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Principles and Practice of Pharmaceutical Medicine Edited by Andrew J Fletcher, Lionel D Edwards, Anthony W Fox, Peter Sto...
Principles and Practice of Pharmaceutical Medicine Edited by Andrew J Fletcher, Lionel D Edwards, Anthony W Fox, Peter Sto...
Principles and Practice of Pharmaceutical Medicine Edited by Andrew J Fletcher, Lionel D Edwards, Anthony W Fox, Peter Sto...
Principles and Practice of Pharmaceutical Medicine Edited by Andrew J Fletcher, Lionel D Edwards, Anthony W Fox, Peter Sto...
vi                                                              CONTENTSSection IV: Applied Aspects of Drug               ...
CONTENTS                                                                       vii35   Publishing Clinical Studies . . . ....
Principles and Practice of Pharmaceutical Medicine Edited by Andrew J Fletcher, Lionel D Edwards, Anthony W Fox, Peter Sto...
x                                      ABOUT THE EDITORSpharmaceutical medicine at Kings College,         marketing and ca...
Principles and Practice of Pharmaceutical Medicine Edited by Andrew J Fletcher, Lionel D Edwards, Anthony W Fox, Peter Sto...
xii                                      LIST OF CONTRIBUTORSPapaluca, Amati M. EMEA, London, UK                   Turner,...
Principles and Practice of Pharmaceutical Medicine Edited by Andrew J Fletcher, Lionel D Edwards, Anthony W Fox, Peter Sto...
Principles and Practice of Pharmaceutical Medicine Edited by Andrew J Fletcher, Lionel D Edwards, Anthony W Fox, Peter Sto...
532                                                        INDEXcase-control study designs 224             clinical protoc...
INDEX                                                     533  choice of contract 512±13             diagnostic procedures...
534                                                        INDEXdrug screening process 41±2                essential hyper...
INDEX                                                           535  examples 444                             Good Clinica...
536                                                            INDEXintegrated summary 61, 63                        drug ...
INDEX                                                       537Misuse of Drugs                                drug researc...
538                                                         INDEXpatient compliance (cont.)                    definition ...
INDEX                                                         539population extrapolation and ethnic           Proprietary...
540                                                      INDEXsafety parameters 21                     special study desig...
INDEX                                                         541   non-clinical 55±64                        Orphan Drug ...
Principles and practice of pharmaceutical medicine (wiley)
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Principles and practice of pharmaceutical medicine (wiley)
Principles and practice of pharmaceutical medicine (wiley)
Principles and practice of pharmaceutical medicine (wiley)
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Transcript of "Principles and practice of pharmaceutical medicine (wiley)"

  1. 1. Principles and Practice of Pharmaceutical Medicine Edited by Andrew J Fletcher, Lionel D Edwards, Anthony W Fox, Peter Stonier Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-98655-0 (Hardback); 0-470-84629-1 (Electronic) Principles and Practice of Pharmaceutical Medicine
  2. 2. Principles and Practice of Pharmaceutical Medicine Edited by Andrew J Fletcher, Lionel D Edwards, Anthony W Fox, Peter Stonier Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-98655-0 (Hardback); 0-470-84629-1 (Electronic)Principles and Practice ofPharmaceutical Medicine Andrew J Fletcher Temple University, Pennsylvania, USA Lionel D Edwards Novartis and Pharma Pro Plus Inc, New Jersey, USA Anthony W Fox EBD Group Inc, Carlsbad, California, USA Peter Stonier Consultant in Pharmaceutical Medicine, Surrey, UK
