Pediatric Non-Clinical Drug Testing E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Veröffentlichungsjahr: 2011

Beschreibung

This book explains the importance and practice of pediatric drug testing for pharmaceutical and toxicology professionals. It describes the practical and ethical issues regarding non-clinical testing to meet US FDA Guidelines, differences resulting from the new European EMEA legislation, and how to develop appropriate information for submission to both agencies. It also provides practical study designs and approaches that can be used to meet international requirements. Covering the full scope of non-clinical testing, regulations, models, practice, and relation to clinical trials, this text offers a comprehensive and up-to-date resource.

Leseprobe

Table of Contents

Title Page

Copyright

Dedication Page

Preface

Acknowledgments

Contributors

Chapter 1: Introduction

1.1 Introduction

1.2 Use of Animals to Support Pediatric Drug Development

1.3 Current Regulatory Perspectives

1.4 Considerations in Conducting Nonclinical Pediatric Studies

1.5 Conclusion

1.6 Acknowledgments

References

Chapter 2: Overview of Pediatric Diseases and Clinical Considerations on Developing Medicines for Children

2.1 Overview of Pediatric Diseases

2.2 Clinical Considerations on Developing Medicines for Children

2.3 Importance of Clinical Trials

2.4 Importance of Age “SUB” Classification for Safety and Efficacy

2.5 Benefit and Risk Stratification

2.6 Adapted Formulation

2.7 Conclusion

2.8 Acknowledgment

References

Chapter 3: Nonclinical Safety Assessment for Biopharmaceuticals: Challenges and Strategies for Juvenile Animal Testing

3.1 Introduction

3.2 Biopharmaceuticals are Different

3.3 Strategy for Testing of Biopharmaceuticals in Juvenile Animals

3.4 Conclusion

3.5 Acknowledgments

References

Chapter 4: FDA Approach to Pediatric Testing

4.1 Introduction

4.2 History of Drug Regulation

4.3 Drugs, Children, and Legislation

4.4 Pediatric Rule

4.5 Best Pharmaceuticals for Children Act

4.6 Toxicities in Children

4.7 FDA's Approach to Nonclinical Pediatric Testing

4.8 The International Conference on Harmonisation (ICH)

4.9 The European Union (EU) and The European Medicines Agency (EMA) Approach to Pediatric Testing

4.10 Conclusion

References

Chapter 5: Pediatric Drug Development Plans

5.1 Introduction

5.2 Regulations and Requirements

5.3 Nonclinical Juvenile Toxicology in Pediatric Plans

5.4 Experiences with Pediatric Development

5.5 Conclusion

References

Chapter 6: Application of Principles of Nonclinical Pediatric Drug Testing to the Hazard Evaluation of Environmental Contaminants

