Pharmacovigilance. A Practical Approach

Contributors
Preface
Acknowledgments
Introduction
Contents
Section 1 The Regulatory Environment and the Pharmacovigilance Quality System
Chapter 1 Does Regulation Drive Science or Does Science Drive Regulation?
Introduction
Important Events in Pharmacovigilance
Important Pharmacovigilance Organizations
National and Regional Regulatory Systems
The World of Regulatory Science
EMA Pharmacovigilance Risk Assessment Committee
New Wave of Global PV Regulation—Are We Closer to Harmonization?
Key Activities That Make Up a PV System
The European Union Qualified Person for Pharmacovigilance
The Rise of the National QPPV (N-QPPV)
Conclusion
References
Section 2 Preclinical Safety Assessment
Chapter 2 Absorption, Distribution, Metabolism and Excretion, Pharmacokinetics, and Safety Pharmacology
Introduction
Basic Principles of Absorption, Distribution, Metabolism, and Excretion
Basic Pharmacokinetics Parameters
Therapeutic Index and Safety Margins
Safety Pharmacology Evaluation
Conclusion
References
Chapter 3 Preclinical Safety Assessment: General and Genetic Toxicology
Introduction
Objectives of Nonclinical Safety Assessment
Overview of General Toxicity Studies
Genetic Toxicity and Carcinogenicity
Other Toxicity Studies
Conclusion
References
Chapter 4 Pharmacogenetics
Introduction
Background in Human Genetics
Application of Genetics in Drug Discovery and Development
Genetic Basis of Drug Response: Insights From Pharmacogenetics
Pharmacogenetics of Marketed Compounds
Direct-to-Consumer Pharmacogenetic Testing
Conclusion
List of Definitions
References
Section 3 First-In-Human Trials
Chapter 5 Safety Planning for First-in-Human Trials
Introduction
The Process of Safety Planning for FIH Studies
Reviewing the Relevant Data
Safety Pharmacology Studies
Toxicology Studies
Drug Metabolism/Pharmacokinetic and Pharmacodynamic Studies
Other Data
Potential Risks and Safety Monitoring: Key Questions
Do preclinical toxicology and toxicokinetic data fully support the dose range proposed and the estimated safety margin in humans?
Does safety monitoring in the FIH study protocol adequately address preclinical safety issues identified?
Does the proposed study have adequate subject and cohort stopping rules?
Does the protocol have adequate gating of subject inclusion?
Conclusion
References
Chapter 6 Pharmacokinetic and Pharmacodynamic Considerations in Safety Evaluation
Introduction
Pharmacokinetic and Pharmacodynamic parameters and markers of interest
Differences in Pharmacokinetics between large and small molecules
Intrinsic and Extrinsic factors that affect Pharmacokinetics
Intrinsic factors
Extrinsic factors
Modeling approaches to characterize dose– and exposure–safety relationship
Applications of Pharmacokinetics in “real-world” settings
Communication of clinical pharmacology-related information
Conclusions
References
Section 4 Safety Assessment in Clinical Trials
Chapter 7 Safety Monitoring in Clinical Trials
Introduction
Safety Planning
Data Collection and Evaluation
Reporting and Communication of Safety Information
Conclusion
References
Chapter 8 Introduction to Quantitative Methods and Visual Analytics in Drug Safety Data in Clinical Trials
Introduction
Role of Quantitative Methods and Visual Analytics in Drug Safety Assessment
Enhancing Drug Safety Assessment via Quantitative and Visual Analytics
Guidance on Using Quantitative Methods and Visual Analytics in Drug Safety
A Structured Approach to the Statistical Analysis of Drug Safety Data
Leveraging a Question-Based Approach
Some Examples of Graphs in Drug Safety
Adverse Events
Bar Charts
Tornado Plot
Dot Plot
Forest Plot
Volcano Plot
Clinical Laboratory Data
Bar Charts
Shift Plot
Line Plot
Box Plot
Evaluation of Drug-Induced Serious Hepatotoxicity Plot
Conclusion
References
Chapter 9 Product Aggregate Safety Assessment
Introduction
Evolution of Aggregate Safety Assessment Planning
Importance of Safety Planning
Processes Supported by Aggregate Safety Assessments
Components of Safety Assessment Planning
How an ASAP Supports IND Safety Reporting of Anticipated Events
Conclusion
References
Chapter 10 Data Monitoring Committees
Introduction
The Evolution of DMC Over Time
Types of DMCs
Determining The Need for a DMC
Operational Considerations for DMCs
Regulatory Guidances on DMCs
Statistical Support of DMCs
Disclosure of DMC Assessments from Interim Looks at the Data
Conclusion
References
Section 5 Signal and Risk Management
Chapter 11 Methods of Signal Detection and Signal Management
Introduction
Data Sources and AE Reporting
Signals
Signal Detection
Signal Validation
Signal Assessment
Determining Benefit–Risk
Safety Governance in Pharmacovigilance
Safety Governance Framework
Safety Oversight Board
Safety Management Teams19
First-In-Human Review Committee20,21
Internal Safety Advisory Groups
Safety Governance Support
