Principles and Practice
of Pharmaceutical Medicine
         Second Edition
Principles and Practice
of Pharmaceutical Medicine
                    Second Edition


                            Edited...
Copyright ß 2007      John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester,
                      West Sussex PO19...
Contents

Preface to the First Edition                                               ix
Preface to the Second Edition     ...
vi     CONTENTS

11 Site Management                                                          127
   Barry Miskin
12 Good C...
CONTENTS    vii

27 Patient Compliance: Pharmionics, a New Discipline                                355
                ´...
viii       CONTENTS

42 Publishing Clinical Studies                                                       565
   Anthony W...
Preface to the First Edition

Pharmaceutical medicine is a relatively new, but rapidly growing, academic discipline. As th...
Preface to the Second Edition

Since the first edition of this book, pharmaceutical medicine has only become more diverse a...
About the Editors

LIONEL D. EDWARDS, MB, BS, LRCP, MRCS, DipRCOG, FFPM, is Senior Director of Medical Affairs
for Novarti...
xiv     ABOUT THE EDITORS

Pharmaceutical Sciences, at the University of California, San Diego. His publications span seve...
Contributors

Anbar, Dan ClinPro Inc., 1661 Route 22 West, Round Brook, NJ 08805, USA.
Email: dan.anbar@clinproinc.com
Bal...
xvi    CONTRIBUTORS

Drucker, R. Technomark Consulting Services Ltd, King House, 11 Westbourne Grove, London W2 4UA, UK.
E...
CONTRIBUTORS      xvii

     ´                      ´
Labbe, Etienne UCB S.A., Allee de la Recherche, 60, 1070 Brussels, B...
xviii    CONTRIBUTORS

Tabusso, Giuliana Via Melchiorre Gioia 47, 20124 Milan, Italy.
Email: giulianatabusso@libero.it
Til...
SECTION I
Overview of Pharmaceutical
Medicine
1 ThePharmaceuticalPractitioners
    of
        Practice and
                      Medicine
             Anthony W. Fox


...
4     CH1   THE PRACTICE AND PRACTITIONERS OF PHARMACEUTICAL MEDICINE

medicine (in no particular order): ethics, chemis- ...
FURTHER READING        5

professionals should enquire from the relevant         have to be well informed about the divers...
2 Pharmaceutical Medicine
    as a Medical Specialty
             Michael D. Young and Peter D. Stonier




Medicine is an...
8     CH2   PHARMACEUTICAL MEDICINE AS A MEDICAL SPECIALTY




                                                         Re...
CH2 PHARMACEUTICAL MEDICINE AS A MEDICAL SPECIALTY        9

attitudes to what they can and should expect of           Tab...
10      CH2 PHARMACEUTICAL MEDICINE AS A MEDICAL SPECIALTY

obesity, attention deficit, hyperactivity and even             ...
CH2 PHARMACEUTICAL MEDICINE AS A MEDICAL SPECIALTY                         11

                              3600

       ...
12      CH2 PHARMACEUTICAL MEDICINE AS A MEDICAL SPECIALTY

  follows: first, continued learning about the safety          ...
CH2 PHARMACEUTICAL MEDICINE AS A MEDICAL SPECIALTY        13

1990s have seen the impact of enabling biomole-          eva...
14      CH2 PHARMACEUTICAL MEDICINE AS A MEDICAL SPECIALTY

more permeable than that of full-term babies, chil-       ing ...
2.1   EDUCATION AND TRAINING IN PHARMACEUTICAL MEDICINE        15

end are physicians/businessmen, who are the            ...
16      CH2 PHARMACEUTICAL MEDICINE AS A MEDICAL SPECIALTY

