Nonclinical Safety Assessment

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

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