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- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Sprache: Englisch
Most medicines have never been adequately tested for safety and efficacy in pediatric populations and preterm, infants and children are particularly vulnerable to adverse drug reactions.
Pediatric Drug Development: Concepts and Applications, Second Edition, addresses the unique challenges in conducting effective drug research and development in pediatric populations.
This new edition covers the legal and ethical issues of consent and assent, the additional legal and safety protections for children, and the appropriate methods of surveillance and assessment for children of varying ages and maturity, particularly for patient reported outcomes. It includes new developments in biomarkers and surrogate endpoints, developmental pharmacology and other novel aspects of global pediatric drug development. It also encompasses the new regulatory initiatives across EU, US and ROW designed to encourage improved access to safe and effective medicines for children globally.
From an international team of expert contributors Pediatric Drug Development: Concepts and Applications is the practical guide to all aspects of the research and development of safe and effective medicines for children.
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Seitenzahl: 1548
Veröffentlichungsjahr: 2013
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Contents
Cover
Title Page
Copyright
List of Contributors
Preface
Part I: Past, Present, and Future of Pediatric Drug Development
Chapter 1: Introduction: Pediatric Drug Development and Therapeutics: Continued Progress for Better Drugs for Children
References
Chapter 2: History of Children and the Development of Regulations at the FDA
2.1 Introduction and Early History
2.2 Product Label Changes
2.3 FDA Pediatric Initiatives with Voluntary Compliance
2.4 Initial Pediatric Mandate
2.5 Additional Protections for Children Participating in Studies
2.6 Federal Pediatric Initiatives – First Decade Experience
2.7 Food and Drug Administration Act of 2007 – Third Generation of Pediatric Initiatives
2.8 Food And Drug Administration Safety and Innovation Act of 2012 – Fourth Generation of Pediatric Initiatives
2.9 Summary And Conclusions
Chapter 3: Population Dynamics, Demographics and Disease Burden of Infants and Children across the World
3.1 Introduction
3.2 Demographics
3.3 General Disease Burden
3.4 Specific Disease Burden
3.5 Demographic Factors and Disease Burden
3.6 Conclusion
References
Chapter 4: Pharmaceutical Economics and Market Access for Pediatric Medications
4.1 Introduction
4.2 Major Economic Disincentives to Pediatric R&D
4.3 Government Programs for Overcoming Economic Disincentives to Pediatric Drug Trials
4.4 Impact of Incentive Programs to Increase Availability of Pediatric Medicines and Child-Friendly Formulations
4.5 Non-Government Approaches for Overcoming Economic Disincentives to Pediatric Drug Trials: Cancer and Cystic Fibrosis as Special Case Examples
4.6 Remaining Challenges to Access for Pediatric Medicines in a Global Marketplace
4.7 The Future
4.8 Acknowledgement
References
Chapter 5: The Global Pediatric Market and Drivers of Pediatric Drug Development
5.1 Introduction
5.2 The Size and “Value” of the Global Pediatric Market
5.3 The Pediatric Market in the USA Today
5.4 The Pediatric Market Outside North America and Europe
5.5 The Current US Pediatric Drug Pipeline
5.6 A New Time of Transformation
References
Chapter 6: Industry Benchmarks in Pediatric Clinical Trials
6.1 Introduction
6.2 The Future for Pediatric Trials
References
Part II: Ethical Underpinnings
Chapter 7: Ethical and Practical Considerations in Conducting Neonatal Research
7.1 Introduction
7.2 Current Neonatal Practice: Challenges for Clinical Trials
7.3 Ethical Considerations in Neonatal Clinical Trials
7.4 Regulations for Research with Nonviable Neonates or Neonates of Uncertain Viability
7.5 Special Topics in Neonatal Research: Blood Volume Limits in Neonatal Studies
7.6 Finding a Path Forward for Neonatal Product Development
References
Chapter 8: Ethical Considerations in Conducting Pediatric Research
8.1 Background
8.2 The Principle of Scientific Necessity
8.3 Appropriate Balance of Risk and Potential Benefit
8.4 Parental Permission and Child Assent
8.5 Summary
References
Chapter 9: The Consent and Assent Process in Pediatric Clinical Trials
9.1 Introduction
9.2 Guidance and obligations
9.3 The Process of Consent and Assent
9.4 Conclusion
References
Part III: Regulatory Guidelines for Pediatric Drug Development
Chapter 10: A Sponsor's Perspective of US Regulations
References
Chapter 11: FDA Experience of Extrapolation of Efficacy to the Pediatric Population from Adult and Other Data
11.1 Introduction
11.2 Background
11.3 History
11.4 Principles of Extrapolation of Efficacy
11.5 The FDA's experience of extrapolation of efficacy from adult and other data to the pediatric population
11.6 Conclusion
References
Chapter 12: Accelerated Approval and Other Regulatory Approaches to Drug Development for Serious Diseases in Pediatrics
12.1 Introduction
12.2 Regulatory Basis for Accelerated Approval
12.3 Other FDA Programs Available to Speed the Development and Review of Products for Serious or Life-Threatening Diseases: Fast Track and Priority Review
12.4 Use of Accelerated Approval Regulations in Pediatrics
12.5 Use of the Accelerated Approval Regulations in HIV Infection [7]
References
Chapter 13: Rare Diseases and Orphan Drugs
13.1 Introduction
13.2 Rational Approach to Rare Disease Drug Development
13.3 Rare Diseases Past, Present and Future
References
Chapter 14: European Perspective
14.1 Introduction
14.2 Paediatric Committee
14.3 The Future
14.4 Conclusion
References
Chapter 15: Five Years of Pediatric Legislation in the European Union
15.1 Regulatory and Legal Framework in EU
15.2 Sources of Data and Limitations
15.3 Increasing Pediatric Research
15.4 More Medicines Available for Children in the EU
15.5 Increased Information on Medicines Used in Children
15.6 Global Development Activities
15.7 Lessons Learned from the First Five Years
References
Chapter 16: The Japanese Perspective
16.1 Introduction
16.2 Impact of Off-label, Extemporaneous and/or Unapproved Use of Drugs in Japanese health care
16.3 Involvement of the Japan Pediatric Society (JPS) for facilitation of pediatric drug development
16.4 Past and Present Guidance and Notifications for Pediatric Drug Developments in Japan
16.5 Government Efforts to Promote Clinical Trials in Japan
16.6 Efforts to Improve Access to New Products and Therapies
16.7 Medical Innovation Strategies in the Government
16.8 Drug Pricing in the National Healthcare Insurance
16.9 Prospects for the Future
References
Chapter 17: Pediatric Device Development in the United States
17.1 Introduction and Background
17.2 Pediatric Device Regulatory Efforts
17.3 Pediatric Medical Device Development
