DRUG SAFETY EVALUATION

Transcription

1 DRUG SAFETY EVALUATION

2 DRUG SAFETY EVALUATION SHAYNE C. GAD A John Wiley & Sons, Inc., Publication

3 This book is printed on acid-free paper. Copyright # 2002 by John Wiley and Sons, Inc., New York. All rights reserved. Published simultaneously in Canada. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning or otherwise, except as permitted under Sections 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923, (978) , fax (978) Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 605 Third Avenue, New York, NY , (212) , fax (212) , PERMREQ@WILEY.COM. For ordering and customer service, call CALL-WILEY. Library of Congress Cataloging-in-Publication Data: Gad, Shayne C., Drug Safetey evaluation=shayne C. Gad. p. cm. Includes index. ISBN (cloth: alk. paper) 1. Drugs Toxicology. 2. Drugs Testing. I. Title. RA1238. G dc21 Printed in the United States of America

4 To Spunky Dustmop, who always listens so well and is always there.

5 CONTENTS Preface About the Author ix xi Chapter 1 Strategy and Phasing for Drug Safety Evaluation in the Discovery and Development of Pharmaceuticals 1 Chapter 2 Regulation of Human Pharmaceutical Safety 30 Chapter 3 Information Sources: Building and Maintaining Data Files 99 Chapter 4 Screens in Safety and Hazard Assessment 112 Chapter 5 Acute Toxicity Testing in Drug Safety Evaluation 130 Chapter 6 Genotoxicity 176 Chapter 7 Subchronic and Chronic Toxicity Studies 237 Chapter 8 Developmental and Reproductive Toxicity Testing 258 Chapter 9 Carcinogenicity Studies 297 Chapter 10 Safety Assessment of Inhalant Drugs 335 Chapter 11 Irritation and Local Tissue Tolerance in Pharmaceutical Safety Assessment 367 vii

6 viii CONTENTS Chapter 12 Special Concerns for the Preclinical Evaluation of Biotechnology Products 404 Chapter 13 Formulations, Routes, and Dosage Designs 442 Chapter 14 Occupational Toxicology in the Pharmaceutical Industry 505 Chapter 15 Immunotoxicology in Pharmaceutical Development 527 Chapter 16 Large Animal Studies 595 Chapter 17 Chapter 18 The Applicatioin of In Vitro Techniques in Drug Safety Assessment 634 Pharmacokinetics and Toxicokinetics in Drug Safety Evaluation 691 Chapter 19 Safety Pharmacology 737 Chapter 20 Chapter 21 Evaluation of Human Tolerance and Safety in Clinical Trials: Phase I and Beyond 764 Postmarketing Safety Evaluation: Monitoring, Assessing, and Reporting of Adverse Drug Responses (ADRs) 831 Chapter 22 Statistics in Pharmaceutical Safety Assessment 862 Appendix A Selected Regulatory and Toxicological Acronyms 971 Appendix B Definition of Terms and Lexicon of Clinical Observations in Nonclinical (Animal) Studies 975 Appendix C Notable Regulatory Internet Addresses 979 Appendix D Glossary of Terms Used in the Clinical Evaluation of Therapeutic Agents 990 Index 997

7 PREFACE Drug Safety Evaluation has been written with the central objective of presenting an all-inclusive practical guide for those who are responsible for ensuring the safety of drugs and biologics to patients, health care providers, those involved in the manufacture of medicinal products, and all those who need to understand how the safety of these products is evaluated. This practical guide presents a road map for safety assessment as an integral part of the development of new drugs and therapeutics. Individual chapters also address specific approaches to evaluating hazards, including problems that are encountered and their solutions. Also covered are the scientific and philosophical bases for evaluation of specific concerns (e.g., carcinogenicity, development toxicity, etc.) to provide both understanding and guidance for approaching new problems. Drug Safety Evaluation is aimed specifically at the pharmaceutical and biotechnology industries. It is hoped that the approaches and methodologies presented here will show a utilitarian yet scientifically valid path to the everyday challenge of safety evaluation and the problem-solving that is required in drug discovery and development. Shayne C. Gad Cary, North Carolina ix

8 ABOUT THE AUTHOR Shayne C. Gad, Ph.D. (Texas, 1977), DABT, ATS, has been the Principal of Gad Consulting Services since He has more than 25 years of broad based experience in toxicology, drug and device development, document preparation, statistics and risk assessment, having previously been Director of Toxicology and Pharmacology for Synergen (Boulder, CO), Director of Medical Affairs Technical Support Services for Becton Dickinson (RTP, NC) and Senior Director of Product Safety and Pharmacokinetics for G.D. Searle (Skokie, IL). He is a past president and council member of the American College of Toxicology and the President of the Roundtable of Toxicology Consultants. He has previously served the Society of Toxicology on the placement, animals in research [twice each], and nominations committees, as well as president of two SOT specialty sections (Occupational Health and Regulatory Toxicology) and officer of a third (Reproductive and Developmental Toxicity). He is also a member of the Teratology Society, Biometrics Society, and the American Statistical Association. Dr. Gad has previously published 24 books, and more than 300 chapters, papers and abstracts in the above fields. He has also organized and taught numerous courses, workshops and symposia both in the United States and internationally.