Cobert’s Manual of Drug Safety and Pharmacovigilance

COBERT\'S MANUAL OF DRUG SAFETY AND PHARMACOVIGILANCE, SECOND EDITION......Page 1
Table of Contents......Page 5
Introduction to the First Edition......Page 19
Introduction to the Second Edition......Page 20
Contributors......Page 21
Notice......Page 23
The Theory......Page 25
The Practice......Page 28
Phase I......Page 31
Phase III......Page 32
Late Phase Studies......Page 33
Other Study Related Issues......Page 34
Frequently Asked Questions......Page 36
CHAPTER 3: Spontaneous Postmarketing Adverse Events......Page 39
Other Regions......Page 42
Process Issues......Page 43
Frequently Asked Questions......Page 44
A Brief History of the FDA......Page 45
The United States Regulations and Guidances......Page 46
The European Union Directives, Regulations, and Guidances......Page 47
Frequently Asked Questions......Page 49
CHAPTER 5: Adverse Events with New Chemical Entities, Generics, Excipients, Placebos, and Counterfeits......Page 51
Excipients......Page 52
Placebo......Page 53
Placebo and Breaking the Blind in Clinical Trials......Page 54
Generics......Page 55
Adverse Events with Counterfeit, Impure, and Other Nonstandard Products......Page 56
Frequently Asked Questions......Page 57
CHAPTER 6: Acute and Chronic (Late Occurring) Adverse Events, Adverse Events That Disappear (Bendectin), and Diethylstilbesterol......Page 59
Gene Therapy......Page 60
Diethylstilbestrol (DES)......Page 61
Frequently Asked Questions......Page 62
CHAPTER 7: The Mathematics of Adverse Events and a Brief Note on Pharmacoepidemiology......Page 63
Reporting Rates Versus Incidence Rates......Page 64
Other Data Mining Methods......Page 66
Pharmacoepidemiology and Trials......Page 67
AERS......Page 69
Vigibase......Page 70
Motherisk......Page 71
Other Registries and Databases......Page 72
United States......Page 73
European Union......Page 74
Over-the-Counter Drugs......Page 75
Staying Up to Date......Page 76
The Theory......Page 79
CHAPTER 11: Drug Interactions......Page 85
Cytochrome P450......Page 86
Communication......Page 87
CHAPTER 12: AE Volume, Quality, Good Documentation Procedures, and Medical Records......Page 89
Archiving......Page 91
Good Documentation Practices......Page 92
Seriousness......Page 93
Expectedness......Page 95
Relatedness (Causality)......Page 96
Methodology......Page 97
Health Authority Guidance and Requirements......Page 98
United States FDA......Page 99
CIOMS I Assessment of Causality......Page 100
Comment......Page 101
AE Coding......Page 103
Drug Names and Drug Dictionaries......Page 107
Multiple Names and Name Changes......Page 108
WHO Drug Dictionary Enhanced......Page 109
The Future......Page 110
Clinical Trial Reporting......Page 111
Expedited IND Reports (Alert Reports, 7- and 15-Day IND Reports)......Page 112
IND Annual Reports......Page 114
Other Clinical Trial (IND) Reporting Issues......Page 115
European Union Requirements......Page 116
Canadian Requirements......Page 117
Elsewhere......Page 118
Postmarketing ICSRs Versus Clinical Trial ICSRs......Page 119
Sources of AEs......Page 121
Follow-Up......Page 122
MedWatch to Manufacturer Program......Page 123
European Union Regulations......Page 124
Frequently Asked Questions......Page 125
NDA Periodic Reports......Page 127
PSURs to the FDA......Page 128
Postmarketing Periodic Reports......Page 129
PSURs......Page 130
Frequently Asked Questions......Page 132
CHAPTER 18: Epidemiology and Pharmacoepidemiology: What Are They? What Are Their Limitations and Advantages?......Page 133
Aggregate Reports......Page 134
Case-Control Study......Page 135
Cohort Study......Page 136
Frequently Asked Questions......Page 137
The Signal......Page 139
Signal Sources and Generation......Page 140
Data Mining......Page 141
Other Sources of Signal Data......Page 142
Putting It All Together......Page 143
Computerized Tools for Signal Detection and Workup......Page 146
Investigating a Signal......Page 147
Interpreting a Signal......Page 148
MHRA Comments on Signal Detection......Page 150
Frequently Asked Questions......Page 151
CHAPTER 20: Information Technology, Databases, and Computers......Page 153
Required Safety Database Functionality......Page 154
Database Support......Page 156
Data Transmission (E2B)......Page 157
