Nonclinical Safety Assessment: A Guide to International Pharmaceutical Regulations


Providing a comprehensive, international overview of the regulatory requirements for safety assessment for new drug approvals, each chapter in Nonclinical Safety Assessment is written by experts who have direct, firsthand involvement in drug development in the regions where they are located. International coverage includes World Health Organization (WHO) principles and regional variations, including EMEA guidance, U.S. FDA, and Asia-Pacific. The text provides insights into the future of nonclinical drug testing ...

See more details below
Other sellers (Hardcover)
  • All (9) from $133.92   
  • New (6) from $136.86   
  • Used (3) from $133.92   


Providing a comprehensive, international overview of the regulatory requirements for safety assessment for new drug approvals, each chapter in Nonclinical Safety Assessment is written by experts who have direct, firsthand involvement in drug development in the regions where they are located. International coverage includes World Health Organization (WHO) principles and regional variations, including EMEA guidance, U.S. FDA, and Asia-Pacific. The text provides insights into the future of nonclinical drug testing and approval and includes a list of resources such as guidelines, guidance, and authoritative non-governmental publications.

Read More Show Less

Editorial Reviews

From the Publisher
“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)
Read More Show Less

Product Details

  • ISBN-13: 9780470745915
  • Publisher: Wiley
  • Publication date: 5/6/2013
  • Edition number: 1
  • Pages: 486
  • Product dimensions: 6.80 (w) x 9.60 (h) x 0.70 (d)

Meet the Author

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.

Read More Show Less

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 Correa, Giuliana Selmi, and Flavio Ailton Duque Zambrone

4.1 Introduction 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

Read More Show Less

Customer Reviews

Be the first to write a review
( 0 )
Rating Distribution

5 Star


4 Star


3 Star


2 Star


1 Star


Your Rating:

Your Name: Create a Pen Name or

Barnes & Review Rules

Our reader reviews allow you to share your comments on titles you liked, or didn't, with others. By submitting an online review, you are representing to Barnes & that all information contained in your review is original and accurate in all respects, and that the submission of such content by you and the posting of such content by Barnes & does not and will not violate the rights of any third party. Please follow the rules below to help ensure that your review can be posted.

Reviews by Our Customers Under the Age of 13

We highly value and respect everyone's opinion concerning the titles we offer. However, we cannot allow persons under the age of 13 to have accounts at or to post customer reviews. Please see our Terms of Use for more details.

What to exclude from your review:

Please do not write about reviews, commentary, or information posted on the product page. If you see any errors in the information on the product page, please send us an email.

Reviews should not contain any of the following:

  • - HTML tags, profanity, obscenities, vulgarities, or comments that defame anyone
  • - Time-sensitive information such as tour dates, signings, lectures, etc.
  • - Single-word reviews. Other people will read your review to discover why you liked or didn't like the title. Be descriptive.
  • - Comments focusing on the author or that may ruin the ending for others
  • - Phone numbers, addresses, URLs
  • - Pricing and availability information or alternative ordering information
  • - Advertisements or commercial solicitation


  • - By submitting a review, you grant to Barnes & and its sublicensees the royalty-free, perpetual, irrevocable right and license to use the review in accordance with the Barnes & Terms of Use.
  • - Barnes & reserves the right not to post any review -- particularly those that do not follow the terms and conditions of these Rules. Barnes & also reserves the right to remove any review at any time without notice.
  • - See Terms of Use for other conditions and disclaimers.
Search for Products You'd Like to Recommend

Recommend other products that relate to your review. Just search for them below and share!

Create a Pen Name

Your Pen Name is your unique identity on It will appear on the reviews you write and other website activities. Your Pen Name cannot be edited, changed or deleted once submitted.

Your Pen Name can be any combination of alphanumeric characters (plus - and _), and must be at least two characters long.

Continue Anonymously

    If you find inappropriate content, please report it to Barnes & Noble
    Why is this product inappropriate?
    Comments (optional)