17.4 Elements of Review
17.5 Innovation and Unmet Needs
17.6 Conclusion
References
Part IV: Preclinical Safety Assessment
Chapter 18: Preclinical Safety Assessment: Introduction and Overview
References
Chapter 19: Juvenile Animal Toxicity Assessments: Decision Strategies and Study Design
19.1 Introduction
19.2 Decision Strategies Impacting Conduct and Design of Juvenile Animal Studies
19.3 Different Study Types
19.4 Key Study Design Considerations
19.5 Differences Between Study Designs for Small Molecule Pharmaceuticals and Biopharmaceuticals
19.6 Designs Considerations in Specific Organ Systems
19.7 Conclusions
References
Chapter 20: Absorption, Distribution, Metabolism and Excretion (ADME) and Pharmacokinetic Assessments in Juvenile Animals
20.1 Introduction
20.2 General Considerations
20.3 Effect of Age on ADME in laboratory animals
20.4 Conclusion
References
Chapter 21: A Global Regulatory Perspective
21.1 Introduction
21.2 US process
21.3 EU process
21.4 Pediatric Plans and Global Regulation
21.5 Global Nonclinical Approach
21.6 Lessons Learned
References
Chapter 22: Disease-Specific Models to Enhance Pediatric Drug Development
22.1 Introduction
22.2 Nonclinical Studies Using Animal Models
22.3 Conclusion and Future Directions
References
Part V: Pharmacological Principles in Pediatric Drug Development
Chapter 23: Pediatric Clinical Pharmacology in Regulatory and Drug Development Sciences: Lessons Learned and the Path Forward
23.1 Introduction
23.2 Pediatric Clinical Pharmacology Study Design Considerations in 2012
23.3 Problems in Designing Pediatric Drug Development Studies
23.4 Examples of Lessons Learned from Pediatric Studies Conducted Under BPCA and PREA
23.5 The Path Ahead Under FDASIA
23.6 Summary
References
Chapter 24: Development and Clinical Trial Design
24.1 Introduction
24.2 Study Population
24.3 Treatments
24.4 Outcome Variables
24.5 Human Subjects Protection
24.6 Conclusions
References
Chapter 25: Developmental Hepatic Pharmacology in Pediatrics
25.1 Introduction
25.2 Neonates and Infants
25.3 Older Infants and Children 2–16 Years
25.4 Conclusions
25.5 Future Directions
References
Chapter 26: Applications of Population Pharmacokinetics for Pediatric Drug Development
26.1 Introduction
26.2 Regulatory Considerations for Designing Pediatric PK studies
26.3 Study Design Considerations for Pediatric PK studies
26.4 Applications of Population PK in pediatric drug development
26.5 Unique Considerations in the Pediatric Population
26.6 Future Challenges and Application of POPPK
References
Chapter 27: Applications of Pharmacogenomics to Pediatric Drug Development
27.1 Introduction
27.2 Ontogeny vs Pharmacogenomics
27.3 Pharmacogenomic Information in Labeling
27.4 Pharmacogenomics of Serious Adverse Drug Reactions in Pediatrics
27.5 Relabeling Approved Drugs with Pediatric PGX Information
27.6 Trial Designs for Incorporating PGX Information into Pediatric Studies
27.7 Future Considerations
References
Chapter 28: Pharmacometrics Applications to Pediatric Trials
28.1 Introduction
28.2 Applications of Pharmacometric Analysis
28.3 Evidence of Effectiveness
28.4 Dosing Recommendations for Pediatric Labeling
28.5 Future Challenges
28.6 Conclusion
References
Part VI: Clinical Trial Operations
Chapter 29: Brain and Central Nervous System Development: Physiological Considerations for Assessment of Long-Term Safety
29.1 Introduction
29.2 Neurological Assessments in Pediatric Disease
29.3 Safety Assessment in CNS Disease
29.4 Nervous System Development
29.5 Neurophysiologic Development and Assessment Endpoints
References
Chapter 30: Cognitive Development Considerations for Long-term Safety Exposures in Children
30.1 Introduction
30.2 Mechanisms of Medication Effects on Cognition
30.3 Assessment of Change in Cognition
30.4 Summary
References
Chapter 31: Cardiovascular Issues and the QT Interval
31.1 Cardiovascular Development Changes and Implications for Treatment with Cardiovascular Drugs: Deficient Data Supporting Dosing for Efficacy and Safety
31.2 Developmental Changes in Infants and Children and Implications for Understanding Cardiotoxocity of Non-cardiovascular Drugs
31.3 Conclusion
References
Chapter 32: Pediatric Bone and Adult Bone – Physiological Differences
32.1 Introduction
32.2 Medications Associated with Impaired Skeletal Health
32.3 Conclusions
References
Chapter 33: Issues Related to Organ Development: Renal
33.1 Introduction
33.2 Maturation of Renal Functions
33.3 Guidelines on Pediatric Dosing in Relation to Renal Function
33.4 Health Authority Guidelines for the Use of Drugs in Patients with Renal Impairment
References
Chapter 34: Growth and Physical Development
34.1 Introduction
34.2 Methods To Assess Growth, Body Composition and Pubertal Development
34.3 Summary
References
Chapter 35: Development of Drugs for Pediatric Cancers
35.1 Introduction
35.2 Epidemiology and Principles of Chemotherapy for Childhood Cancers
35.3 History of Pediatric Oncology Drug Development
35.4 Challenges in the Development of Pediatric Cancer Therapeutics
35.5 Impact of Legislation on Drug Development for Pediatric Cancers
35.6 Identification of Promising Therapies
35.7 Recommendations for Nonclinical Development of Pediatric Drugs in Oncology
35.8 Design of Pediatric Studies
35.9 Drug Development for Childhood Cancer: The Path Forward
References
Part VII: Clinical Trial Operations and Good Clinical Trials
Chapter 36: Recruitment and Retention in Pediatric Clinical Trials: Focus on Pediatric Research Networks in the US and EU
36.1 Introduction
36.2 Empirical Evidence and Recruitment
36.3 Recruitment and Retention Locally
36.4 Organization and Structure of Pediatric Research Networks
36.5 Funding
36.6 Activities and Operations
36.7 Conclusions
References
Chapter 37: Recruitment and Retention of Minority Populations in Clinical Trials
37.1 Introduction
37.2 Minority Populations in the United States
37.3 Importance of Including Minority Pediatric Populations in Clinical Trials
37.4 Challenges in Recruitment and Retention of Minority Children in Clinical Trials
37.5 Strategies to Enhance and Effective Recruit Minority Children into Clinical Trials
37.6 Conclusions
References
Chapter 38: Conducting Clinical Trials in Developing and Emerging Countries: Review and Case Study
38.1 Introduction
38.2 Benefits of Globalization
38.3 Challenges Facing Globalized Trials
38.4 Trends in the Globalization of Clinical Trials
38.5 Conclusions
References
Chapter 39: Globalization of Pediatric Clinical Trials with a Focus on Emerging Countries
39.1 Introduction
39.2 Background of Regional Differences
39.3 The Impact of Regional Differences on Pediatric Clinical Trials
39.4 Actions to Minimize Data Variability in Multi-national Pediatric Clinical Trials
39.5 Pediatric Clinical Trials in Emerging Countries
39.6 Conclusion
References
Part VIII: Clinical Efficacy and Safety Endpoints
Chapter 40: Clinical Laboratory Testing in Clinical Trials for Pediatric Subjects
