Pediatric Drug Development: Concepts and Applications is designed as a reference and textbook and is meant to address the science of differences between the pediatric and adult subject in the development of pharmaceutical products. Considered are the ethics and medical needs of proper understanding the pediatric and adult differences, the business case for proper development of drugs for children, as well as the technical feasibility studies and processes that are necessary for a proper pediatric drug development program. The applications of these approaches will benefit all stakeholders and ultimately not only educate but also provide better and safer drugs for pediatric patients.

Table of Contents

PREFACE xiii 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 Risperdal 1 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

Author Biography

Andrew E. Mulberg , MD, is Director of Pediatric Drug Development for Johnson and Johnson Pharmaceutical Research and Development, LLC, in Titusville, New Jersey, and is has been editor for four editions of the best-selling 5-Minute Pediatric Consult . 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.