6.1 Introduction

6.2 Regulatory Perspective for Environmental Toxicant Testing Relevant to Children's Exposures

6.3 Study Protocols that Include Juvenile Animals and that are used to Assess Toxicity for Environmental Chemicals

6.4 Special-purpose (Nonguideline) Studies

6.5 The use of Juvenile Animal Toxicity Data in Risk Assessment for Environmental Toxicants

6.6 Summary

Chapter 7: Nonclinical Testing Procedures—Pharmacokinetics

7.1 Introduction

7.2 Adme-related Factors to Consider in Juvenile Toxicity Studies

7.3 Practical Considerations in Juvenile Animal Experiments

7.4 Conclusion

References

Chapter 8: Preclinical Development of a Pharmaceutical Product for Children

8.1 Introduction

8.2 Building the Nonclinical Strategy

8.3 Juvenile Animal Studies—General Considerations

8.4 Conclusions

References

Chapter 9: Juvenile Toxicity Study Design for the Rodent and Rabbit

9.1 Purpose

9.2 Introduction

9.3 General Considerations Regarding Toxicology Studies Conducted for Submission to Regulatory Agencies

9.4 Collection of Pharmacodynamic and Kinetic Data (PK/TK) for Dosage Selection

9.5 The Timing of First Exposure

9.6 When to Use Mice, Rats, or Rabbits

9.7 Route and Method of Administration

9.8 Group Sizes and Selection of Animals for Study

9.9 Identification of Animals

9.10 Growth and Development Parameters for Evaluation

9.11 Feed Consumption

9.12 Clinical Pathology

9.13 Cholinesterase Assessments

9.14 Physical Landmarks

9.15 Nipple Evaluation

9.16 Sexual Maturation

9.17 Behavioral Evaluations

9.18 Reproduction

9.19 Functional Immunotoxicity Evaluations

9.20 Acknowledgments

References

Chapter 10: Dog Juvenile Toxicity

10.1 Introduction

10.2 Experience

10.3 Program Design

10.4 Study Design

10.5 Treatment Techniques

10.6 Toxicokinetics and Metabolism

10.7 Evaluation Techniques

10.8 Summary

References

Chapter 11: Use of the Swine Pediatric Model

11.1 Introduction

11.2 Advantages/Disadvantages of the Minipig Model

11.3 Postnatal Development of the Pig Compared with the Humans

11.4 Testing Strategy and Study Designs

11.5 Study Performance

11.6 Example Experiment: Ciprofloxacin Toxicity in the Neonatal Minipig

11.7 Take-Home Summary

11.8 Acknowledgments

References

Chapter 12: Juvenile Immunodevelopment in Minipigs

12.1 Introduction: why Juvenile Development Studies and Why in Minipigs?

12.2 Study Design

12.3 Animals

12.4 Hematology and Clinical Chemistry

12.5 Lymphocyte Subset Analysis

12.6 Pathology

12.7 Summary

References

Chapter 13: Use of Primate Pediatric Model

13.1 Background and General Considerations for Using Juvenile Nonhuman Primates

13.2 Postnatal Development Phases and Terminology

13.3 Postnatal Development—General Considerations

13.4 Postnatal Development of Selected Organ Systems and Functions in Cynomolgus monkeys

13.5 Example of an NHP Juvenile Toxicity Study Design

13.6 Conclusions: use of NHPs in Juvenile Toxicity Testing

13.7 Acknowledgments

References

Chapter 14: Approaches to Rat Juvenile Toxicity Studies and Case Studies: a Pharmaceutical Perspective

14.1 Introduction

14.2 Planning Nonclinical Juvenile Rat Studies

14.3 Study Design: General Practices

14.4 Dose Selection Considerations

14.5 Approach to Dose-Range-Finding Juvenile Rat Studies

14.6 Conclusion

14.7 Case Studies

14.8 Acknowledgments

References

Appendix I: Maturation of Organ Systems in Various Species

Resources

Appendix II: Sample Juvenile Toxicity Testing Protocol

A2.1 Objectives

A2.2 Proposed Study Schedule

A2.3 Guidelines for Study Design

A2.4 Regulatory Compliance

A2.5 Quality Assurance

A2.6 Sponsor

A2.7 Responsible Personnel

A2.8 Test, Control, Positive Control Article(s) and Immunological Materials

A2.9 Safety

A2.10 Dose Formulation and Analysis

A2.11 Test System

A2.12 Husbandry

A2.13 Experimental Design

A2.14 In-Life Procedures, Observations, and Measurements

A2.15 Laboratory Evaluations

A2.16 Terminal Procedures

A2.17 Histology and Histopathology

A2.18 Computerized Systems

A2.19 Statistical Analysis

A2.20 Amendments and Deviations

A2.21 Retention of Records, Samples, and Specimens

A2.22 Reporting

A2.23 Animal Welfare

References

Index

For further information visit: the book web page http://www.openmodelica.org, the Modelica Association web page http://www.modelica.org, the authors research page http://www.ida.liu.se/labs/pelab/modelica, or home page http://www.ida.liu.se/~petfr/, or email the author at [email protected]. Certain material from the Modelica Tutorial and the Modelica Language Specification available at http://www.modelica.org has been reproduced in this book with permission from the Modelica Association under the Modelica License 2 Copyright © 1998–2011, Modelica Association, see the license conditions (including the disclaimer of warranty) at http://www.modelica.org/modelica-legal-documents/ModelicaLicense2.html. Licensed by Modelica Association under the Modelica License 2.

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Library of Congress Cataloging-in-Publication Data:

Pediatric non-clinical drug testing : principles, requirements, and practice / edited by Alan M. Hoberman, Elise M. Lewis.

p. ; cm.—

Includes bibliographical references.

ISBN 978-0-470-44861-8 (cloth)

I. Hoberman, Alan M. II. Lewis, Elise M.

[DNLM: 1. Drug Evaluation, Preclinical–United States.

2. Age Factors–United States. 3. Child–United States.

4. Drug Approval–United States. 5. Drug Toxicity–prevention & control–United States.

6. Infant–United States. 7. Models, Animal–United States. QV 771]

615.7'040287–dc23

2011043323

Preface

Nonclinical pediatric testing is a “hot topic.” This text is solely dedicated to pediatric testing and targets the specific needs and effects associated with juvenile test animals and, ultimately, juvenile humans. It not only covers the actual aspects of testing but also deals with the associated clinical and regulatory aspects that require updating in this rapidly changing area.