2.2 Some background to                                   and s...
2.2 SOME BACKGROUND TO PHARMACEUTICAL PHYSICIAN EDUCATION AND TRAINING          17

taken on board quickly and efficiently ...
18      CH2 PHARMACEUTICAL MEDICINE AS A MEDICAL SPECIALTY

most effective solution to a learning need and,               ...
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Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
Principles And Practice Of Pharmaceutical Medicine
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 Pharmaceutical Sciences, at the University of California, San Diego. His publications span several areas of pharmaceutical medicine, for example, regulation, pharmacology, clinical trials, pharmacovigilance, analgesics, migraine, genotoxicology, and metabolism, and he is named as inventor on several patents. He is on the editorial boards of several journals, and serves in a more senior capacity for two of them. Tony is proud to be an Essex man, researches the history of that County, and has been elected as a fellow of the Royal Geographical and the Royal Numismatic Societies. PETER D. STONIER, BA, BSc, PhD, MBChB, MRCPsych, FRCP, FRCPE, FFPM has 29 years experience in pharmaceutical medicine. He is a graduate of Manchester Medical School, qualifying in 1974, following a BSc degree in physiology (University of Birmingham) and a PhD in protein chemistry (University of Sheffield). He is a pharmaceutical physician and was Medical Adviser with the UK Hoechst Group of companies from 1977, serving as Medical Director and Board Director until 2000. Currently, he is Director of Education and Training of the Faculty of Pharmaceutical Medicine, Royal Colleges of Physicians of the UK. He is Medical Director of Amdipharm Plc, and of Medical Resource Provider Axess Ltd. Formerly, he was President of the International Federation of Associations of Pharmaceutical Physicians (IFAPP) and Chairman of the British Association of Pharmaceutical Physicians. He is a past- President of the Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians, UK. He is Visiting Professor in pharmaceutical medicine at the University of Surrey, which under his direction introduced the first MSc degree in Pharmaceutical Medicine in 1993, which is now part of the Postgraduate Medical School of the University. His publications include edited works in human psychopharmacology, pharmaceutical medicine, clinical research, medical marketing, and careers in the pharmaceutical industry. He is a member of the Association of Pharmaceutical Physicans and Investigators (APPI). Professor Stonier has been elected a Fellow of the Royal Society for the encouragement of Arts, Manufactures and Commerce.
  12. 12. Contributors Anbar, Dan ClinPro Inc., 1661 Route 22 West, Round Brook, NJ 08805, USA. Email: dan.anbar@clinproinc.com Ball, Graham Good Clinical Research Practices Consultants, Lakehurst, Ontario, Canada, and Oxford, UK. Barrett, Jane 2 Falcon Way, Wokingham, Berkshire RG41 3HD, UK. Email: janebarrett@doctors.org.uk Belsey, Jonathan JB Medical, The Old Brickworks, Chapel Lane, Little Cornard, Sudbury, Suffolk CO10 0PB, UK. Email: jbelsey@jbmedical.com Bohaychuk, Wendy Good Clinical Research Practices Consultants, Lakehurst, Ontario, Canada, and Oxford, UK. Boyer, J. Gregory Accreditation Council for Pharmacy Education, Chicago, IL, USA Castle, Win M. Formerly of GlaxoSmithKline, Philadelphia, PA, USA. Email: winwinsituation@earthlink.net Chaponis, Robert J. US Medical Operations, Pfizer Inc., 235 East 42nd Street, New York, NY 10017, USA. Email: robert.j.chaponis@pfizer.com Choi, Han W. Oracle Investment Management Inc., 200 Greenwich Ave 3rd Fl., Greenwich, CT 06830, USA. Email: hchoi@oraclepartners.com Cobb, Ronald R. RiverWood BioConsulting Inc., 8909 SW 75th Street, Gainesville, FL 32608, USA. Croft, Sara Shook, Hardy and Bacon International LLP, London, UK and Shook, Hardy and Bacon LLP, Kansas City, MO, USA Curry, Stephen H. Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14627, USA. Email: stephenhcurry@earthlink.net Dabbous, Omar H. Health Economics & Clinical Outcomes Research, Medical Affairs, Centocor Inc., 800 Ridgeview Drive, Horsham, PA 19044, USA. DeCory, Heleen H. UCB, 755 Jefferson Road, Rochester, NY, USA Dreskin, Howard J. 7809 Via Optuntia, Carlsbad, CA 92009, USA. Formerly of GlaxoSmithKline, Philadelphia, PA, USA. Email: howard.dreskin@adelphia.net
