Drug Safety Evaluation, Third Edition

Informationen zum Autor Shayne Cox Gad, BS, PhD, DABT, has more than 39 years of experience in regulatory toxicology, drug and device development, statistics, and risk assessment. He is Principal of Gad Consulting Services, a firm with eight employees and more than 500 clients worldwide in the pharmaceutical and medical device industries. He is Past President of the American College of Toxicology (ACT), the Roundtable of Toxicology Consultants, and three of the Society of Toxicology's specialty sections. Dr. Gad received the 2008 ACT Lifetime Contribution Award and has authored or edited 47 books (10 with Wley) and more than 350 chapters, articles, and abstracts. Has preparated 110 INDs and 8 NDAs and teaches 3-5 professional education courses a year. Klappentext Diese neue Auflage von Drug Safety Evaluation als praktischer Leitfaden bietet eine Road Map für die Leistungsfähigkeit und Bewertung von Sicherheitsüberprüfungen als integraler Bestandteil bei der Entwicklung neuer Arzneimittel und Therapeutika. Dieses Buch wurde vollständig überarbeitet, bleibt aber den Kernzielen der Vorgängerausgaben treu. Es ist ein umfasssender und praxisorientierter Leitfaden für diejenigen, die für die Entwicklung neuer Arzneimittel verantwortlich sind, die Sicherheit einer immer größer werdenden Zahl an Therapeutika gewährleisten müssen, und die solche Maßnahmen finanzieren. Zusammenfassung Diese neue Auflage von Drug Safety Evaluation als praktischer Leitfaden bietet eine Road Map für die Leistungsfähigkeit und Bewertung von Sicherheitsüberprüfungen als integraler Bestandteil bei der Entwicklung neuer Arzneimittel und Therapeutika. Dieses Buch wurde vollständig überarbeitet, bleibt aber den Kernzielen der Vorgängerausgaben treu. Es ist ein umfasssender und praxisorientierter Leitfaden für diejenigen, die für die Entwicklung neuer Arzneimittel verantwortlich sind, die Sicherheit einer immer größer werdenden Zahl an Therapeutika gewährleisten müssen, und die solche Maßnahmen finanzieren. Inhaltsverzeichnis PREFACE xxvABOUT THE AUTHOR xxvii1 The Drug Development Process and the Global Pharmaceutical Marketplace 11.1 Introduction 11.2 The Marketplace 11.3 History of Modern Therapeutics 41.4 The Drug Development Process 61.5 Strategies for Development: Large Versus Small Company or the Short Versus Long Game 71.6 Safety Assessment and the Evolution of Drug Safety 111.7 The Three Stages of Drug Safety Evaluation in the General Case 11References 122 Regulation of Human Pharmaceutical Safety: Routes to Human Use and Market 132.1 Introduction 132.2 Brief History of US Pharmaceutical Law 132.3 FDAMA Summary: Consequences and Other Regulations 192.4 Overview of US Regulations 212.5 Organizations Regulating Drug and Device Safety in the United States 242.6 Process of Pharmaceutical Product Development and Approval 252.8 Toxicity/Safety Testing: Cellular and Gene Therapy Products 332.9 Toxicity Testing: Special Cases 352.10 International Pharmaceutical Regulation and Registration 412.11 Combination Products 502.12 Conclusions 55References 55Further Reading 573 Data Mining: Sources of Information for Consideration in Study and Program Design and in Safety Evaluation 593.1 Introduction 593.2 PC-Based Information Products: Laser DISC 653.3 Conclusions 65References 654 Screens in Safety and Hazard Assessment 674.1 Introduction 674.2 Characteristics of Screens 684.3 Uses of Screens 704.4 Types of Screens 714.5 Criterion: Development and Use 714.6 Analysis of Screening Data 734.7 Univariate Data 73References 765 Formulations, Routes, and Dosage Regimens 795.1 Mechanisms 815.2 Common Routes 835.3 Formulation of Test Materials 965.4 Dosing Calculations 1055.5 Calculating Material Requirements 1055.6 Excipients 106References 1116 Nonclinical Manifestations, Mechanisms, and End Points of Drug Toxicity 1156.1 Manifestations 1156....

