This practical guide presents a road map for safety assessment as an integral part of the development of new drugs and therapeutics.

Table of Contents

• Acknowledgement
• Preface
• About the Author
• Chapter 1: The Drug Development Process and the Global Pharmaceurical Marketplace
• 1.1 Introduction
• 1.2 The Marketplace
• 1.3 History of Modern Therapeutics
• 1.4 The Drug Development Process
• 1.5 Strategies for Development: Large versus Small Company or the Short versus Long Game
• 1.6 Safety Assessment and the Evolution of Drug Safety
• 1.7 The Three Stages of Drug Safety Evaluation in the General Case
• 1. References
• Chapter 2. Regulation of Human Pharmaceutical Safety
• 2.1 Introduction
• 2.2 Brief History of US Pharmaceutical Law
• 2.3 FDAMA Summary: Consequences and Other Regulations
• 2.4 Overview of US Regulations
• 2.5 Organizations Regulating Drug and Device Safety in the United States
• 2.6 Process of Pharmaceutical Product Development and Approval
• 2.7 Testing Guidelines
• 2.8 Toxicity/Safety Testing: Cellular and Gene Therapy Products
• 2.9 Toxicity Testing: Special Cases
• 2.10 International Pharmaceutical Regulation and Registration
• 2.11 Combination Products
• 2.12 Conclusions
• 2. References
• 2. Further Reading
• Chapter 3. Data Mining
• 3.1 Introduction
• 3.2 PC‐Based Information Products: Laser Disc
• 3.3 Conclusions
• 3. References
• Chapter 4. Screens in Safety and Hazard Assessment
• 4.1 Introduction
• 4.2 Characteristics of Screens
• 4.3 Uses of Screens
• 4.4 Types of Screens
• 4.5 Criterion: Development and Use
• 4.6 Analysis of Screening Data
• 4.7 Univariate Data
• 4. References
• Chapter 5. Formulations, Routes, and Dosage Regimens
• 5.1 Introduction
• 5.2 Mechanisms
• 5.3 Common Routes
• 5.4 Formulation of Test Materials
• 5.5 Dosing Calculations
• 5.6 Calculating Material Requirements
• 5.7 Excipients
• 5. References
• Chapter 6. Nonclinical Manifestations, Mechanisms, and End Points of Drug Toxicity
• 6.1 Introduction
• 6.2 Manifestations
• 6.3 Mechanisms of Toxicity
• 6.4 End Points Measured in General Toxicity Studies
• 6.5 Complications
• 6. References
• Chapter 7. Pilot Toxicity Testing in Drug Safety Evaluation
• 7.1 Introduction
• 7.2 Range‐Finding Studies
• 7.3 Acute Systemic Toxicity Characterization
• 7.4 Screens
• 7.5 Pilot and DRF Studies
• 7. References
• Chapter 8. Repeat‐Dose Toxicity Studies
• 8.1 Introduction
• 8.2 Objectives
• 8.3 Regulatory Considerations
• 8.4 Study Design and Conduct
• 8.5 Study Interpretation and Reporting
• 8. References
• Chapter 9. Genotoxicity
• 9.1 Introduction
• 9.2 ICH Test Profile
• 9.3 DNA Structure
• 9.4 Cytogenics
• 9.5 In Vitro Cytogenic Assays
• 9.6 In Vivo Cytogenic Assays
• 9.7 Sister Chromatid Ecchange Assays
• 9. References
• Chapter 10. QSAR Tools for Drug Safety
• 10.1 Structure–Activity Relationship
• 10.2 SAR Modeling Methods
• 10.3 Applications in Toxicology
• 10.4 Genotoxicity
• 10.5 Comparison of Available Models/Applications
• 10. References
• Chapter 11. Immunotoxicology in Drug Development
• 11.1 Introduction
• 11.2 Overview of the Immune System
• 11.3 Immunotoxic Effects
• 11.4 Immunosuppression
• 11.5 Immunostimulation
• 11.6 Regulatory Positions
• 11.7 Evaluation of the Immune System
• 11.8 Nonspecific Immunity Function Assay
• 11.9 T‐cell‐dependent Antibody Response (TDAR)
• 11.10 Approaches to Compound Evaluation
• 11.11 Problems and Future Directions
• 11. References
• Chapter 12. Nonrodent Animal Studies
• 12.1 Introduction
• 12.2 Comparison Between Rodent and Nonrodent Experimental Design
• 12.3 Differences in Study Activities
• 12.4 Nonrodent Models
• 12.5 Dog
• 12.6 The Ferret
• 12.7 The Pig
• 12.8 Nonhuman Primates
• 12.9 Statistics in Large Animal Studies
• 12.10 Summary
• 12. References
• Chapter 13. Developmental and Reproductive Toxicity Testing
• 13.1 Introduction
• 13.2 ICH Study Designs
• 13.3 Methodological Issues
• 13.4 Developmental Studies in Primates
• 13.5 Data Interpretation
• 13.6 Juvenile and Pediatric Toxicology
• 13.7 In Vitro Tests for Developmental Toxicity
