Nonclinical Safety Assessment – A Guide to International Pharmaceutical Regulations

Dr. William J Brock, Brock Scientific Consulting, USA Dr. Bill Brock is Principal of Brock Scientific Consulting and manages R&D programs for clients in the pharmaceutical, chemical, food and consumer product industries. He is the Past-President of American Board of Toxicology, serves on the Board of Directors for the Academy of Toxicological Sciences and is an Associate Editor for the International Journal of Toxicology. Dr. Brock has served in a leadership capacity in various organizations within the Society of Toxicology, the American College of Toxicology and is co-chair of the nonclinical section of the Drug Information Association. Dr. Kenneth Hastings, sanofi-aventis, USA Dr Hastings was Associate Director for Pharmacology/Toxicology in the Office of New Drugs, US Food and Drug Administration, from 2003 to 2007. He currently is Associate Vice President for Regulatory Policy at sanofi-aventis. He has served in several professional societies, including the American Board of Toxicology (currently President), the American College of Toxicology (currently President-Elect), the Society of Toxicology (Past President of the Immunotoxicology Specialty Section), and as Co-Chair of the Nonclinical Special Interest Committee of the Drug Information Association.

List of Contributors xvii Preface xix Part I International Regulations and Nonclinical Studies for Pharmaceuticals 1 1 Introduction 3 Kathy M. McGown and William J. Brock 1.1 The Global Pharmaceutical Market 6 1.2 Looking to the Future 9 1.3 Legal and Regulatory Considerations in Drug Development 10 1.4 The Drug Development Process General Considerations 12 2 ICH: History and Nonclinical Guidances 17 Jan-Willem van der Laan and Kenneth L. Hastings 2.1 Introduction 17 2.2 Organization of the ICH 19 2.3 The ICH Process 20 2.4 Animal Welfare and Alternative Methods 22 2.5 ICH M3 23 2.6 New Initiatives and Topics 24 3 Food and Drug Administration: Nonclinical Program and Pharmaceutical Approval 27 William J. Brock and Kenneth L. Hastings 3.1 Legislative Authority of the FDA 27 3.2 Nonclinical Drug Development and the FDA 31 3.3 Nonclinical Testing: General Conditions and Considerations 34 3.4 Toxicity Testing: Small Molecules and Traditional Pharmaceuticals 34 3.5 Toxicity Testing of Pharmaceuticals The General Approach 35 3.6 First-in-Human Dosing: Results from Nonclinical Studies 37 4 Nonclinical Pharmaceutical Development in MERCOSUR and Brazil 41 Cristiana Leslie Corr^ea, Giuliana Selmi, and Flavio Ailton Duque Zambrone 4.1 Introduction 41 4.2 MERCOSUR 41 4.3 Brazil 44 5 Nonclinical Safety Assessment: Canada 57 Jamie L. Doran and Mark T. Goldberg 5.1 Introduction 57 5.2 Organization of Health Canada 58 5.3 The Regulatory Framework for Drug Approval in Canada 60 5.4 Nonclinical Assessment in Canada 64 5.5 Clinical Trial Applications 70 5.6 Special Regulatory Considerations 74 6 European Pharmaceutical Regulation Nonclinical Testing Requirements 79 Adam Woolley and Jan Willem van der Laan 6.1 Introduction 79 6.2.1 Overview 82 6.3 Nonclinical Testing in the Support of Clinical Trials 86 6.4 Overview 96 7 South Africa 99 Fariza Feraoun and Malik Feraoun 7.1 Introduction 99 7.2 Country Information 100 7.3 The Regulatory Aspects 101 7.4 The Nonclinical Safety Assessment 109 7.5 Conclusion 114 8 Asia Pacific: China 117 Lijie Fu and Qingli Wang 8.1 Introduction 117 8.2 History of Drug Administration 118 8.3 The Provisions for Drug Registration 122 8.4 The SFDA 123 8.5 The SFDA Affiliated Organizations 123 8.6 General Registration Procedures 125 8.7 Pharmaceutical Application 125 8.8 Import Drug Application 127 8.9 Testing Guidelines and Safety Evaluation 129 8.10 GLP Compliance in China 131 8.11 Animal Welfare Requirements 133 9 Pharmaceutical Regulations for Nonclinical Safety Assessment in Japan 135 Kazuichi Nakamura and Osamu Fueki 9.1 History of Regulation for Nonclinical Safety Assessment in Japan 135 9.2 Approval Application of New Drugs in Japan 136 9.3 Current Nonclinical Safety Guidelines Available in Japan 139 9.4 Current Trends of Conduct of Nonclinical Safety Evaluation in Japan 139 9.5 Safety Assessment of Unapproved Drugs 142 9.6 Necessity of 3Rs (Reduction/Refinement/Replacement) of Animal Studies 142 9.7 Attitude of Japanese Pharmaceutical Companies and the Regulatory Agency toward Nonclinical Safety Assessment 142 10 Indian Regulatory Process for Nonclinical Drug Development 145 K.S. Rao and S. Natesan 10.1 Introduction 145 10.2 Drug Development 146 10.3 Quality Systems 147 10.4 Nonclinical Drug Development Key Regulatory