Cobert's Manual of Drug Safety and

Pharmacovigilance Edition

Barton Cobert, MD, FACP, FACG,

BLCMD Associates Wcstfield. Jersey

JONES & BARTLETT G

Contents

Introductions xix

Contributors • . xxi

Noticc . • •

1 The Thcory and of Drug 1

Thcory . . . . . 1 . . . . . . . . . 1

Advcrse . . . . . . . . . . Adverse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Adverse Reaction 2 Serious Adverse Event and Serious Reaction . • • . . . • . . . . . . . . 2

3 Suspected Adverse Drug Reaction 3 Serious, Adverse Drug . . . . . . . . . . . . . . . . . . . . . . . . . 3 Serious, Expected. Adverse Drug • . . . • . . • • . . • . . . . . . 3 Suspected . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Suspected, Unexpected, Serious

(Drug) Reaction . . . . . . . . . . . . . . . . . . 3

Unexpected Adverse . . . . . . . . . . . . 4 Unlisted Adverse 4 Expected • . • . . • • . . . • . . . • • . . . . . . . . . . . . 4

The Practice . . • • • . . . • • . . . • . . . . . . . . 4

2 Clinical Trials, Clinical Research Organizations, Phases and Trials 7 Phase 7 Phase II 8 Phase III 8 Phase IV 9 Late Phase Studies 9 Investigator-Initiated Trials or Studies 10 Other Study Related Issues 10 Frequently Asked Questions 12

Chapter 3 Spontaneous Postmarketing Adverse Events United States Regulations 18 European Union 18 Other Regions 18 Process Issues 19 Frequently Asked Questions 20

Chapter 4 The Theory of Drug Safety 21 A Brief History of the 21 Regulations, and Guidances 22 The United States Regulations and Guidances 22 The European Union Directives, Regulations, and Guidances 23 Frequently Asked Questions 25

Chapter 5 Adverse Events with New Chemical Entities, Generics, Excipients, Placebos, and Counterfeits 27 Generics 28 Excipients 28 Placebo 29 Other AEs 30 Placebo and Breaking the Blind in Clinical Trials 30 Picking up AEs to Excipients 31 Generics 31 Adverse Events with Counterfeit, Impure, and Other Products 32 Frequently Asked Questions 33

Chapter 6 Acute and Chronic (Late Occurring) Adverse Events, Adverse Events That Disappear (Bendectin), and Diethylstilbesterol 35 Bendectin: A Alert 36

Market 36 Return to the Market in Canada and Europe 36

Adriamycin 36 Gene Therapy 36 Antiretroviral Drugs 37 Diethylstilbestrol (DES) 37

Delayed Onset of Malignancy (Long Latency) 37 Actions Taken 38

The for Long-Latency AEs 38 Frequently Asked Questions 38

Contents

Chapter 7 The Mathematics of Adverse Events and Brief Note on Pharmacoepidemiology 39 Weber Effect 40 Secular Effects 40 Reporting Rates Versus Rates 40

Proportional Reporting Rate (PRR), Also Known As . . . 41 Other Data Mining Methods 42

and Trials . . . . Randomized Clinical or . .

ontrol Study 44 Study 44 C.ase-C ontrol Study 44

Chapter 8 Where Data 45 AERS 45 Clinical Trial Data 46 The Uppsala Monitoring Centre • 46 Vigibase 46 EMEA EudraVigilance Database 47 Motherisk 47 Health Canada 48 MHRA 48 Teratology Data 48 General Practice Research Database (GPRD) 48 Other Registries and Databases 48

Chapter 9 Regulations, Directives, Guidances, and 49 United . European Union 50 The Practice . 51

Drugs 51 United States European Union 52

Staying Up to Date 52 Literature 52

Meetings and Conferences 53 The Internet 53

Chapter 10 Children, Elderly, and Other Special (Vulnerable) Groups 55 Background 55 The Theory . 55

Children . 55 United States 56 In the European Union 56 The Elderly 57 The ICH and Guidelinc 57 FDA Guideline and 58 Other Special Groups 58

58 African 59

Contents

Chapter Drug Interactions 61 Cytochrome P450 62 Frequency 63 Communication 63

Chapter 12 AE Volume, Quality, Good Documentation Procedures, and Medical Records 65 Archiving 67 Record Retention Times 68 Good Documentation Practices 68