Safety Databases......Page 158
Health Level 7 (HL-7)......Page 159
Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT)......Page 160
CDER (Center for Drug Evaluation and Research)......Page 161
The Safety Portal......Page 163
MedWatch......Page 164
Safety Databases......Page 165
CBER (Center for Biologics Evaluation and Research)......Page 166
OTCs (Over-the-Counter Products)......Page 167
Prescription Drug User Fee Act (PDUFA) and FDAAA......Page 168
The Tome......Page 169
FDA Publications and Updates......Page 170
Frequently Asked Questions......Page 172
CHAPTER 22: The European Medicines Agency (EMA, EMEA)......Page 175
Volume 9A Postmarketing PV......Page 177
European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCePP)......Page 178
Future Changes......Page 179
Frequently Asked Questions......Page 180
CHAPTER 23: The Qualified Person for Pharmacovigilance......Page 183
Practicalities......Page 184
Frequently Asked Questions......Page 185
CHAPTER 24: United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA)......Page 187
Regulations......Page 188
Drug Analysis Prints (DAPs)......Page 189
Comments......Page 190
CHAPTER 25: Health Canada/Santé Canada......Page 191
E-mail Notifications and RSS Feeds......Page 192
AE Reporting......Page 193
Risk Management......Page 194
WHO Programme for International Drug Monitoring......Page 195
Publications......Page 196
CHAPTER 28: Data Privacy and Security......Page 197
United States Health Insurance Portability and Accountability Act (HIPAA)......Page 198
The European Union and the Privacy Directive......Page 199
Safe Harbor......Page 200
Canada......Page 201
Japan......Page 202
CHAPTER 29: The Roles and Interactions of Companies, Governments, Nongovernmental Organizations (NGOs), and Others in the World of Pharmacovigilance......Page 203
The Pharmaceutical Companies......Page 204
Governments......Page 205
Litigation, Lawyers, and Legalities......Page 207
Organizations for Drug Safety Personnel......Page 208
Frequently Asked Questions......Page 209
CHAPTER 30: Risk: What Is It? Risk Management and Assessment, Risk Evaluation and Minimization Systems (REMS), and Risk Management Plans (RMPs)......Page 211
Why Risk Management?......Page 212
The FDA......Page 213
The Proposed REMS......Page 214
Classwide REMS......Page 216
When Is an RMP Needed?......Page 217
The PV Plan......Page 218
Practicalities, Coordination, and Other Comments......Page 219
Risk Management within Pharma Companies......Page 220
Comments and Suggestions......Page 221
The First Guidance: Premarketing Risk Assessment......Page 223
The Second Guidance: Development and Use of Risk Minimization Action Plans......Page 228
The Third Guidance: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment......Page 229
Data Management Committees......Page 235
Investigational Review Boards/Ethics Committees......Page 238
CHAPTER 33: Product Quality Issues......Page 241
Frequently Asked Questions......Page 245
Investigator Brochure (IB)......Page 247
United States Safety Labeling for Marketed Products......Page 248
Other Countries......Page 250
OTC Labeling in the United States......Page 251
Frequently Asked Questions......Page 252
Situation in the United States......Page 253
FDA Guidance for Industry—2002......Page 254
Situation in the European Union......Page 255
AEs in Pregnant Partners of Males Taking a Drug......Page 256
Motherisk......Page 257
Frequently Asked Questions......Page 258
CHAPTER 36: CIOMS......Page 259
CIOMS II (1992): International Reporting of Periodic Drug-Safety Update Summaries......Page 260
CIOMS III (1995 and 1998/1999): Guidelines for Preparing Core Clinical Safety Information on Drugs (1995), Including New Proposals for Investigator’s Brochures (1998/1999)......Page 261
CIOMS IV (1998): Benefit–Risk Balance for Marketed Drugs: Evaluating Safety Signals......Page 262
CIOMS V (2001): Current Challenges in Pharmacovigilance: Pragmatic Approaches......Page 263
Systematic Approach to Managing Safety Data......Page 268
Other Points......Page 269
Frequency of Review of Safety Information......Page 270
Regulatory Reporting and Communications of Safety Information from Clinical Trials......Page 271
CIOMS VII (2006): Development Safety Update Report (DSUR)......Page 272
Other Areas......Page 273
