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William Gregory. Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition)
Thank You
Contents
Introductions. Introduction to the First Edition
Introduction to the Second Edition
Introduction to the Third Edition
Contributors
Notice
CHAPTER. 1. The Theory and Definitions of Drug Safety — Pharmacovigilance
The Theory
Adverse Event (AE) — ICH
Adverse Event (AE) — EMA
Adverse Event/Experience (AE) — FDA
Adverse Reaction (AR)
Serious Adverse Event and Serious Adverse Reaction (SAE/SAR)
Non-serious Adverse Event and Non-serious Adverse Reaction (NSAE/NSAR)
Suspected Adverse (Drug) Reaction (SAR/SADR) — FDA
Serious, Unexpected, Suspected Adverse Reaction (SUSAR)
Serious, Expected, Suspected Adverse Reaction
Unexpected Adverse Event — FDA
Unexpected Adverse Reaction — EMA
Unlisted Adverse Reaction — EMA
Expected (Listed versus Labeled)
The Practice
CHAPTER. 2. Clinical Trials, Clinical Research Organizations, Phases I–IV, and Investigator-Initiated Trials
Introduction
Phase I
Phase II
Phase III
Phase IV
Late Phase Studies
Investigator-Initiated Research
Other Study-Related Issues
Frequently Asked Questions
CHAPTER. 3. Spontaneous Post-marketing Adverse Events
Introduction
United States Regulations
European Union Requirements
Other Regions
Process Issues
Frequently Asked Questions
CHAPTER. 4. The Theory of Drug Safety — Pharmacovigilance
A Brief History of the FDA
Regulations, Laws, and Guidances
The United States Regulations and Guidances
The European Union Legislation (including Directives and Regulations), and Guidance
Frequently Asked Questions
CHAPTER. 5. The Mathematics of Adverse Events and a Brief Note on Pharmacoepidemiology
Introduction
Case Report or Individual Case Safety Report
Aggregate Reports
Reporting Rates versus Risk
Why We Can’t Calculate Good Rates
Quantitative Signal Detection Methods
Other Data Mining Methods
CHAPTER. 6. Epidemiology and Pharmacoepidemiology: What Are They? What Are Their Limitations and Advantages?
Introduction
Randomized Controlled Trial
Adaptive Clinical Trials
Cohort Study
Case-Control Study
Nested Case-Control Study
Confidence Intervals
Frequently Asked Questions
CHAPTER. 7. Regulations, Directives, Guidance, Laws and Consensus Documents
United States
European Union
Consensus Documents
The Practice
Over-the-Counter Drugs
United States
European Union
Staying Up to Date
Scientific/Medical Literature
Meetings and Conferences
The Internet
CHAPTER. 8. The United States Food and Drug Administration
Introduction
Center for Drug Evaluation and Research
The Safety Reporting Portal
Risk Management
MedWatch
Safety Databases
Other Useful FDA Web Pages
Center for Biologics Evaluation and Research
Center for Devices and Radiologic Health
Over-the-Counter Products
Drug Safety Oversight Board
Prescription Drug User Fee Act
Prescription Drug User Fee Act: Five-Year Plan
Food and Drug Administration Act (FDAAA) of 2007
21st Century Cures Act
FDA Reauthorization Act of 2017
The Sentinel System and ARIA
What is Expected from Drug Companies by the FDA?
What is Expected from Consumers and Healthcare Professionals by the FDA?
FDA Publications and Updates
Drug Safety Inspections
Frequently Asked Questions
CHAPTER. 9. The European Medicines Agency
Introduction
Registration Procedures in the EU
European Medicines Agency
Organization and Structure
Risk Management
EudraVigilance — The EU Safety Database
What Is Not in the Scope of EMA?