List of contents

PREFACE xxvABOUT THE AUTHOR xxvii1 The Drug Development Process and the Global Pharmaceutical Marketplace 11.1 Introduction 11.2 The Marketplace 11.3 History of Modern Therapeutics 41.4 The Drug Development Process 61.5 Strategies for Development: Large Versus Small Company or the Short Versus Long Game 71.6 Safety Assessment and the Evolution of Drug Safety 111.7 The Three Stages of Drug Safety Evaluation in the General Case 11References 122 Regulation of Human Pharmaceutical Safety: Routes to Human Use and Market 132.1 Introduction 132.2 Brief History of US Pharmaceutical Law 132.3 FDAMA Summary: Consequences and Other Regulations 192.4 Overview of US Regulations 212.5 Organizations Regulating Drug and Device Safety in the United States 242.6 Process of Pharmaceutical Product Development and Approval 252.8 Toxicity/Safety Testing: Cellular and Gene Therapy Products 332.9 Toxicity Testing: Special Cases 352.10 International Pharmaceutical Regulation and Registration 412.11 Combination Products 502.12 Conclusions 55References 55Further Reading 573 Data Mining: Sources of Information for Consideration in Study and Program Design and in Safety Evaluation 593.1 Introduction 593.2 PC-Based Information Products: Laser DISC 653.3 Conclusions 65References 654 Screens in Safety and Hazard Assessment 674.1 Introduction 674.2 Characteristics of Screens 684.3 Uses of Screens 704.4 Types of Screens 714.5 Criterion: Development and Use 714.6 Analysis of Screening Data 734.7 Univariate Data 73References 765 Formulations, Routes, and Dosage Regimens 795.1 Mechanisms 815.2 Common Routes 835.3 Formulation of Test Materials 965.4 Dosing Calculations 1055.5 Calculating Material Requirements 1055.6 Excipients 106References 1116 Nonclinical Manifestations, Mechanisms, and End Points of Drug Toxicity 1156.1 Manifestations 1156.2 Mechanisms of Toxicity 1166.3 End Points Measured in General Toxicity Studies 1166.4 Complications 126References 1267 Pilot Toxicity Testing in Drug Safety Evaluation: MTD and DRF 1297.1 Introduction 1297.2 Range-Finding Studies 1307.3 Acute Systemic Toxicity Characterization 1387.4 Screens 1507.5 PILOT and DRF Studies 154References 1568 Repeat-Dose Toxicity Studies 1598.1 Objectives 1598.2 Regulatory Considerations 1618.3 Study Design and Conduct 1628.4 Study Interpretation and Reporting 165References 1669 Genotoxicity 1699.1 ICH Test Profile 1699.2 DNA Structure 1699.3 Cytogenetics 1769.4 In Vitro Cytogenetic Assays 1939.5 In Vivo Cytogenetic Assays 1969.6 Sister Chromatid Exchange Assays 197References 19910 QSAR Tools for Drug Safety 20910.1 Structure-Activity Relationships 20910.2 SAR Modeling Methods 21010.3 Applications in Toxicology 21210.4 Genotoxicity 21510.5 Comparison of Available Models/Applications 216References 22211 Immunotoxicology in Drug Development 22511.1 Introduction 22511.2 Overview of the Immune System 22711.3 Immunotoxic Effects 22911.4 Immunosuppression 23111.5 Immunostimulation 23511.6 Regulatory Positions 24011.7 Evaluation of the Immune System 24511.8 Nonspecific Immunity Function Assay 25111.9 T-Cell-Dependent Antibody Response (TDAR) 25311.10 Approaches to Compound Evaluation 25911.11 Problems and Future Directions 263References 26412 Nonrodent Animal Studies 26912.1 Introduction 26912.2 Comparison Between Rodent and Nonrodent Experimental Design 26912.3 Differences in Study Activities 27012.4 Nonrodent Models 27012.5 Dog 27012.6 The Ferret 27312.7 The Pig 27512.8 Nonhuman Primates 27912.9 Statistics in Large Animal Studies 28312.10 Summary 288References 28813 Developmental and Reproductive Toxicity Testing 29113.1 Introduction 29113.2 ICH Study Designs 29313.3 Methodological Issues 29813.4 Developmental Studies in Primates 30313.5 Data Interpretation 30413.6 Juvenile and Pediatric Toxicology 31013.7 In Vitro Tests for Developmental Toxicity 31213.8 Appraisal of Current Approaches for Determining Developmental and Reproductive Hazards 316References 31714 Carcinogenicity Studies 32114.1 Introduction 32114.2 Mechanisms and Classes of Carcinogens 32214.3 Genotoxic Carcinogens 32214.4 Epigenetic Carcinogens 32514.5 Regulatory Requirements and Timing 32814.6 Species and Strain 32814.7 