Safety Governance Process
Conclusion
List of Definitions
References
Further Reading
Chapter 12 Causality Assessment
Introduction
Definitions
The Process of Determining Causality
Systematic Approaches
A Practical Approach to Causality Assessment: Elements to Consider
Conclusion
References
Chapter 13 Examples of Adverse Drug Reactions: Drug-Induced Liver Injury, Renal, Skin, Immune-Mediated Events, and Major Adverse Cardiac Events
Liver: Causality Assessment Indrug-Induced Liver Injury in Adults
Renal
Skin
Immune-Mediated Reactions
Cardiovascular
Conclusion
References
Chapter 14 Internal Safety Advisory Groups
Providing Consultations
Preparing a Preread Data Package for Consult
ISAG Meeting for the Consult
Maintaining ISAG Metrics
Standardizing Safety Data Collection, Analysis, and Presentation
Example of the AbbVie Hepatic ISAG
Enhancing ISAG Expertise and Knowledge Sharing
References
Chapter 15 Benefit–Risk Management
Introduction
Historical Background
Structured Benefit–Risk Assessment
Integrating the Life-Cycle Approach to Benefit–Risk Within a Biopharmaceutical Company
Considerations for Key Benefits and Key Risks
Graphic Visualization of Benefit–Risk Assessments
Quantitative Benefit–Risk Assessments
Role of the Patient in Benefit–Risk Assessment
Role of the Patient in Developing Risk Minimization Tools
Conclusion
Appendix 1. Review of Risk Minimization
References
Section 6 Role of Epidemiology and Realworld Evidence
Chapter 16 Role of Epidemiology and Pharmacoepidemiology in the Biopharmaceutical Industry
Introduction
Epidemiology Across the Drug Life Cycle
Reviewing Published Evidence
References
Chapter 17 Real-World Pharmacoepidemiology Studies
Introduction
Broader Integration of RWE in Regulatory Decision-Making
Real-World Data Sources
Multi data Source Efforts
Study Designs
Decision-Grade Real-World Evidence
Assessing and Addressing Potential Sources of Bias
Transparency of Reporting
Challenges and Opportunities
References
Section 7 Special Populations and Special Topics
Chapter 18 Pharmacovigilance in Pregnancy
Introduction
Medication Use in Pregnant Females
Stages of Embryo-Fetal Development
Thalidomide and History of Regulations
Developmental and Reproductive Toxicology
Contraceptive Measures in Clinical Trials
Seminal Fluid Exposure During Pregnancy
Inclusion of Pregnant Females in Clinical Trials
Inclusive Health Care in Special Populations in Clinical Trials
Rationale for Postmarketing Safety Surveillance During Pregnancy
Methods of Postmarketing Surveillance
Pharmacovigilance by the Sponsor
Pregnancy Registries
Complementary Data Sources
Conclusion
References
Chapter 19 Pharmacovigilance in Pediatrics
Introduction
Legislation for Pediatric Drug Development
Unique Considerations in the Pediatric Population
Unique Pharmacovigilance Challenges for Children
Safety Data Collection to Improve Characterization of the Safety Profile of Medications Used in the Pediatric Population
Conclusion
References
Chapter 20 Pharmacovigilance in the Elderly
Introduction
Conclusion
References
Chapter 21 Vaccine Pharmacovigilance
Introduction
Modern Vaccine History Related to Pharmacovigilance
Monitoring Vaccine Safety During Prelicensure
Postlicensure
Benefit-Risk—the Provider and Consumer Levels
The Future of Vaccine Safety
References
Chapter 22 Application of Human Factors and Health Literacy in Pharmacovigilance
Introduction
Human Factors
Health Literacy
Conclusion
References
Chapter 23 Medical Device Safety Oversight and Surveillance
Introduction
Medical Device Regulation in the United States
Medical Device Development and Approval Pathways
Tools and Methods of Device Risk Management and Safety Surveillance
Design Control as a Safety Tool and Risk Mitigation
The Birth of a (Hypothetical) Device
Hazard Domains in Medical Devices
Use Error
Risk Quantification in the Device World: Three Ps
Postmarket Surveillance of Medical Devices
Other Sources of Complaints
Reporting of Complaints
Reportable Malfunctions
Nonreportable Complaints
Combination Products
Combination = Sum of Parts
Software as a Medical Device
Conclusion
Acknowledgment
References
Section 8 The Next Frontier
Chapter 24 Information Technology in Pharmacovigilance: Current State and Future Directions
Introduction to Pharmacovigilance Information Technologies
Pharmacovigilance Data and Data Flow
Pharmacovigilance Information Technologies for Adverse Event Report Capture
Surveillance Process Technology
Signal and Risk Assessment Technology
Pharmacovigilance Information Technologies for Risk Minimization
Additional Information Technologies for Patient Safety
Conclusion
Acknowledgment
Appendix I: General PV Technology Framework
Chapter 25 The Future of Pharmacovigilance
Background
Medical Assessment
Cognitive and Behavioral Science
Data Science
Benefit-Risk: Bringing It All Together
Conclusion
References
Index

