal products have been authorised. 4671

• The ICH E2D guideline ‘Post-Approval Safety Data Management: Definitions and Standards 4672 for Expedited Reporting’, November 2003 CPMP/ICH/3945/03, which provides further 4673 guidance on definitions and standards for post approval expedited reporting, as well as good 4674 case management practices. 4675

• The ICH M1 standard ‘Medical Dictionary for Regulatory Activities (MedDRA)’ in the latest 4676 version and related guidelines and Points to Consider documents. The MedDRA terminology 4677 is designed to support the classification, retrieval, presentation and communication of medical 4678 information throughout the medicinal product regulatory life cycle. 4679

• The ICH M2 standard ‘Electronic Transmission of Individual Case Safety Reports Message 4680 Specification (ICH ICSR DTD Version 2.1)’ CHMP/ICH/285/95 modification, which provides 4681 the standards for the safety messages, which can contain one or more ICSRs. 4682

• The ICH M2 Recommendations: 4683 • EWG M2 Recommendation to the ICH Steering Committee Electronic Standards for the 4684

Transfer for the Regulatory Information (ESTRI) General Recommendation – Procedure 4685 (10NOV2005) 4686

PART III 139/198

• EWG M2 Recommendation to the ICH Steering Committee Electronic Standards for the 4687 Transfer of Regulatory Information (ESTRI) General Recommendation – ESTRI 4688 Gateway (10NOV2005) 4689

• EWG M2 Recommendation to the ICH Steering Committee Electronic Standards for the 4690 Transfer of Regulatory Information (ESTRI) Physical Media Recommendation – Floppy 4691 Disks (10NOV2005) 4692

• EWG M2 Recommendation to the ICH Steering Committee Electronic Standards for the 4693 Transfer of Regulatory Information (ESTRI) Physical Media Recommendation – CD-R 4694 10NOV2005 4695

• EWG M2 Recommendation to the ICH Steering Committee Electronic Standards for the 4696 Transfer of Regulatory Information (ESTRI) Physical Media Recommendation – DVD-4697 RAM 10NOV2005 4698

• EWG M2 Recommendation to the ICH Steering Committee Electronic Standards for the 4699 Transfer of Regulatory Information (ESTRI) File Format Recommendation - PDF 4700 10NOV2005 4701

• EWG M2 Recommendation to the ICH Steering Committee Electronic Standards for the 4702 Transfer of Regulatory Information (ESTRI) File Format Recommendation – XML 4703 10NOV2005 4704

• EWG M2 Recommendation to the ICH Steering Committee Electronic Standards for the 4705 Transfer of Regulatory Information (ESTRI) Information Transfer Recommendation - 4706 EDIINT AS1 10NOV2005 4707

• The ICH M5 EWG ‘Routes of Administration Controlled Vocabulary’, 4708 CPMP/ICH/175860/2005, which provides standard terms for routes of administration. 4709

• The ICH M5 EWG ‘Units and Measurement Controlled Vocabulary’, 4710 EMEA/CHMP/ICH/175818/2005, which provides standard terms for units and measurements. 4711

• The Standard Terms on Pharmaceutical Dosage Forms as published by the Council of Europe 4712 as ‘Standard Terms on Pharmaceutical Dosage Forms, Routes of Administration and 4713 Containers’ in the latest version. 4714

• The ‘Note for Guidance on the Electronic Data Interchange (EDI) of Individual Case Safety 4715 Reports (ICSRs) and Medicinal Product Reports (MPRs) in pharmacovigilance during the pre- 4716 and post- authorisation phase in the European Economic Area (EEA)’, (EMEA/115735/2004) 4717 (adopted at Community level in September 2004). 4718

• The EMEA guidance ‘Technical Documentation – EudraVigilance Human Version 7.0 4719 Processing of Safety Messages and ICSRs’, (EMEA/H/20665/04) (adopted at Community 4720 level in July 2004). 4721

• ‘Detailed guidance on the European database of Suspected Unexpected Serious Adverse 4722 Reactions (EudraVigilance – Clinical Trial Module), (ENTR/CT4, Revision 1, April 2004). 4723

As technical standards are evolving over time, the above reference documents may require revision 4724 and maintenance. In this context, the latest version of these documents should always be taken into 4725 account. 4726

For general terms and definitions reference should be made to the documents listed in chapter. 4727

3. Message Format and Message Processing Rules 4728

Safety Messages including one or several ICSRs need to follow the specifications as outlined in the 4729 ‘Technical Documentation – EudraVigilance Human Version 7.0 Processing of Safety Messages and 4730 ICSRs’ (EMEA/H/20665/04). 4731

PART III 140/198

Medicinal Product Messages including one or several medicinal product reports need to follow the 4732 specifications as outlined in the 4733

• EudraVigilance Medicinal Product Dictionary (EVMPD) Version 2.0 Technical 4734 Specifications, 9 November 2004 (EMEA/140190/2004) and the 4735

• EudraVigilance Medicinal Product Dictionary (EVMPD) Version 2.0 Message and 4736 Acknowledgement Specifications, 8 December 2004 (EMEA/178966/2004). 4737

For details refer also to Chapter III.11, Section 9. 4738

With regard to the Safety and Medicinal Product Report Message processing, the specifications as 4739 outlined in the ‘Note for guidance on the electronic data interchange (EDI) of individual case safety 4740 reports (ICSRs) and medicinal product reports (MPRs) in pharmacovigilance during the pre- and post- 4741 authorisation phase in the European Economic Area (EEA)’ (EMEA/115735/2004) need to be 4742 followed. 4743

4. Definition of ‘Exceptional Circumstances’ 4744

Technical tools (EVWEB) have been made available by the Agency to interested EDI partners, 4745 specifically Small and Medium Size Enterprises (SMEs), to facilitate compliance with the electronic 4746 reporting requirements as defined in Community legislation. 4747

With regard to the provisions set out in Regulation (EC) No. 726/2004, Article 24(2) and Directive 4748 2001/83/EC, Article 104(1), ‘exceptional circumstances’ are defined as mechanical, programme, 4749 electronic or communication failures that prevent electronic reporting as described in chapter IV of the 4750 ‘Note for Guidance on the Electronic Data Interchange (EDI) of Individual Case Safety Reports 4751 (ICSRs) and Medicinal Product Reports (MPRs) in pharmacovigilance during the pre- and post- 4752 authorisation phase in the European Economic Area (EEA)’ (EMEA/115735/2004). 4753

5. Preparation of Individual Case Safety Reports (ICSRs) 4754

All medical and administrative data, required to comply with the ICH E2A, E2B(M), ICH E2D, ICH 4755 M1, ICH M2 and Community guidelines and standards as referred to in Chapter III.2 should be 4756 reported electronically in a fully structured format. 4757

Any supporting information related to the case should be sufficiently described within an ICSR with 4758 reference to the documents that are held by the sender (ICH A.1.8.2: ‘List of documents held by 4759 sender’), which may need to be provided on request. 4760

It is recognised that it is often difficult to obtain all details on a specific case. However, the complete 4761 information for an individual case, that is available to the sender, has to be reported in each ICSR. 4762 This applies to all types of ICSRs, i.e. reports with initial information on the case, follow-up 4763 information and cases highlighted for nullification (ICH E2B(M) A.1.13: ‘Report nullification’ set to 4764 ‘yes’ and ICH E2B(M) A.1.13.1: ‘Reason for nullification’ completed). 4765

The information available should always be reported in a fully structured format using all the relevant 4766 E2B(M) data elements and the applicable standard terminology. 4767

In accordance with the international guideline in pharmacovigilance (ICH E2D), a case narrative, i.e. a 4768 complete medical description of the case (ICH E2B(M) B.5.1: ‘Case narrative including clinical 4769 course, therapeutic measures, outcome and additional relevant information’) should be provided at 4770 least for all serious cases. This case narrative should be a medical report containing all known relevant 4771 clinical and related information, including patient characteristics, therapy details, medical history, 4772 clinical course of the event(s), diagnosis, adverse drug reactions (ADR(s)) including the outcome, 4773

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laboratory evidence (including normal ranges) and any other information that supports or refutes an 4774 ADR. The narrative should serve as a comprehensive, stand-alone “medical report”. 4775

It was agreed by Heads of Medicines Agencies18 that Competent Authorities in Member States as well 4776 as Iceland, Liechtenstein and Norway should also provide such case narratives if provided by a health 4777 care professional, the Marketing Authorisation Holder or any other source. The complete information 4778 on the case should always be provided by the Competent Authorities in full compliance with ICH 4779 E2B(M), M1, M2 and Community guidelines and standards. 4780

The use of Community languages in adverse reaction reporting is described in Chapter III.11, 4781 Section 8 and Chapter I.4. 4782

6. Handling of Copies of Articles Published in the Worldwide Literature 4783

When reports from the world-wide literature (ICH E2B(M) A.2.2) are submitted as ICSRs, copies of 4784 the literature article along with the translation in English (where applicable) should be provided to the 4785 Agency and Competent Authorities in Member States as well as Iceland, Liechtenstein and Norway in 4786 line with the reporting rules as defined in Chapter I.4, Section 3.2. 4787

Until standards for the electronic transmission of attachments (e.g. copies of literature articles) are 4788 developed in the frame of ICH, the sender should follow the rules outlined below: 4789

• Literature articles reportable to the Agency should be provided in PDF format with the file 4790 name identical to the worldwide case identifier (ICH E2B(M) A.1.10) reported in the ICSR 4791 and sent via e-mail to the following e-mail address: EVLIT@emea.eu.int 4792

• Literature articles reportable to Competent Authorities in Member States as well as Iceland, 4793 Liechtenstein and Norway should be reported as paper copies to the Competent Authorities. 4794

7. Compliance with Required Reporting Timeframes 4795

Marketing Authorisation Holders and Competent Authorities in Member States as well as Iceland, 4796 Liechtenstein and Norway should ensure that the timeframes regarding the expedited reporting 4797 requirements as defined in Community legislation and in Chapters I.4, Section 2 and I.6, Section 2.4 4798 are adhered to. 4799

Fall-back procedures in case of system failure for electronic case reporting are described in the ‘Note 4800 for Guidance on the Electronic Data Interchange (EDI) of Individual Case Safety Reports (ICSRs) and 4801 Medicinal Product Reports (MPRs) in Pharmacovigilance during the Pre -and Post-authorisation Phase 4802 in the European Economic Area (EEA)’. 4803

8. Electronic Re-transmission of Cases between Multiple Senders and Receivers 4804

The electronic re-transmission of cases refers to the electronic transmission of ICSRs between 4805 multiple senders and receivers, e.g. where a case was first reported by a Marketing Authorisation 4806 Holder to the Competent Authorities in Member States as well as Iceland, Liechtenstein and Norway 4807 and from there to the Agency. 4808

Based on the reporting obligations in pharmacovigilance, ICSRs are re-transmitted between different 4809 senders and receivers. During this re-transmission process, information on the case should not be 4810 omitted or changed if no new information on the case is available to the re-transmitting sender. 4811

Exceptions are the following: 4812

18 Heads of Medicines Agencies Meeting, 24 February 2005; EMEA Management Board Meeting March 2005

PART III 142/198

• ‘Sender’s (case) safety report unique identifier’ (ICH E2B(M) A.1.0.1) 4813 • ‘Date of this transmission’ (ICH E2B(M) A.1.3) 4814 • ‘Date report was first received from source’ (ICH E2B(M) A.1.6) for initial reports 4815 • ‘Date of receipt of the most recent information for this report’ (ICH E2B(M) A.1.7) 4816 • Sender and receiver details (ICH E2B(M) A.3: ‘Information on sender and receiver of case 4817

safety report’) 4818 • Sender’s comments (ICH E2B(M) B.5.4: ‘Sender's comments’) and the 4819 • English translation of the free text fields in the ICSRs. 4820

In addition, any EDI partner should adhere to the ICH E2B(M) rules regarding the provision of 4821 follow-up information, i.e. the ‘Worldwide unique case identification number’ (ICH E2B(M) A.1.10) 4822 should be maintained in accordance with the ICH E2B(M) guideline. Non-adherence to these 4823 administrative requirements endangers the electronic case management, leads to unnecessary 4824 duplication of reports at the receiver’s database and should therefore be avoided. 4825

