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Principles And Practice Of Pharmaceutical Medicine

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Principles And Practice Of Pharmaceutical Medicine

  1. 1. Principles and Practice of Pharmaceutical Medicine Second Edition
  2. 2. Principles and Practice of Pharmaceutical Medicine Second Edition Edited by Lionel D. Edwards Novartis and Pharma Pro Plus Inc. New Jersey, USA Andrew J. Fletcher Temple University School of Pharmacy, Philadelphia, USA Anthony W. Fox EBD Group Inc., California, USA and Munich, Germany and Skaggs SPPS, University of California, San Diego Peter D. Stonier Consultant in Pharmaceutical Medicine, Richmond, Surrey, UK
  3. 3. Copyright ß 2007 John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England Telephone (þ44) 1243 779777 Email (for orders and customer service enquiries): cs-books@wiley.co.uk Visit our Home Page on www.wileyeurope.com or www.wiley.com All Rights Reserved. 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 under the terms of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1T 4LP, UK, without the permission in writing of the Publisher. Requests to the Publisher should be addressed to the Permissions Department, John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England, or emailed to permreq@wiley.co.uk, or faxed to (þ44) 1243 770620. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The Publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the Publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. Other Wiley Editorial Offices John Wiley & Sons Inc., 111 River Street, Hoboken, NJ 07030, USA Jossey-Bass, 989 Market Street, San Francisco, CA 94103-1741, USA Wiley-VCH Verlag GmbH, Boschstr. 12, D-69469 Weinheim, Germany John Wiley & Sons Australia Ltd, 42 McDougall Street, Milton, Queensland 4064, Australia John Wiley & Sons (Asia) Pte Ltd, 2 Clementi Loop #02-01, Jin Xing Distripark, Singapore 129809 John Wiley & Sons Canada Ltd, 6045 Freemont Blvd, Mississauga, Ontario, L5R 4J3, Cananda Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Anniversary Logo Design: Richard J. Pacifico Library of Congress Cataloging-in-Publication Data Principles and practice of pharmaceutical medicine/edited by Lionel D. Edwards ... [et al.]. – 2nd ed. p.; cm. Includes bibliographical references and index. ISBN 978-0-470-09313-9 (cloth: alk. paper) 1. Drug development. 2. Drugs–Research. 3. Pharmacology. I. Edwards, Lionel D. [DNLM: 1. Drug Evaluation. 2. Drug Industry–organization & administration. QV 736 P9567 2007] RM301.25.P75 2007 615’.19–dc22 2007011029 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-470-09313-9 Typeset in 10.5/12.5 pt Times by Thomson Digital, India Printed and bound in Great Britain by Antony Rowe Ltd., Chippenham, Wilts This book is printed on acid-free paper responsibly manufactured from sustainable forestry in which at least two trees are planted for each one used for paper production.
  4. 4. Contents Preface to the First Edition ix Preface to the Second Edition xi About the Editors xiii Contributors xv SECTION I: OVERVIEW OF PHARMACEUTICAL MEDICINE 1 1 The Practice and Practitioners of Pharmaceutical Medicine 3 Anthony W. Fox 2 Pharmaceutical Medicine as a Medical Specialty 7 Michael D. Young and Peter D. Stonier 3 Clinical Research Education and Training for Biopharmaceutical Staff 25 Peter Marks SECTION II: DRUG DISCOVERY AND DEVELOPMENT 41 Introduction 41 4 Drug Discovery: Design and Serendipity 43 Ronald R. Cobb and Leslie J. Molony 5 Pharmaceutics 51 Anthony W. Fox 6 Nonclinical Toxicology 63 Frederick Reno 7 Informed Consent 75 Anthony W. Fox 8 Phase I: The First Opportunity for Extrapolation from Animal Data to Human Exposure 79 Stephen H. Curry, Dennis McCarthy, Helen H. DeCory, Matthew Marler and Johan Gabrielsson 9 Phase II and Phase III Clinical Studies 101 Anthony W. Fox 10 Phase IV Drug Development: Post-Marketing Studies 119 Lisa R. Johnson-Pratt
  5. 5. vi CONTENTS 11 Site Management 127 Barry Miskin 12 Good Clinical Practices 139 Wendy Bohaychuk and Graham Ball 13 Quality Assurance, Quality Control and Audit 159 Rita Hattemer-Apostel 14 The Unique Role of Over-the-Counter Medicine 179 Paul Starkey SECTION III: SPECIAL POPULATIONS AND REQUIRED SPECIAL STUDIES 191 Introduction 191 15 Drug Research in Older Patients 193 Lionel D. Edwards 16 Drug Development Research in Women 203 Lionel D. Edwards 17 Clinical Research in Children 223 Lionel D. Edwards 18 Racial and Ethnic Issues in Drug Registration 231 ´ Lionel D. Edwards, J.M. Husson, E. Labbe, C. Naito, M. Papaluca Amati, S. Walker, R. Williams and H. Yasurhara 19 Hepatic and Renal Failure 249 Anthony W. Fox 20 Drug Interactions 255 Anthony W. Fox and Anne-Ruth van Troostenburg de Bruyn 21 Orphan Drugs 265 Bert Spilker SECTION IV: APPLIED ASPECTS OF DRUG DEVELOPMENT 277 Introduction 277 22 Biotechnology Products and Development 279 David A. Shapiro and Anthony W. Fox 23 Pharmacoeconomics: Economic and Humanistic Outcomes 291 Raymond J. Townsend, Jane T. Osterhaus and J. Gregory Boyer 24 Pharmacoepidemiology and the Pharmaceutical Physician 303 Hugh H. Tilson 25 Statistical Principles and Application in Biopharmaceutical Research 313 Dan Anbar 26 Data Management 345 T.Y. Lee and Michael Minor