The Pharmacovigilance Risk Assessment Committee
Post-marketing PV EU Regulation
Volume 10 Clinical Trial PV
The EMA Website
European Network of Centers for Pharmacoepidemiology and Pharmacovigilance
Newsletters and RSS Feeds
Comments
Agence Nationale de Sécurité des Médicaments et Produits de santé
Missions
Scope
Organization
Frequently Asked Questions
CHAPTER. 10. The EU Qualified Person for Pharmacovigilance
Introduction
Practicalities
Frequent QPPV Inspection Findings by the EMA
Frequently Asked Questions
CHAPTER. 11. The Uppsala Monitoring Centre
WHO Programme for International Drug Monitoring
Key Functions of UMC
CHAPTER. 12. Council for International Organizations of Medical Sciences
Introduction
CIOMS I (1990): International Reporting of Adverse Drug Reactions
CIOMS II (1992): International Reporting of Periodic Drug-Safety Update Summaries
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)
CIOMS IV (1998): Benefit–Risk Balance for Marketed Drugs: Evaluating Safety Signals
CIOMS V (2001): Current Challenges in Pharmacovigilance: Pragmatic Approaches
CIOMS VI (2005): Management of Safety Information from Clinical Trials
Regulatory Reporting and Communications of Safety Information from Clinical Trials
CIOMS VII (2006): Development Safety Update Report (DSUR)
CIOMS VIII (2010): Signal Detection (Points to Consider in Application of Signal Detection in Pharmacovigilance)
CIOMS/WHO Working Group on Vaccine Pharmacovigilance (2012): Definitions and Applications of Terms for Vaccine Pharmacovigilance
CIOMS IX (2014): Practical Approaches to Risk Minimization for Medicinal Products
CIOMS X (2016): Evidence Synthesis and Meta-analysis
CIOMS SMQs (2016): Development and Rational Use of Standardized MedDRA Queries: Retrieving Adverse Drug Reactions with MedDRA — Second Edition
CIOMS (2017): Guide to Active Vaccine Safety Surveillance
CHAPTER. 13. Where Data Reside
Introduction
FDA Adverse Event Reporting System
FAERS Public Dashboard
FAERS Quarterly Data Files
Redacted ICSRs
Clinical Trial Data
The Uppsala Monitoring Centre
VigiBase
EMA EudraVigilance Database
Motherisk
Health Canada
MHRA
Teratology Data
General Practice Research Database and Clinical Practice Research Datalink
Other Registries and Databases
CHAPTER. 14. Information Technology, Databases, and Computers
Introduction
Required Safety Database Functionality
Data Entry
Workflow
Administration
Vendor Support and Information Technology Issues
Validation
Labeling Functions
Reporting Functions
Data Export and Import
Pharmacovigilance Functions
Database Support
Data Entry
Data Transmission (E2B)
E2B(R3)
Safety Databases
Database Migration
Health Level 7
Clinical Data Interchange Consortium
Systematized Nomenclature of Medicine Clinical Terms
Frequently Asked Question
CHAPTER. 15. Adverse Events with New Chemical Entities, Generics, Excipients, Placebos, and Counterfeits
Introduction
Generics
Excipients
Placebo
Other Manufacturers’ Drugs’ AEs
Placebo and Breaking the Blind in Clinical Trials
Picking up AEs Due to Excipients
Generics
Adverse Events with Counterfeit, Impure, and Other Non-standard Products
Online Pharmacies
Frequently Asked Questions
CHAPTER. 16. Children, Elderly, and Other Special (Vulnerable) Groups
Theory. Children
In the United States
In the European Union
The Elderly
FDA and the ICH E7 Guideline
FDA Guidance and Geriatric Rule
EMA
Other Special Groups
Women
African Americans
CHAPTER. 17. Pregnancy and Lactation
Introduction
Situation in the United States
Pregnancy
Lactation
Females and Males of Reproductive Potential
FDA Guidance on Pregnancy Registries — 2002
Good Epidemiologic Practices
Regulatory Reporting Requirements
Situation in the European Union
Lactation
AEs in Pregnant Partners of Males Taking a Drug
Other Resources
perinatology.com
Motherisk
Teratology Registries and Organizations
Frequently Asked Questions
CHAPTER. 18. Acute and Chronic (Late Occurring) Adverse Events, Adverse Events That Disappear (Bendectin) and Diethylstilbesterol
