Cobert's Manual of Drug Safety and Pharmacovigilance

Contents
Thank You
Manual 4 Introductions
Authors
Chapter Contributions
Notice
Chapter 1 The History and Theory of Drug Safety and Pharmacovigilance
	The Why
	A Brief History, Focusing on the US FDA
	Regulations, Laws, and Guidances
	The United States and EU Laws, Regulations, Guidances, Guidelines, Directives and Practices
	Safety & PV Operational Considerations
	The Mission of a Safety Group
	Frequently Asked Questions
Chapter 2 Primary Definitions relevant to Safety & Pharmacovigilance
	Introduction
	The Theory
		Adverse Event (AE)
		Adverse Event/Experience (AE) — FDA
		Adverse Reaction (AR)
		Serious Adverse Event and Serious Adverse Reaction (SAE/SAR)
		Suspected Adverse (Drug) Reaction (SADR) — FDA
		Serious, Unexpected, Suspected Adverse Reaction (SUSAR)
		Serious, Expected, Suspected Adverse Reaction (SESAR)
		Unexpected Adverse Event — FDA
		Unexpected Adverse Reaction — EMA
		Unlisted Adverse Reaction — EMA
		Expected (Listed versus Labeled)
	The Practice
		Q&A
Chapter 3 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 4 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 5 The European Medicines Agency
	Introduction
	Due to Brexit, the EMA moved from London to Amsterdam, The Netherlands and the number of EU countries is back to 27. Note that there is a pathway for additional jurisdictions to enter the EU. 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 Pharmaco epidemiologyand Pharmacovigilance
	Newsletters and RSS Feeds
	Comments
	Agence Nationale de Sécurité des Médicaments et Produits de santé
		Missions
		Scope
		Organization
	Frequently Asked Questions
Chapter 6 Council for International Organizations of Medical Sciences (CIOMS)
	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):
	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 Japanese Translation Available
	CIOMS (2017): Guide to Active Vaccine Safety Surveillance
	CIOMS ICH Terms and Definitions
	CIOMS (2020) Drug Induced Liver Injury (DILI)
	CIOMS XI Patient Involvement in the Development, Regulation and Safe Use of Medicines (2022)
	CIOMS XII (2023, Draft) — Benefit-Risk Balance for Medicinal Products
	Additional Working Groups
Chapter 7 International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (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
	E2B: Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports
		The E2B(R3) 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
		Sources of Individual Case Safety Reports
		Good Case Management Practices
	E2E: Pharmacovigilance Planning
		Background and Scope
		The Sections of a Pharmacovigilance Plan
		Pharmacovigilance Plan
	E2F: Development Safety Update Report
	E19: Optimization of Safety Data Collection
	M1: MedDRA® Terminology (Medical Dictionary for Regulatory Activities)
Chapter 8 The Uppsala Monitoring Centre
	UMC and the WHO Program for International Drug Monitoring
	Key Functions of UMC
		Benefits of the UMC
		Pharmacovigilance Communications
		Why a chapter on the UMC?
Chapter 9 Biopharmaceutical Companies
	Introduction
	Big and Somewhat Big Pharma
	Mid-sized and Small Pharma
	Contract/Clinical Research Organizations (CROs)
	Mergers, Acquisitions, and Bankruptcies
Chapter 10 The Safety Department’s Role in Cross-Functional areas
	Introduction
	General Remarks
	Clinical Operations & Development
		Investigator Training and Meetings
		Interim Analysis, Annual and final study reporting
		Signal Detection & Benefit Risk Assessment
		Project Planning & Development
		Abstracts and Poster Presentations
	Data Management
	CROs
	Marketing and Sales
	The Labeling Department
	The Legal Department
	Regulatory Affairs Department
	The Quality and Compliance Department
	New Business Due Diligence
	Pre-Clinical Toxicology and Pharmacology
	Signaling and Epidemiology Groups
	The Medical Information/Medical Affairs Department
	Manufacturing (Product Quality Complaints)
		General Remarks
Chapter 11 Organization of a Typical Drug Safety Department
	Introduction
	Organization
		Small to Mid-Size Companies
		Large Companies
	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
		Qualified (Responsible) Person for Pharmacovigilance
	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 12 Clinical Trial Phases and Investigator-Initiated Trials
	Introduction
		Initiating the Research
	Phase I
	Phase II
	Phase III
	Phase IV
	Late Phase Studies
	Investigator-Initiated Research
	Other Study-Related Issues
	Frequently Asked Questions
Chapter 13 Data Monitoring Committees and Investigational Review Boards/Ethics Committees
	Data Monitoring Committees
	Investigational Review Boards/Ethics Committees
	Frequently Asked Questions
Chapter 14 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 15 Seriousness, Expectedness, and Causality
	Introduction
	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 16 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
	WHO Drug Global
	EudraVigilance Medicinal Product Dictionary
	Future
	Frequently Asked Question
Chapter 17 Spontaneous Post-marketing Adverse Events
	Introduction
	Why is Post-Market Data Different from Clinical Data?