  13. 13. xvi CONTRIBUTORS Drucker, R. Technomark Consulting Services Ltd, King House, 11 Westbourne Grove, London W2 4UA, UK. Email: rdrucker@technomark.com Dziewanowska, Zofia Ligand Pharmaceuticals Inc., 10275 Science Center Drive, San Diego, CA 92121, USA. Email: zofia@ligand.com Edwards, Lionel D. Novartis Pharmaceuticals Corporation, US CD&MA, Building 501/Room 216, One Health Plaza, East Hanover, NJ 07936-1080, USA. Email: lionel.edwards@novartis.com Fletcher, Andrew J. Temple University School of Pharmacy, PHARM-QA/RA, 3307 North Broad Street, Philadelphia, PA 19140, USA. Email: andrew.fletcher@temple.edu Fox, Anthony W. EBD Group Inc., 2032 Corte del Nogal #120, Carlsbad, CA 92011, USA and Neuhauser Straße 3, Munich, D-80331, Germany. Email: awfox@ebdgroup.com; ¨ Freidank-Muschenborn, Edda International Regulatory Affairs, Engelhard Arzneimittel GmbH, Herzbergstrasse 3, 61138 Niederdorfelden, Germany. Email: e.mueschenborn@engelhard-am.de Gabrielsson, Johan AstraZeneca R&D, Wilmington, DE, USA Geba, Gregory P. Novartis Pharmaceuticals Corporation, One Health Plaza, Building 701, East Hanover, NJ 07936-1080, USA. Email: gregory.geba@novartis.com Griffin, John P. John Griffin Associates Ltd, Quartermans, Digswell Lane, Digswell, Welwyn, Hertfordshire AL7 1SP, UK. Email: JQmans5@aol.com Hammad, Gamal 24 Cassiobury Park Avenue, Watford, Hertfordshire WD18 7LB, UK. Email: haithamgbr@talk21.com Hanson-Divers, Christine Cary, NC, USA Hattemer-Apostel, Rita Verdandi AG, Wieslergasse 2, 8049 Zurich, Switzerland. Email: rha@verdandi.ch Hoxie, Thomas Hoxie & Tso LLP, 374 Millburn Avenue, Suite 300E, Millburn, NJ 07041, USA Hughes, R. Graham Technomark Consulting Services Ltd, King House, 11 Westbourne Grove, London W2 4UA, UK. Email: rghughes@technomark.com Husson, J.M. Paris, France Johnson-Pratt, Lisa R. Wynnewood, PA, USA. Email: lisa_johnsonpratt_md@merck.com Kennedy, William Consultant, Delaware, USA; formerly V.P. Regulation Affairs. Email: consultkennedy@aol.com ¨ Konig, Anja International Regulatory Affairs, Engelhard Arzneimittel GmbH, Herzbergstrasse 3, 61138 Niederdorfelden, Germany. Email: an.koenig@engelhard-am.de
  14. 14. CONTRIBUTORS xvii ´ ´ Labbe, Etienne UCB S.A., Allee de la Recherche, 60, 1070 Brussels, Belgium. Email: Etienne.Labbe@UCB-Group.com Lee, T.Y. ACER/EXCEL Inc., USA. Lopez, Gabriel 6 Pleasantville Road, New Vernon, NJ 07976, USA. Email: lopezg4@yahoo.com Marler, Matthew Department of Psychiatry, University of California, San Diego, CA, USA McCarthy, Dennis AstraZeneca R&D, Wilmington, DE, USA Mann, Ronald D. 42 Hazleton Way, Waterlooville, Hampshire PO8 9BT, UK. Email: ronmann@professormann.com Marks, Peter Pfizer Inc., 50 Pequot Avenue, MS 6025-C4247, New London, CT 06320, USA. Email: Peter.Marks@pfizer.com ´ Metry, Jean-Michel AARDEX Ltd, Untermueli 6, Postfach 2026, 6302 Zug, Switzerland. Email: jm.metry@aardex.ch Minor, Michael ACER/EXCEL Inc., USA Miskin, Barry University of Florida, College of Medicine, PO Box 8068, Jupiter, FL 33468, USA. Email: miskinmd@aol.com Molony, Leslie J. RiverWood BioConsulting Inc., 8909 SW 75th Street, Gainesville, FL 32608, USA. Email: lmolony@riverwoodbio.com Naito, C. Teikyo University, Japan Osterhaus, Jane T. Wasatch Health Outcomes, Park City, UT and Carlsbad, CA, USA. Email: jtosterhaus@mindspring.com Packard, Linda Formerly American Academy of Pharmaceutical Physicians, Research Triangle Park, NC, USA Papaluca Amati, M. EMEA, London, UK Pratt, Timothy Shook, Hardy and Bacon International LLP, London, UK and Shook, Hardy and Bacon LLP, Kansas City, MO, USA Rahman, Mirza I. Health Economics & Clinical Outcomes Research, Medical Affairs, Centocor Inc., 800 Ridgeview Drive, Horsham, PA 19044, USA. Email: mrahman@cntus.jnj.com Reno, Frederick Merritt Island, FL, USA. Email: fred_reno@msn.com Shapiro, David A. Integrated Quality Resources, PO Box 8530, Rancho Santa Fe, CA 92067, USA. Email: dshapiro@idun.com Spilker, Bert Bert Spilker Associates, 8004 Overhill Road, Bethesda, MD 20814-1145, USA. Email: bspilker@comcast.net Starkey, Paul Formerly SmithKline Beecham Healthcare, Parsippany, NJ, USA. Email: pgvstar@aol.com Stonier, Peter D. 5 Branstone Road, Kew, Richmond, Surrey TW9 3LB, UK. Email: peterstonier@btinternet.com