Introduction
Bendectin®: A False Alert. Market Removal
Return to the Market in Canada and Europe
Adriamycin®
Gene Therapy
Anti-retroviral Drugs
Diethylstilbestrol (DES)
Delayed Onset of Malignancy (Long Latency)
Actions Taken
Future for Long-Latency AEs
Frequently Asked Question
CHAPTER. 19. Drug Interactions
Introduction
Cytochrome P450
Drug–Food, Drug–Alcohol, Drug–Disease and Other Interactions
Frequency
Communication
CHAPTER. 20. Product Quality Issues
Introduction
Counterfeiting
Frequently Asked Question
CHAPTER. 21. AE Volume, Quality, Good Documentation Procedures, and Medical Records
Introduction
Archiving
Record Retention Times
Good Documentation Practices
CHAPTER. 22. Seriousness, Expectedness, and Causality
Seriousness
Expectedness
Relatedness (Causality)
Methodology
Global Introspection
Algorithms
Comment
Health Authority Guidance and Requirements
United States FDA
European Union
CIOMS I Assessment of Causality
Uppsala Monitoring Centre (WHO)
Judgment of Cases When Received Versus at the Time of Periodic Reporting and Signaling
Summary and Comments
CHAPTER. 23. Coding of Adverse Events and Drug Names
Introduction
AR/AE Coding. MedDRA
Regulatory Status
MedDRA in Practice
Standardized MedDRA Queries (SMQs)
Training
Systematized Nomenclature of Medicine — Clinical Terms
AE Severity Coding
Drug Names and Drug Dictionaries
Multiple Names and Name Changes
WHODrug Global
EudraVigilance Medicinal Product Dictionary
Future
Frequently Asked Question
CHAPTER. 24. Expedited and Aggregate Reporting in Clinical Trials
Expedited Reporting
Clinical Trial Reporting
United States Requirements for Expedited IND Reports
Expedited IND Reports (Alert Reports, 7-Day and 15-Day IND Reports)
IND Annual Reports
Other Clinical Trial (IND) Reporting Issues
European Union Requirements. Expedited Reporting in Clinical Trials
Development Safety Update Reports
When to Start Collecting Serious AEs in Trials
Canadian Requirements
Elsewhere
Bottom Line
CHAPTER. 25. Post-marketing Spontaneous ICSR/SAE Reporting
General Principles
Post-marketing ICSRs versus Clinical Trial ICSRs
Sources of AEs
Literature and Publications
Other Sources of Reports
Follow-Up
Notes on United States Requirements for Post-marketing NDA Reporting of SAEs
MedWatch to Manufacturer Program
Reports from the FDA via the Freedom of Information Act
Instructions on Filling Out the MedWatch Form
European Union Regulations
General Comments
Frequently Asked Questions
CHAPTER. 26. Periodic Adverse Drug Experience Reports, and Periodic Safety Update Reports/Periodic Benefit Risk Evaluation Reports
Introduction
NDA Periodic Reports
PSURs to the FDA
Post-marketing Periodic Reports
Section 1: Narrative Summary and Analysis
Section 2: Narrative Discussion of Actions Taken
Section 3: Index Line Listing
Section 4: ICSRs
Other Reports
Periodic Safety Update Reports
PSUR in ICH E2C(R2) Format: The Periodic Benefit–Risk Evaluation Report
Frequently Asked Question
CHAPTER. 27. Signals and Signaling in the Context of Risk Management
The Signal — Definition
Signal Sources and Generation
Increased Frequency
Data Mining
Other Sources of Signal Data
Putting It All Together
Organizational Team
Signal Workup
Prioritize
Arrange and Review
The Workup
The Conclusions and Next Steps
The Safety Committee
Computerized Tools for Signal Detection and Workup
Key Documents on Signaling and Good PV Practices. FDA Guidance on Good Pharmacovigilance Practices of 3/2005
Investigating a Signal
Interpreting a Signal
EU GVP Module IX — Signal Management (2012: Revision 1, Delivered Nov 2017)
Frequently Asked Questions
CHAPTER. 28. Risk: What Is It? Risk Management and Assessment, Risk Evaluation and Mitigation Strategies, and Risk Management Plans
Introduction
Why Risk Management?
The US FDA
The Proposed REMS
The Approved REMS
Roles of Key REMS Participants
Comments
Shared System REMS
REMS Template
Comments
European Union RMPs
When is an RMP Needed?