40.1 Introduction
40.2 Mechanical Issues: Operational Constraints and Phlebotomy Volumes
40.3 Establishment of Normal Values and Reference Ranges
40.4 Use of Normal Values for Laboratory Interpretation
40.5 Sickle Cell Disease and Other Hematological Disorders
40.6 Cystic Fibrosis (CF)
40.7 Conclusion
References
Chapter 41: Surrogate Endpoints: Application in Pediatric Clinical Trials
41.1 Introduction
41.2 Definition of “Surrogate Endpoint”
41.3 History of Surrogate Endpoints
41.4 Controversy with Surrogate Endpoints
41.5 Why Continue with Surrogate Endpoints?
41.6 Statistical Evaluation of Surrogate Endpoints
41.7 Surrogate Endpoints in Pediatric Trials
41.8 Future Areas for Surrogate Endpoints in Pediatric Research
41.9 Conclusion
References
Chapter 42: Clinical Outcome Assessments for Clinical Trials in Children
42.1 Introduction
42.2 Steps in Identification of a COA to measure treatment benefit
42.3 Establishing Other Measurement Properties
42.4 Adaptation of COA across contexts of use
42.5 Planning for Pediatric Development
42.6 Conclusions
References
Chapter 43: Challenges Evaluating the Safety of Pediatric Therapeutic Agents in Clinical Trials and Post-Marketing Surveillance
43.1 Introduction
43.2 Challenges
43.3 Conclusion
References
Chapter 44: Biomarkers and Endpoints in Rare Diseases
44.1 Introduction
44.2 Clinical Endpoints
44.3 Biomarkers in Clinical Development Programs
44.4 Biomarkers as Endpoints
44.5 Conclusions
References
Part IX: Formulation, Chemistry and Manufacturing Controls
Chapter 45: Formulation, Chemistry and Manufacturing Controls
45.1 Introduction: Challenges to a Successful Pediatric Formulation
45.2 Pharmcokinetic Aspects of Pediatric Delivery
45.3 Specifics of Formulation Development: Ingredient Considerations
45.4 Pediatric Dosage Forms
45.5 Liquid Dosage Forms
45.6 Solid Dosage Forms
45.7 Extemporaneous Formulations
45.8 Conclusion
References
Chapter 46: Drug Delivery Challenges for the Pediatric Patient: Novel Forms for Consideration
46.1 Introduction
46.2 Novel Technologies to Evaluate Taste: Electronic Tongue
46.3 Novel Uses of Polymers
46.4 Novel Oral Dosage Forms
46.5 Nanoparticle Technologies
46.6 Drug Delivery Devices
46.7 Transdermal Drug Delivery
46.8 Auto-injectors
46.9 A New Model of Drug Manufacturing
References
Chapter 47: The Jelly Bean Test: A Novel Technique to Help Children Swallow Medications
47.1 Introduction
47.2 Training Children to Swallow
47.3 Mechanism of Swallowing
47.4 Learning How to Swallow Pills
47.5 Discussion
References
Index
This edition first published 2013 © 2013 by John Wiley & Sons Ltd.
First edition published 2009 by John Wiley & Sons, Inc., Hoboken, New Jersey
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Library of Congress Cataloging-in-Publication Data
Pediatric drug development [electronic resource] : concepts and applications / [edited by] Andrew E. Mulberg, Dianne Murphy, Julia Dunne, Lisa L. Mathis. – Second edition.
1 online resource.
Includes bibliographical references and index.
Description based on print version record and CIP data provided by publisher; resource not viewed.
ISBN 978-1-118-31206-3 – ISBN 978-1-118-31213-1 – ISBN 978-1-118-31205-6 – ISBN 978-1-118-31215-5 (cloth) I. Mulberg, Andrew E., editor of compilation. II. Murphy, M. Dianne, editor of compilation. III. Dunne, Julia, 1954- editor of compilation. IV. Mathis, Lisa L., editor of compilation.
[DNLM: 1. Child. 2. Drug Evaluation–methods. 3. Age Factors. 4. Clinical Trials as Topic–standards. 5. Drug Evaluation–ethics. 6. Drug Evaluation–standards. QV 771]
RJ560
615′.190083–dc23
2013005181
A catalogue record for this book is available from the British Library.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.
Cover image credit: iStockphoto
Cover design by OptaDesign.co.uk
List of Contributors
Susan M. Abdel-Rahman
University of Missouri – Kansas City
Developmental PK/PD Core Laboratory
Division of Pediatric Clinical Pharmacology and Medical Toxicology
Children's Mercy Hospitals and Clinics
Kansas City, MO, USA
Pieter P. Annaert
Laboratory for Pharmacotechnology and Biopharmacy
Department of Pharmaceutical Sciences
Katholieke Universiteit Leuven (KU Leuven)
Leuven, BE
Graham P. Bailey
Drug Safety Sciences
Janssen Research and Development
Beerse, BE
Martin Otto Behm
Merck and Co., Inc.
North Wales, PA, USA
Daniel K. Benjamin Jr
Duke Clinical Research Institute
Duke University Medical Center
Durham, NC, USA
Leandra N. Berry
Center for Autism Research
The Children's Hospital of Philadelphia
Philadelphia, PA, USA
Lisa Blaskey
The Children's Hospital of Philadelphia
Philadelphia, PA, USA
Katia Boven
Global Clinical Development
Janssen
Titusville, NJ, USA
Gilbert J. Burckart
Pediatric Clinical Pharmacology Group
Office of Clinical Pharmacology
Office of Translational Sciences, CDER
US Food and Drug Administration
Silver Spring, MD, USA
Laurie B. Burke
Office of New Drugs
Center for Drug Evaluation and Research
Food and Drug Administration
Silver Spring, MD, USA
Carolyn A. Campen
External Innovation – Oncology
Janssen Pharmaceutical R&D
Raritan, NJ, USA
Jacqueline Carleer
Belgian Federal Agency for Medicines and Health Products
Timothy P. Coogan
Biologics Toxicology
Janssen Research and Development LLC
Spring House, PA, USA
Therese Cvetkovich
Food and Drug Administration
Center for Drug Evaluation and Research
Office of Surveillance and Epidemiology
Division of Risk Assessment
US Food and Drug Administration
Silver Spring, MD, USA
Alexandar Cvetkovich Muntañola
INC Research LCC
Barcelona, ES
Karen L. Davis-Bruno
Division of Metabolism & Endocrinology Products
Food and Drug Administration
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MD, USA
Luc M. De Schaepdrijver
Drug Safety Sciences
Janssen Research and Development
Beerse, BE
Loeckie L. de Zwart
Drug Safety Sciences
Janssen Research and Development
Beerse, BE
Luc Dekie
Europe
Biomedical Systems
Brussels, BE
Martha Donoghue
Office of Hematology and Oncology Products
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MD, USA
Julia Dunne
Vigilance and Risk Management in Medicines (VRMM)
Medicines and Healthcare Products Regulatory Agency
London, UK
Carla Epps
Division of Gastroenterology and Inborn Errors Products
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MD, USA
Chris Feudtner
Department of Medical Ethics
The Children's Hospital of Philadelphia
University of Pennsylvania
Philadelphia, PA, USA
Jogarao V.S. Gobburu
Center for Translational Medicine School of Pharmacy
University of Maryland
Baltimore, MD, USA
Dionna Green
Pediatric Clinical Pharmacology Group
Office of Clinical Pharmacology
Office of Translational Sciences
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MD, USA
Sergio Guerrero
Accelerium Clinical Research
Monterrey, MX
Ethan D. Hausman
Food and Drug Administration
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MD, USA
