Cobert's Manual of Drug Safety and Pharmacovigilance, 2nd Edition

Completely revised and updated, the Manual of Drug Safety and Pharmacovigilance, Second Edition is a how-to manual for those working in the fields of drug safety, clinical research, pharmacology, regulatory affairs, government and legal professions. This comprehensive and practical guide discusses the theory and the practicalities of drug safety (also known as pharmacovigilance) and side effects, as well as providing essential information on drug safety and regulations, including: recognizing, monitoring, reporting and cataloging serious adverse drug reactions. The Manual of Drug Safety and Pharmacovigilance, Second Edition teaches the ins and outs of drug safety in the industry, hospitals, FDA, and other health agencies both in the US and around the world, and presents critical information about what is done when confronted with a drug safety problem. Important Notice: The digital edition of this book is missing some of the images or content found in the physical edition. 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

Completely revised and updated, the Manual of Drug Safety and Pharmacovigilance, Second Edition is a how-to manual for those working in the fields of drug safety, clinical research, pharmacology, regulatory affairs, government and legal professions. This comprehensive and practical guide discusses the theory and the practicalities of drug safety (also known as pharmacovigilance) and side effects, as well as providing essential information on drug safety and regulations, including: recognizing, monitoring, reporting and cataloging serious adverse drug reactions.

The Manual of Drug Safety and Pharmacovigilance, Second Edition teaches the ins and outs of drug safety in the industry, hospitals, FDA, and other health agencies both in the US and around the world, and presents critical information about what is done when confronted with a drug safety problem.