The information collected from international sources and contained herein would benefit all scientific and regulatory people associated with drug development or safety testing of drugs.

This book will prove valuable to international regulatory personnel, in understanding and referencing appropriate designs and concerns; to toxicologists and pharmacokinetics personnel working in industrial, academic, and clinical settings; to regulatory affairs personnel, regarding submission of dossiers; and to physicians involved in safety considerations regarding treatment of children with pharmaceuticals.

This single book will provide the major reference that will be used to obtain historical experience, appropriate rationales for developing the pediatric investigational plan (PIP), and appropriate methods for selection of species and study designs for conducting the necessary pediatric evaluations in animals.

The primary market includes toxicologists, teratologists, developmental neurotoxicologists, and pharmacokineticists who generally have Ph.D. degrees and attend meetings such as the Society of Toxicology, American College of Toxicology, Teratology Society, European Toxicology Society, European Teratology Society, the Japanese Toxicology Society, and the Japanese Teratology Society. A secondary market includes the regulatory affairs professional, who is responsible for interacting with the toxicologists in developing the regulatory submissions. The professionals are generally BS- and Ph.D.-level personnel working in pharmaceutical companies, CROs, and various international regulatory bodies. Their primary meetings are those associated with the Drug Information Association (DIA), an international society dedicated to bringing information to the regulatory community. The tertiary market is the academic toxicology and pediatric medical communities, where this book could be used as a textbook for toxicology and pediatric medicine courses.

Although nonclinical and clinical testing needs for drugs for pediatric populations have been discussed for more 40 years, ethical, political, and practical issues continue to plague pediatric testing and labeling. A new European regulation on pediatric medicines became mandatory for the European Medicines Agency (EMA) in 2008. This book describes the practical issues regarding nonclinical testing to meet FDA guidelines, differences resulting from the new EMA legislation, and ways to develop appropriate information for submission to both agencies, as well as provides practical study designs and approaches that can be used to meet international requirements. It focuses on considerations regarding nonclinical testing models, including (i) lack of fully comparable models, and how to address these problems; (ii) inadequate historical experience, and provides examples of current historical experience with multiple species; and (iii) practical difficulties in using the clinical route of exposure in the animal model, and provides information on how to overcome these problems.

Several books and manuscripts exist that include chapters on pediatric testing requirements and responses of specific organ systems, but these do not address the most recent EMA requirement, which are relevant to all applications to the EMA and which will be shared on a monthly basis with the FDA, specifically, the PIP, which will be addressed in this document. Similarly, none of them include historical control information for multiple species in a single compendium.

Acknowledgments

The editors gratefully acknowledge all the assistance given to the individual authors in compiling this book. Contributors have chosen to personally thank these people and organizations, without whose valuable assistance, this book would not have been compiled and published in their own chapters.

Contributors

Pieter P. Annaert, Department of Pharmaceutical Sciences, Katholieke Universtiteit Leuven, Leuven, Belgium

Graham P. Bailey, Toxicology/Pathology - Global Preclinical Development J&J Pharmaceutical Research and Development, Division of Janssen, Beerse, Belgium

John F. Barnett, Neurobehavioral Toxicology Department, Charles River Laboratories Preclinical Services, Horsham, PA

Paul C. Barrow, CiToxLAB, Evreux Cedex, France

Kimberly C. Brannen, Reproductive Toxicology, Charles River Laboratories Preclinical Services, Horsham, PA

Gary J. Chellman, Developmental and Reproductive Toxicology, Charles River Laboratories, Preclinical Services, Reno, NV

Timothy P. Coogan, Biologics Toxicology, Centocor Research & Development, Inc, Radnor, PA

Luc M. De Schaepdrijver, Toxicology/Pathology Global Preclinical Development, Janssen R&D, a division of Janssen Pharmaceutica NV, Beerse, Belgium

Loeckie L. de Zwart, Drug Metabolism and Pharmacokinetics—Global Preclinical Development, J & J Pharmaceutical Research & Development, Beerse, Belgium

Niels-Christian Ganderup, Ellegaard Göttingen Minipigs, Dalmose, Denmark

Alan M. Hoberman, Research Department, Charles River Laboratories Preclinical Services, Horsham, PA

Frieke Kuper, TNO Quality of Life, Zeist, Netherlands

Susan B. Laffan, Safety Assessment Reproductive Toxicology, GlaxoSmithKline, King of Prussia, PA