• 13.8 Appraisal of Currrent Approaches for Determining Developmental and Reproductive Hazards
• 13. References
• Chapter 14. Carcinogenicity Studies
• 14.1 Introduction
• 14.2 Mechanisms and Classes of Carcinogens
• 14.3 Genotoxic Carcinogens
• 14.4 Epigenetic Carcinogens
• 14.5 Regulatory Requirements and Timing
• 14.6 Species and Strain
• 14.7 Animal Husbandry
• 14.8 Dose Selection
• 14.9 Group Size
• 14.10 Route of Administration
• 14.11 Study Duration
• 14.12 Survival
• 14.13 End Points Measured
• 14.14 Transgenic Mouse Models
• 14.15 Interpretation of Results: Criteria for a Positive Result
• 14.16 Statistical Analysis
• 14.17 Weight‐of‐Evidence Factors for Consideration in a Carcinogenicity Assessment Document (CAD)
• 14.18 Conclusions
• 14. References
• Chapter 15. Histopathology in Nonclinical Pharmaceutucal Safety Assessment
• 15.1 Introduction
• 15.2 Clinical Pathology
• 15. References
• Chapter 16. Irritation and Local Tissue Tolerance in Pharmaceutucal Safety Assessment
• 16.1 Introduction
• 16.2 Factors Affecting Irritation Responses and Test Outcome
• 16.3 Primary Dermal Irritation (PDI) Test
• 16.4 Other Nonparenteral Route Irritation Tests
• 16.5 Ocular Irritation Testing
• 16.6 Vaginal Irritation
• 16.7 Acute Primary Vaginal Irritation Study in the Female Rabbit
• 16.8 Parenteral Irritation/Tolerance
• 16.9 Problems in Testing (and Their Resolutions)
• 16.10 Phototoxicity
• 16.11 Hemocompatibility
• 16. References
• Chapter 17. Pharmacokinetics and Toxicokinetics in Drug Safety Evaluation
• 17.1 Introduction
• 17.2 Regulations
• 17.3 Principles
• 17.4 Pharmacokinetics
• 17.5 Laboratory Methods
• 17.6 Sampling Methods and Intervals
• 17.7 Study Types
• 17.8 Analysis of Data
• 17.9 Physiologically Based Pharmacokinetic (PBPK) Modeling
• 17.10 Points to Consider
• 17.11 Biologically Derived Materials
• 17.12 Points to Consider
• 17. References
• Chapter 18. Safety Pharmacology
• 18.1 Introduction
• 18.2 Regulatory Requirements
• 18.3 Study Designs and Principles
• 18.4 Organ System‐Specific Tests
• 18.5 Cardiovascular
• 18.6 Central Nervous System
• 18.7 Respiratory/Pulmonary System
• 18.8 Secondary Organ System
• 18.9 Renal Function Tests
• 18.10 Summary
• 18. References
• Chapter 19. Special Concerns for the Preclinical Evaluation of Biotechnology Products
• 19.1 Introduction
• 19.2 Regulation
• 19.3 Preclinical Safety Assessment
• 19.4 Recombinant DNA Technology
• 19.5 Immunogenicity/Allergenicity
• 19.6 Monoclonal Antibody Technology
• 19.7 Bioprocess Technology
• 19.8 Gene Therapy Products
• 19.9 Vaccines
• 19.10 Special Challenges
• 19.11 Planning a Safety Evaluation Program
• 19.12 Challenges: Biosimilars
• 19. References
• Chapter 20. Safety Assessment of Inhalant Drugs and Dermal Route Drugs
• 20.1 Introduction
• 20.2 Inhaled Therapeutics
• 20.3 The Pulmonary System
• 20.4 Penetration and Absorption of Inhaled Gases and Vapors
• 20.5 Deposition of Inhaled Aerosols
• 20.6 Absorption and Clearance of Inhaled Aerosols
• 20.7 Pharmacokinetics and Pharmacodynamics of Inhaled Aerosols
• 20.8 Methods for Safety Assessment of Inhaled Therapeutics
• 20.9 Parameters of Toxicity Evaluation
• 20.10 Inhalation Exposure Techniques
• 20.11 The Utility of Toxicity Data
• 20.12 Formulation and Potential Mucosal Damage
• 20.13 Therapeutic Drug Delivery by the Dermal Route
• 20. References
• Chapter 21. Special Case Products: Imaging Agents
• 21.1 Introduction
• 21.2 Imaging Agents
• 21. References
• Chapter 22. Special Case Products: Drugs for Treatment of Cancer
• 22.1 Introduction
• 22.2 Dose Conversions
• 22. References
• Chapter 23. Pediatric Product Safety Assessment (2006 Guidance, Including Juvenile Toxicology)
• 23.1 Introduction
• 23.2 Issues to Consider Regarding Juvenile Animal Studies
• 23.3 General Considerations in Designing Toxicity Studies in Juvenile Animals
• 23.4 Study Designs and Considerations
• 23. References
• Chapter 24. Use of Imaging, Imaging Agents, and Radiopharmaceuticals in Nonclinical Toxicology
• 24.1 Introduction
• 24.2 X‐ray