  3. 3. Principles and Practice of Pharmaceutical Medicine Edited by Andrew J Fletcher, Lionel D Edwards, Anthony W Fox, Peter Stonier Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-98655-0 (Hardback); 0-470-84629-1 (Electronic)Copyright # 2002 by John Wiley & Sons, Ltd., Baffins Lane, Chichester, West Sussex PO19 1UD, UK National 01243 779777 International (‡44) 1243 779777 e-mail (for orders and customer service enquiries): cs-books@wiley.co.uk Visit our Home Page on: http://www.wiley.co.uk or http://www.wiley.comAll Rights Reserved. No part of this publication may be reproduced, stored in a retrievalsystem, 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 Act1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham CourtRoad, London W1P 0LP, UK, without the permission in writing of the publisher.Other Wiley Editorial OfficesJohn Wiley & Sons, Inc., 605 Third Avenue,New York, NY 10158±0012, USAWILEY-VCH Verlag GmbH, Pappelallee 3,D-69469 Weinheim, GermanyJohn Wiley & Sons Australia, Ltd., 33 Park Road, Milton,Queensland 4064, AustraliaJohn Wiley & Sons (Asia) Pte, Ltd., 2 Clementi Loop #02±01,Jin Xing Distripark, Singapore 129809John Wiley & Sons (Canada), Ltd., 22 Worcester Road,Rexdale, Ontario M9W 1L1, CanadaLibrary of Congress Cataloging-in-Publication DataBritish Library Cataloguing in Publication DataA catalogue record for this book is available from the British LibraryISBN 0-471-98655-0Typeset in 10/11.5 pt Times from the authors disks by Kolam Information Services Pvt. Ltd., Pondicherry, IndiaPrinted and bound in Great Britain by Antony Rowe Ltd, ChippenhamThis 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. Principles and Practice of Pharmaceutical Medicine Edited by Andrew J Fletcher, Lionel D Edwards, Anthony W Fox, Peter Stonier Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-98655-0 (Hardback); 0-470-84629-1 (Electronic) ContentsAbout the Editors . . . . . . . . . . . . . . . . . . . . . . . . ix 8 Good Clinical Practices . . . . . . . . . . . . . . . 69 Wendy Bohaychuk and Graham BallList of Contributors . . . . . . . . . . . . . . . . . . . . . . xiPreface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii 9 Quality Assurance, Quality Control and Audit . . . . . . . . . . . . . . . . . . . . . . . . . . 85Section I: Overview of Donna Cullen Pharmaceutical Medicine 10 Phase I: The First Opportunity for 1 Pharmaceutical Medicine as a Medical Extrapolation from Animal Data Speciality . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 to Human Experience . . . . . . . . . . . . . . . . 95 Michael D. Young Stephen Curry, Dennis McCarthy, Heleen H. DeCory Matthew Marler 2 What Pharmaceutical Medicine Is and and Johan Gabrielsson Who Does It . . . . . . . . . . . . . . . . . . . . . . . . 13 W. Wardell and Susan Toland 11 Phase II and Phase III Clinical and Anthony W. Fox Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 Anthony W. Fox 3 Competency-based Training System for Clinical Research Staff . . . . . . . . . . . . . . . 17 12 Phase IV Drug Development: Jay D. Miller Post-marketing Studies . . . . . . . . . . . . . . 133 Lisa R. Johnson-PrattSection II: Drug Discovery and Development 13 Over-the-counter Medicines . . . . . . . . . . 141 Paul Starkey Introduction . . . . . . . . . . . . . . . . . . . . . . . . 30 Lionel D. Edwards and Section III: Special Populations Anthony W. Fox Introduction . . . . . . . . . . . . . . . . . . . . . . . 154 4 Drug Discovery: Design and Lionel D. Edwards Serendipity . . . . . . . . . . . . . . . . . . . . . . . . . 31 Leslie J. Molony 14 Drug Research in Older Patients . . . . . . 157 5 Pharmaceutics . . . . . . . . . . . . . . . . . . . . . . 45 Lionel D. Edwards Anthony W. Fox 15 Drug Development Research 6 Non-clinical Toxicology . . . . . . . . . . . . . . 55 in Women . . . . . . . . . . . . . . . . . . . . . . . . . 165 Frederick Reno Lionel D. Edwards 7 Informed Consent . . . . . . . . . . . . . . . . . . . . 65 16 Clinical Research in Children . . . . . . . . . 183 Anthony W. Fox Lionel D. Edwards
  5. 5. vi CONTENTSSection IV: Applied Aspects of Drug 26 Emergency and Compassionate-use INDs and Accelerated NDA or ANDA Development ApprovalsÐProcedures, Benefits Introduction . . . . . . . . . . . . . . . . . . . . . . . 190 and Pitfalls . . . . . . . . . . . . . . . . . . . . . . . . 299 Anthony W. Fox Anthony W. Fox17 Biotechnology Products and Their 27 Japanese Regulations . . . . . . . . . . . . . . . 307 Development . . . . . . . . . . . . . . . . . . . . . . 191  Etienne Labbe David Shapiro and Anthony W. Fox 28 The Development of Human Medicines Control in Europe from Classical18 Orphan Drugs . . . . . . . . . . . . . . . . . . . . . 203 Times to the Year 2000 . . . . . . . . . . . . . . 325 Bert Spilker John Griffin19 Pharmacoeconomics: Economic 29 Ethnic Issues in Drug Registration . . . . 347 and Humanistic Outcomes . . . . . . . . . . . 