Pharmaceutical Development Series: Drug Safety Evaluation

Editor/Author Gad, Shayne Cox
Publication Year: 2017
Publisher: Wiley

Single-User Purchase Price: $350.00
Unlimited-User Purchase Price: $525.00
ISBN: 978-1-119-09739-6
Category: Health & Medicine - Pharmaceutical Science
Image Count: 135
Book Status: Available
Table of Contents

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

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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