Requirements 148 10.5 Nonclinical Safety Assessment Key Approval Requirements 149 10.6 Data Required for Clinical Study Approval 151 10.7 Animal Toxicology 154 10.8 Animal Pharmacology 166 10.9 Safety Assessment Requirements: Indian Schedule Yand International Guidelines 168 10.10 Good Laboratory Practice Quality System in India 168 10.11 Safety Assessment Test Facilities in India 171 10.12 Investigational New Drug Application for Undertaking Clinical Trials 173 11 Asia Pacific: Australia 175 Douglas Francis 11.1 Introduction 175 11.2 Australian Therapeutic Goods Administration (TGA) 176 11.3 Clinical Trials in Australia 183 11.4 Nonclinical Data to Support the Conduct of Clinical Trials in Australia and Marketing Application to the TGA 188 Part II Toxicology Studies Supporting Clinical Development 197 12 Repeated-Dose Toxicity Studies in Nonclinical Drug Development 199 Shana Azri-Meehan and Louise Latriano 12.1 Introduction 199 12.2 General Considerations 200 12.3 Study Design Considerations 205 12.4 Study Observations and Assessments 211 13 Evaluation of Potential Carcinogenicity 219 James A. Popp and Matthew S. Bogdanffy 13.1 Introduction 219 13.2 Preparation for the Carcinogenicity Study 223 13.3 Elements of the Protocol/Study Plan 228 13.4 Study Performance 241 13.5 Alternative Models to Evaluate Potential Carcinogenicity in Lieu of a 2-Year Mouse Study 244 13.6 Special Consideration for Carcinogenicity Evaluation of Biotherapeutics 247 13.7 Regulatory Implications of a Study Identifying an Animal Carcinogenic Response 248 13.8 Interpreting the Relevance of Positive Results for Human Safety 249 13.9 Communicating the Results in the Product Label 251 14 Genetic Toxicology 255 Mark W. Powley 14.1 Background 255 14.2 Regulations Guiding Drug Development 256 14.3 Genotoxic Impurities 261 14.4 Regulatory Decision Making 263 15 Developmental and Reproductive Toxicology 265 Robert M. Parker and Raymond G. York 15.1 Introduction 265 15.2 Standard Reproduction and Developmental Toxicity Study Designs 266 15.3 Timing of Preclinical Developmental and Reproductive Toxicity Studies 273 15.4 Based on Disease Indication 275 15.5 Based on Pharmaceutical Characteristic 279 15.6 Other Reasons to Conduct Preclinical Reproductive and Developmental Toxicity Studies 291 15.7 Excipients 293 15.8 Conclusion 293 16 Juvenile Animal Toxicity Studies: Regulatory Expectations, Decision Strategies and Role in Paediatric Drug Development 297 Melissa S. Tassinari, Luc M. De Schaepdrijver, and Mark E. Hurtt 16.1 Introduction 297 16.2 Regulatory Environment 298 16.3 Relevance and Place in Drug Development 302 16.4 Strategies for Decision Making: When are Studies Needed and Appropriate? 304 16.5 Case Studies: Application of Data Review and Decision Making 307 16.6 Summary 309 17 Immunotoxicology 313 Leigh Ann Burns-Naas and Marc J. Pallardy 17.1 Introduction 313 17.2 Regulatory Expectations for the Immunotoxicology Evaluation of Pharmaceuticals 314 17.3 Special Considerations 335 17.4 Summary 342 References 342 18 Nonclinical Safety Assessment: Biotechnology-Derived Pharmaceuticals 347 Christopher E. Ellis, Melanie T. Hartsough, Martin D. Green, and Hanan Ghantous 18.1 Introduction 347 18.2 Unique Characteristics of Biopharmaceuticals 348 18.3 Species Selection 349 18.4 Immunogenicity 356 18.5 Biological Activity/Pharmacodynamics 358 18.6 Pharmacokinetics/Toxicokinetics 359 18.7 Nonclinical Safety Assessment 362 18.8 Tissue Cross-Reactivity (TCR) 371 18.9 Clinical Starting Dose Selection for Biopharmaceuticals 373 18.10 Comparability 375 19 International Safety Regulations for Vaccine Development 381 Robert V. House 19.1 Introduction 381 19.2 What "Toxicities" have been Attributed to Vaccination? 381 19.3 How Vaccines are (Slightly) Different from Other Biopharmaceuticals 383 19.4 Regulatory Framework for Assessing Safety of Vaccines 383 19.5 Parameters Monitored 387 19.6 Clinical Safety Assessment of Vaccines 389 19.7 Summary 390 20 Phototoxicity and Photocarcinogenicity 393 Robert E. Osterberg, Christopher P. Sambuco, and Paul Donald Forbes 20.1 History of Phototoxicity, Photocarcinogenicity and Photogenotoxicity Testing at the US Food and Drug Administration (FDA) 393 20.2 FDA Photosafety Testing Guidance 397 20.3 Status of In Vivo Testing for Photocarcinogenesis 417 20.4 Photocarcinogenesis Study Designs 418 20.5 Photo Co-Carcinogenesis 418 20.6 Future Testing Concepts, with Emphasis on Biomarkers 423 21 Degradants, Impurities, Excipients and Metabolites 431 Robert E. Osterberg and Mark W. Powley 21.1 Degradants, Impurities, and Excipients 431 21.2 Metabolites 442 References 446 Index 449