Chapter 13 Seriousness, Expectedness, and Causality 69 Seriousness 69 Expectedness 71 Relatedness (Causality) 72 Methodology 73

Global Introspection 73 74

Comment 74 Health Authority Guidance and Requirements 74 United States FDA 75 European Union 76

I Assessment of Causality 76 Uppsala Monitoring Centre (WHO) 77

of Cases Received Versus at the Time of Periodic Reporting and Signaling 77

Comment 77

Chapter Coding of AEs and Drug 79 AE Coding 79

MedDRA 79 Status 80

(SMQs) 82 SNOMED CT 82

AE Severity Coding 83 Drug Names and Drug 83 Multiple Names and Name Changes 84 WHO Drug Dictionary 85 EudraVigilance Medicinal Product Dictionary (EVMPD) 86 The 86

Chapter Expedited and Aggregate Reporting in Clinical Trials 87 Expedited Reporting 87 Clinical Trial Reporting 87 United States for Expedited Reports 88 Expedited IND Reports (Alert Reports, 7- and IND Reports) 88 IND Reports 90 Other Clinical Trial (IND) Reporting Issues 91 When to Start Collecting Serious AEs in Trial 92 European Union Requirements 92

Expedited Reporting in Clinical Trials 92

Contents

Annual Safety Reports Canadian 93 Elsewhere 94

Chapter Postmarketing Spontaneous Reporting 95 General Principles 95 Postmarketing Versus Clinical Trial IC 95

of AEs 97 and 98

Other Sources of Reports 98 Iollow-Up 98 Notes on United States Requirements for NDA Reporting of Es 99

to 99 Reports EDA via the Freedom of Information Act Instructions on Eilling Out the Form European Union Regulations Canadian Regulations 101 Australian Regulations 101 Frequently Asked Questions 101

Chapter 17 Periodic Adverse Drug Experience Reports (PADERS): NDA Periodic Reports and Periodic Safety Update Reports (PSURs) 103 NDA Periodic Reports 103 PSURs to the FDA 104 Postmarketing Periodic Reports

Section Summary and Analysis Section 2: Narrative I 105 Section 3: I ine 106 Section 4: 1 DA or RS

Reports PSURs PSURs to EDA Frequently Asked Questions 108

Chapter 18 Epidemiology and Pharmacoepidemiology: What Are They? What Are Their Limitations and Advantages? 109 Case Report or Individual Case Safety Report (1CSR) Aggregate Reports Randomized Clinical Trial (RCT)

Study Cohort Study Nested ontrol Study Confidence Frequently Asked Questions

Chapter 19 Signals and Signaling in the Context of Risk Management 115 The Signal. 115 Signal Sources and Generation Increased Frequency 117 Data Mining

x Contents

Other Sources of Signal Data Putting All Together

Organizational Team 119 Workup 119

119 Arrange and Review 119 The Workup 120 The Conclusions and Next Steps 121 The Safety Committee 121

Tools for Signal Detection and Workup 122 Key Documents on Signaling and Good PV Practices 123

The FDA Guidance on Good Practices of 3/2005 Investigating a Signal 123 Interpreting a Signal 124 European Union Volume on Signal Detection 126 MHRA Comments on Signal Detection 126 Frequently Asked Questions 127

Chapter 20 Information Technology, Databases, and Computers 129 Required Safety Database Functionality 130 Database Support 132 Data Entry 133 Data Transmission (E2B) 133 The Future of E2B (R3) 134 Safety Databases 134 Database Migration Health Level 7 (HL-7) 135

136 Clinical Terms CT) . . 136

21 United States Food and Drug Administration (FDA) and MedWatch . . 137 CDER (Center for Drug Evaluation and Research) The Safety Portal 139 Risk Management 140 MedWatch 140 Safety Databases 141 Other Useful FDA Web Pages 142 CBER (Center for Biologics Evaluation and Research) 142 CDRH (Center for Devices and Radiologie Health) 143 OTCs Products) 143 Drug Safety Board 144 Prescription Drug User Fee Act (PDUFA) and FDAAA 144 Prescription Drug User Fee Act Five-Year Plan 145 Sentinel Initiative 145 The Tome 145 What Expected Drug Companies by the FDA 146 What Is Expected from Consumers and Healthcare Professionals by the FDA 146 FDA Publications and Updates 146 Drug Safety Inspections 148 Frequently Asked Questions 148