9. Electronic Reporting through Company’s Headquarters 4826

The Marketing Authorisation Holder’s Qualified Person (QP) responsible for pharmacovigilance 4827 should ensure that all ICSRs are submitted electronically to the relevant Competent Authorities in 4828 Member States as well as Iceland, Liechtenstein and Norway and the Agency in line with the reporting 4829 rules defined in Community legislation. If a pharmaceutical company decides to centralise the 4830 electronic reporting of the ICSRs (e.g. reporting through the company’s headquarter), it is the 4831 Marketing Authorisation Holder’s (e.g. the local affiliate) responsibility to ensure that ICSRs are 4832 submitted electronically to the Competent Authority as applicable. 4833

The following should be taken into account: 4834

• The arrangement should be clearly specified in the Marketing Authorisation Holder’s internal 4835 Standard Operating Procedures (SOPs). 4836

• The Agency and the Competent Authorities in the EEA should be notified in writing about the 4837 arrangement (a template is available at the EudraVigilance website). 4838

• The Marketing Authorisation Holder should be registered with EudraVigilance. 4839 • Whoever is the physical sender of the electronic ICSRs, the Marketing Authorisation Holder 4840

in the country will remain the contact point for all pharmacovigilance related matters and 4841 responsible for the compliance with the pharmacovigilance obligations as defined in 4842 Community legislation. 4843

For the reporting from the Competent Authorities in the EEA to the Marketing Authorisation Holder, 4844 the same principles apply, i.e. Competent Authorities in Member States as well as Iceland, 4845 Liechtenstein and Norway report electronically to the address of the headquarter instead of that of the 4846 local affiliate. 4847

10. Interim Electronic Reporting Measures by Regulatory and Industry Stakeholders 4848

By 20 November 2005, when electronic reporting, save in exceptional circumstances, is mandatory for 4849 all authorised medicinal products in the Community, Competent Authorities in the EEA and 4850 Marketing Authorisation Holders, who are not in the position to report electronically in accordance 4851 with ICH E2B(M), should use the EudraVigilance web application, EVWEB or any other system fully 4852 compliant with the ICH and Community guidelines and standards as well as the principles described in 4853 this Part (Volume 9A, Part III), to report electronically all EU and non-EU related ICSRs. 4854

In accordance with Community legislation, the Competent Authorities in the EEA are responsible for 4855 electronic provision of adverse reactions occurring within their respective territory to EudraVigilance. 4856

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11. Specific Provisions for the Electronic Reporting to EudraVigilance 4857

11.1 EudraVigilance Database Modules 4858

On the basis of the requirements defined in Community legislation to set up a data-processing network 4859 and a pharmacovigilance database as described in Chapter III.1, two EudraVigilance modules for 4860 medicinal products for human use were established to address the collection of the different types of 4861 adverse reactions reportable in the frame of the EU pharmacovigilance activities. 4862

These modules are as follows: 4863

• EudraVigilance Clinical Trial Module (EVCTM) (in line with the requirements defined in 4864 Directive 2001/20/EC and implementing texts). 4865

• EudraVigilance Post-Authorisation Module (EVPM) (in line with the requirements as defined 4866 in Regulation (EC) No. 726/2004, Directive 2001/83/EC and Community guidelines). 4867

11.2 Data Collected in EudraVigilance 4868

Different types of adverse reaction data related to all medicinal products authorised in the EU – 4869 independent of the authorisation procedure- are currently collected in EudraVigilance based on the 4870 reporting obligations of Competent Authorities in the EEA and of Marketing Authorisation Holders. 4871 These data are collected in the EudraVigilance Post-Authorisation Module. 4872

In addition, adverse reaction data, suspected unexpected serious adverse reactions (SUSARs) that 4873 occur in clinical trials conducted in the EU, are collected in the EudraVigilance Clinical Trial Module. 4874

11.2.1 Adverse Reaction Data Collected in EVPM 4875

Marketing Authorisation Holders report to the Agency in accordance with Regulation (EC) No. 4876 726/2004, Article 24(1) and (2): 4877

• All suspected serious unexpected adverse reactions occurring in the territory of a third 4878 country; 4879

• Any suspected transmission via a medicinal product of any infectious agent occurring in the 4880 territory of a third country; 4881

• Any other suspected serious adverse reactions occurring within the Community and not 4882 directly reported by a health care professional (e.g. literature reports). 4883

In addition, Marketing Authorisation Holders report to the Agency in accordance with Directive 4884 2001/83/EC Article 104(4): 4885

• All suspected serious unexpected adverse reactions occurring in the territory of a third 4886 country; 4887

• Any suspected transmission via a medicinal product of any infectious agent occurring in the 4888 territory of a third country. 4889

Competent Authorities in Member States as well as Iceland, Liechtenstein and Norway report to the 4890 Agency in accordance with Regulation (EC) No. 726/2004(25): 4891

• Suspected serious adverse reactions that have taken place on their territory. 4892

In addition, Competent Authorities in Member States as well as Iceland, Liechtenstein and Norway 4893 report to the Agency in accordance with Directive 2001/83/EC as amended, Article, 105(3): 4894

• Suspected serious adverse reactions that have taken place on their territory 4895

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With regard to further details of the reporting requirements, please refer to Chapter I.4, Part II and 4896 Chapter III.11, Section 4. 4897

Furthermore, sponsors of clinical trials, report in accordance with Directive 2001/20/EC, Article 17 4898 and the ‘Detailed guidance on the European database of a Suspected Unexpected Serious Adverse 4899 Reactions (EudraVigilance – Clinical Trial Module)’ (ENTR/CT4, Revision 1, April 2004): 4900

• Suspected Unexpected Serious Adverse Reactions related to spontaneous reports; 4901

• Suspected Unexpected Serious Adverse Reactions arising from organised data collection 4902 systems other than interventional clinical trials. 4903

11.2.2 Adverse Reaction Data Collected in EVCTM 4904

In accordance with Directive 2001/20/EC, Article 17(3)(a), Competent Authorities in Member States 4905 as well as Iceland, Liechtenstein and Norway shall see to it that 4906

• All suspected unexpected serious adverse reactions (SUSARs) to an investigational medicinal 4907 product are entered in EVCTM (i.e. taking place on their territory or on the territory of a third 4908 country). 4909

Furthermore, sponsors of clinical trials, report in accordance with Directive 2001/20/EC, Article 17 4910 and the ‘Detailed guidance on the European database of a Suspected Unexpected Serious Adverse 4911 Reactions (EudraVigilance – Clinical Trial Module)’ (ENTR/CT4, Revision 1, April 2004): 4912

• Suspected Unexpected Serious Adverse Reactions related to interventional clinical trials 4913 (phase I-IV). 4914

11.3 Data Quality of ICSRs Transmitted Electronically 4915

EudraVigilance should contain all reports of adverse reactions reportable according to Community 4916 legislation to support the pharmacovigilance activities and European risk management strategy. This 4917 applies to all medicinal products, i.e. investigational medicinal products (IMPs) or authorised 4918 medicinal products regardless of the authorisation procedure. 4919

In addition, EudraVigilance should be based on the highest internationally recognised data quality 4920 standards including those outlined in the report of the CIOMS Working Group V ‘Current Challenges 4921 in Pharmacovigilance: Pragmatic Approaches’. 4922

To achieve these objectives, all Competent Authorities in Member States as well as Iceland, 4923 Liechtenstein and Norway 19 and Marketing Authorisation Holders should fully adhere to 4924

• The electronic reporting requirements as defined in Community legislation; 4925

• The concepts of data structuring, coding and reporting in line with the guidelines and 4926 standards referred to in Chapter III.2 and the principles outlined in Chapters III.3 to III.10. 4927

This is a pre-requisite to establish a properly functioning European pharmacovigilance system 4928 (EudraVigilance) intended to support the European risk management strategy. 4929

11.4 Reporting of all Serious Cases from outside the EEA 4930

For non-centrally approved medicinal products, Marketing Authorisation Holders experience problems 4931 to determine the expectedness for serious cases from outside the EEA and to decide if the case is 4932

19 With the exception specified in Chapter III.5 related to the decision of the Heads of Medicines Agencies.

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reportable to the Agency. This is due to the fact that for nationally approved medicinal products the 4933 SPCs vary in the different Member States. 4934

To facilitate the process of determining the expectedness of adverse reactions based on different SPCs 4935 in Member States, Marketing Authorisation Holders are requested to report for nationally authorised 4936 medicinal products, electronically all suspected serious adverse reactions that occur in a third country 4937 to EudraVigilance. 4938

To achieve a consistent set of reports (suspected serious adverse reactions that occur in a third 4939 country) for all medicinal products, regardless of the authorisation procedure, Marketing Authorisation 4940 Holders are also requested to follow this approach for medicinal products authorised through the 4941 centralised, decentralised or mutual recognition procedures. According to the current Community 4942 legislation, the Marketing Authorisation Holder is required to report all suspected serious unexpected 4943 adverse reactions that occur in third countries on an expedited basis to the Agency and to all 4944 Competent Authorities in Member States as well as Iceland, Liechtenstein and Norway where the 4945 medicinal product is authorised. Since these data are accessible in EudraVigilance for all Competent 4946 Authorities in Member States as well as Iceland, Liechtenstein and Norway, Competent Authorities 4947 may advise the Marketing Authorisation Holders to electronically transmit all third country reports 4948 only to EudraVigilance. A list of those Competent Authorities, which do not require receipt of third 4949 country reports that have been reported electronically to EudraVigilance by Marketing Authorisation 4950 Holders is published on the EudraVigilance website. 4951

11.5 Retrospective Electronic Population of EudraVigilance 4952

The back-population of EudraVigilance has to be seen in the light of the best collaborative effort 4953 between all involved stakeholders to support the European risk management strategy and the 4954 protection of public health. It is an attempt to retrospectively populate the system electronically with 4955 the ICSRs that were reportable to the Agency in line with Community legislation since 1 January 4956 199520 (the date when the Agency was established). Furthermore, the back-population of 4957 EudraVigilance is considered vital in the context of Article 28 of Regulation (EC) No 726/2004. 4958

A phased approach should be followed with the retrospective back-population of EudraVigilance 4959 taking into account: 4960

• To start with ICSRs that occurred since 1st January 1995 related to centrally authorised 4961 medicinal products and mutually recognised medicinal products and as a next step to continue 4962 with ICSRs related to other nationally authorised products, and 4963

• All serious cases from within or outside the Community without the need to reassess 4964 expectedness according to the current Summary of Product Characteristics, and 4965

• The most recent version of the case report. 4966

The standard for the retrospective electronic population of EudraVigilance is a common core set of 4967 data based on the fields of the CIOMS I form in accordance with the applicable ICH standards and 4968 guidelines referred to in Chapter II.2. A mapping of the CIOMS I form to the applicable ICH E2B(M) 4969 data elements is provided in Chapter III.11, Section 6. 4970

The technical specifications regarding the retrospective transmission rules are described in 4971 Chapter III.11, Section 7. 4972

In this context it needs to be recognized that the back populated data may vary from the original 4973 information submitted on an expedited basis in accordance with Community legislation at the time the 4974 case was initially reported, for example as part of the conversion of the legacy data to the ICH 4975 20 Regulation (EC) No 726/2004 and Directive 2001/83/EC

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E2B(M) and M1 standards. As a result, the data submitted retrospectively to back populate 4976 EudraVigilance should not be used for retrospective pharmacovigilance inspections and checking of 4977 previous reporting compliance. 4978

The responsibilities related to the collaborative effort to back populate EudraVigilance are as follows: 4979

• Competent Authorities in Member States as well as Iceland, Liechtenstein and Norway should 4980 provide all serious cases that occurred in their territory. Where no electronic reports or only 4981 limited data are available in structured format by Competent Authorities, those Competent 4982 Authorities should see to it that the data are entered in EudraVigilance. 4983

• Marketing Authorisation Holders should provide all serious cases that occurred outside the 4984 EEA. 4985

• With regard to the new Member States, Marketing Authorisation Holders should provide all 4986 serious cases for the period 1st January 1995 to 1st May 2004. 4987

• The handling of Community languages should follow the recommendations outlined in 4988 Chapter III.11, Section 8. 4989

• ICSRs already reported electronically to EudraVigilance (EudraVigilance Clinical Trial 4990 Module or EudraVigilance Post-Authorisation Module) should not be included as part of the 4991 retrospective population of EudraVigilance. 4992

• All Marketing Authorisation Holders and Competent Authorities in Member States as well as 4993 Iceland, Liechtenstein and Norway should take the necessary steps to ensure that complete 4994 retrospective population of EudraVigilance is completed no later than 20 November 2006. 4995

11.6 Mapping of the CIOMS I Form to the Applicable ICH E2B(M) Data 4996 Elements and Technical Specifications 4997

This Chapter refers to the mapping of the CIOMS I form to the applicable ICH E2B(M) data elements 4998 as referred to in Chapter III.11, Section 5. The standard for the retrospective electronic population of 4999 EudraVigilance is a common core set of data based on the fields of the CIOMS I form in accordance 5000 with the applicable ICH standards and guidelines referred to Chapter III.2, for which a mapping is 5001 provided in Table 1. The principles as outlined in Chapter III.5 apply accordingly. 5002

11. TABLE 1: STANDARD FOR THE ELECTRONIC PROVISION OF RETROSPECTIVE ICSR DATA IN LINE WITH 5003 CIOMS I AND E2B(M) DATA ELEMENTS 5004

CIOMS I Field E2B(M) Data Element Comments

B.1.1 ‘Patient Initial’

1. Patient

B.1.1.1 ‘Patient medical record number(s) and the source(s) of the record number (if allowable)’

In case a patient identification number is available this information should be reported in the field B.1.1.1.

