Drug Safety Evaluation 3rd Edition PDF presents a road map for safety assessment as an integral part of the development of new drugs and therapeutics.
Helps readers solve scientific, technical, and regulatory issues in preclinical safety assessment and early clinical drug development
Explains scientific and philosophical bases for evaluation of specific concerns – including local tissue tolerance, target organ toxicity and carcinogenicity, developmental toxicity, immunogenicity, and immunotoxicity
Covers the development of new small and large molecules, generics, 505(b)(2) route NDAs, and biosimilars
Revises material to reflect new drug products (small synthetic, large proteins and cells, and tissues), harmonized global and national regulations, and new technologies for safety evaluation
Adds almost 20% new and thoroughly updates existing content from the last edition
Table of Contents
PREFACE xxv
ABOUT THE AUTHOR xxvii
1 The Drug Development Process and the Global Pharmaceutical Marketplace 1
1.1 Introduction 1
1.2 The Marketplace 1
1.3 History of Modern Therapeutics 4
1.4 The Drug Development Process 6
1.5 Strategies for Development: Large Versus Small Company or the Short Versus Long Game 7
1.6 Safety Assessment and the Evolution of Drug Safety 11
1.7 The Three Stages of Drug Safety Evaluation in the General Case 11
References 12
2 Regulation of Human Pharmaceutical Safety: Routes to Human Use and Market 13
2.1 Introduction 13
2.2 Brief History of US Pharmaceutical Law 13
2.3 FDAMA Summary: Consequences and Other Regulations 19
2.4 Overview of US Regulations 21
2.5 Organizations Regulating Drug and Device Safety in the United States 24
2.6 Process of Pharmaceutical Product Development and Approval 25
2.8 Toxicity/Safety Testing: Cellular and Gene Therapy Products 33
2.9 Toxicity Testing: Special Cases 35
2.10 International Pharmaceutical Regulation and Registration 41
2.11 Combination Products 50
2.12 Conclusions 55
References 55
Further Reading 57
3 Data Mining: Sources of Information for Consideration in Study and Program Design and in Safety Evaluation 59
3.1 Introduction 59
3.2 PC‐Based Information Products: Laser DISC 65
3.3 Conclusions 65
References 65
4 Screens in Safety and Hazard Assessment 67
4.1 Introduction 67
4.2 Characteristics of Screens 68
4.3 Uses of Screens 70
4.4 Types of Screens 71
4.5 Criterion: Development and Use 71
4.6 Analysis of Screening Data 73
4.7 Univariate Data 73
References 76
5 Formulations, Routes, and Dosage Regimens 79
5.1 Mechanisms 81
5.2 Common Routes 83
5.3 Formulation of Test Materials 96
5.4 Dosing Calculations 105
5.5 Calculating Material Requirements 105
5.6 Excipients 106
References 111
6 Nonclinical Manifestations, Mechanisms, and End Points of Drug Toxicity 115
6.1 Manifestations 115
6.2 Mechanisms of Toxicity 116
6.3 End Points Measured in General Toxicity Studies 116
6.4 Complications 126
References 126
7 Pilot Toxicity Testing in Drug Safety Evaluation: MTD and DRF 129
7.1 Introduction 129
7.2 Range‐Finding Studies 130
7.3 Acute Systemic Toxicity Characterization 138
7.4 Screens 150
7.5 PILOT and DRF Studies 154
References 156
8 Repeat‐Dose Toxicity Studies 159
8.1 Objectives 159
8.2 Regulatory Considerations 161
8.3 Study Design and Conduct 162
8.4 Study Interpretation and Reporting 165
References 166
9 Genotoxicity 169
9.1 ICH Test Profile 169
9.2 DNA Structure 169
9.3 Cytogenetics 176
9.4 In Vitro Cytogenetic Assays 193
9.5 In Vivo Cytogenetic Assays 196
9.6 Sister Chromatid Exchange Assays 197
References 199
10 QSAR Tools for Drug Safety 209
10.1 Structure–Activity Relationships 209
10.2 SAR Modeling Methods 210
10.3 Applications in Toxicology 212
10.4 Genotoxicity 215
10.5 Comparison of Available Models/Applications 216
