Pediatric Non–Clinical Drug Testing: Principles, Requirements, and Practice

Enables readers to successfully perform non–clinical drugtesting, meeting international requirements

Although the non–clinical and clinical testing needs of drugsfor pediatric populations have been discussed and debated for morethan forty years, many ethical, political, and practical issuesremain unresolved, making pediatric drug testing and labeling achallenge for pharmaceutical and toxicology professionals. Writtenand edited by a team of leading international experts, this bookexplains both the importance and the practice of non–clinicalpediatric drug testing. Moreover, it guides readers through thecomplex set of international rules and regulations governing thepractice today.

Following the authors′ clear advice, readers will be able tomeet FDA guidelines for non–clinical pediatric drug testing, frominitial study design to submission of results for approval.Moreover, the authors describe key differences between the FDAguidelines and European Medicines Agency (EMA) legislation,enabling readers to devise and conduct studies, analyze theresults, and then compile appropriate information for submission toboth agencies.

Pediatric Non–Clinical Drug Testing offers clear guidancefor managing the key challenges of non–clinical testing models,helping readers overcome the difficulties associated with:

Lack of fully comparable models

Inadequate historical experience

Specific needs and effects associated with testing animals

Practical problems using the clinical route of exposure inanimal models

The book′s appendix features a sample juvenile toxicity testingprotocol that readers can use as a template for their ownexperimental designs.

In addition to toxicologists and pharmacokineticists, this bookis recommended for drug regulators who need to develop and enforcedrug testing standards to protect children. It is also recommendedas a textbook for toxicology and pediatric medicine courses.

Acknowledgments xi

Contributors xiii

1. Introduction 1
Elise M. Lewis, Luc M. De Schaepdrijver, and Timothy P.Coogan

2. Overview of Pediatric Diseases and Clinical Considerations onDeveloping Medicines for Children 29
Bert Suys and Jose Ramet

3. Nonclinical Safety Assessment for Biopharmaceuticals:Challenges and Strategies for Juvenile Animal Testing 41
Timothy P. Coogan

4. FDA Approach to Pediatric Testing 59
Robert E. Osterberg

5. Pediatric Drug Development Plans 79
Kimberly C. Brannen and Beatriz Silva Lima

6. Application of Principles of Nonclinical Pediatric DrugTesting to the Hazard Evaluation of Environmental Contaminants93
Susan L. Makris

7. Nonclinical Testing Procedures Pharmacokinetics115
Loeckie L. de Zwart, Johan G. Monbaliu, and Pieter P.Annaert

8. Preclinical Development of a Pharmaceutical Product forChildren 129
Graham P. Bailey, Timothy P. Coogan, and Luc M. DeSchaepdrijver

9. Juvenile Toxicity Study Design for the Rodent and Rabbit141
Alan M. Hoberman and John F. Barnett

10. Dog Juvenile Toxicity 183
Keith Robinson, Susan Y. Smith, and Andre Viau

11. Use of the Swine Pediatric Model 213
Paul C. Barrow

12. Juvenile Immunodevelopment in Minipigs 231
Andr´e H. Penninks, Geertje J.D. van Mierlo, Frieke Kuper,Cor J. Snel, Niels–Christian Ganderup, and Andr´e P.M.Wolterbeek

13. Use of Primate Pediatric Model 255
Gerhard F. Weinbauer, Gary J. Chellman, Allan Dahl Rasmussen andElvira Vogelwedde

14. Approaches to Rat Juvenile Toxicity Studies and CaseStudies: a Pharmaceutical Perspective 281
Susan B. Laffan and Lorraine Posobiec

Appendix 1 Maturation of Organ Systems in Various Species301

Appendix 2 Sample Juvenile Toxicity Testing Protocol 303

Index 331

ELISE M. LEWIS, PhD, is Director of Reproductive andNeurobehavioral Toxicology at Charles River Preclinical Services,Horsham, PA.

Overall, this is a very useful book in bringing togethermany of the aspects associated with JA toxicology testing ofpharmaceuticals for the first time, especially for those new tothis growing field, with the chapters on study designconsiderations being especially useful.   (BritishToxicology Society New, 1 November 2012)

The book is an essential reference for internationalregulatory personnel, toxicologists, pharmacokineticists,scientists working in the pharmaceutical industry, academics andphysicians and pharmacists concerned about the safe use ofmedicines in children.   (PharmaceuticalJournal, 11 September 2012)

No other single resource combines pediatric drugdevelopment considerations with the most recent regulatoryrequirements and the approach to selecting and testing innonclinical models. This is a unique and comprehensive referencethat will inform and guide readers through the challenges andapproaches to the safe and effective use of medications inchildren.   (Doody s, 17 August 2012)