Contents

Chapter 22 The European Agency (EMA, EMEA) 151 Volume 9A Postmarketing PV Volume 10 Clinical Trial PV The EMA Website European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCePP) Newsletters and RSS Comments I Changcs

Premarketing

Frequently Asked Questions

Chapter 23 The Qualified Person for Pharmacovigilance Practicalities Frequent QP Inspection Findings by the EMA 161 Frequently Asked Questions 161

Chapter 24 United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) 163 The Yellow Card 164 Black Triangle Products [ • ] 164 Regulations 164 Inspections 165

Industry Page: A One-Stop Resource Drug Analysis Prints (DAPs) 165 Providing Cases to MA E-mail Service Reporting AEs in the United Kingdom Good Pharmacovigilance Practice Guide Publication

Purple Book") Comments

Chapter 25 Health Canada 167 E-mail Notifications and RSS Feeds

Chapter 26 Australian Therapeutic Goods Administration (TGA) AE Reporting Risk Management

Chapter 27 The Uppsala Monitoring Centre 171 WHO Programme for International Drug Monitoring Publications

Chapter 28 Data Privacy and Security United States Health Insurance Portability and Accountability Act

174 The European Union and the Privacy Directive Safe Harbor Canada 177 Japan

xfl Contents

Chapter 29 The and Interactions of Companies, Nongovernmental Organizations (NGOs), and Others in the World of Pharmacovigilance 179 The Pharmaceutical Companies 180

181 The Media 183 NGOs and Lobbies 183 Industry Organizations 183 Litigation, Lawyers, and Legalities 183 Other Groups 184 Organizations for Drug Safety Personnel 184 Conclusions and Comments . . . . . . . 185 Frequently Asked 185

Chapter 30 Risk: What Is Risk Management and Assessment, Risk Evaluation and Minimization Systems (REMS), and Risk Management Plans (RMPs) 187 Why Risk Management? 188 The FDA 189 The Proposed REMS 190

Comments 191 REMS 192

REMS Template 192 Comments 192

European Union Risk Management Plans (RMPs) 193 When Is an RMP Needed? 193 The Safety Specification (Part I ) . . . . . . . . . . . . 194

The Nonclinical Section 194 The Clinical Section 194 The PV Plan . 194 Practicalities, Coordination, and Comments Risk Management Within Pharma Companies • 196 Comments and Suggestions 197

Chapter 31 The United States Three Risk Guidances of 2005 199 The First Guidance: Premarketing Assessment 199

Size of the Safety Database 199 Long-Term Controlled Safety Trials . 200 Diversity 201 Exploring Dose Effects 201 Drug Interactions 201 Comparative Safety Data 201 Large Simple Safety Studies . . . . . . . . 202 Medication Errors 202 Assessing During 202 Data Analysis and Interpretation . . . . . . . . . . . . . . . 203

The Second Guidance: Development and of Risk Minimization Action Plans 204 The Third Guidance: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment . . . 205

Signals: Good Reporting Practice 205 Developing a Case Series 205 Data Mining 206

Contents

Signals Warrant Eurther 206 Reporting Rates Versus Rates 207

Studies 207 207

ries 208 208

o\ Plan 209

Chapter 52 Data Management ( ommittees Data Management C ommittees Investigational Boards/1 C ommittees 214

Chapter Product Quality Issues Drugs . 120

Biologics 220 221

Frequently Asked Questions 221

Chapter 34 Drug Labeling 223 Investigator Brochure (1B) 223 Clinical Core Safety Information 224 United States Safety Labeling for Marketed Products 224 European Lnion Safety label ing for Marketed Products 226 Other C 226 OTC Labeling in the United States 227 I Asked Questions 228

C and I 229 Situation in the States 229 Proposed ( hanges by I DA 2 30 I DA Guidance for 2 30 Practices 2 31