  15. 15. xviii CONTRIBUTORS Tabusso, Giuliana Via Melchiorre Gioia 47, 20124 Milan, Italy. Email: giulianatabusso@libero.it Tilson, Hugh H. Office of the Dean, School of Public Health, University of North Carolina, Chapel Hill, NC 27599-7400, USA. Email: hugh_tilson@unc.edu Townsend, Raymond J. Elan Pharmaceuticals, 7475 Lusk Boulevard, San Diego, CA 9212, USA. Email: ray.townsend@elan.com Turner, Nadia Astra-Zeneca Pharmaceuticals, Macclesfield, UK van Troostenburg de Bruyn, Anne-Ruth Takeda Global R&D Centre (Europe), Arundel Great Court, 2 Arundel Street, London WC2R 3DA, UK. Email: vantoar@tiscali.co.uk Vogel, John R. John R. Vogel Associates Inc., 328 Pualoa Nani Place, Kihei, HI 96753, USA. Email: vogelj001@hawaii.rr.com; john@jrvogel.com Walker, S. Centre of Medicine Research, Carlshalton, UK Wells, Marilyn J. Hampton University, Hampton, VA 23668, USA Williams, R. US Pharmacopia, Rockville, MD, USA Yasurhara, H. Teikyo University, Japan Yeon, Howard B. Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. Email: hyeon@partners.org Young, Michael D. MDY-Associates, Philadelphia, PA, USA. Email: MichaelDYoungMD@aol.com
  16. 16. SECTION I Overview of Pharmaceutical Medicine
  17. 17. 1 ThePharmaceuticalPractitioners of Practice and Medicine Anthony W. Fox Pharmaceutical medicine is unquestionably a strate efficacy, tolerability and purity in drug young medical specialty. The first university chair products (and their equivalents in diagnostics and in pharmaceutical medicine is less than 10 years old, devices), pharmaceutical medicine has become and there are no great buildings or institutions evidence based; it is interesting to note that the dedicated to it, unlike venerable medical specialties more venerable medical specialties are now imitat- such as chest medicine, neurology, physiology, ing the supposed ‘new kids on the block’ with the pharmacology and so on. Possibly because of its recent emphasis on evidence-based approaches to youth, this is a specialty that can be misunderstood the patient. by those outside it. Even among practitioners of It is therefore not surprising that the diverse and pharmaceutical medicine, there can be surprise overlapping discipline of pharmaceutical medicine when they consider their own diversity. is populated by practitioners with varied educa- Nonetheless, elements of what we recognize tional backgrounds. There can be no doubt that today as the practice of pharmaceutical medicine clinical experience is always a good prelude to a have existed for a long time. Withering’s identifi- career in pharmaceutical medicine. But dental sur- cation of Digitalis purpurea as a treatment for what geons, medical practitioners, nurses, pharmacists, was then called ‘dropsy’ and the clinical trial of physiotherapists, psychologists and many other citrus fruit conducted by Lind are examples of drug members of the allied health professions have all discovery and investigation. Sequential clinical found satisfying careers in this specialty. trial designs have been borrowed from as far Few medical specialties involve working in a-field as the discipline of engineering and date teams with as large a number of other professions from the mid-twentieth century. The techniques as of pharmaceutical medicine. For example, gen- shared with the fields of epidemiology and public eral practitioners regularly work with nurses, health health are obvious and also well established. Every visitors, administrators, hospital colleagues and prescription written in ordinary clinical practice is social workers; radiologists might add radiogra- a clinical trial of some sort, where n ¼ 1, because phers and physicists to this list and delete the health human beings are anisogenetic; this even applies to visitors and social workers. But, by way of compar- identical twins as they age or are exposed to dif- ison, the following list of nouns, all of which have ferent environments. Ever since the need to demon- their own professions, comprise pharmaceutical Principles and Practice of Pharmaceutical Medicine, 2nd Edition Edited by L. D. Edwards, A. J. Fletcher, A. W. Fox and P. D. Stonier # 2007 John Wiley & Sons, Ltd ISBN: 978-0-470-09313-9
