Editors William J. Brock Brock Scientific Consulting, Montgomery Village, USA Kenneth L. Hastings Sanofi, Bethesda, USA Kathy M. McGown FoxKiser, USA

• List of Contributors xviiPreface xixPart I International Regulations and Nonclinical Studies for Pharmaceuticals 11 Introduction 3Kathy M. McGown and William J. Brock1.1 The Global Pharmaceutical Market 61.2 Looking to the Future 91.3 Legal and Regulatory Considerations in Drug Development 101.4 The Drug Development Process – General Considerations 122 ICH: History and Nonclinical Guidances 17Jan-Willem van der Laan and Kenneth L. Hastings2.1 Introduction 172.2 Organization of the ICH 192.3 The ICH Process 202.4 Animal Welfare and Alternative Methods 222.5 ICH M3 232.6 New Initiatives and Topics 243 Food and Drug Administration: Nonclinical Program and Pharmaceutical Approval 27William J. Brock and Kenneth L. Hastings3.1 Legislative Authority of the FDA 273.2 Nonclinical Drug Development and the FDA 313.3 Nonclinical Testing: General Conditions and Considerations 343.4 Toxicity Testing: Small Molecules and Traditional Pharmaceuticals 343.5 Toxicity Testing of Pharmaceuticals – The General Approach 353.6 First-in-Human Dosing: Results from Nonclinical Studies 374 Nonclinical Pharmaceutical Development in MERCOSUR and Brazil 41Cristiana Leslie Corr^ea, Giuliana Selmi, and Flavio Ailton Duque Zambrone4.1 Introduction 414.2 MERCOSUR 414.3 Brazil 445 Nonclinical Safety Assessment: Canada 57Jamie L. Doran and Mark T. Goldberg5.1 Introduction 575.2 Organization of Health Canada 585.3 The Regulatory Framework for Drug Approval in Canada 605.4 Nonclinical Assessment in Canada 645.5 Clinical Trial Applications 705.6 Special Regulatory Considerations 746 European Pharmaceutical Regulation – Nonclinical Testing Requirements 79Adam Woolley and Jan Willem van der Laan6.1 Introduction 796.2.1 Overview 826.3 Nonclinical Testing in the Support of Clinical Trials 866.4 Overview 967 South Africa 99Fariza Feraoun and Malik Feraoun7.1 Introduction 997.2 Country Information 1007.3 The Regulatory Aspects 1017.4 The Nonclinical Safety Assessment 1097.5 Conclusion 1148 Asia Pacific: China 117Lijie Fu and Qingli Wang8.1 Introduction 1178.2 History of Drug Administration 1188.3 The Provisions for Drug Registration 1228.4 The SFDA 1238.5 The SFDA Affiliated Organizations 1238.6 General Registration Procedures 1258.7 Pharmaceutical Application 1258.8 Import Drug Application 1278.9 Testing Guidelines and Safety Evaluation 1298.10 GLP Compliance in China 1318.11 Animal Welfare Requirements 1339 Pharmaceutical Regulations for Nonclinical Safety Assessment in Japan 135Kazuichi Nakamura and Osamu Fueki9.1 History of Regulation for Nonclinical Safety Assessment in Japan 1359.2 Approval Application of New Drugs in Japan 1369.3 Current Nonclinical Safety Guidelines Available in Japan 1399.4 Current Trends of Conduct of Nonclinical Safety Evaluation in Japan 1399.5 Safety Assessment of Unapproved Drugs 1429.6 Necessity of 3Rs (Reduction/Refinement/Replacement) of Animal Studies 1429.7 Attitude of Japanese Pharmaceutical Companies and the Regulatory Agency toward Nonclinical Safety Assessment 14210 Indian Regulatory Process for Nonclinical Drug Development 145K.S. Rao and S. Natesan10.1 Introduction 14510.2 Drug Development 14610.3 Quality Systems 14710.4 Nonclinical Drug Development – Key Regulatory Requirements 14810.5 Nonclinical Safety Assessment – Key Approval Requirements 14910.6 Data Required for Clinical Study Approval 15110.7 Animal Toxicology 15410.8 Animal Pharmacology 16610.9 Safety Assessment Requirements: Indian Schedule Yand International Guidelines 16810.10 Good Laboratory Practice Quality System in India 16810.11 Safety Assessment Test Facilities in India 17110.12 Investigational New Drug Application for Undertaking Clinical Trials 17311 Asia Pacific: Australia 175Douglas Francis11.1 Introduction 17511.2 Australian Therapeutic Goods Administration (TGA) 17611.3 Clinical Trials in Australia 18311.4 Nonclinical Data to Support the Conduct of Clinical Trials in Australia