Reporting Requirements 231 Situation in the European Union 231 Lactation 232

in Pregnant Partners of Males Taking a Drug 232 Other Resources 233

233 Molherisk . . . 233 Teratologv Registries and Organizations 2 34

requcntlv Asked Questions 234

36 2 35 1 (1990): International Reporting of Adverse Drug 236

11 (1992): International Reporting of Periodic Update Summaries 2 36 CIOMS and for Prrparing

Clinical Safety Information on Drugs Including New Proposais for Brochures 237 CIOMS Bencfit-Risk Balance for Marketed Drugs: Evaluating Safety Signals 238

Contents

CIOMS V (2001): Current Challenges in Pharmacovigilance: Pragmatic Approaches 239 CIOMS (2005): Management of Safety Information from Clinical Trials . . 244 General Principles and Ethical Considerations 244 Systemic Approach to Managing Safety Data 244 Data Collection and Management 245 Other Points 245 Risk Identification and Evaluation 246 Frequency of Review of Safety Information 246 Analysis and Evaluation 247 Statistical Approaches 247 Regulatory Reporting and Communications of Safety Information from Clinical Trials 247 CIOMS VII (2006): Development Safety Update Report (DSUR) 248 CIOMS VIII (2010): Signal Detection (Points to Consider in Application of Signal Detection in Pharmacovigilance) 249 Other Areas 249

Chapter 37 International Conference on Harmonization (ICH) 251 E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting 251

Definitions 252 What Should Be Reported to Regulatory Authorities as Expedited Reports? . . 252 Reporting Time Frames 252 Minimum Criteria for Reporting 252 Managing Blinded Cases 253 Other Issues 253

The E2B(R2) and M2 253 E2C(R1) Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs 254 E2D: Postapproval Safety Data Management: Definitions and Standards for Expedited Reporting 258

Definitions 258 Sources of Individual Case Safety Reports 259 Standards for Expedited Reporting 260 Good Case Management Practices 260

E2E: Pharmacovigilance Planning 261 Background and Scope 262

The Sections of a Pharmacovigilance Plan 262 Pharmacovigilance Plan 263

E2F: Development Safety Update Report 264

Chapter 38 Pharmaceutical Companies 267 Big and Somewhat Big Pharma 267 Midsized and Pharma 269 Clinical Research Organizations, Also Called Contract Research Organizations (CRO) 269 Mergers, Acquisitions, and Bankruptcies 270

Chapter 39 Universities and Medical Centers 271 The Act in the United States 271 Clinical Research Units 272

Contents

Drug Safety Training in Academia 272 Academic 273 RADAR (Northwestern University) 274

Chapter 40 Organization of a Typical Drug Safety Department 275 Management 275 The Qualified Person 275 Triage Unit 275 Case Assessment and Prioritization 276 Data Entry Unit 276 Case Processing Unit 277 Medical Case Review 277 Transmission Unit 277 Regulatory Unit 277 Legal Unit 277 Signaling, Pharmacovigilance, Pharmacoepidemiology, Medical Information, or Medical Affairs Unit 277 Aggregate Report Preparation 278 Labeling Review and Update for Safety 278 278 Information Liaison 279 Standard Operating Procedure (SOP) Creation and Maintenance 279 Training 280 Quality 280 Safety (AE) Exchange Agreement Function: Creation and Maintenance. . . . 280 Literature Review 281 Data Dictionary Maintenance 281 Coding Unit 281 Planning and Project 282 Risk Management 282 Liaison to Safety 282

Chapter 41 How an Case Safety Report (1CSR) Is Handled from Start to Finish 283 AE Sources and Arrival in the Safety Department 284 Triage 286 Database Entry 287 Quality Review 288

288 Medical Review 288 Case 288 Case Distribution and Transmission 289 Tracking 289 Investigator Notification 290 15 Calendar Days and Day 0 Versus Day 1 291

Chapter 42 The Safety Role in Clinical Research, Marketing and Labeling, Regulatory, Due and Legal Issues 293 Clinical Research 293

CROs 296 Marketing and Sales 296 The Labeling Department 297

xvi Contents

The Legal Department 297 Regulatory Affairs Department 298 The Quality and Compliance Department 298 New Business Due Diligence 298 Toxicology and Pharmacology 299 Signaling and Epidemiology Groups 299 The Medical Information Department 299 Manufacturing (Product Quality Complaints) 299