EU RMP Content
Part I: Product(s) Overview (GVP V. B.4)
Part II: Safety Specification (GVP V.B.5)
General considerations for generic products and advanced therapy medicinal products (GVP V.B.5.1)
Epidemiology of the indication(s) and target population(s) (GVP V.B.5.2 RMP part II Module SI)
The Non-clinical part of the safety specification (GVP V.B.5.3 RMP part II, Module SII)
Clinical trial exposure (GVP V.B.5.4 RMP part II, Module SIII)
Populations not studied in clinical trials (GVP V.B.5.5 RMP part II, Module SIV)
Post-authorization experience (GVP V.B.5.6 RMP part II, Module SV)
Additional EU requirements for the safety specification (GVP V.B.5.7 RMP part II, Module SVI)
Identified and potential risks (GVP V.B.5.8 RMP part II, Module SVII)
Summary of the safety concerns (GVP V.B.5.9 RMP part II, Module SVIII)
Part III: PV Plan, Including Post-authorization Safety Studies (GVP V.B.6 RMP part III)
Routine PV activities (GVP V.B.6.1 RMP part III)
Additional PV activities (GVP V.B.6.2 RMP part III)
Summary table of additional PV activities (GVP V.B.6.3 RMP part III)
Part IV: Plans for Post-authorization Efficacy Studies (GVP V.B.7 RMP part IV)
Part V: Risk Minimization Measures (Including Evaluation of the Effectiveness of Risk Minimization Activities) (GVP V.B.8 RMP part V)
Routine risk minimization activities
SmPC and PL
Evaluation of the effectiveness of non-routine risk minimization activities
Summary of risk minimization measures
Part VI: Summary of the RMP (GVP V.B.9 RMP part VI)
General Remarks on the EU RMP
Practicalities, Co-ordination, and Other Comments
Risk Management within Pharma Companies
Comments and Suggestions
CHAPTER. 29. Data Monitoring Committees and Investigational Review Boards/Ethics Committees. Data Monitoring Committees
Investigational Review Boards/Ethics Committees
Frequently Asked Questions
CHAPTER. 30. Pharmaceutical Companies
Introduction
Big and Somewhat Big Pharma
Mid-sized and Small Pharma
Contract/Clinical Research Organizations
Mergers, Acquisitions, and Bankruptcies
CHAPTER. 31. Organization of a Typical Drug Safety Department
Introduction
Management
Qualified (Responsible) Person for Pharmacovigilance
Triage Unit
Case Assessment and Prioritization
Data Entry Unit
Case Processing Unit
Medical Case Review
Transmission Unit
PV Regulatory Intelligence
Regulatory Unit
Legal Unit
Signaling, Pharmacovigilance, Pharmacoepidemiology, Medical Information or Medical Affairs Unit
Aggregate Report Preparation
Labeling Review and Update for Safety
Archive/File Room
Information Technology/Informatics Liaison
Quality Documents Creation and Maintenance
Training
Quality Assurance/Control
Safety (AE) Exchange Agreement Function: Creation and Maintenance
Literature Review
Data Dictionary Maintenance
Coding Unit
Planning and Project Management/Operations
Risk Management
Liaison to External Organizations/Drug Safety Intelligence
PV Worker Education, Skills, and Profile
Education
Skills
Profile
Frequently Asked Question
CHAPTER. 32. How an Individual Case Safety Report (ICSR) is Handled from Start to Finish
Introduction
AE Sources and Arrival in the Safety Department
Triage
Database Entry
Quality Review
Follow-Up
Medical Review
Case Closure
Case Distribution and Transmission
Tracking
Investigator Notification
15 Calendar Days and Day 0 versus Day 1
CHAPTER. 33. PV Quality System
Introduction
CHAPTER. 34. Training
Introduction
Organizational Structure and Site Information
Computer, Forms, Electronic, and Print Resources
What is Pharmacovigilance?
Corporate and Drug Safety SOPs, Working Documents, Guidelines, and Manuals
Medical Dictionary for Regulatory Activities (MedDRA®) and Other Dictionaries
Safety Database
Workflow
Partner and CRO Interactions. Signaling and Pharmacovigilance
Academic Training
Other External Training
CHAPTER. 35. Audits and Inspections
The Basics
Scope of the Audit
How an Inspection Flows
Findings
Penalties
Common Inspection Findings
The Response to the Inspection or Audit
The Corrective Action Preventive Action Plan (CAPA)
FDA Safety Inspections
Comments on EMA and MHRA Inspections
Quality Systems and Inspection Preparation in Companies
Key Documents
Summary and Comments
CHAPTER. 36. Pharmacovigilance System Master File
Introduction
Pharmacovigilance System Master File (Guideline on Good Pharmacovigilance Practice Module II)
Comment
Additional comments:
CHAPTER. 37. Ethical Issues and Conflicts of Interest∗
Introduction
Dynamics in Play in Regard to Drug Safety and Companies
Data Safety Management Boards and Ethics Committees/Institutional Review Boards
Safety Assessment Committee
Dynamics in Play in Regard to Drug Safety and Health Agencies
Dynamics in Play in Regard to Drug Safety and Academic and Nonacademic Healthcare Facilities
Dynamics in Play in Regard to Drug Safety and Consumer Groups, Disease Groups, and the Internet (Blogs, Websites, Social Media, etc.)