Whitney S. Helms
Division of Hematology, Oncology, Toxicology
Office of Hematology and Oncology Products
US Food and Drug Administration
Silver Spring, MD, USA
Ralf Herold
Pediatric Medicines Section
European Medicines Agency
London, UK
Kevin D. Hill
Duke University Medical Center
Durham, NC, USA
Steven Hirschfeld
USPHS Rapid Deployment Force-1
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Bethesda, MD, USA
Kachi Illoh
Division of Neurology Products
Food and Drug Administration
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MD, USA
Jennifer L. Ingram-Ross
Janssen Research & Development, LLC
Raritan, NJ, USA
Pravin Jadhav
Merck Sharp and Dohme
Upper Gwynedd, PA, USA
Ralph E. Kauffman
University of Missouri – Kansas City
Division of Pediatric Pharmacology and Medical Toxicology
Children's Mercy Hospitals and Clinics
Kansas City, MO, USA
Geetinder Kaur
Department of Women's and Children's Health and Department of Biostatistics
Institute of Translational Medicine
University of Liverpool
Liverpool, UK
Sruthi Tallapragada King
Division of Gastroenterology and Inborn Error Products
Office of Drug Evaluation III
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MD, USA
Mallika Lala
Piramal Healthcare Ltd
Mumbai, IN
Matthew M. Laughon
Department of Pediatrics
Division of Neonatal-Perinatal Medicine The University of North Carolina at Chapel Hill
Chapel Hill, NC, USA
Cindy Levy-Petelinkar
Project and Systems Excellence
Projects, Clinical Platforms and Sciences
GlaxoSmithKline
Research & Development
King of Prussia, PA, USA
Jennifer S. Li
Duke University
Durham, NC, USA
Beatriz Silva Lima
Department of Pharmacological Sciences
Nonclinical Safety and Regulatory Science Research Group, at iMED.UL
Lisbon University, Faculty of Pharmacy
Lisbon, PT
Samuel Maldonado
Pediatric Drug Development Center of Excellence
Janssen Research and Development
Raritan, NJ, USA
Ashley J. Malins
Department of Medical Oncology
Dana-Farber Cancer Institute Boston, MA
Lisa L. Mathis
Amgen Incorporated
Thousand Oaks, CA, USA
Ann W. McMahon
Office of Pediatric Therapeutics
Office of the Commissioner
Food and Drug Administration
Silver Spring, MD, USA
Gerard P. McNally
McNeil Consumer Healthcare
Fort Washington, PA, USA
Niraj R. Mehta
Division of Bioequivalence and GLP Compliance
Office of Scientific Investigations
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MD, USA
Christopher-Paul Milne
Center for the Study of Drug Development
Tufts University Medical School
Boston, MA
University of Edinburgh
Edinburgh, UK
Geert Molenberghs
Universiteit Hasselt and Katholieke Universiteit Leuven
Diepenbeek, BE
Jeremiah D. Momper
Office of Clinical Pharmacology
Office of Translational Sciences
Food and Drug Administration
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MD, USA
Johan G. Monbaliu
Drug Safety Sciences
Janssen Research & Development Janssen Pharmaceutica NV
Beerse, BE
Andrew E. Mulberg
Division of Gastroenterology and Inborn Error Products
Office of Drug Evaluation III
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MD, USA
Padmaja Mummaneni
Genomics Group, Office of Clinical Pharmacology/OTS
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MD, USA
Dianne Murphy
Office of Pediatric Therapeutics
Office of the Commissioner
US Food and Drug Administration
Silver Spring, MD, USA
Hidefumi Nakamura
Division for Clinical Trials
Clinical Research Center
National Center for Child Health and Development
Tokyo, JP
Robert M. Nelson
Office of Pediatric Therapeutics,
Office of the Commissioner
US Food and Drug Administration
Silver Spring, MD, USA
Kathleen A. Neville
University of Missouri – Kansas City;
Experimental Therapeutics in Pediatric Cancer Program
Divisions of Pediatric Clinical Pharmacology and Medical Toxicology and Hematology/Oncology
Children's Mercy Hospitals and Clinics
Kansas City, MO, USA
Shunsuke Ono
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Tokyo, JP
Benjamin Ortiz
The Center for Advanced Pediatrics, PC
Norwalk, New York, USA
Elektra J. Papadopoulos
Officer of New Drugs
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MD, USA
Anne R. Pariser
Office of New Drugs
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MD, USA
Devin Pastoor
Center for Translational Medicine School of Pharmacy
University of Maryland
Baltimore, MD, USA
Donald L. Patrick
University of Washington
Seattle Quality of Life Group
Seattle, WA, USA
Mary Pipan
The Children's Hospital of Philadelphia
Division of Developmental Medicine and Metabolism
Philadelphia, PA, USA
Aniruddha M. Railkar
Johnson & Johnson Pharmaceutical Research and Development LLC
Spring House, PA, USA
Gregory Reaman
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MD
George Washington University School of Medicine and Health Sciences
Washington, DC, USA
William J. Rodriguez
Office of Pediatric Therapeutics
Office of the Commissioner Food and Drug Administration
Department of Pediatrics George Washington Medical School
Washington, DC, USA
Michelle D. Roth-Cline
Office of Pediatric Therapeutics
US Food and Drug Administration
Silver Spring, MD, USA
Alisha J. Rovner
Department of Behavioral Health and Nutrition
University of Delaware
Newark, DE, USA
Agnès Saint-Raymond
Human Medicines Special Areas
European Medicines Agency
London, UK
Joy H. Samuels-Reid
Division of Anesthesiology, General Hospital, Respiratory, Infection Control and Dental Devices
Office of Device Evaluation
Center for Devices and Radiological Health
US Food and Drug Administration
Silver Spring, MD, USA
E. Michael D. Scott
Independence HealthCom Strategies Group Inc
Philadelphia, PA, USA
M. Renee Simar
Pediatric Clinical Trials
Simar and Associates, LLC
Austin, TX, USA
Rosalind L. Smyth
Institute of Child Health University College London (UCL)
London, UK
Kristen M. Snyder
Division of Pediatric Hematology/Oncology
Department of Pediatrics
Monroe Carell Jr. Children's Hospital at Vanderbilt
Nashville, TN, USA
Robbyn E. Sockolow
Division of Pediatric Gastroenterology and Nutrition
Weill Cornell Medical College
New York Presbyterian Hospital
Center for Advanced Digestion Care
New York, NY, USA
Aliza B. Solomon
Weill Cornell Medical College
New York Presbyterian Hospital
Center for Advanced Digestion Care
New York, NY, USA
Bert Suys
GZA Hospitals
Antwerp
University Hospital
Leuven, BE
Francisco A. Sylvester
University of Connecticut Health Center, Farmington, CT
Connecticut Children's Medical Center
Hartford, CT, USA
Melissa S. Tassinari
Office of New Drugs
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MD, USA
Rebecca Thompson Penna
Center for Autism Research
Children's Hospital of Philadelphia
Philadelphia, PA, USA
Paolo Tomasi
European Medicines Agency
London, UK
Priya Venkataraman-Rao
Division of Reproductive, Gastro-Renal and Urological Devices (DRGUD)
US Food and Drug Administration
Silver Spring, MD, USA
Paul P. Wang
Seaside Therapeutics, Inc.
