Title Details

Steven A. Silber, MD, is Vice President for Drug Development and Safety with McNeil Pediatrics, Ortho-McNeil Women's Health and Urology, in Fort Washington, Pennsylvania.

John N. van den Anker, MD, PhD, is Executive Director of the Pediatric Pharmacology Research Unit and Director of Pediatric Clinical Pharmacology at the Children's National Medical Center, Washington, DC, and Professor of Pediatrics, Pharmacology and Physiology at George Washington University, Washington, DC, as well as an Adjunct Professor of Pediatrics at Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.

CONTRIBUTORS xv

PART I PAST, PRESENT, AND FUTURE OF PEDIATRIC DRUG DEVELOPMENT

1 A New Model for Children 3
Andrew E. Mulberg, John N. van den Anker, and Steven A. Silber

2 History of Pediatric Drug Development and Therapeutics 7
Stephen P. Spielberg

3 Perspectives on Pediatric Clinical Trials: The Good, the Bad, and the Ugly 11
Greg Koski

4 Population Dynamics, Demographics, and Disease Burden of Infants and Children Across the World 21
Christopher-Paul Milne

5 Pharmaceutical Economics and Applications to Pediatrics: Business Case Development 39
Christopher-Paul Milne

6 Pediatric Market Dynamics 59
Anne F. Clothier

7 Industry Benchmarks in Pediatric Clinical Trials 65
Cindy Levy-Petelinkar and Carolyn A. Campen

8 Novel Organizational Strategies for Advancing Pediatric Products: Business Case Development 69
Donald P. Lombardi

PART II ETHICAL UNDERPINNINGS

9 Additional Protections for Children Enrolled in Clinical Investigations 81
Robert M. Nelson

10 Ethical Issues in Neonatal Drug Development 103
Gerri R. Baer

11 Ethical Principles of Pediatric Research and Drug Development: A Guide Through National and International Frameworks and Applications to a Worldwide Perspective 115
Klaus Rose

PART III REGULATORY GUIDELINES FOR PEDIATRIC DRUG DEVELOPMENT: STIMULATION OF PEDIATRIC DRUG RESEARCH BY REGULATORY AUTHORITIES

12 United States Perspective 133
Samuel Maldonado

13 European Perspective 137
Klaus Rose

14 Japanese Perspective 153
Hidefumi Nakamura and Shunsuke Ono

15 Regulatory Considerations for Study of Generic Drugs Under Best Pharmaceuticals for Children Act: NICHD and FDA Collaboration 165
Sandra Cottrell and Brahm Goldstein

PART IV PRECLINICAL SAFETY ASSESSMENT

16 Introduction and Overview 175
Timothy P. Coogan

17 Preclinical Juvenile Toxicity Assessments and Study Designs 181
Luc M. De Schaepdrijver and Graham P. Bailey

18 Absorption, Distribution, Metabolism, and Excretion (ADME) and Pharmacokinetic Assessments in Juvenile Animals 201
Loeckie L. de Zwart, Johan G. Monbaliu, and Pieter P. Annaert

PART V PHARMACOLOGICAL PRINCIPLES IN PEDIATRIC DRUG DEVELOPMENT

19 Pediatric Clinical Pharmacology: Why, Where, How, When? 225
John N. van den Anker

20 Developmental Pharmacology Issues: Neonates, Infants, and Children 231
Natella Y. Rakhmanina and John N. van den Anker

21 Developmental Hepatic Pharmacology in Pediatrics 243
Martin Otto Behm

22 Applications of Pharmacogenomics to Study Design in Pediatrics 259
Nadine Cohen and Seth Ness

23 General Principles of Population Pharmacokinetics in Pediatrics 277
Mahesh Samtani and Hui Kimko

24 Development of Oncology Drugs for Children 285
Robin Norris, Wayne Rackoff, Steven Hirschfeld, and Peter C. Adamson

PART VI CLINICAL TRIAL OPERATIONS: UNDERSTANDING DIFFERENCES BETWEEN PEDIATRIC AND ADULT STUDY SUBJECTS—DEVELOPMENT ISSUES RELATED TO ORGAN DEVELOPMENT AND ENDPOINT CHOICES

25 Brain and Central Nervous System Development: Physiological Considerations for Assessment of Long-Term Safety 301
Eugene Schneider

26 Cognitive Development Considerations for Long-Term Safety Exposures in Children 313
Mary Pipan

27 Cardiovascular and QTc Issues 337
Bert Suys and Luc Dekie

28 Renal Function Issues 351
Katia Boven

29 Growth and Physical Maturation 363
Alisha J. Rovner and Babette S. Zemel

PART VII CLINICAL TRIAL OPERATIONS AND GOOD CLINICAL TRIALS

30 The Consent Process in Pediatric Clinical Trials 387
M. Renee Simar

31 Recruitment and Retention in Pediatric Clinical Trials 405
M. Renee Simar

32 Certification of Pediatric Clinical Investigators 417
A. Procaccino

33 Considerations and Barriers for Pediatric Patient Recruitment Strategy for Clinical Trials 419
Jennifer Niesz and Andrew E. Mulberg

34 Conducting Clinical Trials in Developing Countries: A Case Study 431
Leonard R. Friedland and Jacqueline M. Miller

35 The Importance of Geographic Differences in Pediatric Clinical Trials 437
Alexandar Cvetkovich Munta~nola

36 Partnering with Industry: Academic Medical Centers and Clinical Research Centers 451
Kate Owen, Matthew Hill, Sandra Cottrell, and Brahm Goldstein

PART VIII CLINICAL EFFICACY AND SAFETY ENDPOINTS

37 Laboratory Monitoring of Efficacy and Safety Parameters in Clinical Trials for Pediatric Subjects 467
Andrew E. Mulberg and Samuel Maldonado

38 Breath Testing in Pediatrics 481
Gigi Veereman-Wauters

39 Surrogate Endpoints: Application in Pediatric Clinical Trials 501
Geert Molenberghs and Camille Orman

40 Patient-Reported Outcomes in Pediatric Drug Development 513
Margaret Rothman and Leah Kleinman

41 Safety Monitoring in Pediatric Clinical Trials 525
Seth V. Hetherington

42 Pharmacovigilance: Assessing Safety Postapproval 543
Karen M. Kaplan

PART IX FORMULATION, CHEMISTRY, AND MANUFACTURING CONTROLS

43 Formulation of Pediatric Dosage Forms 553
Gerard P. McNally and Aniruddha M. Railkar

44 Drug Delivery Challenges for the Pediatric Patient: Novel Forms for Consideration 567
Edward J. Roche

45 Oral Drug Delivery Challenges for the Pediatric Patient 573
Michael R. Hoy

46 The Jelly Bean Test: A Novel Technique to Help Children Swallow Medications 581
Robbyn E. Sockolow and Aliza B. Solomon

PART X CASE STUDIES: SUCCESSES FOR CHILDREN

47 A Case Study of Psychiatric Research in Children: The Risperdal1 Example 589
Magali Haas

48 Topiramate Case Study 599
Seth L. Ness, Ursula Merriman, and Jeffrey S. Nye

49 Ascent Pediatrics: A Model for Successful Pediatric Drug Development 605
Emmett Clemente

50 Case Study for the Development of an Enteric-Coated and High-Buffered Pancreatic Enzyme Product 611
Tibor Sipos

APPENDIX Reference Tables and Figures 625

INDEX 657