Written by multidisciplinary experts in the fields of pharmaceutical and patient safety, Pharmacovigilance: A Practical Approach, Second Edition, provides a succinct, easy-to-digest overview of an increasingly critical area of medical safety. From cover to cover, this concise resource offers essential information for physicians and other health care professionals, clinical researchers, and regulators who need a comprehensive, up-to-date source of information on the principles and practice of pharmacovigilance.

• Presents vital, easy-to-read, cutting-edge information on patient safety, the pharmacology regulatory landscape, and the current and future use of digital technologies
• Provides up-to-date coverage of hot topics in the field, including pharmacodynamic and safety precision medicine, immunogenicity, vaccine hesitancy and safety, genetic toxicology, and adverse events
• Contains new chapters on pre-clinical safety assessment, pharmacogenetics, first-in human trials, product aggregate safety assessment, data monitoring committees, and more
• Offers new and expanded coverage of pharmacovigilance in early pre-clinical drug development through post-marketing surveillance, as well as a blueprint for training future pharmacovigilance professionals
• Includes real-world case studies to ensure content is relevant and applicable to everyday practice
• Discusses a range of topics across disciplines and how they relate to pharmacovigilance, including behavioral science, patient perspectives, and risk communication
• An eBook version is included with purchase. The eBook allows you to access all of the text, figures and references, with the ability to search, customize your content, make notes and highlights, and have content read aloud. Additional digital ancillary content may publish up to 6 weeks following the publication date

Thao Doan is Group Medical Director, Pharmacovigilance and Patient Safety, Epidemiology and R&D Quality Assurance, AbbVie, North Chicago, IL, United States; Adjunct Faculty, Loyola University Stritch School of Medicine, Maywood, IL, United States; Adjunct Faculty, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Fabio Lievano is Vice President, Patient Safety, Scientific Collaborations, and New Business Advancement, Pharmacovigilance and Patient Safety, Epidemiology and, R&D Quality Assurance, AbbVie, North Chicago, IL, United States; Adjunct Faculty, Loyola University Stritch School of Medicine, Maywood, IL, United States; Adjunct Faculty, Northwestern University Feinberg School of Medicine, Chicago, IL, United States.

Linda Scarazzini is Senior Vice President, Pharmacovigilance and Patient Safety, Epidemiology and R&D Quality Assurance, Chief Safety Officer, AbbVie, North Chicago, IL, United States.

Charles Schubert is former Vice President, Oncology, Pharmacovigilance and Patient Safety, Epidemiology and R&D Quality Assurance, AbbVie, North Chicago, IL, United States.

Barbara Hendrickson is Clinical Associate, Department of Pediatrics, University of Chicago, Chicago, IL, United States