Cambridge, MA, USA
Robert M. Ward
Department of Clinical Pharmacology
University of Utah
Salt Lake City, UT, USA
Erica L. Wynn
Division of Gastroenterology & Inborn Errors Products
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MD, USA
Lynne P. Yao
Office of New Drugs
Center for Drug Evaluation and Research
US Food and Drug Administration,
Silver Spring, MD, USA
Anne Zajicek
Obstetric and Pediatric Pharmacology and Therapeutics Branch
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Uniformed University of the Health Sciences
Bethesda, MD, USA
Babette S. Zemel
Division of Gastroenterology and Nutrition
Children's Hospital of Philadelphia
Philadelphia, PA, USA
Preface
“A hundred children, a hundred individuals who are people – not people-to-be, not people of tomorrow, but people now, right now – today.”
Janusz Korczak, How To Love A Child
I learned a number of years ago about Janusz Korczak (1878–1942), a children's advocate, who spoke of a Declaration of Children's Rights long before any such document was drawn up by the Geneva Convention (Korczak, 1924) or the United Nations General Assembly (Korczak, 1959), through my mentor and friend, Steven Spielberg, MD, PhD. The spirit expressed in these words underlies the passion for the revitalization and refreshment of this second edition of Pediatric Drug Development.
The decision to edit a second version is, for any book, one that takes months of preparation and engagement with the publisher. Wiley has been enthusiastic in supporting us and we mutually believe that the need to discuss new issues in pediatric drug development was critical. Much has happened in the regulatory environment to continue to encourage and promulgate specific protection of infants and children. Particularly, the newly permanent Food and Drug Administration Safety and Innovation Act (FDASIA) has made permanent legislation to facilitate drug development for children, known as the Best Pharmaceuticals for Children Act (BPCA) and requirements for pediatric studies under the Pediatric Research Equity Act (PREA) from 2003.
This second edition reviews the impact of this new legislation but also reenergizes the reader to understand the scientific principles and practice required to synthesize the most effective drug development programs for children. New topics are covered that reflect developments in regulatory and technological advances, in orphan diseases, in inborn errors of metabolism and in global regulatory changes and experiences from Europe and Japan, as well as insights into device development. Critical new additions on pharmacogenomics and pharmacometrics have supplemented the Clinical Pharmacology section within this second edition, which has also attempted to provide the foundation of knowledge for effective global pediatric drug development written by experts.
It is with great pride and satisfaction that I thank my Associate Editors, Dianne Murphy, Julia Dunne and Lisa Mathis, who are well renowned for their expertise in pediatric drug development, for their contributions and work ethic. It is humbling to work with people who have for years demonstrated to us all their tireless energy, motivation and shared passion for the work that we do on behalf of the children of this world. Each, in her own right, has been a distinguished, well-known partner in global pediatric drug development, and also expert in helping to refine concepts that have facilitated drug development for children in the US and globally over the years. Their partnership was critical to the success of this second edition and I give my heartfelt thanks. Jon Peacock, our Development Editor at Wiley, has been patient and rigorous in his pursuit of a great second edition with us. I thank my own children, Nathaniel and Rebecca (Bekah) and my wife, Elyse, for the blessings of their love and support always of my “projects”.
Thomas Friedman, noted author, has cited that the world is becoming smaller, and he has written that the “world is flat”. Despite his advocacy of globalization in the 21st century focusing on global markets, we, as contributors to pediatric drug development, also deal with global issues affecting children. As experts in pediatrics across the world, we are required to protect – and to voice the needs of the world's children, speaking with one voice, whether it be in French, Japanese or English or some other language. Stakeholders involved in drug development, including academia, industry and the FDA and other regulatory agencies, must strive and continue to develop plans and actions that collaboratively and proactively benefit public health affecting children. The goal of development and facilitation of reaching these milestones is mutually important for all stakeholders, and especially for the children of the world.
Dr. Seuss (Theodor Geisel) said: “Will you succeed? Yes, you will indeed! Ninety-eight and three quarters percent guaranteed.” I believe that we are well on our way and we can aim for that final one and a quarter percent with this second edition.
The views expressed in this book are of the Editors. No official endorsement by the US Food and Drug Administration is provided or to be inferred.
Thank you.
Andrew E. Mulberg, MD, FAAP Principal Editor
Pediatric Drug Development: Concepts and Applications, 2ndEdition
Cherry Hill, New Jersey
Part I
Past, Present, and Future of Pediatric Drug Development
Chapter 1
Introduction: Pediatric Drug Development and Therapeutics: Continued Progress for Better Drugs for Children
Andrew E. Mulberg1 Lisa L. Mathis2, Julia Dunne3, and Dianne Murphy4
1Division of Gastroenterology and Inborn Error Products, Office of Drug Evaluation III, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
2Amgen Incorporated, Thousand Oaks, CA, USA
3Vigilance and Risk Management in Medicines (VRMM), Medicines and Healthcare Products, Regulatory Agency, London, UK
4Office of Pediatric, Therapeutics, Office of the Commissioner, US Food and Drug Administration, Silver Spring, MD, USA
While it has been less than four years since the publication of the first edition of this book, pediatric drug development has advanced dramatically in a global manner. Science in the area of pediatric drug development has advanced exponentially because of legislative incentives and requirements directed towards the development of studies of medications for use in the pediatric population [1–5]. This process has been facilitated, when appropriate, by the ability to maximize the use of data from adults and other pediatric populations to extrapolate efficacy, so that only pharmacokinetic or dynamic studies and safety assessments are required in the pediatric population [6]. Preclinical studies, which now may include juvenile animal models as needed, are conducted to ensure that there is sufficient safety information available to begin studies in children.
Children have unique vulnerabilities, as they are in an evolving process of continuing to grow and develop. Juvenile animal models have been developed and data from these studies, combined with existing data from adults and limited clinical pharmacology studies in pediatrics, have resulted in significant advances in modeling and simulations. These methods have reduced the burden of the necessity for children to be involved in clinical studies. This approach not only results in the efficient use of resources, but also provides an ethical advantage by limiting children's exposure to clinical trials and decreasing the time it may take for a medication to be labeled with data on use in the appropriate pediatric population.
The advances made in nonclinical studies, modeling and simulation do not eliminate the need for clinical trials in pediatrics. There are still many challenges, such as the development of meaningful endpoints that can be applied across nations and cultures. This is necessary when one considers the need for studies to be multinational in order to enroll a sufficient number of patients to assess adequately the safety and efficacy of a medication. This fact is illustrated by the studies of fosinopril for the treatment of hypertension. The trials conducted to support the marketing application in the adult population enrolled 220 patients in nine US centers over five months, while the pediatric trials required 70 study sites in three countries over a period of 12 months in order to enroll approximately the same number of patients (253 patients) to support safety and efficacy.
According to the National Health Interview Survey performed in 2009, more than 9.5 million children in the United States had a health problem for which prescription medication had been taken regularly for at least three months [7]. It is difficult to tell if medication use in pediatrics is increasing overall, but we do know that utilization trends are dynamic in this population [8]. Although it is estimated that the pediatric population accounts for less than 10% of all medication use in the United States, pediatric patients who need medications to treat illness and/or conditions should have access to medications that have been adequately studied for use in children.
However, although there have been striking advances in some areas, there is still much that needs to be learned. Pediatric drug development has experienced dramatic advances in the last two decades. The number of medications labeled for use in the pediatric population has increased from approximately 25% to approximately 50% [9]. While this is an obvious gain, it should not be forgotten that this important work needs to continue, given that approximately half of medications still lack evidence-based information on use in children.