Animal Husbandry 33014.8 Dose Selection 33014.9 Group Size 33114.10 Route of Administration 33214.11 Study Duration 33214.12 Survival 33214.13 End Points Measured 33314.14 Transgenic Mouse Models 33514.15 Interpretation of Results: Criteria for a Positive Result 33814.16 Statistical Analysis 33814.17 Weight-of-Evidence Factors for Consideration in a Carcinogenicity Assessment Document (CAD) 34414.18 Conclusions 345References 34515 Histopathology in Nonclinical Pharmaceutical Safety Assessment 35115.1 Introduction 35115.2 Clinical Pathology 355References 35616 Irritation and Local Tissue Tolerance in Pharmaceutical Safety Assessment 35916.1 Introduction 35916.2 Factors Affecting Irritation Responses and Test Outcome 35916.3 Primary Dermal Irritation (PDI) Test 36016.4 Other Nonparenteral Route Irritation Tests 36216.5 Ocular Irritation Testing 36216.6 Vaginal Irritation 36416.7 Acute Primary Vaginal Irritation Study in the Female Rabbit 36516.8 Parenteral Irritation/Tolerance 36716.9 Problems in Testing (and Their Resolutions) 37016.10 Phototoxicity 37116.11 Hemocompatibility 377References 37817 Pharmacokinetics and Toxicokinetics in Drug Safety Evaluation 38117.1 Introduction 38117.2 Regulations 38217.3 Principles 38217.4 Pharmacokinetics 39517.5 Laboratory Methods 39517.6 Sampling Methods and Intervals 39717.7 Study Types 40017.8 Analysis of Data 40217.9 Physiologically Based Pharmacokinetic (PBPK) Modeling 40417.10 Points to Consider 40517.11 Biologically Derived Materials 40617.12 Points to Consider 410References 41018 Safety Pharmacology 41318.1 Regulatory Requirements 41418.2 Study Designs and Principles 41518.3 Organ System-Specific Tests 41618.4 Cardiovascular 41618.5 Central Nervous System 41918.6 Respiratory/Pulmonary System 42218.7 Secondary Organ System 42718.8 Renal Function Tests 42818.9 Summary 428References 42819 Special Concerns for the Preclinical Evaluation of Biotechnology Products 43319.1 Regulation 43619.2 Preclinical Safety Assessment 43719.3 Recombinant DNA Technology 43919.4 Immunogenicity/Allergenicity 44019.5 Monoclonal Antibody Technology 44119.6 Bioprocess Technology 44619.7 Gene Therapy Products 44619.8 Vaccines 44919.9 Special Challenges 45219.10 Planning a Safety Evaluation Program 45419.11 Challenges: Biosimilars 458References 45920 Safety Assessment of Inhalant Drugs and Dermal Route Drugs 46120.1 Inhaled Therapeutics 46120.2 The Pulmonary System 46120.3 Penetration and Absorption of Inhaled Gases and Vapors 46220.4 Deposition of Inhaled Aerosols 46320.5 Absorption and Clearance of Inhaled Aerosols 46420.6 Pharmacokinetics and Pharmacodynamics of Inhaled Aerosols 46420.7 Methods for Safety Assessment of Inhaled Therapeutics 46520.8 Parameters of Toxicity Evaluation 46720.9 Inhalation Exposure Techniques 47020.10 The Utility of Toxicity Data 47320.11 Formulation and Potential Mucosal Damage 47320.12 Therapeutic Drug Delivery by the Dermal Route 474References 47621 Special Case Products: Imaging Agents 48321.1 Introduction 48321.2 Imaging Agents 483References 48722 Special Case Products: Drugs for Treatment of Cancer 48922.1 Introduction 489References 49323 Pediatric Product Safety Assessment (2006 Guidance, Including Juvenile Toxicology) 49523.1 Introduction 49523.2 Issues to Consider Regarding Juvenile Animal Studies 49823.3 General Considerations in Designing Toxicity Studies in Juvenile Animals 49923.4 Study Designs and Considerations 500References 50124 Use of Imaging, Imaging Agents, and Radiopharmaceuticals in Nonclinical Toxicology 50324.1 Introduction 50324.2 X-ray 50524.3 Positron Emission Tomography (PET) 50524.4 Single-photon Emission Computed Tomography (SPECT) 50524.5 Computed Tomography (CT) 50624.6 Magnetic Resonance Imaging (MRI) 50624.7 Optical Imaging 50724.8 Ultrasound 50824.9 Nanoparticle Contrast Agents 50924.10 Radiopharmaceuticals 50924.11 Applications of Preclinical Imaging in Laboratory Animals 50924.12 Nonclinical Safety Assessment for Imaging Agents 51524.13 Radiopharmaceuticals 51724.14 Nonclinical Late Radiation Toxicity Studies 51924.15 Study Design 519References 52025 Occupational Toxicology in the Pharmaceutical Industry 52325.1 Introduction 52325.2 Occupational Toxicology