  18. 18. 4 CH1 THE PRACTICE AND PRACTITIONERS OF PHARMACEUTICAL MEDICINE medicine (in no particular order): ethics, chemis- oneself and what one does not like to do at work! try, pharmacology, computational modeling, phar- But, nonetheless, there will usually be an opportu- maceutics, project planning, toxicology, regulatory nity to gain some management experience and affairs, logistics, quality control engineering, skills and to look at the therapeutic enterprise biostatistics, pharmacogenomics, clinical trials, from a different angle: Appropriate scepticism politics, economics, public relations, teaching, with regard to the wanted and unwanted effects pharmacovigilance, marketing, finance, technical of drugs, and the ways they may be properly and writing, data automation, actuarial analysis, infor- improperly promoted, is best learned inside the mation science, publishing, public health, interna- industry and applied outside it. ‘Clinical re-entry’ tional aid and development, intellectual property after two or three years of pharmaceutical medicine and other types of laws. However, this is not an will not be associated with being out of date in exhaustive list. Surely, there can be no other indus- terms of knowledge and skills base, although re- try with as many diverse professionals as this one entry after 10 years almost certainly will. Those where all have the welfare of other human beings as attempting the latter should anticipate the need for their ultimate concern? And for those with a life- re-training. long thirst to learn on a cross-disciplinary basis, this breadth of intellectual interaction is a magnet. Conversance with, if not advanced capability in, these specialties should therefore be an early goal 1.1 Organizations and of any career in pharmaceutical medicine. Those educational systems who remain in the industry thereafter usually value their initial generalist experience. But eventually, Most countries in the developed world have one or for most practitioners, the opportunity will exist more national societies or academies devoted to the either to remain as a generalist in pharmaceutical specialty of pharmaceutical medicine. All hold medicine or to sub-specialize within one or more education and training as central to their mission, areas in the list shown above. whereas some societies will engage in regulatory But, perhaps the greatest difference between this or political debates when particular issues arise. specialty and all other specialties is the value The first formal post-graduate qualification to placed on versatility, adaptability, communication acquire in pharmaceutical medicine is a Diploma skills and teamwork. Physicians and pharmacists in Pharmaceutical Medicine (DipPharmMed). It must learn that in pharmaceutical medicine, they requires two years of part-time study and tests the are unlikely to be as predominant as decision knowledge basis for the specialty. This diploma has makers as they were in clinical practice. Those been examined by the Royal Colleges of Physi- who can become an expert in some subject and cians (RCP) in the United Kingdom for more than be respected for it by people both inside and outside 30 years, and its possession qualifies the holder for the company, even though they may never have membership in the Faculty of Pharmaceutical heard of that particular disease or drug before three Medicine (MFPM). The Belgian Academy has months ago, will do well if they can match such more recently introduced a diploma which is knowledge with superior inter-personal skills. recognized reciprocally with that in the United Knowing when to lead, when to follow and when Kingdom, and accordingly, there is periodic to get out of the way, rather than presuming a exchange of examiners. Switzerland is likely to leadership role in all situations, will always be be the next, and progress toward an analogous valued in this specialty. goal (‘Board certification’) is being made in Finally, what about those who do not stay in the North America. At least two years’ experience in speciality? Any clinician who spends just two or clinical medicine and prescribing is a matriculating three years in pharmaceutical medicine but then qualification for these diplomas; in countries where returns to his or her clinical calling, will have the roles of pharmacists, physician’s assistants and benefited, if only having learned something about nurses include prescribing responsibility, these