211 Lionel D. Edwards, J.M. Husson Raymond J. Townsend, Jane  A. Kumagai, E. Labbe, C. Naito, T. Osterhaus and M. Papaluca, S. Walker, R. Williams J. Gregory Boyer M. Weintraub and H. Yasurhara20 Pharmacoepidemiology and the Pharmaceutical Physician . . . . . . . . . . . 223 Section VI: Medical Services Hugh Tilson Introduction . . . . . . . . . . . . . . . . . . . . . . . 36421 Statistical Principles and Their Anthony W. Fox Application in Biopharmaceutical Research . . . . . . . . . . . . . . . . . . . . . . . . . . 231 30 An Introduction to Medical Affairs . . . . 365 Dan Anbar Gill Price22 Data Management . . . . . . . . . . . . . . . . . 259 31 Drug Labeling . . . . . . . . . . . . . . . . . . . . . 371 T.Y. Lee and Michael Minor Anthony W. Fox23 Patient Compliance . . . . . . . . . . . . . . . . . 269 32 Organizing and Planning Local,  Jean-Michel Metry Regional, National and International Meetings and Conferences . . . . . . . . . . . 37524 Complementary Medicines . . . . . . . . . . . 281 Zofia E. Dziewanowska, Anthony W. Fox Linda Packard and Lionel D. EdwardsSection V: Drug Registration 33 Drug Surveillance . . . . . . . . . . . . . . . . . . 379 Howard J. Dreskin and Introduction . . . . . . . . . . . . . . . . . . . . . . . 288 Win M. Castle Anthony W. Fox 34 Disease ManagementÐWhat Does25 United States Regulations . . . . . . . . . . . 289 It Mean? . . . . . . . . . . . . . . . . . . . . . . . . . . 389 William Kennedy Roy Lilley
  6. 6. CONTENTS vii35 Publishing Clinical Studies . . . . . . . . . . . 403 40 Outsourcing Clinical Drug Anthony W. Fox Development Activities to Contract Research Organizations (CROs): Critical Success Factors . . . . . . . . . . . . . 461Section VII: Legal and Ethical John R. Vogel Aspects 41 The Third World . . . . . . . . . . . . . . . . . . . 483 Introduction . . . . . . . . . . . . . . . . . . . . . . . 414 Gamal Hammad Sara Croft and Tim Pratt 42 Financial Aspects of Clinical Trials . . . . 50136 Pharmaceutical Product Liability . . . . . 421 R. Graham Hughes and Han W. Choi and N. Turner Howard B. Yeon 43 The Impact of Managed Care on37 Patents . . . . . . . . . . . . . . . . . . . . . . . . . . . 431 the US Pharmaceutical Industry . . . . . . . 513 Gabriel Lopez Robert Chaponis, Christine Hanson-Divers and38 Fraud and Misconduct in Marilyn J. Wells Clinical Research . . . . . . . . . . . . . . . . . . . 441 Frank Wells AppendixÐUseful Internet Links . . . . . . . . . . 529 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531Section VIII: Business Aspects39 The Multinational Corporations: Cultural Challenges, the Legal/Regulatory Framework and the Medico-commercial Environment . . . . . . . . . . . . . . . . . . . . . . . 453 R. Drucker and R. Graham Hughes
  7. 7. Principles and Practice of Pharmaceutical Medicine Edited by Andrew J Fletcher, Lionel D Edwards, Anthony W Fox, Peter Stonier Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-98655-0 (Hardback); 0-470-84629-1 (Electronic) About the EditorsANDREW J. FLETCHER, MB, BChir, (Cantab), the efficacy subcommittee Topic 5 (AcceptabilityMS (Columbia), FFPM, DipPharmMedRCP, is of Foreign Clinical Data) of the InternationalSenior Assistant Editor of The Merck Manuals, Committee on Harmonization (ICH).Merck & Co. Inc. and Adjunct Professor of He is a Fellow of the Faculty of PharmaceuticalPharmaceutical Health Care at Temple University Medicine and an Adjunct Professor at Temple Uni-School of Pharmacy. He graduated from Cam- versity Graduate School of Pharmacology. He hasbridge University and St. Bartholomews Hospital, taught `Drug Development for PERI for over tenLondon, briefly trained in Neurosurgery, joined years and is on the teaching faculty of the NationalCIBA-GEIGY in the UK as Medical Advisor, Association of Physicians. He is a founder memberthen European Medical Director, for Syntex, then of the American Academy of Pharmaceutical Phys-joined Merck, first in the international division after icians.graduating in business from Columbia University,New York City, he joined the Merck Manual as ANTHONY (`Tony) W. FOX, BSc, MBBS,Assistant Editor. He teaches pharmaceutical medi- FFPM, MD (Lond), DipPharmMedRCP, CBiol,cine, bioethics, and medical and scientific writing at FIBiol, is President of EBD Group, San Diego.Temple Universitys School of Pharmacy. He is a From The Royal London Hospital, after generalfounder member and ex-trustee of the American clinical training he was Rotary InternationalAcademy of Pharmaceutical Physicians. Fellow at Emory University (Atlanta), and CIBA- Geigy Fellow at Harvard. Industrial positions atLIONEL