Elise M. Lewis, Reproductive and Neurobehavioral Toxicology, Charles River Preclinical Services, Horsham, PA

Beatriz Silva Lima, EMA Pediatrics Committee Chair and University of Lisbon, Lisbon, Portugal

Susan L. Makris, EPA Office of Research and Development, National Center for Environmental Assessment, Washington, DC

Johan G. Monbaliu, Drug Metabolism and Pharmacokinetics—Global Preclinical Development, J & J Pharmaceutical Research & Development, Beerse, Belgium

Robert E. Osterberg, Aclairo Pharmaceutical Development Group Inc, Vienna, VA

André H. Penninks, Experimental Immunology, TNO Triskelion BV, Zeist, Netherlands

Lorraine Posobiec, Safety Assessment Reproductive Toxicology, GlaxoSmithKline, King of Prussia, PA

José Ramet, Department of Paediatrics, Universitair Ziekenhuis Antwerpen UZA, Antwerp, Belgium

Allan Dahl Rasmussen, Regulatory Toxicology and Safety Assessment, H. Lundbeck A/S, Valby, Denmark

Keith Robinson, Reproductive Toxicology, Charles River Laboratories, Preclinical Services Montreal, Quebec, Canada

Susan Y. Smith, Bone Research, Charles River Laboratories, Preclinical Services Montreal, Quebec, Canada,

Cor J. Snel, Reproductive Toxicology, TNO Triskelion BV, Zeist, Netherlands

Bert Suys, Congenital and Pediatric Cardiology, University Hospital Antwerp, Belgium

Geertje J.D. van Mierlo, The Experimental Immunology Group, TNO Triskelion BV, Zeist, Netherlands

Andre Viau, Inhalation Toxicology, Charles River Laboratories, Preclinical Services Montreal, Quebec, Canada

Elvira Vogelwedde, Safety Assessment, Covance Laboratories GmbH, Münster, Germany

Gerhard F. Weinbauer, Developmental and Reproductive Toxicology, Covance Laboratories GmbH, Muenster, Germany

André P.M. Wolterbeek, Reproductive and Developmental Toxicology, TNO Triskelion BV, Zeist, Netherlands

Chapter 1

Introduction

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

1.1 Introduction

Children, like adults, benefit from the continuing advances in biomedical research, including the use of animal models, to evaluate the safety and efficacy of pharmaceutical products, medical devices, and biopharmaceuticals. These advances in biomedical research are central to the ongoing improvements in medical care and public health policies that are intended to prevent or lower the incidence of childhood illnesses or diseases, improve the quality of life for pediatric patients, and ultimately, save or prolong the lives of millions of children around the world. Despite these advances, the looming concern is that children do not benefit equally from these overall advances in biomedical research. This is demonstrated by the continued “off-label” use of medicines to treat childhood illnesses and diseases and the lack of investment in formulations specifically for children regardless of legislative progress [1]. This problem is illustrated by the World Health Organization (WHO) estimate that nearly 9 million children younger than 5 years and more than 1.8 million young people older than 15 years die each year and an even greater number of young people suffer from illnesses that hinder their normal growth and development [2].

To understand the full complexity of this problem, one must be aware of the various illnesses or disabilities that affect “children,” a grouping that includes all individuals from preterm newborn infants to 18-year-old adolescents. As shown in Table 1.1, diseases that can occur in the pediatric population include, but are not limited to, bacterial, viral, and parasitic infections; nutritional diseases; congenital anomalies; cancer; or diseases of the various organ systems (e.g., immune, nervous, cardiovascular, musculoskeletal, gastrointestinal, respiratory, or urogenital). Some of the most common childhood illnesses are presented in Table 1.2. As mentioned by Crosse “Although children suffer from many of the same diseases as adults and are often treated with the same drugs, only about one-third of the drugs that are prescribed for children have been studied and labeled for pediatric use” [3].

Table 1.1 Disease States Observed in Children

Source: Modified from Ref. 90

Bacterial infections and mycosesParasitic diseasesMusculoskeletal diseasesStomatognathic diseasesOtorhinolaryngologic diseasesEye diseasesCardiovascular diseasesCongenital, hereditary, and neonatal diseases and abnormalitiesNutritional diseasesImmunologic diseasesMental disordersViral diseasesNeoplasmsDigestive diseasesRespiratory tract diseasesNervous system diseasesMetabolic diseasesHematologic and lymphatic diseasesSkin and connective tissue diseasesEndocrine diseasesDisorders of environmental etiology/exposureUrogenital diseases

Table 1.2 Common Childhood Illnesses