The recent Institute of Medicine report, Safe and Effective Medicines for Children: Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act, documents that “Pediatric drug studies remain particularly limited in certain areas, including the use of medications with neonates and the long-term safety and effectiveness of drugs for all pediatric age groups” [10]. The frequent lack of information about the long-term safety of drugs used with children is a special worry, both for drugs that may be used for decades for chronic conditions, as well as for drugs for which short-term use may have adverse consequences on a child's development months or years later. Many drugs commonly used with premature and sick neonates are older drugs that have not been adequately evaluated in studies with this vulnerable age group.
In order to achieve this goal, as set out by the IOM, to recruit sick neonates and pediatric subjects in clinical trials, there are certain operational realities. The IOM states, “To improve pediatric studies of drugs and biologics and their evaluation, it is important for FDA to continue to expand initiatives to strengthen the science base for its work, analyze shortcomings in pediatric studies, and develop innovative strategies to meet the specific challenges of pediatric trials” [10]. This can only be accomplished with mutual responsibility and partnership, with FDA focusing on the role of academics and private practitioners to facilitate pediatric drug development. Integration of public/private partnerships in collaboration with regulatory agencies should be a pathway for expediting and achieving some of the scientific advancements necessary to reach the goal of sound global scientific pediatric drug development programs.
Another area of dramatic change has been the globalization of pediatric studies and the implementation of the European regulations which require pediatric studies when a product is to be utilized in the pediatric population. Both the FDA and the European Medicines Agency have committed to sharing regulatory information on a regular basis in order to protect children from becoming a global commodity, and also to ensure that the best pediatric questions are being addressed by pediatric product development trials.
The FDA and the National Institutes of Health are working with organizations such as the American Academy of Pediatrics, the FDA Advisory Committees and academia. The goal is to ensure that children are protected in the course of research, that only qualified investigators are involved in studies with children, and that the best available study design and analytic methods are applied to answer the important questions that will shape pediatric therapeutics in the future.
Additional information is available at www.fda.gov/cder/pediatric/index.htm or www.fda.gov/ScienceResearch/SpecialTopics/PediatricTherapeuticsResearch/default.htm
References
1. Specific requirements on content and format of labeling for human prescription drugs; Revision of ‘Pediatric Use’ subsection in the labeling; Final rule. Federal Register 1994; Dec 59: 64240–64250.
2. Pediatric Patients; Regulations Requiring Manufacturers To Assess the Safety and Effectiveness of New Drugs and Biological Products; Final Rule. Federal Register 1998 Dec;63: 66631–66672.
3. Pediatric studies of drugs, Section 111 Of The Food And Drug Modernization Act 21 United States Code 355a; 1997.
4. The Pediatric Research Equity Act; 2003 Jan: www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM077853.pdf.
5. The Food and Drug Administration Safety and Innovation Act: Title V; 2012: www.gpo.gov/fdsys/pkg/BILLS-112s3187enr/pdf/BILLS-112s3187enr.pdf
6. Dunne J, Rodriguez WJ, Murphy MD et al. Extrapolation of adult data and other data in pediatric drug-development programs. Pediatrics 2011;128(5): e1242–9 (epub).
7. Bloom B, Cohen RA & Freeman G. Summary health statistics for U.S. children: National Health Interview Survey, 2009. National Center for Health Statistics. Vital Health Stat 2010;10(247).
8. Chai G, Governale L, McMahon AW, et al. Trends of Outpatient Prescription Drug Utilization in U.S. Children, 2002–2010. Pediatrics 2012;130(1).
9. Sachs H, Avant D, Lee CS, et al. Pediatric Information in Drug Product Labeling. JAMA 2012 May; 307(18): 1914–1915: http://jama.jamanetwork.com/article.aspx?volume=307&issue=18&page=1914.
10. Institute of Medicine Report on Safe and Effective Medicines for Children. 2012 Feb: www.iom.edu/Reports/2012/Safe-and-Effective-Medicines-for-Children.aspx
Chapter 2
History of Children and the Development of Regulations at the FDA
Steven Hirschfeld1 and Robert M. Ward2
1USPHS Rapid Deployment Force-1, Eunice Kennedy Shriver National, Institute of Child Health and Human Development, Bethesda, MD, USA
2Department of Clinical Pharmacology, University of Utah, Salt Lake City, UT, USA
2.1 Introduction and Early History
Children have played pivotal roles in the development of regulations and laws to ensure that medications are both safe and effective. Efforts to protect children from dangerous or adulterated drugs are interwoven with the development of governmental protections of the larger population. Although legislative and policy efforts to protect children began decades ago, these efforts sometimes led to unintended consequences that failed to provide the expected outcomes. The history of these efforts identifies the origins of impediments and successes in pediatric studies that inform future efforts to protect children through drug therapy grounded in adequate and well-controlled studies.
With the FDA Modernization Act of 1997, voluntary studies of drugs in the pediatric population began to increase, and these have been complemented with the requirement to study new drugs in pediatric patients through the Pediatric Research Equity Acts of 2003, 2007 and 2012. These variably successful efforts to protect children from harmful products highlights the achievements of these more recent regulatory efforts and help to inform future measures to stimulate pediatric studies of drugs.
2.1.1 A Civics Lesson that Most of us have Forgotten
When the United States was founded in the 18th century, the federal system attempted to balance the rights and responsibilities of states with those of the central government. The federal government itself had several components to balance each other, with each having a core function. The Legislative Branch, consisting of two parts, establishes federal law in the context of the United States Constitution. The Executive Branch, through the Office of the President, has veto power over new laws, although that can be overridden. The Executive Branch, however, primarily implements the law through the development of policy and the issuance of regulations. Federal law invests the Executive Branch with the authority to issue regulations.
While law is developed directly through the elected representatives, regulations are developed by technical experts guided by political appointees of the Executive Branch. The purposes of the regulations are to provide additional rights or constraints and to allocate responsibilities. Regulations are intended to facilitate outcomes that may not otherwise occur, and to prevent outcomes that may otherwise occur. Regulations must be based on laws, and the underlying law or laws are always cited in federal regulations.
The Supreme Court rules on the acceptability of law, if requested, based on current interpretation of the Constitution. Lower courts, if requested, have the authority to determine the acceptability of regulations issued by the Executive Branch.
During the 19th century, only men could vote, children were considered property and anyone could sell any product for which they could find a buyer. As reading became more prevalent and printed media became more accessible, stories that captured public attention were used to influence the political process in the United States.
At that time, “medicinal products” could be made by anyone and sold for whatever use the originator claimed, although the usual ulterior motive was monetary. Attempts to regulate the manufacture and sale of food and medicinal products during the 19th century never resulted in a federal law. Debates about the balance between free enterprise and protections were never settled.
It was not until the 20th century that several widely reported scandals affecting children, with examples in the following paragraphs, resulted in the establishment of a legal and regulatory framework that addressed the basic principles of product labeling, safety, efficacy and justice. The extension of these principles specifically to address the health needs of children continued into the 21st century.
The emergence of immunotherapy, to prevent infectious diseases, in Europe in the late 19th century stimulated similar efforts in the United States. In the autumn of 1901 in St. Louis, about twenty children died after receiving horse anti-serum that was contaminated with tetanus toxin. This incident was reported widely and proved to be the essential event to persuade the United States Congress to enact the Biologics Control Act of 1902 to require the safety and purity of biologics intended for human use.