  19. 19. FURTHER READING 5 professionals should enquire from the relevant have to be well informed about the diversity of Academy or Royal College whether they may formal recognitions that may be held by those also sit this examination. who can contribute to the industry and its regula- Beyond the diploma, the European Economic tion. Area (the European Union plus Iceland, Norway Lastly, is there any evidence for all this opti- and Liechtenstein) will probably soon recognize mism? In the year 2000, the American Academy of pharmaceutical medicine as a medical specialty on Pharmaceutical Physicians (AAPP) polled its the official list and national medical registers. members on their career choices and factors asso- Achieving the Certificate of Specialized Training ciated with satisfaction. More than 90% of the (CSST) will require completion of a modular, part- members indicated overall satisfaction with their time program of Higher Medical Training (HMT) choice of pharmaceutical medicine. This propor- for which the diploma will be the matriculating tion was higher than any other that has been qualification. Whether or not holding the CSST, it reported by learned societies from similar surveys will also become possible to revalidate specifically in other medical sub-specialties in the United as a pharmaceutical physician. States. International compatibility and recognition of these qualifications would seem essential in a pro- fession whose activities are being increasingly globalized. Many employment opportunities in Further reading pharmaceutical medicine are with companies that have become international conglomerates. Intra- Fox AW. 2001. What is pharmaceutical medicine? Clin. Res. 1: 28–30. company transfers and international job applica- Smethurst D. 2004. Pharmaceutical medicine: making tions can only be facilitated by universally the leap. Student BMJ 12: 45–58 (see also http:// recognized and accredited qualifications. www.studentbmj.com/issues/04/02/careers/66.php, Many other qualifications are also of benefit in accessed 28 July 2005). pharmaceutical medicine, even if the holder was Stonier PD (ed.). 2003. Careers with the Pharmaceu- already a physician, nurse or pharmacist. These tical Industry, 2nd edition. John Wiley & Sons, Ltd: will be more or less specific to that long list given Chichester (ISBN 0-470-84328-4). above, many of which have their own diplomas and Useful web sites on careers and/or qualifications university degrees. Human resources departments (http://): www.fpm.org; www.acrp.org.
  20. 20. 2 Pharmaceutical Medicine as a Medical Specialty Michael D. Young and Peter D. Stonier Medicine is an art that has been practiced since to an era of focused treatments, after aeons of using time immemorial. The use of herbs and natural homespun remedies and then watching hopefully medicaments to relieve pain or to aid the sick in for the crisis or the fever to pass, has accompanied coping with their afflictions has been a part of all the recent revolutions in the understanding of bio- societies. In the Western world, medicine has logical processes and in technical and biotechnical developed at least since the time of the Greeks capabilities. These developments have allowed us and Romans – the Hippocratic oath reminds us of to produce pure therapeutic agents and establish this nearly 2500-year history. However, the pro- their safe and effective use. gress of medicine has been very different from that The exponential growth in scientific knowledge, of many other arts within society. It has come of age particularly over the last 100 years, has brought after an incredibly long maturation period. As a about a paradigm shift in our approach to pharma- function capable of offering a successful treatment ceuticals. Until the twentieth century, the sale and for a human ailment, medicine is very much a use of medicines and medical devices was almost development of the last 100–150 years. Indeed, entirely unregulated by governments. It was a case the major advances have come in the last 50–75 of caveat emptor, with only the drug taker’s com- years. mon sense to protect against the dangers of the so- The role of physicians in society has changed called patent medicines and ‘snake oils’. The over the centuries. It may have reached its nadir obvious abuses in these situations eventually led during the early renaissance, when the general to government intervention, professional regula- attitude was, as Shakespeare said, ‘Trust not the tion and requirements that drugs be pure and una- physician; his antidotes are poison’. From nine- dulterated. With advances in science and in the teenth century onwards, with their growing diag- ability to define and establish drug efficacy came nostic understanding and their therapeutic agents a requirement to demonstrate that drugs were also becoming increasingly effective, physicians have safe. Finally, as late as the second half of the come to be increasingly valued. Today, much of the twentieth century, came the legal requirement to practice of medicine in all of its subspecialities is establish that pharmaceuticals were effective based on a physician’s diagnosis and treatment before they were marketed. These legal require- with drugs, devices or surgery. This radical change ments reflected changes in social attitudes and Principles and Practice of Pharmaceutical Medicine, 2nd Edition Edited by L. D. Edwards, A. J. Fletcher, A. W. Fox and P. D. Stonier # 2007 John Wiley & Sons, Ltd ISBN: 978-0-470-09313-9