and Marketing Application to the TGA 188Part II Toxicology Studies Supporting Clinical Development 19712 Repeated-Dose Toxicity Studies in Nonclinical Drug Development 199Shana Azri-Meehan and Louise Latriano12.1 Introduction 19912.2 General Considerations 20012.3 Study Design Considerations 20512.4 Study Observations and Assessments 21113 Evaluation of Potential Carcinogenicity 219James A. Popp and Matthew S. Bogdanffy13.1 Introduction 21913.2 Preparation for the Carcinogenicity Study 22313.3 Elements of the Protocol/Study Plan 22813.4 Study Performance 24113.5 Alternative Models to Evaluate Potential Carcinogenicity in Lieu of a 2-Year Mouse Study 24413.6 Special Consideration for Carcinogenicity Evaluation of Biotherapeutics 24713.7 Regulatory Implications of a Study Identifying an Animal Carcinogenic Response 24813.8 Interpreting the Relevance of Positive Results for Human Safety 24913.9 Communicating the Results in the Product Label 25114 Genetic Toxicology 255Mark W. Powley14.1 Background 25514.2 Regulations Guiding Drug Development 25614.3 Genotoxic Impurities 26114.4 Regulatory Decision Making 26315 Developmental and Reproductive Toxicology 265Robert M. Parker and Raymond G. York15.1 Introduction 26515.2 Standard Reproduction and Developmental Toxicity Study Designs 26615.3 Timing of Preclinical Developmental and Reproductive Toxicity Studies 27315.4 Based on Disease Indication 27515.5 Based on Pharmaceutical Characteristic 27915.6 Other Reasons to Conduct Preclinical Reproductive and Developmental Toxicity Studies 29115.7 Excipients 29315.8 Conclusion 29316 Juvenile Animal Toxicity Studies: Regulatory Expectations, Decision Strategies and Role in Paediatric Drug Development 297Melissa S. Tassinari, Luc M. De Schaepdrijver, and Mark E. Hurtt16.1 Introduction 29716.2 Regulatory Environment 29816.3 Relevance and Place in Drug Development 30216.4 Strategies for Decision Making: When are Studies Needed and Appropriate? 30416.5 Case Studies: Application of Data Review and Decision Making 30716.6 Summary 30917 Immunotoxicology 313Leigh Ann Burns-Naas and Marc J. Pallardy17.1 Introduction 31317.2 Regulatory Expectations for the Immunotoxicology Evaluation of Pharmaceuticals 31417.3 Special Considerations 33517.4 Summary 342References 34218 Nonclinical Safety Assessment: Biotechnology-Derived Pharmaceuticals 347Christopher E. Ellis, Melanie T. Hartsough, Martin D. Green, and Hanan Ghantous18.1 Introduction 34718.2 Unique Characteristics of Biopharmaceuticals 34818.3 Species Selection 34918.4 Immunogenicity 35618.5 Biological Activity/Pharmacodynamics 35818.6 Pharmacokinetics/Toxicokinetics 35918.7 Nonclinical Safety Assessment 36218.8 Tissue Cross-Reactivity (TCR) 37118.9 Clinical Starting Dose Selection for Biopharmaceuticals 37318.10 Comparability 37519 International Safety Regulations for Vaccine Development 381Robert V. House19.1 Introduction 38119.2 What "Toxicities" have been Attributed to Vaccination? 38119.3 How Vaccines are (Slightly) Different from Other Biopharmaceuticals 38319.4 Regulatory Framework for Assessing Safety of Vaccines 38319.5 Parameters Monitored 38719.6 Clinical Safety Assessment of Vaccines 38919.7 Summary 39020 Phototoxicity and Photocarcinogenicity 393Robert E. Osterberg, Christopher P. Sambuco, and Paul Donald Forbes20.1 History of Phototoxicity, Photocarcinogenicity and Photogenotoxicity Testing at the US Food and Drug Administration (FDA) 39320.2 FDA Photosafety Testing Guidance 39720.3 Status of In Vivo Testing for Photocarcinogenesis 41720.4 Photocarcinogenesis Study Designs 41820.5 Photo Co-Carcinogenesis 41820.6 Future Testing Concepts, with Emphasis on Biomarkers 42321 Degradants, Impurities, Excipients and Metabolites 431Robert E. Osterberg and Mark W. Powley21.1 Degradants, Impurities, and Excipients 43121.2 Metabolites 442References 446Index 449

“As a toxicologist with a quarter-century of experience in pharmaceutical drug development, I found the reading of this book thoroughly enjoyable and useful.”  (British Toxicology Society Newsletter, 1 October 2013)