Abstract
Pediatric Non-Clinical Drug Testing has set out to tackle a very complex, relevant, and critical area of reproductive toxicology which was originally the vision of the late Dr Mildred S. Christian and was completed under the editorship of colleagues Dr Alan Hoberman and Dr Elise Lewis. Dr Christian was a pioneer in the area of reproductive toxicology and was keen on further developing this important element of reproductive drug testing. Given the fact that the United States initiated pediatric regulation in 1997, finalizing it in 2006, the European Medicines Agency (EMA) finalized similar—but not identical—regulations in 2008, and after many years of studying pediatric drug testing, the Japanese Ministry of Health, Labour, and Welfare initiated the preparation of similar guidelines in October of 2010. It is surprising that this is the first textbook—at least of which I am aware—that deals with this pediatric testing in any in-depth and useful way. Clearly, the need for a collection of these data in a single publication was long overdue.
The book is organized into 14 chapters starting with an excellent introductory chapter that provides an excellent overview of the use of juvenile animals and also included several quite useful tables, for example, Table 1.7 (Comparison of Age Categories by Species), Table 1.8 (FDA/EMA Organ Systems of Concern and Corresponding Age of General Development in Humans), and Table 1.9 (Critical Factors in Species Selection). There are considerable data presented in these tables, which are easily used and are helpful in not only understanding the issues involved with juvenile animals but also in constructing appropriate testing strategies for both the United States and Europe. Chapter 2 adds additional complexities including the diseases and clinical considerations necessary for developing pediatric medicines. Chapter 3 addresses the issues involved in biopharmaceutical drug development including species cross-reactivity, dosage selection, immunogenicity, pharmacokinetics, and absorption, distribution, metabolism, and excretion (ADME) from the pediatric perspective. Figure 3.1 presents a decision tree for developing strategies. The chapter describes in more detail the specifics of the decision tree strategy. Chapters 4 and 5 cover the history of development of testing of drugs for exposures to juvenile populations at the United States Food and Drug Administration (USFDA). The development includes discussions of the 1937 Elixir of Sulfanilamide Incident, the thalidomide incident in 1962, the passing and further development of the FDA Modernization Act, the passing of the Pediatric Labeling Rule in 1994 and its reauthorization in 2003, and a comparison of USFDA and EMA approaches to pediatric testing and regulatory considerations for the development of a Pediatric Investigation Plan. Chapter 6 details the juvenile animal testing protocols that can be used to assess environmental toxicity as well as endocrine screening and testing protocols. It further emphasizes the fact that while the United States Environmental Protection Agency (EPA) has made no formal decision on the evaluation of juvenile animals, the concepts and approaches are similar and provides 4 examples of studies that have been required by EPA for specific pesticides. Chapter 7 describes the nonclinical testing procedures used to determine the age-related differences in ADME among various species and how they extrapolate to humans. Chapter 8 continues the ADME testing as it relates to regulatory authorities with discussions of the types of variations and what various agencies require. Chapters 9 through 13 robustly describe juvenile study designs and strategies for rodents, rabbits, dogs, minipigs, swine, and primates. These chapters are well written and provide excellent, in-depth information on the pharmacodynamic and pharmacokinetic data for dose selection, the timing of the first exposure, route and method of administration, group size, and animal selection procedures as well as the many critical measurements that must be made to adequately complete these studies and fundamental regulatory requirements that might apply. Each chapter is reasonably complete and underscores the specific regulatory aspects for that particular species. Chapter 14 describes different approaches to rat juvenile toxicity studies as well as case studies for pharmaceutical testing. Since there is no standard juvenile study and each must be handled on a case-by-case basis, the chapter emphasizes designing the nonclinical study to fit the clinical plan and how best to approach the design. In addition, there are 2 case studies presented to help guide the reader through the overall process of study design. To further clarify the specifics of these types of protocols, a sample study protocol outline for a juvenile rat study is provided in Appendix 2.
There is some redundancy within the chapters with respect to regulations; however, this also permits the authors of each chapter to underscore the relevant regulations to the species and topic at hand rather than have to refer back to another generalized section on regulations, which may not be as clear to the reader. Appendix 1 presents a list of references regarding the “Maturation of Organ Systems in Various Species,” which is an excellent starting point; however, all references are no more recent than 2003, and some more recent publications might have been included. Appendix 2 noted above is quite detailed as well as functional as it presents a “Sample Juvenile Toxicity Testing Protocol.” Although some of the species described are infrequently used in practical applications, their inclusion lends a breadth of knowledge to this growing field in reproductive toxicity testing and provides excellent background understanding for comparisons to assist the reader in grasping the intricacies of juvenile animal testing.
In summary, Pediatric Non-Clinical Drug Testing is an excellent text in which it has assembled the current thinking on juvenile animal testing procedures from both European and the US regulatory perspectives with authors from both sides of the Atlantic well represented. The topics are thoroughly investigated, and the text has practical sample protocol applications and case studies as well as the theoretical development of the testing procedures. I found the text to be thorough, easy to read, practical, and relevant to this quickly developing field. I highly recommend this publication for inclusion in the personal library of all those developing drugs and for those in the field of reproductive and developmental toxicology. It provides a reliable reference for this growing field of study that will only become more important going forward.
Finally, on a personal note, I am particularly pleased that the authors and editors (especially to Millie’s husband, Dr Alan Hoberman) dedicated this book to my friend and colleague, Millie Christian, who was such a positive force in the area of reproductive toxicology for many years with over 120 publications, the founding editor of this journal (International Journal of Toxicology) and a founder of Argus Research Laboratories as just a few of her many remarkable achievements. While you may not always have agreed with her, you certainly had to respect her arguments for her position. This publication is an excellent tribute to a quality scientist who left us much too soon.
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