1a. Country A.1.1 ‘Identification of the country of the primary source’

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CIOMS I Field E2B(M) Data Element Comments

B.1.2.1a ‘Date of Birth’ format’

2. DOB (Date of Birth)

B.1.2.1b ‘Date of Birth’

B.1.2.2a ‘Age value’

B.1.2.2b ‘Age unit’

2a. Age

B.1.2.3 ‘Patient age group (as per reporter)’

If the age is not available at least the age group should be provided in B.1.2.3 if known

3. Sex B.1.5 ‘Patient Sex’

4. Weight B.1.3 ‘Weight (Kg)’

5. Height B.1.4 ‘Height (cm)’

B.2.i.4a ‘Date of start of reaction/event’ format

6. Reaction onset

B.2.i.4b ‘Date of start of reaction/event’

If known, the start date for each reaction should be reported.

7. Describe Reaction(s)

Verbatim term B.2.i.0 ‘Reaction/event as reported by the primary source’

Reaction/Event (MedDRA LLT)

B.2.i.1 ‘Reaction/event in MedDRA terminology (Lowest Level Term)’

THE REACTION MUST BE REPORTED IN MEDDRA VERSION 4.0 OR SUPERIOR

Outcome of Reaction/Event

B.2.i.8 ‘Outcome of reaction/event at the time of last observation’

Narrative B.5.1 ‘Case narrative including clinical course, therapeutic measures, outcome and additional relevant information’

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CIOMS I Field E2B(M) Data Element Comments

B.5.2 ‘Reporter's comments’

B.5.3 ‘Sender's diagnosis/syndrome and/or reclassification of reaction/event’

B.5.4 ‘Sender's comments’

8. Seriousness A.1.5.1. ‘Serious’ -Yes/no

Patient died A.1.5.2. ‘Seriousness criteria (more than one can be chosen)’ Results in death

Involved or prolonged inpatient hospitalisation

A.1.5.2. ‘Seriousness criteria (more than one can be chosen)’ Requires inpatient hospitalization or prolongation of existing hospitalization

Involved persistence or significant disability or incapacity

A.1.5.2. ‘Seriousness criteria (more than one can be chosen)’ Results in persistent or significant disability/incapacity (as per reporter's opinion)

Life threatening A.1.5.2. ‘Seriousness criteria (more than one can be chosen)’ Is life-threatening

Congenital anomaly/ Birth defect

A.1.5.2. ‘Seriousness criteria (more than one can be chosen)’ Is a congenital anomaly/birth defect

Other medically important event

A.1.5.2. ‘Seriousness criteria (more than one can be chosen)’

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CIOMS I Field E2B(M) Data Element Comments

Other medically important condition B.4.k.2.1 ‘Proprietary medicinal product name’ B.4.k.2.2 ‘Active substance name(s)’

14. Suspect Drug

B.4.k.1 ‘Characterization of drug role must be set as “suspect”

Reporting the suspect drug the field B.4.k.1 Characterization of drug role should be set as “suspect”

B.4.k.6 ‘Dosage text

B.4.k.5 ‘Structured Dosage Information’ B.4.k.5.1 ‘dose (number)’

B.4.k.5.2 ‘dose (unit)’ B.4.k.5.3 ‘number of separate dosages’ B.4.k.5.4 ‘number of units in the interval’

B.4.k.5.5 ‘definition of the interval unit’ B.4.k.5.6 ‘cumulative dose to first reaction (number)’ B.4.k.5.7 ‘cumulative dose to first reaction (unit)’

15. Daily dose

B.4.k.6 Dosage text

16. Route of administration B.4.k.8 ‘Route of administration’

17. Indication for use B.4.k.11.a ‘MedDRA version for indication’ B.4.k.11.b ‘Indication for use in the case’

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CIOMS I Field E2B(M) Data Element Comments

B.4.k.12a ‘Date of start of drug’ format

18. Therapy dates

B.4.k.12b ‘Date of start of drug’

B.4.k.15a ‘Duration of drug administration’ format

B.4.k.15b ‘Duration of drug administration’

B.4.k.14a ‘Date of last administration’ format

19. Therapy duration

B.4.k.14 ‘Date of last administration’

In case the date of stop of drug administration is available it should be reported in B.4.k.14a/ B.4.k.14b

Not in CIOMS I B.4.k.16 ‘Action taken with the drug’

If this information is available in the sender’s database this info should be provided

21. Did reaction reappear after reintroduction

B.4.k.17.1 ‘Did the reaction recur on re-administration?’

-yes/no/unknown

22. Concomitant drug and dates of administration

The same mapping applies as for the suspect drug and should be repeated as reported for the CIOMS fields 14-21. The drug characterisation field B.4.k.1 should be set to “concomitant”

23. Other relevant history B.1.7 ‘Relevant medical history and concurrent conditions (not including reaction/event)

In case structured information is available regarding the medical history, the fields in section

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CIOMS I Field E2B(M) Data Element Comments

B.1.7.1 ‘Structured information on relevant medical history including onset and resolution date as well as relevant comments (repeat as necessary)’

B.1.7 ‘Relevant medical history and concurrent conditions (not including reaction/event)’ should be completed as applicable i.e. B.1.7.1 ‘Structured information on relevant medical history including onset and resolution date as well as relevant comments (repeat as necessary)’

B.1.7.2 ‘Text for relevant medical history and concurrent conditions (not including reaction/event)

In case no structured information is available B.1.7.2 ‘Text for relevant medical history and concurrent conditions (not including reaction/event)’ should be completed

Section A.3.1 ‘Sender’ A.3.1.1 Type - Pharmaceutical company - Regulatory authority - Health professional - Regional pharmacovigilance center - WHO collaborating center for international drug monitoring - Other (e.g. distributor, study sponsor, or contract research organization)

A.3.1.2 ‘Sender identifier’

A.3.1.3 ‘Person responsible for sending the report’

24a. Name and address of manufacturer

A.3.1.4 ‘Sender’s address, fax, telephone and E-mail address’

The information on the sender reflecting the information in CIOMS I 24.a, should be provided in Section A.3.1 ‘Sender’

24b. MFR. Control Number

A.1.10 ‘Worldwide unique case identification number’

A worldwide unique case identification number

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CIOMS I Field E2B(M) Data Element Comments

needs to be assigned, if the report is generated for the 1st time for electronic reporting.

The ICH format of the worldwide unique case identifier (country code-company or regulator name-report number) should always be used, and copied into field A.1.10.1 or A.1.10.2. as appropriate.

The ‘original’ case number as reflected at the CIOMS I form should be reported in the field A.1.11.2.

A.1.6a ‘Date the report was first received from source’ format

24c. Date received by manufacturer

A.1.6b ‘Date report was first received from source’

24d. Reported source

A.1.4 ‘Report type’

Type of report - Spontaneous report - Report from study - Other - Not available to sender (unknown)

If the report refers to ‘Report from study’, the type of study must be reflected in the field A.2.3.3 ‘Study type in which the reaction(s)/event(s) were observed’

25a. Report type A.1.7a ‘Date of receipt of the most recent information for this report’ format A.1.7b ‘Date of receipt of the most recent information for this report’

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CIOMS I Field E2B(M) Data Element Comments

Additional Information required to allow for the appropriate management of ICSRs in line with ICH

E2B(M)

Only the last updated version of the ICSR should be transmitted

A.2 ‘Primary source(s) of information’

A.2.1.1 ‘Reporter identifier’ (name or initials)

A.2.1.2 ‘Reporter’s address’

A.2.1.3 ‘Country’

A.2.1.4 ‘Qualification’ − Physician − Pharmacist − Other health professional − Lawyer − Consumer or other non health professional

A.2.2 ‘Literature reference(s)’ A.2.3 ‘Study identification’ A.2.3.1 ‘Study name’ A.2.3.2 ‘Sponsor study number’ A.2.3.3 ‘Study type in which the reaction(s)/event(s) were observed’ − Clinical trials − Individual patient use; (e.g. “compassionate use” or named patient basis) − Other studies (e.g., pharmacoepidemiology, pharmacoeconomics, intensive monitoring, PMS, etc.)

A.1.11 ‘Other case identifiers in previous transmissions’ -yes A.1.11.1 ‘Source(s) of the case identifier (e.g., name of the company, name of regulatory agency)’

A.1.11.2 ‘Case identifier(s)’

At least one of the mandatory fields in the primary source section must be completed

5005

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11.7 Retrospective Electronic Population of EudraVigilance: Transmission Rules 5006

The ICSRs to be transmitted in the frame of the retrospective population of EudraVigilance (see 5007 Chapter III.11, Section 5) should follow the ICH and Community guidelines and standards as 5008 described in Chapter III.2 and Chapter III.11, Section 6, including the medical information coded in 5009 MedDRA. 5010

The retrospectively transmitted ICSRs need to be clearly flagged in EudraVigilance to exclude these 5011 reports from expedited reporting compliance checks. 5012

To achieve a consistent flagging of these ICSRs, the ICH E2B(M) message header field M.1.1 5013 (‘Message Type’) should include the specification ‘backlog’ instead of ‘ichicsr’. The field value is 5014 case sensitive and should be reported in lower case. 5015

The following rules will be applied to the ICSR transmissions flagged according to this rule: 5016

• The 15-day (expedited) reporting compliance, as set out in Community legislation, will not be 5017 applied. 5018

• The business rules will be applied in line with the EMEA guidance ‘Technical Documentation 5019 – EudraVigilance Human Version 7.0 Processing of Safety Messages and ICSRs’ 5020 (EMEA/H/20665/04) 5021

• ICH E2B(M) fields requiring MedDRA coding will accept MedDRA LLTs with a MedDRA 5022 version, from version 4.0 upwards. 5023

• The data quality of the ICSRs related to the retrospective population of the EudraVigilance 5024 system is expected to be the same level as for the ICSRs submitted on an expedited basis to 5025 the EMEA, following the specifications outlined in Chapter III.11, Sections 3 and 6. 5026

The sender of retrospectively transmitted ICSRs as described in Chapter III.11, Section 5 should 5027 perform some initial testing with the EMEA, using the EudraVigilance test system (EVTEST) before 5028 transmitting the retrospective ICSRs to the EudraVigilance production environment (EVPROD). 5029

The retrospective ICSRs should be transmitted through the EudraVigilance Gateway or for non-5030 gateway users by means of EVWEB. 5031

Backlog messages should not contain more than 100 retrospective ICSRs. EudraVigilance will return 5032 an acknowledgment message for each ‘backlog’ message. The acknowledgement message for the 5033 backlog message will follow the ICH E2B(M)/M2 standards. 5034

11.8 Handling of Community Languages 5035

The pharmacovigilance data in EudraVigilance should be available in one commonly understandable 5036 Community language to be able to support the scientific assessment and evaluation by relevant 5037 experts. 5038

The E2B(M) concept is based on the fact that structured and coded information in the ICSRs is used 5039 for data outputs of pharmacovigilance systems (e.g. listings) and for signal detection. However, for 5040 scientific case assessment and signal evaluation the medical summary provided in the case narrative 5041 fields, specifically in section ICH E2B(M) B.5: ‘Narrative case summary and further information’ is 5042 normally required. 5043

Taking into account the international dimension of pharmacovigilance, English translations of ICSRs 5044 are performed by the Marketing Authorisation Holders. Marketing Authorisation Holders should 5045 therefore report ICSRs to EudraVigilance in English. 5046