  6. 6. CONTENTS vii 27 Patient Compliance: Pharmionics, a New Discipline 355 ´ Jean-Michel Metry 28 Monitoring Drug Concentrations in Clinical Practice 375 Anthony W. Fox 29 Generics 381 J.D. Gabriel Lopez and J.D. Thomas Hoxie 30 Complementary Medicines 387 Anthony W. Fox SECTION V: DRUG REGULATION 393 Introduction 393 31 United States Regulations 395 William Kennedy 32 Special US Regulatory Procedures: Emergency and Compassionate INDs and Accelerated Product Approvals 407 Anthony W. Fox 33 The Development of Human Medicines Control in Europe from Classical Times to the Year 2000 415 John P. Griffin 34 Medicines Regulation in the European Union 443 Anne-Ruth van Troostenburg de Bruyn and Giuliana Tabusso 35 Japanese Regulations 487 ´ Etienne Labbe 36 Drug Registration and Pricing in the Middle East 509 Edda Freidank-Mueschenbornfs SECTION VI: MEDICAL SERVICES 517 Introduction 517 37 Medical Affairs 519 Gregory P. Geba 38 Drug Labeling 529 Anthony W. Fox 39 Drug Surveillance 535 Howard J. Dreskin and Win M. Castle 40 Data Mining 545 Mirza I. Rahman and Omar H. Dabbous 41 Risk Management in Product Approval and Marketing 557 Anthony W. Fox
  7. 7. viii CONTENTS 42 Publishing Clinical Studies 565 Anthony W. Fox 43 Organizing and Planning Local, Regional, National and International Meetings and Conferences 575 Zofia Dziewanowska and Linda Packard 44 Drug Withdrawals from the Market – Causes and Consequences 579 Ronald D. Mann SECTION VII: LEGAL AND ETHICAL ASPECTS OF PHARMACEUTICAL MEDICINE 585 Introduction 585 45 Introduction to Bioethics for Pharmaceutical Professionals 587 Andrew J. Fletcher 46 Pharmaceutical Medicine and the Law 595 Sarah Croft and Timothy Pratt 47 Pharmaceutical Product Liability 605 Han W. Choi and Howard B. Yeon 48 Patents 619 Gabriel Lopez 49 Fraud and Misconduct in Clinical Research 631 Jane Barrett SECTION VIII: BUSINESS ASPECTS 643 Introduction 643 50 The Multinational Corporations: Cultural Challenges, the Legal/Regulatory Framework and the Medico-commercial Environment 645 R. Drucker and R. Graham Hughes 51 Advertising and Marketing 653 Jonathan Belsey 52 Middle East, India, China and the Far East: Pharmaceutical Medicine in the East 665 Gamal Hammad 53 Financial Aspects of Clinical Trials 689 R.G. Hughes and N. Turner 54 Outsourcing Clinical Drug Development Activities to Contract Research Organizations (CROs): Critical Success Factors 701 John R. Vogel 55 The Impact of Managed Care on the US Pharmaceutical Industry 725 Robert J. Chaponis, Christine Hanson-Divers, and Marilyn J. Wells Appendix: Useful Internet Links 745 Index 749
  8. 8. Preface to the First Edition Pharmaceutical medicine is a relatively new, but rapidly growing, academic discipline. As these trends continue into the 21st century, pharmaceutical physicians are increasingly regarding consultancy work and contract research organization (CRO) affiliation as good career opportunities, and now recognize the need for continuing education and training in this broad spectrum discipline. As editors, we would like to thank our contributors for their expertise, their dedication, and their vision. We would like to thank and acknowledge the work and counsel of our colleague Robert Bell, MD, MRPharmS, who helped us greatly during the early part of this project. We would also like to thank and acknowledge the enormous help, encouragement, and patience of the team at John Wiley & Sons, Inc., UK, with whom we have worked closely over these past few years, among whom we have particularly stressed (!) Michael Davis, Deborah Reece, Hannah Bradley, Lewis Derrick, and Hilary Rowe. Lastly, we would like to thank our families, and friends, who have withstood the frequent telephone calls, e-mails, and meetings, often late into the night. Indeed, to all who made this project possible, both authors and non-authors, we thank you. We are certain that this specialty, and our patients, even though we may help them vicariously, will benefit because of your contributions. Andrew Fletcher Lionel Edwards Tony Fox Peter Stonier