	Timelines for Post-Marketing Reporting
	Sources of Spontaneous AEs
	United States Regulations
	European Union Requirements
	Other Regions
	Process Issues
	Frequently Asked Questions
Chapter 18 Generics, Excipients, Placebos, and Counterfeits
	Introduction
	Generics
	Excipients
	Placebo
	Placebo and Breaking the Blind in Clinical Trials
	Picking up AEs Due to Excipients
	Other Manufacturers’ Drugs’ AEs
	Generics
	Counterfeit, Impure, and Other Non-standard Products
		Online Pharmacies
		Authors’ Comments for PV Personnel
	Frequently Asked Questions
Chapter 19 Artificial Intelligence and Pharmacovigilance
	Overview
	AI and PV
	Comments
Chapter 20 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
	Q&A
Chapter 21 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 Postmarketing 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 22 Post-marketing Aggregate Safety Reporting
	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 23 The Mathematics of Adverse Events
	Introduction
	Case Report or Individual Case Safety Report
	Aggregate Reports
		Spontaneous Reports
	Reporting Rates versus Risk
		Numerator calculations
		Denominator calculations
	Quantitative Signal Detection Methods
	Other Data Mining Methods
Chapter 24 Pharmacoepidemiology: Its Practical Use in the World of Drug Safety
	Introduction
	Tools for Evaluating Drug Safety
		The Randomized Controlled Clinical Trial
	Pharmacoepidemiologic Study Designs
		The Cohort Study
		The Case-Control Study
		The Nested Case-Control Study
		Confidence Intervals
	Conclusions
	Frequently Asked Questions
Chapter 25 Signals and Signaling in the Context of Risk Management
	The Signal — Definition
	Signal Sources and Generation
	Increased Freque
	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 26 Risk Assessment, Evaluation, Management, Mitigation, & Strategy
	Introduction
	Why Risk Management?
	The US FDA
	The Proposed REMS from the Applicant/Company
	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)
		Part III: PV Plan, Including Post-authorization Safety Studies (GVP V.B.6 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 ofRisk Minimization Activities) (GVP V.B.8 RMP part V)
		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 27 Drug Interactions
	Introduction
	Cytochrome P450
		Drug–Food, Drug–Alcohol, Drug–Disease and Other Interactions
	Frequency
	Communication
Chapter 28 The Many Players in the World of Pharmacovigilance
	Introduction
	Pharmaceutical (Biopharmaceutical) 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 29 Pharmacovigilance System Master File
	Introduction
	The EU Pharmacovigilance System Master File (Guideline on Good Pharmacovigilance Practice Module II)
	Comment
Chapter 30 The Qualified (Individual) Person(s) Responsible for Pharmacovigilance
	Single Point of Responsibility for Post-Marketing Pharmacovigilance
	The US has yet to require a single qualified person for pharmacovigilance, which can contribute to a lesser degree of understanding of requirements when US-only organizations expand outside the USA
	Practicalities
	Frequent QPPV Inspection Findings by the EMA
	Frequently Asked Questions
Chapter 31 Product Labeling
	Introduction
	Investigator Brochure
	Company Core Safety Information
	United States 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 32 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 33 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
	Health Canada
	MHRA
	Teratology Data
	General Practice Research Database and Clinical Practice Research Datalink
	Other Registries and Databases
Chapter 34 Information Technology and the Safety Database
	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)
	Database Migration
	Clinical Data Interchange Consortium
	Systematized Nomenclature of Medicine Clinical Terms
	Frequently Asked Question
Chapter 35 Data Privacy and Security
	Introduction
	United States Health Insurance Portability and Accountability Act (HIPAA)
	The European Union and the Privacy Regulation & Directive
	Data Privacy in Clinical Trials and Product Development
	Frequently Asked Question
Chapter 36 Children, Elderly, and Other Special (Vulnerable) Groups
	The 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 37 Acute and Chronic (Late Occurring) Adverse Events, Adverse Events That Disappear
	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 38 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
	Other Resources
		perinatology.com
		Teratology Registries and Organizations
	Frequently Asked Questions
Chapter 39 Product Quality Issues
	Introduction
		Basics
		Manufacturing Considerations
		Product Recall
	Counterfeiting & Falsified Products
	General Remarks
	Frequently Asked Question
Chapter 40 Safety Data Volume, Archival, Record Retention, and Good Documentation Procedures
	Introduction
		Databases
	Archiving
	Record Retention Times
	Good Documentation Practices
Chapter 41 PV Quality System
	Introduction
Chapter 42 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 43 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 44 Ethical Issues and Conflicts of Interest
	Introduction
	Dynamics in Play Regarding Drug Safety and Companies
	Data Safety Management Boards and Ethics Committees/Institutional Review Boards
	Safety Assessment Committee
	Dynamics in Play Regarding Drug Safety and Health Agencies
	Dynamics in Play in Regard to Drug Safety and Academic and Non-academic Healthcare Facilities
	Dynamics in Play Regarding Drug Safety and Consumer Groups, Disease Groups, and the Internet (Blogs, Websites, Social Media, etc.)
	Dynamics in Play Regarding Drug Safety and Lawyers/Litigation
	Codes of Conduct
	Comments and Summary
Chapter 45 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
	A google search on “universities partnering with pharmaceutical companies” will reveal many instances of these arrangements. Bad Behavior
	The Sunshine Act
Chapter 46 Vaccinovigilance
	Differences between Vaccinovigilance and Pharmacovigilance
		Causality versus Attribution
		Temporal Association
		Drugs are Metabolized; Vaccines are Processed
		Incidence and Prevalence of Adverse Event Symptoms
		Vaccine Efficacy
	United States Initiative: The Vaccine Adverse Events Reporting System
	GACVS and the European Commission
	Vaccine Adverse Event Reporting
	European Union System
	Sources of Additional Information
Chapter 47 Real-World Issues: Case Studies
	Introduction
	Ongoing Activities
	Case Studies
	Fialuridine
	Fen–Phen
	Nomifensine
	TGN-1412/TAB08
Chapter 48 Medical Marijuana and Pharmacovigilance
	Overview
	US Federal Regulatory Action
	Efficacy
	Safety
	Canada
	Europe
	Comments
	Bottom Line
Abbreviations