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However, Competent Authorities in Member States as well as Iceland, Liechtenstein and Norway can 5047 report case narratives, to EudraVigilance and to the Marketing Authorisation Holders in the national 5048 language. For these reports, Competent Authorities should provide case translations in the English 5049 language when requested by the EMEA or another Competent Authority for the evaluation of potential 5050 signals. Such translation must be provided within 24 hours or the next working day. 5051

11.9 Population of the EVMPD 5052

To permit the correct identification of medicinal products related to adverse reactions reported in line 5053 with the reporting obligations set out in Community legislation as well as data analysis and signal 5054 detection, the Agency and Competent Authorities request all Marketing Authorisation Holders to enter 5055 each medicinal product for which they holds a marketing authorisation within the EEA, in the 5056 EudraVigilance Medicinal Product Dictionary (EVMPD). 5057

Each medicinal product needs to be uniquely identifiable with regard to the adverse reactions reported 5058 to EVPM and EVCTM as outlined in Chapter III.11, Section 2.1. 5059

This also refers to investigational medicinal products, which are defined in Directive 2001/20/EC, 5060 Article 2 (d) and which include medicinal products with a marketing authorisation. Such requirement 5061 is reflected in the 'Detailed guidance on the European clinical trials database (EUDRACT Database)’ 5062 (ENTR/CT 5), which states the following: ‘Each product will be identified in a product dictionary. 5063 The dictionary will be that of EudraVigilance, reflecting the requirements for identification of 5064 products through their development cycle, and with due regard to confidentiality of developmental 5065 products’. 5066

To meet these requirements, Marketing Authorisation Holders are requested to enter information on 5067 the medicinal products, for which they hold a license in the EEA, in the EVMPD in line with the 5068 following guidelines and specifications: 5069

• EudraVigilance Medicinal Product Dictionary (EVMPD) Version 2.0 Technical 5070 Specifications, 9 November 2004 (EMEA/140190/2004). 5071

• EudraVigilance Medicinal Product Dictionary (EVMPD) Version 2.0 Message and 5072 Acknowledgement Specifications, 8 December 2004 (EMEA/178966/2004). 5073

• EudraVigilance (EV) Access Simple Database Version 2.0 8 November 2004 5074 (EMEA/140327/2004). 5075

• EudraVigilance (EV) Access Simple Database Version 2.0 Forms Documentation, 31 January 5076 2005, (EMEA/35416/2005). 5077

• EudraVigilance (EV) Access Simple Database Version 2.0 Step by Step Guide, 8 December 5078 2004, (EMEA/191986/2004). 5079

As technical standards are evolving, the above reference documents may require revision and 5080 maintenance. In this context, the latest version of these documents should always be taken into 5081 account. 5082

11.10 Periodic Transmission of ICSRs in Electronic Format 5083

In line with Regulation (EC) No. 726/2004, Article 24, periodical reports, referred to as Periodic 5084 Safety Update Reports (PSURs), have to be transmitted at defined intervals to the Agency and 5085 Competent Authorities in Member States as well as Iceland, Liechtenstein and Norway. These 5086 periodical reports refer to the obligation of the Marketing Authorisation Holder to maintain detailed 5087 records of all suspected adverse reactions within or outside the Community which are reported to him 5088 by a Healthcare Professional. 5089

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The same principles are laid down in Article 104, Directive 2001/83/EC. 5090

PSURs should follow the content and format of the ICH E2C guideline (see Chapter III.2). 5091

Generally, data from the four following sources of adverse reactions are potentially available to a 5092 Marketing Authorisation Holder and should be included in the PSUR: 5093

• Direct reports to Marketing Authorisation Holder (or under Marketing Authorisation Holder 5094 control): 5095 • Spontaneous notifications from health care professionals. 5096 • Spontaneous notifications from non-health care professionals or from consumers (non-5097

medically confirmed). 5098 • Marketing Authorisation Holder-sponsored clinical studies21 or named-patient 5099

(“compassionate”) use. 5100

• Literature reports 5101

• Adverse reaction reporting systems of regulatory authorities 5102

• Other source data: 5103 • Reports on adverse reactions exchanged between contractual partners (e.g., licensors or 5104

licensees). 5105 • Data in special registries, such as maintained in organ toxicity monitoring centres reports 5106

created by poison control centres. 5107 • Epidemiologic databases. 5108

In line with the reporting rules as defined in Community legislation, notably Article 104(1) of 5109 Directive 2001/83/EC, data from the above sources should to be reported on an expedited basis 5110 electronically in the format of ICSRs to EVPM and on periodic basis in the format of PSURs. 5111

In order to facilitate the scientific evaluation of all safety data as referred above it is important to 5112 collect this information in one common repository and one common format. To achieve this, the 5113 Marketing Authorisation Holder should conduct a periodic electronic transmission of these data to 5114 EudraVigilance in the format of ICSRs (hereafter referred to as periodic ICSRs). 5115

The following procedures and specifications should be followed for periodic transmission of ICSRs in 5116 electronic format (hereafter referred to as periodic ICSRs): 5117

• Transmissions of periodic ICSRs should include all suspected adverse reactions reportable in a 5118 PSUR, which are not transmitted on expedited basis in electronic format to EVPM. Periodic 5119 transmissions of ICSRs should exclude 5120 • All suspected adverse reactions that are reported on expedited basis by the Marketing 5121

Authorisation Holder to EVPM (see Chapter III.11, Section 2.1 and Chapter III.12, 5122 Section 4) and 5123

• All suspected serious adverse reactions that occur within the Community as reported 5124 electronically on expedited basis by Competent Authorities to EVPM. 5125

• Periodic ICSRs should be transmitted at regular intervals by the Marketing Authorisation 5126 Holder but at the latest at the time of submission of the PSUR in line with the time frames 5127 defined in Community legislation. 5128

21 Clinical studies in this context are interpreted as non-interventional studies (with regard to EudraVigilance reporting rules these should be always reported to EVPM; adverse reactions related to interventional clinical trials (Phase I-IV) should be reported to EVCTM).

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• Periodic ICSRs should refer to an active substance or a combination of active substances as 5129 reportable in the relevant PSUR (ICH E2B(M) field B.4.k.2.2: ‘B.4.k.2.2 Active substance 5130 name(s)’). 5131

• Periodic ICSRs should follow the guidelines and standards as outlined in Chapter III.2. 5132

• Periodic ICSRs should follow the message specifications as outlined in Chapter III.3. In 5133 addition the field Message Type (ICH M2: M.1.1) should display the value “psur”. 5134

• All “psur” messages should be addressed to the message receiver identifier ‘EVHUMAN’. 5135

• The business rules are applied as specified in the EMEA guidance ‘Technical Documentation 5136 – EudraVigilance Human Version 7.0 Processing of Safety Messages and ICSRs’ 5137 (EMEA/H/20665/04). 5138

• ICH E2B(M) fields requiring MedDRA coding accept MedDRA LLTs with a MedDRA 5139 version, from version 4.0 upwards. 5140

• The data quality of the back-population of the EudraVigilance system is expected to be the 5141 same level as for the ICSRs submitted on an expedited basis to the EMEA, meeting the 5142 requirements as specified in Chapter III.11, Section 10.1. 5143

11.10.1 Electronic Transmission Rules for Periodic ICSRs 5144

This Chapter refers to the mapping of the CIOMS II and ICH E2C line listing requirements in a PSUR 5145 to the applicable E2B(M) data elements. 5146

The standard for the periodic ICSRs as described in Chapter III.11, Section 10 is a core set of data in 5147 accordance with the applicable ICH standards and guidelines referred to in Chapter III.3, for which a 5148 description is provided in Table 2. The principles as outlined in Chapter III.6 apply accordingly. 5149

11. TABLE 2: ELECTRONIC TRANSMISSION OF PERIODIC ICSR DATA IN LINE WITH CIOMS II, ICH E2C AND 5150 E2B(M) DATA ELEMENTS 5151

ICH E2C Line Listing E2B(M) Data Element Comments

A.1.0.1 ‘Sender’s safety report unique identifier’

MAH NO

A.1.10.1 or A.1.10.2 ‘Worldwide unique case identification number’

A. 1.1 ‘Identification of the country of the primary source’

COUNTRY

A.1.2 ‘Identification of the country where the reaction/event occurred’ If A.1.1 is not

available

SOURCE (type of report) A.1.4 ‘Type of report’ - Spontaneous report - Report from study - Other - Not available to sender (unknown)

If the report refers to ‘Report from study’, the type of study must be reflected in the field A.2.3.3 ‘Study type in which

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ICH E2C Line Listing E2B(M) Data Element Comments

the reaction(s)/event(s) were observed’

RECEIVE DATE A.1.6a ‘Date report was first received from source’ format A.1.6b ‘Date report was first received from source’

B.1.2 ‘Age information’ B.1.2.1.a ‘Date of birth’ format B.1.2.1.b ‘Date of birth’ B.1.2.2 a ‘Age at time of onset of reaction/event’ format B.1.2.2 a ‘Age at time of onset of reaction/event’ B.1.2.3 ‘Patient age group (as per reporter)’

AGE

B.1.2.2.1 ‘Gestation period when reaction/event was observed in the fetus’

SEX B.1.5 ‘Sex’

B.4.k.5 ‘Structured Dosage Information’

B.4.k.5.1 ‘dose (number)’

B.4.k.5.2 ‘dose (unit)’

B.4.k.5.3 ‘number of separate dosages’

B.4.k.5.4 ‘number of units in the interval’

B.4.k.5.5 ‘definition of the interval unit’

B.4.k.5.6 ‘cumulative dose to first reaction (number)’

B.4.k.5.7 ‘cumulative dose to first reaction (unit)’

DAILY DOSE

B.4.k.6 ‘Dosage text’

If B.4.k.5.1-B.4.k.6 is

not available

PART III 159/198

ICH E2C Line Listing E2B(M) Data Element Comments

B.2.i.4a ‘Date of start of reaction/event’ format B.2.i.4b ‘Date of start of reaction/event’ B.2.i.7a ‘Time intervals between suspect drug administration and start of reaction/event’ B.2.i.7b ‘Time intervals between suspect drug administration and start of reaction/event’ unit B.4.k.13.1a ‘Time interval between beginning of drug administration and start of reaction/event’ B.4.k.13.1b ‘Time interval between beginning of drug administration and start of reaction/event’ unit

ONSET OF REACTION/

TIME TO ONSET

B.4.k.13.2a ‘Time interval between last dose of drug and start of reaction/event’ B.4.k.13.2b ‘Time interval between last dose of drug and start of reaction/event’ unit

At least one element completed

B.4.k.12a ‘Date of start of drug’ format B.4.k.12b ‘Date of start of drug’ B.4.k.14a ‘Date of last administration’ format B.4.k.14b ‘Date of last administration’ B.4.k.15a ‘Duration of drug administration’ B.4.k.15b ‘Duration of drug administration’ unit

DATES OF TREATMENT/

TREATMENT DURATION

B.2.i.5a ‘Date of end of reaction/event’ format B.2.i.5b ‘Date of end of reaction/event’ format

PART III 160/198

ICH E2C Line Listing E2B(M) Data Element Comments

B.2.i.6a ‘Duration of reaction/event’ B.2.i.6b ‘Duration of reaction/event’ unit

B.2.i.1 ‘Reaction/event in MedDRA terminology (Lowest Level Term)’

REACTION DESCRIPTION Reactions must be coded as LLT according to E2B(M) in expedited reports and as PT PSUR line listings

B.2.i.0 ‘Reaction/event as reported by the primary source’

OUTCOME B.2.i.8 Outcome of reaction/event at the time of last observation

B.5.2 Reporter's comments COMMENT

B.5.4 Sender's comments

Additional Information required to allow for the appropriate management of periodic ICSRs in line with ICH E2B(M)

Only the last updated version of the ICSR should be transmitted

A.1.5.1. Serious

- - Yes/No

A.1.5.2. Seriousness criteria (more than one can be chosen) - Results in death - Is life-threatening - Requires inpatient hospitalization or prolongation of

existing - hospitalization - Results in persistent or significant disability/incapacity (as

per - reporter's opinion) - Is a congenital anomaly/birth defect - Other medically important condition

A.1.9 Does this case fulfil the local criteria for an expedited report?