E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting......Page 275
The E2B(R2) and M2 Documents......Page 277
E2C(R1) Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs......Page 278
E2D: Postapproval Safety Data Management: Definitions and Standards for Expedited Reporting......Page 282
E2E: Pharmacovigilance Planning......Page 285
The Sections of a Pharmacovigilance Plan......Page 286
E2F: Development Safety Update Report......Page 288
Big and Somewhat Big Pharma......Page 291
Clinical Research Organizations, Also Called Contract Research Organizations (CRO)......Page 293
Mergers, Acquisitions, and Bankruptcies......Page 294
The Bayh-Dole Act in the United States......Page 295
Drug Safety Training in Academia......Page 296
Academic Consultation......Page 297
RADAR (Northwestern University)......Page 298
Triage Unit......Page 299
Data Entry Unit......Page 300
Signaling, Pharmacovigilance, Pharmacoepidemiology, Medical Information or Medical Affairs Unit......Page 301
Archive/File Room......Page 302
Standard Operating Procedure (SOP) Creation and Maintenance......Page 303
Safety (AE) Exchange Agreement Function: Creation and Maintenance......Page 304
Coding Unit......Page 305
Liaison to External Organizations/Drug Safety Intelligence......Page 306
CHAPTER 41: How an Individual Case Safety Report (ICSR) Is Handled from Start to Finish......Page 307
AE Sources and Arrival in the Safety Department......Page 308
Triage......Page 310
Database Entry......Page 311
Case Closure......Page 312
Tracking......Page 313
Investigator Notification......Page 314
15 Calendar Days and Day 0 Versus Day 1......Page 315
Clinical Research......Page 317
Marketing and Sales......Page 320
The Legal Department......Page 321
New Business Due Diligence......Page 322
Manufacturing (Product Quality Complaints)......Page 323
CHAPTER 43: SOPs, Working Documents, Manuals, Guidelines......Page 325
CHAPTER 44: Training......Page 331
Safety Database......Page 333
Partner and CRO Interactions......Page 334
Differences Between Vaccinovigilance and Pharmacovigilance......Page 335
GACVS and the European Commissions......Page 336
Vaccine Adverse Event Reporting......Page 337
Sources of Additional Information......Page 338
Introduction......Page 341
Natalizumab: Short-Term, Self-Limited Adverse Reactions......Page 342
Erythropoietin (EPO): Formulation Change Producing Immunotoxicity......Page 343
Conclusions......Page 344
CHAPTER 47: Business Partners and Exchange of Safety Data......Page 345
The Generic, Boilerplate, or Template Agreement......Page 346
The Safety Agreement Database......Page 347
Health Authority Queries and Requests......Page 348
Safety Databases......Page 349
Data and Mechanisms of Data Exchange......Page 350
Other Issues......Page 351
Comments......Page 352
The Basics......Page 353
Scope of the Audit......Page 354
How an Inspection Flows......Page 355
Common Inspection Findings......Page 356
FDA Inspections......Page 357
Quality Systems and Inspection Preparation in Companies......Page 358
Summary and Comments......Page 359
The Detailed Description of the PV System (Volume 9A Section 2.2)......Page 361
The MHRA Summary of PV Systems (SPS)......Page 362
The Compliance Report (MHRA)......Page 364
Comment......Page 365
CHAPTER 50: Ethical Issues and Conflicts of Interest......Page 367
Dynamics in Play in Regard to Drug Safety and Companies......Page 369
Dynamics in Play in Regard to Drug Safety and Health Agencies......Page 371
Dynamics in Play in Regard to Drug Safety and Academia and Nonacademic Healthcare Facilities......Page 372
Dynamics in Play in Regard to Drug Safety and Consumer Groups, Disease Groups, and the Internet (Blogs, Websites, Social Media, etc.)......Page 373
Comments and Summary......Page 374
CHAPTER 51: Vigilance of Natural Health Products......Page 375
Data Sources and Adverse Reaction Reporting (ARR)......Page 376
ARs and Causality Assessment......Page 377
Initiatives to Strengthen Vigilance of NHPs......Page 378
Summary......Page 381
References......Page 382
CHAPTER 52: Real-World Issues: Fialuridine......Page 385
CHAPTER 53: Real-World Issues: Fen-Phen......Page 389
CHAPTER 54: Real-World Issues: Nomifensine......Page 391
Web Resources......Page 393
Abbreviations......Page 419
Index......Page 423