Dynamics in Play in Regard to Drug Safety and Lawyers/Litigation
Codes of Conduct
Comments and Summary
CHAPTER. 38. The Safety Department’s Role in Clinical Research, CROs, Marketing and Sales, Labeling, Regulatory, Quality, Due Diligence, Legal Issues, Toxicology, Epidemiology, Medical Information and Manufacturing
Clinical Research
CROs
Marketing and Sales
The Labeling Department
The Legal Department
Regulatory Affairs Department
The Quality and Compliance Department
New Business Due Diligence
Toxicology and Pharmacology
Signaling and Epidemiology Groups
The Medical Information/Medical Affairs Department
Manufacturing (Product Quality Complaints)
CHAPTER. 39. Drug Labeling
Investigator Brochure
Company Core Safety Information
United States Safety Labeling for Marketed Products
European Union Safety Labeling for Marketed Products
Other Countries
Comments about Labeling Content
OTC Labeling in the United States
Labeling Update Process
Comments
Frequently Asked Questions
CHAPTER. 40. Universities and Academic Medical Centers
The Bayh–Dole Act in the United States
Clinical Research Units/Academic Study Units
Translational Medicine
Drug Safety Training in Academia. North America
Europe
Academic Consultation
Bad Behavior
The Sunshine Act
CHAPTER. 42. Business Partners and Exchange of Safety Data
Introduction
Why a Written Safety Exchange Agreement is Needed
Telling the Safety Department about a New Contract or Arrangement
The Generic, Boilerplate, or Template Agreement
Developing a Safety Agreement with the Safety Department
Pharmacovigilance Agreement Database
Safety Agreement Contents
Regulatory Status
Regulatory Responsibilities
Regulatory Documents
Health Authority Queries and Requests
Regulatory Submissions
Investigator and Investigational Review Board/Ethics Committee Notifications: Blinding and Unblinding, Data Monitoring Committees (DMCs/DMSBs/DMSCs), Data Safety Boards
Safety Databases
Definitions
Data and Mechanisms of Data Exchange
Signaling, Safety Reviews, and Risk Management
Audits
Other Issues
Soft Points
Comments
Drug Due Diligence
CHAPTER. 43. Data Privacy and Security
Introduction
United States Health Insurance Portability and Accountability Act (HIPAA)
The European Union and the Privacy Regulation & Directive
EU-US Privacy Shield
Frequently Asked Question
CHAPTER. 44. The Roles and Interactions of Companies, Governments, Non-governmental Organizations, and Others in the World of Pharmacovigilance
Introduction
Pharmaceutical Companies
Governments
Media
NGOs and Lobbies
Industry Organizations
Litigation, Lawyers, and Legalities
Other Groups
Organizations for Drug Safety Personnel
Conclusion and Comments
Frequently Asked Question
CHAPTER. 45. Real-World Issues: Case Studies. Fialuridine
Fen–Phen
Nomifensine
TGN-1412/TAB08
CHAPTER. 46. Medical Marijuana and Pharmacovigilance. Overview and Pharmacology
US Federal Regulatory Situation
US State Regulatory Situation
Efficacy
Safety
Canada
Europe
Comments
Bottom Line
CHAPTER. 47. International Council for Harmonisation (ICH)
E1: The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life Threatening Conditions
E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting
Definitions
Managing Blinded Cases
Other Issues
E2B: Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports
The E2B(R2) and M2 Documents
The E2B(R3) and ISO/HL7 Documents
E2C(R2) Periodic Benefit-Risk Evaluation Report and E2C(R2) Q&As
E2C(R2) Periodic Benefit-Risk Evaluation Report (PBRER)
E2D: Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting
Definitions
Sources of Individual Case Safety Reports
Standards for Expedited Reporting
Good Case Management Practices
E2E: Pharmacovigilance Planning
Background and Scope
The Sections of a Pharmacovigilance Plan
Pharmacovigilance Plan
E2F: Development Safety Update Report
E19: Optimisation of Safety Data Collection
M1: MedDRA® Terminology (Medical Dictionary for Regulatory Activities)
Abbreviations
Index
