ICH the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human
Trade Review
“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)
Table of Contents
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