No

Only ‘no’ value allowed

A.1.7 Date of receipt of the most recent information for this report

PART III 161/198

ICH E2C Line Listing E2B(M) Data Element Comments

A.1.11 ‘Other case identifiers in previous transmissions’ - -yes

A.1.11.1 ‘Source(s) of the case identifier (e.g., name of the company, name of regulatory agency)’

A.1.11.2 ‘Other reference number’

A.1.12 Identification number of the report which is linked to this report (repeat as necessary)

B.4.k.1 Characterization of drug role - Suspect/Concomitant/Interacting

B.4.k.2.2 Active substance name(s)

B.4.k.2.1 Proprietary medicinal product name

A.2.1.4 Qualification - Physician - Pharmacist - Other health professional - Lawyer - Consumer or other non health professional

A.2.3.3 ‘Study type in which the reaction(s)/event(s) were observed’ − Clinical trials − Individual patient use; (e.g. “compassionate use” or named patient basis) − Other studies (e.g., pharmacoepidemiology, pharmacoeconomics, intensive monitoring, PMS, etc.)

5152

162/198

5153

5154

5155

5156

5157

5158

5159

PART IV 5160

– Guidelines for Marketing Authorisation Holders 5161

and Competent Authorities on Pharmacovigilance Communication – 5162

PART IV 163/198

<Space for future Guidelines to be developed, subject to separate consultation> 5163

<text> 5164

5165

164/198

5166

5167

5168

5169

5170

5171

5172

PART V 5173

– Guidelines for Marketing Authorisation Holders and Competent 5174

Authorities on Product- or Population-Specific Pharmacovigilance – 5175

PART V 165/198

1. Guideline on Exposure to Medicinal Products During Pregnancy: Need for Post-5176 Authorisation Data 5177

<Text from GL subject to separate consultation; to be inserted later> 5178

http://www.emea.eu.int/pdfs/human/phvwp/31366605en.pdf 5179

5180

PART V 166/198

2. Guideline on Conduct of Pharmacovigilance for Medicines Used by the Paediatric 5181 Population 5182

This Guideline is has recently been the subject of an EMEA public consultation which is currently 5183 being analysed). 5184

5185

167/198

5186

5187

5188

5189

5190

5191

5192

ANNEXES 5193

ANNEXES 168/198

1. Glossary 5194

1.1 General 5195

Abuse of a medicinal product, synonym: Drug abuse 5196

Persistent or sporadic, intentional excessive use of medicinal products which is accompanied by 5197 harmful physical or psychological effects (Article 1,16. of Directive 2001/83/EC). 5198

Adverse event (AE), synonym: Adverse experience 5199

Any untoward medical occurrence in a patient or clinical-trial subject administered a medicinal 5200 product and which does not necessarily have to have a causal relationship with this treatment (Article 5201 2(m) of Directive 2001/20/EC). An adverse event can therefore be any unfavourable and unintended 5202 sign (e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the use of 5203 a medicinal product, whether or not considered related to the medicinal product. 5204

Adverse reaction, synonym: Adverse drug reaction (ADR), Suspected adverse (drug) reaction 5205

A response to a medicinal product which is noxious and unintended and which occurs at doses 5206 normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, 5207 correction or modification of physiological function (Article 1,11. of Directive 2001/83/EC)22. 5208

Response in this context means that a causal relationship between a medicinal product and an adverse 5209 event is at least a reasonable possibility (according to the ICH E2A Guideline, this means that a causal 5210 relationship cannot be ruled out, meaning that there is evidence or arguments to suggest a causal 5211 relationship). 5212

Adverse reaction also includes adverse clinical consequences associated with use of the product 5213 outside the terms of the Summary of Product Characteristics or other conditions laid down for the 5214 marketing and use of the product (including prescribed doses higher than those recommended, 5215 overdoses or abuse). 5216

See also under Adverse event, Serious adverse reaction, Unexpected adverse reaction, Listed adverse 5217 reaction, Reportable adverse reaction, Unlisted adverse reaction 5218

Clinical trial 5219

Any investigation in human subjects intended to discover or verify the clinical, pharmacological 5220 and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to 5221 identify any adverse reactions to one or more investigational medicinal product(s) and/or to study 5222 absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) 5223 with the objective of ascertaining its (their) safety and/or efficacy; This includes clinical trials carried 5224 out in either one site or multiple sites, whether in one or more Member State (Article 2(a) of Directive 5225 2001/20/EC). 5226

An investigational medicinal product is a pharmaceutical form of an active substance or placebo being 5227 tested or used as a reference in a clinical trial, including products already with a marketing 5228 authorisation but used or assembled (formulated or packaged) in a way different from the authorised 5229 form, or when used for an authorised indication, or when used to gain further information about the 5230 authorised form (Article 2(d) of Directive 2001/20/EC). 5231 22 Please note that for the reporting of 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) of Directive 2001/20/EC).

ANNEXES 169/198

Consumer 5232

A person who is not a Healthcare Professional such as a Patient, lawyer, friend or 5233 relative/parents/children of a Patient. 5234

Company Core Data Sheet (CCDS) 5235

A document prepared by the Marketing Authorisation Holder containing, in addition to safety 5236 information, material relating to indications, dosing, pharmacology and other information concerning 5237 the product. 5238

Company Core Safety Information (CCSI) 5239

All relevant safety information contained in the company core data sheet prepared by the Marketing 5240 Authorisation Holder and which the Marketing Authorisation Holder requires to be listed in all 5241 countries where the company markets the product, except when the local regulatory authority 5242 specifically requires a modification. It is the reference information by which listed and unlisted are 5243 determined for the purpose of periodic reporting for marketed products, but not by which expected and 5244 unexpected are determined for expedited reporting. 5245

Data lock point 5246

The date designated as the cut-off date for data to be included in a Periodic Safety Update Report. 5247

Drug abuse 5248

See under Abuse 5249

EU Birth Date (EBD) 5250

The date of the first marketing authorisation for a medicinal product granted in the EU to the 5251 Marketing Authorisation Holder: 5252

• For medicinal products authorised through the centralised procedure, the EU Birth Date is the 5253 date of the marketing authorisation granted by the European Commission, i.e. the date of the 5254 Commission Decision. 5255

• For medicinal products authorised through the mutual recognition or decentralised procedure, 5256 the EU Birth Date is the date of the marketing authorisation granted by the Reference Member 5257 State. 5258

• For medicinal products authorised through purely national procedures (outside the mutual 5259 recognition or decentralised procedure), the Marketing Authorisation Holder may propose a 5260 birth date which can be applied to reporting requirements across the Member States. 5261

See also International Birth Date 5262

Healthcare Professional 5263

For the purposes of reporting suspected adverse reactions, Healthcare Professionals are defined as 5264 medically-qualified persons, such as physicians, dentists, pharmacists, nurses and coroners. 5265

Individual Case Safety Report (ICSR), synonym: Safety report 5266

A document providing the most complete information related to an individual case at a certain point of 5267 time. An individual case is the information provided by a primary source to describe suspected adverse 5268

ANNEXES 170/198

reaction(s) related to the administration of one or more medicinal products to an individual Patient at a 5269 particular point of time23. 5270

International Birth Date (IBD) 5271

The date of the first marketing authorisation for a medicinal product granted to the Marketing 5272 Authorisation Holder in any country in the world. For a medicinal product for which the International 5273 Birth Date is not known, the Marketing Authorisation Holder can designate an International Birth Date 5274 to allow synchronisation of submission of Periodic Safety Update Reports. 5275

Invented name 5276

The name of a medicinal product as it appears in the Product Information, or the common or scientific 5277 name together with a trademark or the name of the Marketing Authorisation Holder followed by the 5278 strength and the pharmaceutical form of the product. 5279

The common name is International Non-proprietary Name (INN) recommended by the World Health 5280 Organization, or if one does not exist, the usual common name. 5281

Listed adverse reaction 5282

An adverse reaction whose nature, severity, specificity and outcome are consistent with the 5283 information in the company core safety information. 5284

Medicinal product 5285

• Any substance or combination of substances presented as having properties for treating or 5286 preventing disease in human beings; or 5287

• Any substance or combination of substances which may be used in or administered to human 5288 beings either with a view to restoring, correcting or modifying physiological functions by 5289 exerting a pharmacological, immunological or metabolic action, or to making a medical 5290 diagnosis (Art 1(2) of Directive 2001/83/EC). 5291

Non-interventional trial 5292

A study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the 5293 terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy 5294 is not decided in advance by a trial protocol but falls within the current practice and the prescription of 5295 the medicine is clearly separated from the decision to include the patient in the study. No additional 5296 diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall 5297 be used for the analysis of the collected data (Article 2(c) of Directive 2001/20/EC). 5298

Periodic Safety Update Report (PSUR) 5299

Periodic safety update reports mean the periodical reports containing the records referred to in Article 5300 104 of Directive 2001/83/EC and in Article 24(3) of Regulation (EC) No 726/2004. 5301

23 In the context of a clinical trial, an individual case is the information provided by a primary source to describe suspected unexpected serious adverse reactions related to the administration of one or more investigational medicinal products to an individual patient at a particular point of time.

ANNEXES 171/198

Post-authorisation study 5302

Any study conducted within the conditions laid down in the Summary of Product Characteristics and 5303 other conditions laid down for the marketing of the product or under normal conditions of use. A post-5304 authorisation study falls either within the definitions of a clinical trial or a non-interventional study 5305 and may also fall within the definition of a post-authorisation safety study. 5306

See also under Clinical trial, Non-interventional trial and Post-authorisation safety study 5307

Post-authorisation safety study (PASS) 5308

A pharmacoepidemiological study or a clinical trial carried out in accordance with the terms of 5309 marketing authorisation, conducted with the aim of identifying or quantifying a safety hazard relating 5310 to an authorised medicinal product (Article 1,15. of Directive 2001/83/EC). 5311

See also under Clinical trial and Non-interventional trial 5312

Risk-benefit balance 5313

An evaluation of the positive therapeutic effects of the medicinal product in relation to the risks related 5314 to its use in terms of quality, safety or efficacy as regards Patients’ or public health (Article 1,28a. of 5315 Directive 2001/83/EC). 5316

See also under Risks related to use of a medicinal product 5317

Risk management system 5318

A risk management system is a set of pharmacovigilance activities and interventions designed to 5319 identify, characterise, prevent or minimise risks relating to medicinal products, including the 5320 assessment of the effectiveness of those interventions. 5321

Risks related to use of a medicinal product 5322

Any risk relating to the quality, safety or efficacy of the medicinal product as regards Patients’ health 5323 or public health and any risk of undesirable effects on the environment (Article 1,28. of Directive 5324 2001/83/EC). 5325

Serious adverse reaction 5326

Serious adverse reaction means an adverse reaction which results in death, is life-threatening, requires 5327 in-patient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant 5328 disability or incapacity, or is a congenital anomaly/birth defect (Article 1,12. of Directive 5329 2001/83/EC). 5330

Life threatening in this context refers to a reaction in which the Patient was at risk of death at the time 5331 of the reaction; it does not refer to a reaction that hypothetically might have caused death if more 5332 severe. 5333

Medical and scientific judgement should be exercised in deciding whether other situations should be 5334 considered serious reactions such as important medical events that might not be immediately life 5335 threatening or result in death or hospitalisation but might jeopardise the Patient or might require 5336 intervention to prevent one of the other outcomes listed above. Examples of such events are intensive 5337 treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 5338 convulsions that do not result in hospitalisation or development of dependency or abuse. 5339

ANNEXES 172/198

Any suspected transmission via a medicinal product of an infectious agent is also considered a serious 5340 adverse reaction. 5341

See also under Adverse reaction 5342

Solicited sources of Individual Case Safety Reports 5343

Organised data collection schemes which include clinical trials, registries, named-patients use 5344 programmes, other patient support and disease management programmes, surveys of patients or 5345 healthcare providers or information gathering on efficacy or patient compliance. 5346

For the purpose of safety reporting, solicited reports should be classified as Study Reports and 5347 therefore should have an appropriate causality assessment by a Healthcare Professional or the 5348 Marketing Authorisation Holder. 5349

See also under Clinical trial, Non-interventional trial and Post-authorisation safety study 5350

Spontaneous report, synonym: Spontaneous notification 5351

An unsolicited communication by a Healthcare Professional or Consumer to a company, regulatory 5352 authority or other organisation (e.g. WHO, a regional centre, a poison control centre) which fulfills the 5353 following three conditions: 5354

• it describes one or more suspected adverse reactions in a patient 5355 • the patient was given one or more medicinal products 5356 • it does not derive from a study or any organised data collection scheme. 5357

Healthcare Professionals or Consumers may be stimulated to report a suspected adverse reaction by 5358 several situations including: 5359

• a Direct Healthcare Professional Communication 5360 • Early Post-Marketing Phase Vigilance (EPPV), e.g. in Japan 5361 • a report in the press 5362 • direct questioning of Healthcare Professionals by company representatives. 5363

In these circumstances, provided the report meets the three conditions above, it should be considered a 5364 spontaneous report. 5365

Unexpected adverse reaction 5366

An adverse reaction, the nature, severity or outcome of which is not consistent with the Summary of 5367 Product Characteristics (SPC) (Article 1,13. of Directive 2001/83/EC)24. This includes class-related 5368 reactions which are mentioned in the SPC but which are not specifically described as occurring with 5369 this product. For products authorised nationally, the relevant SPC is that approved by the Competent 5370 Authority in the Member State to whom the reaction is being reported. For centrally authorised 5371 products, the relevant SPC is the SPC authorised by the European Commission. During the time 5372 period between a CHMP Opinion in favour of granting a marketing authorisation and the Commission 5373 Decision granting the marketing authorisation, the relevant SPC is the SPC annexed to the CHMP 5374 Opinion. 5375

24 Please note that for investigational medicinal products an unexpected adverse reaction is an adverse reaction, the nature or severity of which is not consistent with the applicable Product Information (e.g. the investigator’s brochure for an unauthorised investigational product or the Summary of Product Characteristics for an authorised product) (Article 2(p) of Directive 2001/20/EC).

