Nonclinical Safety Assessment – A Guide to International Pharmaceutical Regulations

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