versus Drug Safety Evaluation 52325.3 Regulatory Pressures in the United States and the European Community 52525.4 Organizational Structure 52625.5 Activities 52725.6 Conclusion 534References 53426 Strategy and Phasing for Nonclinical Drug Safety Evaluation in the Discovery and Development of Pharmaceuticals 53726.1 Introduction 53726.2 Regulatory Requirements 53926.3 Essential Elements of Project Management 54226.4 Screens: Their Use and Interpretation in Safety Assessment 54426.5 Strategy and Phasing 54626.6 Critical Considerations 55026.7 Special Cases in Safety Assessment 55126.8 Summary 551References 55127 The Application of In Vitro Techniques in Drug Safety Assessment 55327.1 Introduction 55327.2 In Vitro Testing in Pharmaceutical Safety Assessment 55527.3 Defining Testing Objective 55827.4 Test Systems: Characteristics, Development, and Selection 55827.5 In Vitro Models 55927.6 Lethality 56027.7 In Silico Methods 57227.8 The Final Frontier and Barrier: Regulatory Acceptance 57327.9 Summary 573References 575Further Reading 58128 Evaluation of Human Tolerance and Safety in Clinical Trials: Phase I and Beyond 58328.1 The Pharmaceutical Clinical Development Process and Safety 58328.1.1 Pharmacokinetics 58928.1.2 Safety of Clinical Trial Subjects 59128.2 Limitations on/of Clinical Trials 59828.3 The Clinical Trial Process 59828.4 Institutional Review Boards (IRBS)/Ethics Committees in the Clinical Trial Process 60228.5 Drug Formulations and Excipients 60428.6 Phase I Designs 60528.7 Clinical Trial Safety Indicators 60928.8 Assessment of Unwanted Drug Effects 621References 62629 Postmarketing Safety Evaluation : Monitoring, Assessing, and Reporting of Adverse Drug Responses (ADRs) 62929.1 Causes of Safety Withdrawals 63729.2 Regulatory Requirements 63829.3 Management of ADR and ADE Data 64129.4 Causality Assessment 64729.5 Courses of Corrective Action 64729.6 Legal Consequences of Safety Withdrawal 648References 65130 Statistics in Pharmaceutical Safety Assessment 65330.1 Introduction 65330.2 Experimental Design 65930.3 Data Recording 66430.4 Generalized Methodology Selection 66530.5 Statistical Analysis: General Considerations 66530.6 Hypothesis Testing of Categorical and Ranked Data 67930.7 Hypothesis Testing: Univariate Parametric Tests 68430.8 Methods for the Reduction of Dimensionality 69430.9 Meta-Analysis 70130.10 Bayesian Inference 70230.11 Data Analysis Applications in Safety Assessment Studies 704References 70831 Combination Products: Drugs and Devices 71131.1 Combination Products 711References 72032 Qualification of Impurities, Degradants, Residual Solvents, Metals, and Leachables in Pharmaceuticals 72132.1 Impurities 72132.2 Residual Solvents 72632.3 Extractables and Leachables 72732.4 Residual Metals and Elements 728References 73033 Tissue, Cell, and Gene Therapy 73133.1 Safety Assessment of Cell Therapy (CT) Products 73233.2 Nonclinical Safety Assessment of Gene Therapy Products (GTPS) 73833.3 Definitions 741References 742Appendix A: Selected Regulatory and Toxicological Acronyms 743Appendix B: Definition of Terms and Lexicon of "Clinical" Observations in Nonclinical (Animal) Studies 745Appendix C: Notable Regulatory Internet Addresses 749Appendix D: Glossary of Terms Used in the Clinical Evaluation of Therapeutic Agents 755Appendix E: Common Vehicles for the Nonclinical Evaluation of Therapeutic Agents 759Appendix F: Global Directory of Contract Pharmaceutical Toxicology Labs 857INDEX 879

Product details

• Authors: Gad, SC Gad, Shayne Cox Gad
• Publisher: Wiley, John and Sons Ltd
• Languages: English
• Product format: Hardback
• Released: 23.12.2016
• EAN: 9781119097396
• ISBN: 978-1-119-09739-6
• No. of pages: 920
• Series: Pharmaceutical Development; Pharmaceutical Development Series; Pharmaceutical Development
• Subjects: Natural sciences, medicine, IT, technology > Chemistry; Chemie, Veterinärmedizin, Medizin, Toxikologie, Pharmakologie, Arzneimittelsicherheit, veterinary medicine, chemistry, Pharmacology & Pharmaceutical Medicine, Pharmakologie u. Pharmazeutische Medizin, Medical Science, Toxicology, Veterinary Pharmacology, Toxicology & Therapeutics, Veterinärmedizin / Pharmakologie, Toxikologie, Therapeutik