ANNEXES 173/198

Unlisted adverse reaction 5376

An adverse reaction that is not specifically included as a suspected adverse effect in the Company 5377 Core Safety Information (CCSI). This includes an adverse reaction whose nature, severity, specificity 5378 or outcome is not consistent with the information in the CCSI. It also includes class-related reactions 5379 which are mentioned in the CCSI but which are not specifically described as occurring with this 5380 product. 5381

ANNEXES 174/198

1.2 Terms in Relation to Risk Management 5382

Additional risk minimisation activity 5383

A risk minimisation activity put in place to reduce the probability of an adverse reaction occurring or 5384 its severity should it occur which is not a routine risk minimisation activity – e.g. additional 5385 educational material or use of one of the other risk minimisation activities in Chapter I.3., Table: 5386 Methods for Risk Minimisation. 5387

Competent Authority 5388

An authority within the EEA responsible for the granting of marketing authorisations for medicinal 5389 products and the supervision of marketing of such products in accordance with the relevant laws and 5390 regulations established under Community law. 5391

For practical purposes, the appropriate authority of the Reference Member State is the contact point 5392 for products authorised via the mutual recognition or decentralised procedures whilst for centrally 5393 authorised products it is the EMEA. 5394

Identified risk 5395

An untoward occurrence for which there is adequate evidence of an association with the medicinal 5396 product of interest. Examples of identified risks include: 5397

• An adverse reaction adequately demonstrated in non-clinical studies and confirmed by clinical 5398 data 5399

• An adverse reaction observed in well-designed clinical trials or epidemiological studies for 5400 which the magnitude of the difference, compared with the comparator group (placebo or 5401 active substance, or unexposed group), on a parameter of interest suggests a causal 5402 relationship 5403

• An adverse reaction suggested by a number of well-documented spontaneous reports where 5404 causality is strongly supported by temporal relationship and biological plausibility, such as 5405 anaphylactic reactions or application site reactions. 5406

Important identified risk, important potential risk or important missing information 5407

An identified risk, potential risk or missing information that could impact on the risk-benefit balance 5408 of the product or have implications for public health. 5409

Missing information 5410

Information about the safety of a medicinal product which is not available at the time of submission 5411 of the EU Risk Management Plan and which represents a limitation of the safety data with respect to 5412 predicting the safety of the product in the marketplace. 5413

Potential risk 5414

An untoward occurrence for which there is some basis for suspicion of an association with the 5415 medicinal product of interest but where this association has not been confirmed. Examples of potential 5416 risks include: 5417

• Non-clinical safety concerns that have not been observed or resolved in clinical studies 5418 • Adverse events observed in clinical trials or epidemiological studies for which the magnitude 5419

of the difference, compared with the comparator group (placebo or active substance, or 5420 unexposed group), on the parameter of interest raises a suspicion of, but is not large enough to 5421 suggest, a causal relationship 5422

ANNEXES 175/198

• A signal arising from a spontaneous adverse reaction reporting system 5423 • An event which is known to be associated with other products of the same class or which 5424

could be expected to occur based on the properties of the medicinal product. 5425

See Adverse Event 5426

Risk management system 5427

A risk management system is a set of pharmacovigilance activities and interventions designed to 5428 identify, characterise, prevent or minimise risks relating to medicinal products, including the 5429 assessment of the effectiveness of those interventions. 5430

Risk minimisation 5431

This is a set of activities used to reduce the probability of an adverse reaction occurring or its severity 5432 should it occur. 5433

Routine pharmacovigilance 5434

Pharmacovigilance activities as specified in Regulation (EC) No 726/2004 and Directive 2001/83/EC 5435 that should be conducted for all medicinal products. 5436

Routine risk minimisation activities 5437

The warnings and information contained within the Summary of Product Characteristics and Patient 5438 Leaflet, and the careful use of labelling and packaging, which aim to reduce the probability of an 5439 adverse reaction occurring or its severity should it occur. 5440

Safety concern 5441

An important identified risk, important potential risk or important missing information. 5442

Significant change in indication 5443

A significant change in indication is one where the target population differs from that previously 5444 authorised. This includes (but is not limited to): a new disease area, a new age group (e.g. paediatric 5445 indication) or a move from severe disease to a less affected population. It may also include a move 5446 from second-line or other therapy or for e.g. oncology products a change to the concomitant 5447 medications in the indication. 5448

See Target population 5449

Similar biological medicinal product 5450

A biological medicinal product which is similar to a reference biological product but does not meet the 5451 conditions in the definition of generic medicinal products, owing to, in particular, differences relating 5452 to raw materials or differences in manufacturing processes of the biological medicinal product and the 5453 reference biological medicinal product. 5454

Target Population 5455

The Patients who might be treated by the medicinal product according to the indication(s) and 5456 contraindication(s) in the Summary of Product Characteristics. 5457

ANNEXES 176/198

1.3 Terms in Relation to Electronic Exchange of Pharmacovigilance Information 5458

Acknowledgement message (ICSRACK) 5459

An EDI Message with the information on the result of the Acknowledgement of Receipt procedure to 5460 acknowledge the receipt of one Safety Message and the Safety Report(s) contained in the Safety File. 5461

Acknowledgement message (MPRACK) 5462

An EDI Message with the information on the result of the Acknowledgement of Receipt procedure to 5463 acknowledge the receipt of one Medicinal Product Report Message and the Medicinal Product 5464 Report(s) contained in the Medicinal Product File. 5465

Acknowledgement of receipt 5466

The procedure by which on receipt of the Safety Message/Medicinal Product Report Message the 5467 syntax and semantics are checked. 5468

Applicant 5469

A pharmaceutical company applying for a marketing authorisation in the EEA. 5470

Competent Authorities 5471

• An authority within the EEA responsible for the granting of marketing authorisations for 5472 medicinal products and the supervision of marketing of such products in accordance with the 5473 relevant laws and regulations established under Community law. 5474

• An authority within the EEA responsible for granting the authorisation to conduct a clinical 5475 trial in at least one Centre located with the Community in accordance with the relevant laws 5476 and regulations established under Community law. 5477

Electronic data interchange (EDI) 5478

Electronic transfer, from computer to computer, of commercial and administrative data using an 5479 agreed standard to structure an EDI message. EDI is based on the use of structured and coded 5480 messages, the main characteristic of which is their ability to be processed by computers and 5481 transmitted automatically and without ambiguity. This makes EDI specific in comparison with other 5482 data exchange such as electronic mail. 5483

EudraVigilance database management system (DBMS) 5484

The pharmacovigilance database defined in Community legislation. 5485

EudraVigilance gateway 5486

The data-processing network as defined in the Community legislation that provides a single point of 5487 contact between Marketing Authorisation Holders, Applicants, sponsors and Competent Authorities in 5488 the EEA. By doing so, the EudraVigilance Gateway is considered a hub and all connections to the EDI 5489 Partners are known as spokes. Safety, Acknowledgement and Medicinal Product Report Messages are 5490 routed through the hub to the desired spoke. 5491

Extensible markup language (XML) 5492

A subset of SGML that is completely compatible with SGML. 5493

ANNEXES 177/198

Gateway 5494

A data exchange service, which consists of all core standards and functionality required for supporting 5495 the ICH standards (e.g. Simple Mail Transfer Protocol (SMTP)/Secure Multipurpose Internet Mail 5496 (SMIME)). 5497

Individual case 5498

The information provided by a primary source to describe suspected adverse reaction(s)/suspected 5499 unexpected serious adverse reactions related to the administration of one or more medicinal 5500 products/investigational medicinal products to an individual patient at a particular point of time. 5501

Individual Case Safety Report (ICSR), synonym: Safety Report 5502

A document providing the most complete information related to an Individual Case at a certain point 5503 of time. 5504

Investigational medicinal product (IMP) 5505

A pharmaceutical form of an active substance or placebo being tested or used as a reference in a 5506 clinical trial, including products already with a marketing authorisation but used or assembled 5507 (formulated or packaged) in a way different from the authorised form, or when used for an 5508 unauthorised indication, or when used to gain further information about the authorised form (Art 1(d) 5509 of Directive 2001/20/EC). 5510

Marketing Authorisation Holders (MAHs) 5511

All Marketing Authorisation Holders holding a valid marketing authorisation for a medicinal product 5512 in the EEA including any part thereof, independent of the authorisation procedure of this medicinal 5513 product. 5514

Medicinal product 5515

• Any substance or combination of substances presented as having properties for treating or 5516 preventing disease in human beings; or 5517

• Any substance or combination of substances, which may be used in or administered to human 5518 beings either with a view to restoring, correcting or modifying physiological functions by 5519 exerting a pharmacological, immunological or metabolic action, or to making a medical 5520 diagnosis (Art 1(2) of Directive 2001/83/EC). 5521

Medicinal product file 5522

The electronic file transmitted in one Message Transaction between one Sender and one Receiver 5523 containing one Medicinal Product Report Message. 5524

Medicinal product report (MPR) 5525

An electronic report with a defined set of data elements to populate and update the EudraVigilance 5526 Medicinal Product Dictionary (EVMPD). A Medicinal Product Report may contain information on an 5527 authorised medicinal product/investigational medicinal product. 5528

Medicinal product report message (MPRM) 5529

An EDI Message including the information provided for one/more Medicinal Product Reports 5530 contained in one Medicinal Product File exchanged between one Sender and one Receiver in one 5531 Message Transaction. 5532

ANNEXES 178/198

Medicinal product report transaction 5533

The complete set of actions in the electronic reporting of Medicinal Product Messages, which 5534 routinely includes the following: 5535

• Creation of a Medicinal Product Report Message 5536 • Transmission of the Medicinal Product Report Message to the Report Receiver 5537 • On receipt of the Medicinal Product Report Message by the Receiver’s Gateway return of an 5538

MDN 5539 • This MDN will be referred to as MPR-MDN 5540 • The MPR-MDN is received and stored by the Report Sender to document the success of the 5541

Medicinal Product Report Message transmission 5542 • The Medicinal Product Report Message is subjected to the Acknowledgement of Receipt 5543

procedure by the Report Receiver 5544 • The Acknowledgement Message is created 5545 • The Acknowledgement Message is returned to the Report Sender (technically the Report 5546

Receiver is a Message Sender for this part of the transaction) 5547 • On receipt of the Acknowledgement Message by the Report Sender’s Gateway return of an 5548

MDN 5549 • This MDN is referred to as MPRACK-MDN 5550 • The MPRACK-MDN is received and stored by the Report Receiver to document the 5551

successful transmission of the Acknowledgement Message 5552 • The Acknowledgement Message is evaluated to document the success of the Report 5553

Transaction 5554

Message 5555

An EDI Message consists of a set of segments, structured using an agreed standard, prepared in a 5556 computer readable format and capable of being automatically and unambiguously processed. 5557

Message disposition notification (MDN) 5558

A notification on the receipt of an EDI Message returned by the Receiver’s Gateway to the Sender’s 5559 Gateway. The MDN concludes a Message Transaction performed between two parties in a Gateway-5560 to-Gateway communication. 5561