Similar media reports, published in 1905 about medicinal products harming children, resulted in the Pure Food and Drug Act in June 1906, which prohibited interstate commerce for products that were not properly labeled, were adulterated, were misbranded or which failed to conform to manufacturing standards. The law had a provision that deviation from manufacturing standards was permitted if the deviations were stated in the product label. Enforcement was through the court system, meaning that anyone challenging a manufacturer would need to file a suit. In 1911, the Supreme Court ruled in the case of the United States vs. Johnson that the law only extended to false and misleading statements regarding the ingredients and did not extend to any claims about the use of the product. Not accepting the outcome of this ruling, Congress enacted in 1911 the Sherley amendment, which extended the authority of the federal government to prosecute false or misleading therapeutic claims, but only in the circumstance where intent to fraud could be established.
The legal authority for the Biologics Control Act and the Pure Food and Drug Act was provided in the authority of the government to regulate products intended for interstate commerce. If a product was produced and used locally, then regulatory authority could only come from state or local authorities.
In 1909, President Theodore Roosevelt presided over the first White House Conference on the Care of Dependent Children. This was in response to a telegram he had received on behalf of social activists, posing the question that if the Secretary of Agriculture was touring the South to understand what the boll weevil was doing to cotton crops, should not the federal government gather the facts regarding why so many children die of infections during the summer. This conference led to the establishment in 1912 of the United States Children's Bureau to coordinate federal policy for children. The Bureau became the primary fact-gathering facility for the status of children for the federal government and was within the Social Security Administration before becoming part of the Department of Health and Human Services under the Administration for Children and Families.
The 1930s established the National Institutes of Health, the Food, Drug and Insecticide Administration (subsequently shortened to the Food and Drug Administration or FDA) and a new law triggered by another tragedy involving children. A chemical company substituted diethylene glycol for ethanol in the manufacture of sulfanilamide, a broad spectrum antibiotic, to improve its solubility in an effort to produce a liquid that could be administered to children. Subsequently, about 100 people died from ingesting this liquid form of the medication. The product was labeled as an elixir, which at the time meant containing ethanol, so the company was prosecuted for misbranding but had no legal responsibility for any of the deaths.
In response to these deaths, the Food, Drug and Cosmetic Act became law in 1938. This Act required safety to be established prior to marketing, disclosure of all active ingredients, directions for use and warnings about misuse unless the product was sold by prescription. It allowed federal inspections of manufacturing facilities, established procedures for the formal review of applications for marketing, explicitly prohibited false claims and extended the scope to cosmetics and devices.
In the early 1960s, the birth of children with multiple malformations related to pregnant women taking the sedative thalidomide led to the Kefauver-Harris Amendment to the Food, Drug and Cosmetic Act. This amendment extended FDA oversight of medications and required a demonstration of efficacy prior to approval of a marketing claim. Additional provisions in the amendment were the need to establish good manufacturing practice (GMP) and maintain production records, the requirement to file an application with the FDA prior to clinical testing (Investigational New Drug application, or IND), an increase in the time for FDA marketing authorization review from 60 to 180 days, the transfer of regulatory authority for drug advertising to the FDA, and the authority to withdraw marketing approval if new evidence indicated lack of safety or effectiveness.
The mechanism of an Investigational New Drug (IND) application is based on two principles. The first is that products may not be used for interstate commerce unless a federal license is granted in the form of marketing authorization. An exception is made for the period of time when a product is under development and is to be tested in humans, based on a request by a product developer to receive an IND. The second principle is that the FDA provides review and oversight for the product development process.
Based on both the new legal requirement for premarketing review of products and a series of scholarly articles documenting human subject research practices that were perceived as exploitative and even abusive, the US Public Health service issued a memo in 1966 requiring all institutions receiving federal funds to establish independent review of proposed human subject research. In 1974, Congress passed the National Research Act, expanding the scope of human subject research review for federally funded projects but allowing each agency to set its own policies and practices.
The National Research Act also established a Commission for the Protection of Human Subjects of Medical and Behavioral Research. The National Commission held hearings and began to issue recommendations. The first recommendations came in 1976 for research enrolling prisoners, and the second set came in 1977 for research enrolling children. The National Commission noted two fundamental principles. The first is that children are different from animals and adults, and thus it is necessary to generate data about children from studies in children. The second principle is that the greatest risk of harm from the use of therapeutics is not to have relevant research.
The National Commission classified research into levels of risk, establishing the concept of minimal risk and differentiating acceptable research into minimal risk and a minor increase over minimal risk but with expected benefits. The benefits may accrue directly to the individual research participant, or to others with similar conditions. In either case, the potential benefits must justify the potential risks in order for the research to proceed.
The National Commission issued a report in 1979 known as the Belmont Report. This stated three principles:
In 1983 the recommendations of the Commission were adapted to become federal regulations.
At the American Academy of Pediatrics (AAP) annual meeting in 1972, Dr. Charles Edwards, former FDA Commissioner, stated that the large majority of medications used in infants and children were prescribed on an empiric basis and lacked sufficient evidence of safety and effectiveness. In 1974, the AAP issued a report commissioned by the FDA called General Guidelines for the Evaluation of Drugs to Be Approved for Use during Pregnancy and, for the Treatment of Infants and Children. This was echoed in the 1977 American Academy of Pediatrics Committee on Drugs policy statement that, “it is not only ethical but also imperative that new drugs to be used in children be studied in children… so the benefits of therapeutic advances will become available to all who may need them.”
In 1977, the FDA adopted the AAP report as a guidance document. A guidance document, unlike a law or regulation, is not legally binding. It represents a default recommendation, but alternative options may be implemented. Also in 1977, the AAP issued Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations. The major points were:
An emphasis on unexpected toxicities.Reasonable evidence for efficacy should exist prior to study in infants and children.Sick children should be enrolled in studies.Active or historical controls preferred over placebo.Decreasing age order for study enrollment.2.2 Product Label Changes
A Product Package Insert for a specific drug product, often referred to as the label, as described in the Code of Federal Regulations (CFR) Title 21 Part 201, contains the following sections:
DescriptionClinical pharmacologyIndications and usageContraindicationsWarningsPrecautionsAdverse reactionsDrug abuse and dependenceOverdosageDosage and administrationHow supplied.General labeling principles are that:
The labeling shall contain a summary of the essential scientific information needed for the safe and effective use of the drug.The labeling shall be informative and accurate, and neither promotional in tone nor false or misleading in any particular.The labeling shall be based, whenever possible, on data derived from human experience. Conclusions based on animal data, but necessary for safe and effective use of the drug in humans, shall be identified as such and included with human data in the appropriate section of the labeling.The Code of Federal Regulations Part 201 Subpart B section 201.57(c)(iv) notes, “If there is a common belief that the drug may be effective for a certain use or if there is a common use of the drug for a condition, but the preponderance of evidence related to the use or condition shows that the drug is ineffective, the Food and Drug Administration may require that the labeling state that there is a lack of evidence that the drug is effective for that use or condition”.
In 1979, the FDA published a regulation establishing a Pediatric Use Subsection in the Precautions Section of Product Package Inserts (21 CFR 201.57 (f)(9)). This regulation stated that, in the absence of substantial evidence for any pediatric population, the label shall state, “Safety and effectiveness in pediatric patients have not been established”.
If use of the drug in premature or neonatal infants, or other pediatric subgroups, is associated with a specific hazard, the hazard shall be described in this subsection of the labeling or, if appropriate, the hazard shall be stated in the “Contraindications“ or “Warnings” section of the labeling and this subsection shall refer to it.