• 24.3 Positron Emission Tomography (PET)
• 24.4 Single‐Photon Emission Computed Tomography (SPECT)
• 24.5 Computed Tomography (CT)
• 24.6 Magnetic Resonance Imaging (MRI)
• 24.7 Optical Imaging
• 24.8 Ultrasound
• 24.9 Nanopractice Contrast Agents
• 24.10 Radiopharmaceuticals
• 24.11 Applications of Preclinical Imaging in Laboratory Animals
• 24.12 Nonclinical Safety Assessment for Imaging Agents
• 24.13 Radiopharmaceuticals
• 24.14 Nonclinical Late Radiation Toxicity Studies
• 24.15 Study Design
• 24. References
• Chapter 25. Occupational Toxicology in the Pharmaceutical Industry
• 25.1 Introduction
• 25.2 Occupational Toxicology versus Drug Safety Evaluation
• 25.3 Regulatory Pressures in the United States and the European Community
• 25.4 Organizational Structure
• 25.5 Activities
• 25.6 Conclusion
• 25. References
• Chapter 26. Strategy and Phasing for Nonclinical Drug Safety Evaluation in the Discovery and Development of Pharmaceuticals
• 26.1 Introduction
• 26.2 Regulatory Requirements
• 26.3 Essential Elements of Project Management
• 26.4 Screens: Their Use and Interpretation in Safety Assessment
• 26.5 Strategy and Phasing
• 26.6 Critical Considerations
• 26.7 Special Cases in Safety Assessment
• 26.8 Summary
• 26. References
• Chapter 27. The Application of In Vitro Techniques in Drug Safety Assessment
• 27.1 Introduction
• 27.2 In Vitro Testing in Pharmaceutical Safety Assessment
• 27.3 Defining Testing Objective
• 27.4 Test Systems: Characteristics, Development, and Selection
• 27.5 In Vitro Models
• 27.6 Lethality
• 27.7 In Silico Methods
• 27.8 The Final Frontier and Barrier: Regulatory Acceptance
• 27.9 Summary
• 27. References
• 27. Further Reading
• Chapter 28. Evaluation of Human Tolerance and Safety in Clinical Trials
• 28.1 The Pharmaceutical Clinical Development Process and Safety
• 28.2 Limitations on/of Clinical Trials
• 28.3 The The Clinical Trial Process
• 28.4 Institutional Review Boards (IRBs)/Ethics Committees in the Clinical Trial Process
• 28.5 Drug Formulations and Excipients
• 28.6 Phase I Designs
• 28.7 Clinical Trial Safety Indicators
• 28.8 Assessment of Unwanted Drug Effects
• 28. References
• Chapter 29. Postmarketing Safety Evaluation
• 29.1 Introduction
• 29.2 Causes of Safety Withdrawals
• 29.3 Regulatory Requirements
• 29.4 Management of ADR and ADE Data
• 29.5 Casualty Assessment
• 29.6 Courses of Corrective Action
• 29.7 Legal Consequences of Safety Withdrawal
• 29. References
• Chapter 30. Statistics in Pharmaceutical Safety Assessment
• 30.1 Introduction
• 30.2 Experimental Design
• 30.3 Data Recording
• 30.4 Generalized Methodology Selection
• 30.5 Statistical Alalysis: General Considerations
• 30.6 Hypothesis Testing of Categorical and Ranked Data
• 30.7 Hypothesis Testing: Univariate Parametric Tests
• 30.8 Methods for the Reduction of Dimensionality
• 30.9 Meta‐Analysis
• 30.10 Bayesian Inference
• 30.11 Data Analysis Applications in Safety Assessment Studies
• 30. References
• Chapter 31. Combination Products: Drugs and Devices
• 31.1 Combination Products
• 31. References
• Chapter 32. Qualification of Impurities, Degradants, Residual Solvents, Metals, and Leachables in Pharmaceuticals
• 32.1 Introduction
• 32.2 Impurities
• 32.3 Residual Solvents
• 32.4 Extractables and Leachables
• 32.5 Residual Metals and Elements
• 32. References
• Chapter 33. Tissue, Cell, and Gene Therapy
• 33.1 Introduction
• 33.2 Safety Assessment of Cell Therapy (CT) Products
• 33.3 Nonclinical Safety Assessment of Gene Therapy Products (GTPS)
• 33.4 Definitions
• 33. References
• Appendix A: Selected Regulatory and Toxicological Acronyms
• Appendix B: Definition of Terms and Lexicon of “Clinical” Observations in Nonclinical (Animal) Studies
• Appendix C: Notable Regulatory Internet Addresses
• Appendix D: Glossary of Terms Used in the Clinical Evaluation of Therapeutic Agents
• Appendix E: Common Vehicles for the Nonclinical Evaluation of Therapeutic Agents
• Appendix F: Global Directory of Contract Pharmaceutical Toxicology Labs
• List of Tables
• List of Illustrations