  21. 21. 8 CH2 PHARMACEUTICAL MEDICINE AS A MEDICAL SPECIALTY Relative influences (%) expectations grounded in the questions that the development of biological and basic sciences had Science made it possible to ask and to answer. The response Providers to these changes has led to the development of the Patients speciality of pharmaceutical medicine. Pharmaceutical medicine can be defined as ‘the 1970s 1980s 1990s 2000s discipline of medicine that is devoted to the dis- covery, research, development, and support of ethi- Figure 2.1 The influencers of healthcare provision cal promotion and safe use of pharmaceuticals, vaccines, medical devices, and diagnostics’ (by- laws of the Academy of Pharmaceutical Physicians healthcare has been unable to meet the demands of and Investigators, APPI). Pharmaceutical medi- unbridled development. This has made the payer/ cine covers all medically active agents from neu- provider a major determiner of the use of pharma- traceuticals, through cosmeceuticals and over-the- ceuticals. All possible treatments cannot be freely counter (OTC) pharmaceuticals, to prescription available to all and a cost-to-benefit consideration drugs. Furthermore, the speciality is not confined has to be introduced. This, in turn, has ensured that to those physicians working within what is classi- pharmaceutical medicine involves pharmacoeco- cally considered the pharmaceutical industry but nomics training and even media training to deal includes those involved in the clinical management with what, for some, may be seen as the rationing or regulation of all healthcare products. It is the and/or the means-testing of access to the totality of basic speciality for physicians within the cosmetics healthcare options. These are significant ethical and nutrition industry for those in the device indus- and social issues, and physicians within the phar- try and for those in ‘not-for-profit’ companies, such maceutical industry or the health regulatory agen- as those responsible for the national blood supplies cies will inevitably be required to provide a and/or for specialized blood products. Further- perspective, both internally and to those outside. more, it is the fundamental discipline for physi- The second new decision maker in the provision cians who are in government health ministries, of healthcare has arrived even more recently as a insurance companies, National Health Trusts or crucial component. These are the end-user or HMO management, drug regulatory agencies or patient groups. The rising status of the physician any other oversight or regulatory function for since the nineteenth century has encouraged a healthcare. paternalistic doctor–patient relationship, with the In the early part of this quarter-century, for a physician clearly in the lead. In recent times, the medicine to be adopted and to sell, it was sufficient nature of this relationship has come under question. that science could conceive of a new treatment, that The advent of holistic medical concepts focused on technology could deliver that treatment, and that the whole patient, and taking into account the clinical research could prove it effective and safe entirety of an individual patient’s life has forced for the physician to use. This is no longer the case. changes in the focusing of any therapeutic interac- Over the past three decades, we have seen the tion. The general increase in educational standards emergence of two major influences in decisions within the developed world and the massive about new advances in healthcare. These are the increase in available information culminating payer–providers and the patient–consumers. Their today with the electronic media and the Internet role in the decision-making process has increased has inevitably produced a more informed patient. rapidly in the last 25 years, as can be seen in This has empowered the patient and led to the Figure 2.1. formation of all kinds of public interest and patient With an increasing proportion of society’s groups. Furthermore, the ability in this century to healthcare budget spent on pharmaceuticals, even think in terms of the maintenance of good health a growth in the percentage of the gross national and even of the abolition of disease (e.g. smallpox product that governments are willing to allocate to and polio) has changed the patient’s and society’s