Chapter 43 SOPs, Working Documents, Manuals, Guidelines 301

Chapter 44 Training 307 Organizational Structure and Site Information 309 Computer, Electronic, and Print Resources 309

Is Pharmacovigilance? 309 Corporate and Drug Safety SOPs, Working Documents, Guidelines, and Manuals 309 Medical Dictionary for Regulatory Activities (MedDRA) and Other Dictionaries 309 Safety Database 309 Workflow 310 Partner and CRO Interactions 310

Signaling and Pharmacovigilance 310 Outside Training

Chapter 45 Vaccinovigilance 311 Lisa Ferstenberg, MD Differences Between Vaccinovigilance and Pharmacovigilance 311 The United States Initiative: VAERS 312 GACVS and the European Commissions 312 Vaccine Adverse Event Reporting 313 The European Union System 314 Sources of Additional Information 314

Chapter 46 Toxic Effects of Immunogenicity to 317 Ana T. Menendez, PhD Introduction 317 Granulocyte-Colony Stimulating Factor (G-CSF): Minimal Antibody Production 318 Thrombopoietin (TPO): Major Immunogenic Toxicity 318 Insulin: Antibodies Without Clinical Toxicity 318 Natalizumab: Short-Term, Adverse Reactions 318 Infliximab: Additional Therapy Needed 319 Enzyme Replacement Therapy: Endogenous Protein Is Absent 319

(EPO): Formulation Change Producing Immunotoxicity . . . 319 Conclusions 320

Chapter 47 Business Partners and Exchange of Safety Data 321 a Written Safety Exchange Agreement Is Needed 322

Telling the Safety Department About a New Contract or Arrangement 322 The Generic, or Template Agreement 322

Contents xv

Safety Agreement with the Safety Department 32 3 The Safety Agreement Database 32 3 The Safety Agreement Contents 324 The Regulatory Status 324 The Regulatory 324 Regulatory Documents 324 Health Authority Queries and Requests 324 Regulatory 325

and Review Board/1 thics C and Data

Management Boards 325 Safety Databases Definitions 52o Data and Data Exchange Signaling. and Risk Management 327 Audits 327 Other 327 Soft Points 328 Comments 328

Chapter 48 Audits and Inspect ions 329 The Basics 329 Scope of the Audit 330 How an 331 Findings 332

332 Common lnspection 3 32 The Response to the lnspection Audit 33 3 Ehe Action Action Plan (( APA) 33 5 I DA Inspections 5 5

on EMA and 3 Quality Systems and lnspection Preparation in C ompanies 3 3*4

Key Documents )

and Comment s 3 35

Chapter 49 of PV Risk-Based Inspections 337 The Detailed Description of the PV System (Volume 9A Section 2.2) 337 The MHRA of PV Systems (SPS) 3 38 The Compliance (MHRA) 340 Comment

Chapter 50 and of 34 3 Dynamics at Play in Regard to Drug Safety and 345 Data Safety Management Boards and 547 Dynamics in Play in Regard to Drug and Health Agencies 347 Dynamics in Play in Regard to Drug Safety and and

Healthcare I 348 Dynamics in Play in Regard to Drug Safety and Groups , Disease Groups , and Internet Websi tes ,

Social Media, etc.) 349 Dynamics in Play in Regard to Drug Safety and 1 itigation 350

xviii Contents

Codes of Conduct 350 Comments and Summary 350

Chapter 51 Vigilance of Natural Health Products 351 MD, CCFP, FCFP, Kevin ND, BHsc,

and Alison Ingham, PhD Prevalence of NHP Use and Safety Issues 352 Data Sources and Adverse Reaction Reporting (ARR) 352 ARs and Causality Assessment 353 Safe Analysis: Signal Evaluation 354 NHP Interactions and Medical Relevance 354 International Collaboration: Methods to Address Regulatory 354 Initiatives to Strengthen Vigilance of NHPs 354 Summary 357

358 References 358

Chapter 52 Issues: Fialuridine 361

Chapter 53 Real-World Issues: Fen-Phen 365

Chapter 54 Real-World Issues: 367

Web Resources 369

Abbreviations 395

Index 399