If a sponsor believes that none of the above apply, alternate wording may be proposed.
If the drug product contains one or more inactive ingredients that present an increased risk of toxic effects to neonates or other pediatric subgroups, a special note of this risk shall be made, generally in the “Contraindications”, “Warnings” or “Precautions” section.
Although this legislation was well intended and did create a specific place for pediatric information, that information was usually that “Safety and effectiveness in pediatric patients have not been established”. Over time, this statement was not thought to be useful, as studies could have been conducted but failed to demonstrate efficacy. However, none of that information was available as it was considered Commercial Confidential information. As so few pediatric studies were being performed, any form of information garnered from such studies was considered to be of public health interest.
This issue of the need for access to the information from pediatric studies was addressed in later legislation. Later legislation also removed Pediatrics as a “Caution” and placed pediatric information in section 8.4.
The year 1983 was notable not only for the publication of the federal Human Subject Protection regulations but also for the establishment of the Orphan Drug Act, which established the principle that incentives, in this case a longer period of exclusivity following marketing authorization and monetary support through grants for premarketing development, can be used by the federal government to address underserved populations with diseases that have a prevalence of less than 200,000.
2.3 FDA Pediatric Initiatives with Voluntary Compliance
By the mid-1990s, the FDA had established regulatory tools to facilitate product labeling for pediatric use on a voluntary base. In 1994 the FDA added a subsection to the Pediatric Use section of the product label, allowing the use of extrapolation of efficacy from adults to children in certain circumstances to decrease the evidence burden for pediatric labeling (21 CFR 201.57(f)(9) with added subsection (iv)).
In 1997, the path to pediatric labeling gained an important tool based on the Orphan Product model. Section 111 of the Food and Drug Administration Modernization Act (FDAMA) extended the incentive opportunity for most drugs, from those restricted to rare diseases to include any intended indication that used the active moiety if the sponsor performed pediatric studies. To maintain public health relevance and quality control over which pediatric studies were performed, the program provided the FDA with a gatekeeper function in that the pediatric data could only be granted an incentive if the FDA asked for the information with a Pediatric Written Request (see Figure 2.1).
Figure 2.1 FDA Pediatric Written Request process.
The requested information did not need to demonstrate efficacy, result in a new pediatric indication or even change the label, but the studies did have to provide credible data that would address knowledge gaps, based on FDA's assessment, in pediatric use. The incentive was a lengthening by six months of either the intellectual property protection from a patent granted to the product by the Patent and Trademark Office of the US Department of Commerce or the marketing exclusivity license granted by the FDA. The incentives are summarized in Table 2.1.
Table 2.1 Pediatric incentives available through FDAMA.
Type of protectionInitial protection, yearsProtection with pediatric incentive, yearsPatent protection for intellectual property2020.5Initial indication for a new drug55.5Supplemental indication for a marketed drug33.5Orphan indication for a drug77.5Some differences between patent protection and exclusivity are worth noting to understand the incentive program. The concept of patents is based in Article I, Section 8, Clause 8 of the United States Constitution, noting that “The Congress shall have power… to promote the progress of science and useful arts, by securing for limited times to authors and inventors the exclusive right to their respective writings and discoveries…” The legal basis is the Patent Act of 1952, codified in Title 35 of the United States Code. A patent is granted for an initial period of 20 years, and it is the responsibility of the patent holder to protect the intellectual property through the court system. Due to the general practice of patenting candidate drugs early in the product development cycle, a substantial portion of the patent duration may have elapsed by the time a product receives an FDA license for marketing. If a patent holder can demonstrate that marketing was reduced by regulatory delays, the patent holder can file for an extension up to five years.
Pediatric exclusivity is different than the usual exclusivity that FDA grants, and is a powerful incentive. Usually, exclusivity is an exclusive marketing license granted by the FDA for the sale of an approved form of a specific product, for a specific approved use of the product for interstate commerce. What is protected is the approved use of a particular product, not the product itself independent of use. Marketing exclusivity is granted with the provision that the FDA will not grant another license to anyone else for the same product for the same use for a fixed period of time. For marketing exclusivity, it is the federal government that takes responsibility for protection. While marketing exclusivity is for the combination of a particular form of a product and its approved use, the pediatric incentive can apply to any approved use of any form of the product that uses what is termed the active moiety. Simply put, all forms of the product with the active moiety now have six months of additional marketing exclusivity.
Following a successful five-year initial experience as part of the 1997 FDAMA, with 49 products receiving pediatric exclusivity, the incentive program became a law in 2002 as the Best Pharmaceuticals for Children Act for another five years.
In addition, The Best Pharmaceuticals for Children Act (BPCA) of 2002:
required a review of safety by an external advisory committee for all products granted exclusivity (see PREA for establishment of the Pediatric Advisory Committee);created the Office of Pediatric Therapeutics in the Office of the Commissioner and required that office to have an ethicist;assigned a role for the National Institutes of Health, and specifically the National Institute for Child Health and Human Development (NICHD), to administer a program for products that would require further pediatric studies if:2.4 Initial Pediatric Mandate
To complement the voluntary programs, the FDA issued a regulation in 1998 requiring pediatric development of a product if the adult condition for which a product was licensed had a relevant pediatric population, and if the product was likely to be used in children due to either a meaningful therapeutic advance over existing therapy or if widespread use was anticipated. Widespread use was calculated to be greater than 50,000 children with the disease or condition, based on the assumption that the threshold for orphan designation was prevalence less than 200,000 and children were about 25% of the population.
Compliance could be deferred so that availability to the adult population would not be delayed. Waivers from compliance were also part of the program in cases where pediatric studies would not be feasible, or where the product was not a therapeutic advance compared to existing products, or the licensed indication was a condition that did not exist in children.
The program was challenged in a court of law on the grounds that, if a manufacturer did not intend for a product to be used in children, the federal government lacked authority to compel pediatric development. The challenge was upheld, which stopped implementation of the regulation.
The authority was then granted by Congress and signed into law in 2003 in the Pediatric Research Equity Act. Similar to its predecessor, the 1998 Pediatric Rule, the Pediatric Research Equity Act (PREA) provided a mandate that covered all drugs and biologics and established a standing FDA Pediatric Advisory Committee.
An algorithm for the application of PREA is shown in Figure 2.2.
Figure 2.2 An algorithm for the application of PREA.
∗PREA Conditions:
(a) Therapeutic advance or widespread use (>50,000 children affected) and all of the following:
(b) Product has preliminary evidence that it may be safe and effective
(c) Age appropriate formulation is feasible
(d) Pediatric clinical studies are feasible.
The mandate and the incentive program have complementary provisions and are contrasted in Table 2.2.
Table 2.2 Comparison of major features of US Pediatric Initiative Programs.
US Pediatric Mandate Program (PREA)US Pediatric Incentive Program (BPCA)Applies to all drugs and biologicals except orphan designationBiologicals and some drugs excluded but includes orphan designationOnly applies to the drug product and indication under reviewApplies to all products with same active moietyOnly applies if an approved or pending indication occurs in adults and childrenEligible indications for study must occur in pediatric populationsOnly applies if there is a meaningful therapeutic advance or widespread useOnly applies when there is underlying patent or exclusivity protection and meets the terms of providing a health benefit∗Mandatory – compliance expectedVoluntary – no compliance expectedMay be used as often as public health need arises