  22. 22. CH2 PHARMACEUTICAL MEDICINE AS A MEDICAL SPECIALTY 9 attitudes to what they can and should expect of Table 2.1 Controlling factors in the adoption physicians. Today, we are very much moving of new therapeutic agents towards a balance in the therapeutic interaction, Influences Controllers/‘gatekeepers’ if not to a patient–doctor relationship. This change is a seminal one for the delivery of healthcare and Medical science Regulatory agencies for the development of new therapeutic agents. Physicians Health professionals For prescription drugs, the major factor bringing Healthcare providers Politicians about the involvement of patient groups was prob- National health ably the revolution in the new drug evaluation services/HMOs process caused by the AIDS epidemic. This terrible Insurance companies affliction occurred at a time when groups within Consumers Patient groups society were forming to fight for their recognition Pharmacists and/or rights quite independent of the occurrence Media of a life-threatening disease. Nonetheless, within the Western world, it is clear that these groups rapidly came to form a vanguard for patients rights progress, pharmaceutical medicine involves the with respect to AIDS. They challenged the patern- combination of the following: first, the medical alism within medicine and insisted on access and sciences to evaluate disease; second, the economic full disclosure of what was going on in pharma- sciences to evaluate the value with respect to costs; ceutical medicine and within academic medical and third, the ethical and social sciences to evaluate politics. Without this openness such patients the utility of any new drug to patients and to society would have lost confidence in pharmaceutical as a whole. companies, the academia and the medical and As with all products, truly successful therapeutic regulatory establishments. Having forced a re- agents are those that meet all the customers’ needs. evaluation and a greater respect for patients’ In today’s and tomorrow’s world, the concept that needs, AIDS Coalition to Unleash Power all that is needed is for medicines to meet the (ACTUP) and others have brought patient repre- scientific requirements of being effective and safe sentatives into the drug development process. Such is essentially an anachronism. It is not just the educated and involved patients have, in their turn, scientific factors and customers that must be satis- come to understand the scientific methodology and fied. Table 2.1 shows that the two other critical the requirement for the adequate testing of new factors or influences outlined in Figure 2.1 produce drugs. Indeed, the requirements have consequently many more customers to be served. become much more acceptable to patients in gen- As members of the public become generally eral. Nevertheless, there is no doubt that these more and more informed, it is inevitable that they proactive patient representative groups have for- will want to take more of a role in deciding on their ever changed the role of the patient in the develop- own health and how any disease that they might ment of therapeutics and of healthcare within have is to be treated. It is important to realize that society. this is likely to change the demand for healthcare. Pharmaceutical medicine is the discipline that Some of the focus will shift to areas not classically specializes within medicine in overseeing the pro- considered as diseases or to health areas considered cess of developing new therapeutics to improve the today as an inevitability of life or a condition for standard of health and the quality of life within which the patient should ‘just take charge’. Typical society. Inevitably, then, it was one of the first examples will be, on the one hand, an increased medical specialities to feel this change in patients’ focus on the quality of life or on the effects of view of the quality of their care. An integral part ageing (such as cognitive dysfunction, menopause, of all progress in healthcare is evaluating the osteoporosis and waning immunological function, needs of patients and society and the gaps in the with consequent increase in vulnerability to dis- present provisions for those needs. To oversee this ease), and, on the other hand, disorders such as