Message transaction 5562

A set of actions encompassing the electronic transmission of an EDI Message (Safety Message, 5563 Acknowledgement Message, Medicinal Product Message) between a Sender and a Receiver including 5564 the return of the Message Disposition Notification for that message. 5565

Partner 5566

An organisation exchanging EDI Messages in the area of pharmacovigilance in the pre- or post-5567 authorisation phase with another organisation. For the purpose of this guideline, EDI partners in the 5568 pre- and post-authorisation phase in pharmacovigilance are as follows: 5569

• Competent Authorities in the EEA 5570 • Marketing Authorisation Holders in the EEA 5571 • Applicants 5572 • Sponsors in the EEA 5573

Receiver 5574

Intended recipient of the EDI Message. 5575

ANNEXES 179/198

Receiver identifier 5576

Identification or combined EDI qualifier and ID of the recipient. 5577

Report receiver 5578

Intended recipient of the transmission of a Safety Message, which for the purpose of these Guidelines 5579 is an EDI Partner. The Receiver is also the intended recipient of the transmission of a Medicinal 5580 Product Report Message, which for the purpose of these Guidelines is an EDI Partner being the 5581 Agency. 5582

Report sender 5583

Person or entity creating a Safety Message as EDI Message in order to submit a Safety Report, which 5584 for the purpose of these Guidelines is an EDI Partner. In the Report Transaction the Report Sender will 5585 always remain the same, whereas with the exchange of messages the “Sender” and “Receiver” roles 5586 will change. The same concepts apply to the organisation creating a Medicinal Product Message as 5587 EDI Message in order to submit a Medicinal Product Report, which for the purpose of these 5588 Guidelines is an EDI Partner being an Applicant, a Marketing Authorisation Holder or a sponsor. 5589

Report transaction 5590

The complete set of actions in the electronic reporting of Safety Messages to comply with regulatory 5591 requirements which routinely includes the following: 5592

• Creation of a Safety Message 5593 • Transmission of the Safety Message to the Report Receiver 5594 • On receipt of the Safety Message by the Receiver’s Gateway return of an MDN 5595 • This MDN will be referred to as ICSR-MDN 5596 • The ICSR-MDN is received and stored by the Report Sender to document the success of the 5597

Safety Message transmission 5598 • The Safety Message is subjected to the Acknowledgement of Receipt procedure by the Report 5599

Receiver 5600 • The Acknowledgement Message is created 5601 • The Acknowledgement Message is returned to the Report Sender (technically the Report 5602

Receiver is a Message Sender for this part of the transaction) 5603 • On receipt of the Acknowledgement Message by the Report Sender’s Gateway return of an 5604

MDN 5605 • This MDN is referred to as ICSRACK-MDN 5606 • The ICSRACK-MDN is received and stored by the Report Receiver to document the 5607

successful transmission of the Acknowledgement Message 5608

The Acknowledgement Message is evaluated to document the success of the Report Transaction. 5609

Safety file 5610

The electronic file transmitted in one Message Transaction between one Sender and one Receiver 5611 containing one Safety Message. 5612

Safety message 5613

An EDI Message including the information provided for one/more Individual Case Safety Reports 5614 contained in one Safety File exchanged between one Sender and one Receiver in one Message 5615 Transaction. 5616

ANNEXES 180/198

Sender 5617

Person or entity creating an EDI Message for transmission. 5618

Sender identifier 5619

Identification (ID) or combined EDI qualifier and ID of the Sender. 5620

Sponsor 5621

An individual, company, institution or organisation, which takes responsibility for the initiation, 5622 management and/or financing of a clinical trial (Art 2(e) of Directive 2001/20/EC). 5623

Standard generalized markup language (SGML) 5624

International Standard (ISO 8879) computer language for describing a document in terms of its 5625 content (text, image) and logical structure (chapters, paragraphs, etc.). It is a standard for how to 5626 specify a document markup language or tag set. Such a specification is itself a document type 5627 definition (DTD). SGML is not in itself a document language, but a description of how to specify one. 5628 It is a metalanguage. 5629

SGML is based on the idea that documents have structural and other semantic elements that can be 5630 described without reference to how such elements should be displayed. 5631

ANNEXES 181/198

2. Abbreviations 5632

ADR Adverse drug reaction AE Adverse event ATC Anatomical-Therapeutic-Chemical Classification CCDS Company Core Data Sheet CCSI Company Core Safety Information CHMP Committee for Medicinal Products for Human Use CMD Coordination Group for Mutual Recognition and Decentralised Procedures CMS Concerned Member State(s) CV Curriculum Vitae DHPC(s) commonly called “DDL(s)”

Direct Healthcare Professional Communication(s) commonly called “Dear Doctor Letter(s)”

DP 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 EudraVigilance Medicinal Product Dictionary EVPM EudraVigilance Post-Authorisation Module FDA US Food and Drug Administration IBD International Birth Date ICH International Conference on Harmonisation ICSR(s) Individual Case Safety Report IMP Investigational medicinal product INN International Non-Proprietary Name IT Information Technology ISPE International Society for Pharmacoepidemiology LLTs Lowest Level Terms MAH(s) Marketing Authorisation Holder(s) MedDRA Medical Dictionary for Regulatory Activities MPR Medicinal Product Report MRP Mutual recognition procedure NUI Non-Urgent Information PAR Public Assessment Report PASS Post-authorisation safety study PhVWP CHMP Pharmacovigilance Working Party PL Package Leaflet PSUR(s) Periodic Update Safety Report(s) RA Rapid Alert RMS Reference Member State(s) SOCs System Organ Classes SPC Summary of Product Characteristics SUSAR(s) Suspected unexpected serious adverse reaction(s) USR Urgent safety restriction WHO World Health Organization

ANNEXES 182/198

3. Guidelines and Terminology Related to Part III 5633

3.1 Guidelines 5634

3.1.1 Note for Guidance on the Electronic Data Interchange (EDI) of Individual 5635 Case Safety Reports (ICSRs) and Medicinal Product Reports (MPRs) in 5636 pharmacovigilance during the pre- and post-authorisation phase in the 5637 European Economic Are (EEA) (EMEA/115735/2004) 5638

Adopted at Community level in September 2004. 5639

<to be inserted later> 5640

3.1.2 Technical Documentation – EudraVigilance Human Version 7.0 Processing 5641 of Safety Messages and ICSRs) (EMEA/H/20665/04) 5642

Adopted at Community level in July 2004. 5643

<to be inserted later> 5644

3.1.3 Detailed Guidance on the European database of Suspected Unexpected 5645 Serious Adverse Reactions (EudraVigilance – Clinical Trial Module) 5646 (ENTR/CT4, Revision 1, April 2004) 5647

<to be inserted later> 5648

3.2 Terminology 5649

See Chapter III.1. This Annex will be updated after the consultation phase in line with future 5650 developments of, amongst others: 5651

• MedDRA 5652 • ICH M5 Routes of Administration 5653 • ICH M5 Units and Measurements 5654 • European Pharmacopoeia 5655

5656

ANNEXES 183/198

4. ICH Guidelines 5657

<ICH Guidelines to be inserted later> 5658

5659

ANNEXES 184/198

5. Templates 5660

5.1 Template for EU Risk Management Plan 5661

<This is under development and will be released as soon as it is available.> 5662

5663

ANNEXES 185/198

5.2 Template for PSUR section "Worldwide Marketing Authorisation Status" 5664

Example of Presentation of Individual Case Histories 5665

5666

Source Type of Case Only Summary Tabulation Line-Listing and Summary Tabulation

1. Direct Reports to MAH

Spontaneous ADR reports*

Studies and compassionate use programmes

S

NS U

NS L**

SA

-

-

+

-

+

+

-

+

2. Literature S

NS U

-

-

+

+

3. Other sources

Regulatory authorities

Contractual partners

Registries

S

S

S

-

+

+

+

-

-

* Medically unconfirmed reports should be provided as a PSUR addendum only on request by regulatory authorities, as a line-listing and/or summary 5667 tabulation. 5668

** Line-listing should be provided as PSUR addendum only on request by regulatory authorities. 5669

S = serious; L = listed; A = attributable to drug by investigator or sponsor; NS = non-serious; U = unlisted 5670

ANNEXES 186/198

5.3 Template for PSUR section "Line-listings of Individual Case Histories" 5671

5672

MAH NO

COUNTRY SOURCE AGE/SEX

DAILY DOSE mg/day

DATE OF ONSET OF REACTION or

time to onset

DATES OF TREATMENT or

treatment duration

REACTION DESCRIPTION

OUTCOME COMMENT

5673 5674

ANNEXES 187/198

5.4 Template for PSUR section "Summary Tabulations" 5675

Number of Reports by Term (Signs, Symptoms and Diagnoses) from Spontaneous (Medically Confirmed), Clinical Study and Literature Cases: All Serious 5676 Reactions 5677

An * indicates an unlisted reaction 5678

Body system/ADR term Spontaneous/

Regulatory bodies Clinical studies Literature

CNS hallucinations* etc. etc. ------------- Sub-total

2

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

0

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

0

-----------

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

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

-----------

-----------

Etc... TOTAL

In a footnote (or elsewhere), the number of patient-cases that represent the tabulated terms should be given (e.g.: x-spontaneous/regulatory, y-clinical 5679 study, and z-literature cases) 5680

** This table is only one example of different possible data presentations which are at the discretion of the Marketing Authorisation Holder (e.g.: 5681 serious and non-serious in the same table or as separate tables, etc.) 5682

5683

ANNEXES 188/198

5.5 Template for Rapid Alert in Pharmacovigilance 5684

5685 5686

<Logo and name of the Competent Authority of the Member State/EMEA> 5687 5688 5689

RAPID ALERT IN PHARMACOVIGILANCE REFERENCE: No of pages:

No of attachments: DATE:

FROM: TO: ALL MEMBER STATES EFTA COUNTRIES CONCERNED EMEA EUROPEAN COMMISSION CHMP CHAIRPERSON RAPPORTEUR (if applicable) REFERENCE MEMBER STATE (if applicable)

TYPE OF RAPID ALERT: Concern about a change in the risk-benefit balance based on: � A series of report(s) of unexpected serious adverse reactions (ADRs) � Reports of an expected ADR suggesting greater severity than known, new long-term sequelae or

identifying new risk factors � A significant increase in the reporting rate of expected serious ADRs � Evidence from studies (clinical trials or epidemiological studies) indicative of unexpected risk or a

change in frequency or severity of a known risk � Knowledge that the efficacy of a medicinal product is not established as assumed to date � Evidence that the risks of a particular product are greater than alternatives with similar efficacy � Other reason - please specify: _____________________________________________ PLANNED ACTIONS: � A suspension or withdrawal of the marketing authorisation � A recall of the medicinal product from the market � An urgent safety restriction or variation � A suspension of use of non authorised product � An urgent need to inform Healthcare Professionals or Patients about an identified risk � Changes in the Summary of Product Characteristics (SPC), such as

� Introduction of new contraindications � Introduction of new warnings � Reduction in the recommended dose � Restriction in the indications � Restriction in the availability of a medicinal product

� Other - please specify: _____________________________________________

The issue could affect (an)other Member State(s) � YES � NO

ANNEXES 189/198

SUBJECT: Please complete as appropriate Invented name(s): __________________________________________________________________ International Non-proprietary Name (INN) or Class: _______________________________________ and please select from the following:

� Centrally authorised (or applied for) product(s) Η � Mutual recognition or decentralised procedure ; � Purely nationally authorised product(s) θ � Simplified registration product(s) θ � Product(s) which has been subject to a referral procedure υ � Other: __________________________________________

Strength(s): Pharmaceutical Form(s) and Dosage(s): Route of Administration(s): Anatomical-Therapeutic-Chemical Classification (ATC code): Marketing Authorisation Holder: Manufacturer (if essential): Indication(s): REASONS FOR RAPID ALERT: <text: relevant summarised evidence>

SOURCE OF INFORMATION: Please select: � Spontaneous Reports � Post-marketing Study � Clinical Trial � Pre-clinical Study � Other (please specify) ______________________________________________

PROPOSED ACTION AND/OR ACTION TAKEN: <text>

INFORMATION REQUESTED: <text>

ADDITIONAL INFORMATION: <text>

PLEASE RESPOND BY <dd/mm/yyyy>

NAME OF PERSON RESPONSIBLE FOR SENDING MESSAGE:

ANNEXES 190/198

5.6 Template for Non-Urgent Information in Pharmacovigilance 5690

5691 5692

<Logo and name of the Competent Authority of the Member State/EMEA> 5693 5694 5695

NON-URGENT INFORMATION IN PHARMACOVIGILANCEREFERENCE: No of pages:

No of attachments: DATE:

FROM: TO: ALL MEMBER STATES EFTA COUNTRIES CONCERNED EMEA EUROPEAN COMMISSION CHMP CHAIRPERSON RAPPORTEUR (if applicable) REFERENCE MEMBER STATE (if applicable)

TYPE OF NON-URGENT INFORMATION: � Pre-signal information � Information on implementation status � Information which might be of interest to other Member States, but does not require a response

(e.g. withdrawal of a product, the outcome of discussions from national safety committees, when to expect an Assessment Report on certain items, current media activity

� Request for information � Organisational matters � Interaction with the FDA � Communication at national level is planned � Other reason - please specify: _____________________________________________

The issue could affect (an)other Member State(s) � YES � NO

ANNEXES 191/198

SUBJECT: Please complete as appropriate Invented name(s): __________________________________________________________________ International Non-proprietary Name (INN) or Class: _______________________________________ and please select from the following:

� Centrally authorised (or applied for) product(s) Η � Mutual recognition or decentralised procedure ; � Purely nationally authorised product(s) θ � Simplified registration product(s) θ � Product(s) which has been subject to a referral procedure υ � Other: __________________________________________

Strength(s): Pharmaceutical Form(s) and Dosage(s): Route of Administration(s): Anatomical-Therapeutic-Chemical Classification (ATC code): Marketing Authorisation Holder: Manufacturer (if essential): Indication(s):

REASONS FOR NON-URGENT INFORMATION: <text: relevant summarised evidence >

SOURCE OF INFORMATION: Please select: � Spontaneous Reports � Post-marketing Study � Clinical Trial � Pre-clinical Study � Other (please specify) ______________________________________________

PROPOSED ACTION AND/OR ACTION TAKEN: <text> INFORMATION REQUESTED: <text> ADDITIONAL INFORMATION: <text>

PLEASE RESPOND BY <dd/mm/yyyy>

NAME OF PERSON RESPONSIBLE FOR SENDING MESSAGE:

ANNEXES 192/198

5.7 Template for Response to Rapid Alert/Non-Urgent Information in 5696 Pharmacovigilance 5697

5698 5699

<Logo and name of the Competent Authority of the Member State/EMEA> 5700 5701 5702

RESPONSE TO <RAPID ALERT / NON-URGENT INFORMATION>

(please delete as appropriate throughout)

IN PHARMACOVIGILANCE REFERENCE: No of pages:

No of attachments: DATE:

FROM:

IN RESPONSE TO THE ORIGINAL MESSAGE FROM <Member State> dated <dd/mm/yyy> TO: ORIGINATING MEMBER STATE EMEA

RESPONSE REQUESTED BY THE ORIGINATOR FOR SUBJECT: Please complete as appropriate Invented name(s): __________________________________________________________________ International Non-proprietary Name (INN) or Class: _______________________________________ and please select from the following:

� Centrally authorised (or applied for) product(s) Η � Mutual recognition or decentralised procedure ; � Purely nationally authorised product(s) θ � Simplified registration product(s) θ � Product(s) which has been subject to a referral procedure υ � Other: __________________________________________

Strength(s): Pharmaceutical Form(s) and Dosage(s): Route of Administration(s): Anatomical-Therapeutic-Chemical Classification (ATC code): Marketing Authorisation Holder: Manufacturer (if essential): Indication(s):

RESPONSE TO RAPID ALERT / NON-URGENT INFORMATION: <text>

ANNEXES 193/198

PROPOSED ACTION AND/OR ACTION TAKEN: <text> ADDITIONAL INFORMATION: <text> NAME OF PERSON RESPONSIBLE FOR SENDING MESSAGE:

ANNEXES 194/198

6. Distribution Requirements and Address Lists for Data Submission 5703

6.1 Distribution Requirements and Address Lists for Periodic Safety Update 5704 Reports 5705

5706

May 2005 PhVWP Drafting Group: no need to re-submit previously submitted PSURs at time of 5707 Renewal (to be checked with Part I final draft) 5708

5709

Status: 12 October 2005 5710 5711

Distribution Requirements 5712 for Periodic Safety Update Reports 5713

5714 Member State/ EEA Country/

Agency

Number of copies Addressee(s)

Austria 2 (paper copies)

• Federal Ministry of Health and Women (1 copy) VIII/A/3 Pharmacovigilance Branch Radetzkystrasse 2 1030 WIEN

• Bundesinstitut für Arzneimittel (1 copy) Unit 2 Possingergasse 38 1160 WIEN

Belgium 1 (CD-ROM + paper copy)

1 additional copy (CD-ROM + paper copy)

Federal Public Service Health, Food Chain Safety and Environment Directorate-General Public Health Protection: Medicinal Products Belgian Centre for Pharmacovigilance Boulevard Bischoffsheim 33, 1st floor 1000 BRUSSEL/BRUXELLES BELGIUM to attention of Rapporteur (if Belgian CHMP Delegate is Rapporteur)

Cyprus 1 (CD-ROM + paper copy)

Ministry of Health Pharmaceutical Services Drug Regulatory Sector 1475 NICOSIA CYPRUS

Czech Republic 1 (CD-ROM + paper copy)

Preference: CD-ROM-only PSUR in searchable

format (pdf, html, MS Word)

Pharmacovigilance Unit State Institute for Drug Control Srobarova 48 100 41 PRAHA 10 CZECH REPUBLIC

Denmark 1 Danish Medicines Agency Consumer Safety Division Axel Heides Gade 1 2300 KØBENHAVN S DENMARK

Estonia All authorisation types: 1

(CD-ROM + paper copy)

Bureau of Drug Information and Pharmacovigilance State Agency of Medicines Nooruse Street 1 50411 TARTU ESTONIA

ANNEXES 195/198

Member State/ EEA Country/

Agency

Number of copies Addressee(s)

Finland • Centralised authorisations:

1 (CD-ROM or paper copy)

1 (additional) paper copy

• National authorisations:

1 (CD-ROM or paper copy) • Mutually recognised

authorisations: 1

(CD-ROM or paper copy)

1 (additional) paper copy

• Attn.: Department of Safety and Drug Information National Agency for Medicines P.O. Box 55 00301 HELSINKI FINLAND

to attention of Rapporteur (if Finnish CHMP Delegate is Rapporteur)

• Attn.: Department of Safety and Drug Information

National Agency for Medicines P.O. Box 55 00301 HELSINKI FINLAND if Finland is Reference Member State

France 2 (paper copies + CD-ROM)

Agence Française de Sécurité Sanitaire des Produits de Santé DEMEB / Unité AMM logistique 143-147, Boulevard Anatole France 93285 SAINT-DENIS CEDEX FRANCE

Germany 2 (paper copies)

• Bundesinstitut für Arzneimittel und Medizinprodukte (2 copies) Friedrich-Ebert-Allee 38 53113 BONN GERMANY

• For vaccines and products derived from blood according to Council Directive 89/381/EC, recombinant coagulation factors and monoclonal antibodies: Paul-Ehrlich-Institut (2 copies) Attn.: Referat A/2 Paul-Ehrlich-Strasse 51-59 63225 LANGEN GERMANY

Greece 1 (paper copy)

Ministry of Health, Welfare National Organization for Medicines Department of Pharmaceutical Studies Adverse Drug Reactions Section 284 Mesogion Av. 15562 HOLARGOS GREECE

Hungary 1 (paper copy)

National Institute of Pharmacy Department of Pharmacovigilance Zrínyi u. 3 1051 BUDAPEST HUNGARY

ANNEXES 196/198

Member State/ EEA Country/

Agency

Number of copies Addressee(s)

Ireland 1 (CD-ROM and/or 1 paper

copy)

Centralised authorisations: CD-ROM & 1 (additional)

paper copy*

Mutually recognised authorisations:

CD-ROM &1 (additional) paper copy*

National authorisations:

CD-ROM & 1 (additional) paper copy

Receipts &Validation Unit Irish Medicines Board Earlsfort Centre Earlsfort Terrace IE-DUBLIN 2 IRELAND *if Ireland is Rapporteur *if Ireland is Reference Member State always

Italy 1 (paper copy)

Agenzia Italiana del Farmaco Via di Sierra Nevada 60 00144 ROMA ITALY

Latvia 1 (CD-ROM + paper copy)

Human Medicines Registration Department State Agency of Medicines of Latvia 15, Jersikas St RIGA 1003 LATVIA

Lithuania Centralised authorisations: 1

CD-ROM only

National and mutually recognised authorisations:

1 paper copy

State Medicines Control Agency Post-Authorisation Evaluation Unit Traku Street 14 01132 VILNIUS LITHUANIA

Luxembourg 1 (paper copy)

Division de la Pharmacie et des Médicaments Villa Louvigny Allee Marconi 2120 LUXEMBOURG LUXEMBOURG

ANNEXES 197/198

Member State/ EEA Country/

Agency

Number of copies Addressee(s)

Malta National Authorisations: 1 paper copy

(CD-ROM + paper copy)

MRP authorisations: If Malta is RMS:

1 paper copy (CD-ROM + paper copy)

If Malta is CMS:

1 Electronic copy only on CD-ROM

Centralised authorisations: If Malta is RMS:

1 paper copy (CD-ROM + paper copy)

If Malta is CMS:

1 Electronic copy only on CD-ROM

Six monthly and annual PSURs: Attn: Pharmacovigilance Staff Post-Licensing Directorate Medicines Authority 198, Rue D’Argens GZIRA GZR 03 MALTA First and subsequent renewal PSURs: Post-Licensing Directorate Medicines Authority 198, Rue D’Argens GZIRA GZR 03 MALTA Interim PSURs: To the person from the Post-Licensing Directorate making the request.

Netherlands 1 (CD-ROM + paper copy)

Medicines Evaluation Board MEB Kalvermarkt 53 P.O. Box 16229 2500 BE DEN HAAG THE NETHERLANDS

Poland 1 (paper copy)

Office for Medicinal Products, Medical Devices and Biocides Pharmacovigilance Unit 41 Zabkowska Street 03 736 WARSZAWA POLAND

Portugal 1 (paper copy)

Attn.: Directorate of Human and Veterinary Medicines and Healthcare Products INFARMED Parque de Saúde de Lisboa Av. do Brasil, 53 1749 – 004 LISBOA PORTUGAL

Slovak Republic 1 (CD-ROM or paper copy)

State Institute for Drug Control Kvetná 11 825 08 BRATISLAVA 25 SLOVAK REPUBLIC

Slovenia 1 (CD-ROM+paper copy)

Agency for Medicinal Products and Medical Devices of the Republic of Slovenia Mali trg 6 1000 LJUBLJANA SLOVENIA

Spain 2 (paper copies)

Agencia Española del Medicamento Calle Alcalá 56 28071 MADRID SPAIN

ANNEXES 198/198

Member State/ EEA Country/

Agency

Number of copies Addressee(s)

Sweden 1 (CD-ROM + paper copy)

2 additional copies (CD-ROM)

Medical Products Agency PO Box 26 75103 UPPSALA SWEDEN Attn.: CHMP Members (1 copy for each Member) Medical Products Agency PO Box 26 75103 UPPSALA SWEDEN

United Kingdom 1 (paper copy)

Medicines and Healthcare products Regulatory Agency PSUR Processing Room 13-1 1, Nine Elms Lane LONDON SW8 5NQ UNITED KINGDOM

Iceland 1 (CD-ROM (preferred) or

paper copy)

Icelandic Medicines Control Agency Eidistorgi 13-15 P.O. Box 180 172 SELTJANARNES ICELAND

Liechtenstein 1 (paper copy)

Kontrollstelle für Arzneimittel Amt für Lebensmittelkontrolle und Veterinärwesen Postplatz 2 9494 SCHAAN LIECHTENSTEIN

Norway 1 (paper copy)

Norwegian Medicines Agency Sven Oftedals vei 8 0950 OSLO NORWAY

EMEA Secretariat 1 paper copy and

1 paper copy or CD-ROM (only for centrally

authorised products)

European Medicines Agency – EMEA Central Information Group (CIG) 7 Westferry Circus Canary Wharf LONDON E14 4HB UNITED KINGDOM

5715