  9. 9. Preface to the Second Edition Since the first edition of this book, pharmaceutical medicine has only become more diverse and has also become widely accepted as a recognized medical specialty, for example, with its first graduates of specialist training in the United Kingdom, to add to those of Switzerland, and Mexico. This has been accompanied by pharmaceutical medicine’s rapid progress toward specialty recognition within the European Community, and many changes in the pharmaceutical environment. So, we have taken this book further with this second edition. There are new chapters on European regulations, risk management, the Middle East, Asia and other topical subjects in pharmaceutical medicine. Those chapters that did appear in the first edition have all been brought up to date. But this book is for all those working in pharmaceutical medicine, regardless of their degrees, titles or affiliations. Although it comprehensively covers the internationally harmonized syllabus for the Diplomas in Pharmaceutical Medicine that are awarded in Belgium, Switzerland and the United Kingdom, this book will also usefully serve those teaching other types of certificates and (usually Master’s) degrees in this field, as well as being a vade mecum for those who are not undertaking academic courses. We would again like to thank the team at John Wiley and Sons, Inc., Chichester (UK). Hannah Bradley got this second edition started, but then went off on a tour around the world; the editors strenuously deny that they are the reason why. Lucy Sayer and Juliet Booker have since piloted the ship to the dock-side, successfully cajoling us into getting this edition done before its second decade. Not least, we would like to thank you, the reader, for your continued support and suggestions. So here is our second edition, it is more than a simple update, and it is even less US-centric than before. Lionel Edwards Andrew Fletcher Tony Fox Peter Stonier
  10. 10. About the Editors LIONEL D. EDWARDS, MB, BS, LRCP, MRCS, DipRCOG, FFPM, is Senior Director of Medical Affairs for Novartis USA, and President of Pharma Pro Plus Inc., a drug development consulting company. Dr. Edwards has been involved in all aspects of clinical trials for over 33 years on many different research drug and devices in 10 therapeutic areas. Previously, he was Vice President of Clinical Research at Bio- Technology Pharmaceutical Corporation, a small biotechnology firm operating both in the United States and internationally. Prior to this, he worked at Noven Inc., a small Skin Patch Technology firm with large internationally licensed partners – CIBA and Rhone Poulenc Rorer. He was Assistant Vice President, International Clinical Research at Hoffman-La Roche, Senior Director of Schering-Plough International Research, and Director of US Domestic Gastrointestinal, Hormonal, and OTC Research Departments. Dr. Edwards chaired the PMA Special Population Committee, and also sat on the Institute of Medicine Committee for Research in Women, sponsored by the US National Instutes of Health. He also served on the efficacy subcommittee Topic 5 (Acceptability of Foreign Clinical Data) for the International Committee on Harmonization (ICH). Dr. Edwards is a Fellow of the Faculty of Pharmaceutical Medicine and an Adjunct Professor at Temple University Graduate School of Pharmacology. He has taught for the Pharmaceutical Education & Research Institute for over 12 years and was on the teaching faculty of the National Association of Physicians. He is a founder member of the American Academy of Pharmaceutical Physicians. Dr. Edwards has homes in New Jersey and Florida. ANDREW J. FLETCHER, MB, BChir, (Cantab), MS (Columbia), DipPharmMedRCP, FFPM was formerly the Senior Assistant Editor of The Merck Manual, and is Adjunct Professor of Pharmaceutical Health Care at Temple University School of Pharmacy. He graduated from Cambridge University and St. Bartholomew’s Hospital, London, briefly trained in Neurosurgery, joined CIBA-Geigy in the UK as Medical Advisor, then European Medical Director for Syntex, and joined Merck, first in the international division after graduating in business studies from Columbia University, New York City, then as Assistant Editor of The Merck Manual. He teaches pharmaceutical medicine, bioethics and medical and scientific writing at Temple University’s School of Pharmacy. He is a founder member and former trustee of the Academy of Pharmaceutical Physicians and Investigators (formerly the American Academy of Pharma- ceutical Physicians). Dr. Fletcher resides in Ohio. ANTHONY (‘Tony’) W. FOX, BSc, MBBS, FFPM, FRCP, MD(Lond), DipPharmMedRCP, CBiol, FIBiol, is President of EBD Group, a consultancy with offices in San Diego and Munich. From the Royal London Hospital, after general clinical training, he was Rotary International Fellow at Emory University (Atlanta) and CIBA-Geigy Fellow at Harvard. Industrial positions at Procter & Gamble and (then) Glaxo Inc. came next. He has also been a clinical and regulatory Vice President within a small pharmaceutical company. Among many societies, Tony was a Charter Member, Trustee, and Education VP of the American Academy of Pharmaceutical Physicians, and is a liveryman guardant of the Worshipful Society of Apothecaries of London. He is an Adjunct (i.e. honorary) Associate Clinical Professor in the Skaggs School of Pharmacy and
  11. 11. xiv ABOUT THE EDITORS