D. EDWARDS, MB, BS, LRCP, MRCS, Procter and Gamble and Glaxo came next. He wasDip RCOG and FFPM., is President of Pharma Pro then Vice-President of a small pharmaceutical com-Plus Inc., a drug development consulting company pany. Among many societies, Tony is Charterand Director Medical Affairs Novartis USA. Previ- Member, Trustee, and Education VP of the Ameri-ously, he was Vice President of Clinical Research at can Academy of Pharmaceutical Physicians. Publi-Bio-Technology Pharmaceutical Corporation, a cations span several areas of pharmaceuticalsmall Biotech firm making a profit with operations medicine, e.g., regulation, pharmacology, clinicalin the US and International marketplaces. Prior to trials, pharmacovigilance, analgesics, migraine,this he worked at Noven, Inc., a small Skin Patch genotoxicology, and metabolism. He has fourTechnology firm with large internationally licensed patents, and five journals use his reviews.partnersÐCiba and Rhone Poulenc Rorer. He wasAssistant Vice-President, International Clinical Re- PETER D. STONIER, BA, BSc, PhD, MBChB,search at Hoffman-La Roche, and Senior Director MRCPsych, FRCP, FRCPE, FFPM has 24 yearsof Schering-Plough International Research, and experience in pharmaceutical medicine. He wasDirector of US Domestic Gastrointestinal, Hormo- Medical and Board Director of the UK Hoechstnal and OTC Research Departments. Dr. Edwards Group of companies until he became a consultanthas been involved in all aspects of clinical trials over in 2000. He is immediate past-President of the Fac-the years on many different research drug devices in ulty of Pharmaceutical Medicine of the Royal10 therapeutic areas. Colleges of Physicians UK. Formerly he was Presi- He served as Chairman of the PMA Special dent of the International Federation of Associ-Population committee for 5 years, also he was on ations of Pharmaceutical Physicians andthe Institute of Medicine Committee for Research Chairman of the British Association of Pharma-in Women, sponsored by the NIH. He served on ceutical Physicians. He is Visiting Professor in
  8. 8. x ABOUT THE EDITORSpharmaceutical medicine at Kings College, marketing and careers in the pharmaceuticalLondon and at the University of Surrey, which industry. He is a graduate of Manchester Medi-under his direction introduced the first MSc cal School, qualifying in 1974, following a BScdegree in Pharmaceutical Medicine in 1993. His degree in physiology and a PhD in proteinpublications include edited works in human psy- chemistry.chopharmacology, clinical research, medical
  9. 9. Principles and Practice of Pharmaceutical Medicine Edited by Andrew J Fletcher, Lionel D Edwards, Anthony W Fox, Peter Stonier Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-98655-0 (Hardback); 0-470-84629-1 (Electronic) List of ContributorsAnbar, Dan Millennium Biostatistics Inc., Bound Hanson Divers, Christine US Scientific InitiativesBrook, NJ, USA and Customer Support, Health Economics and Outcomes Research, AstraZeneca, Apex, NC, USABohaychuk, Wendy Good Clinical Research Prac-tices Consultants, Lakehurst, Ontario, Canada Hammad, G. Watford, UKBoyer, Gregory J. Pharmacia Corporation, Stokie, Hughes, Graham R. Technomark ConsultingIllinois, USA Services, London, UKCastle, Win M. Glaxo Smithkline, Philadelphia, Husson, J.M. Paris, FrancePA, USA Johnson-Pratt, Lisa R. Merck & Co. Inc., NorthChaponis, Robert J. Global Medical Affairs, Phar- Wales, PA, USAmacia Corporation, Peapack, NJ, USA Kennedy, William Consultant Delaware, USAChoi, Han W. former V.P. Regulation AffairsCroft, Sara Shook, Hardy and Bacon, MNP Â Labbe, Etienne Sanofi-Synthelabo, Paris, FranceLondon, UK Lee, T.Y. ACER/EXCEL Inc., USACullen, Donna Auditrial, Fairlawn, NJ, USA Lilley, Roy Independent Health Analyst, formerCurry, Stephen H. President Stephen H. Curry, NHS Trust Chairman, Camberley, Surrey, UKConsulting, Professor of Pharmacology and Physi- Linda, Packaid La Jolla, CA, USAology, University of Rochester, NY, USA Lopez, Gabriel Basking Ridge, NJ, USADeCory, Heleen H. Astra Arcus USA Inc., Ro-chester, USA Marler, Matthew Astra Arcus USA Inc., Roches-Dreskin, Howard J. Glaxo SmithKline Phila- ter, USAdelphia, PA, USA McCarthy, Dennis J. Drug Metabolism and Phar-Drucker, R. Technomark Consulting Services, macokinetics, AstraZeneca Pharmaceuticals LP,London, UK Wilmington, Delaware, USADziewanowska, Zofia La Jolla, CA, USA Â Metry, Jean-Michel AARDEX Ltd, Zug, Switzer- landEdwards, Lionel D. Novartis, East Hanover, USA Miller, Jay D. Amgen Inc., Thousand Oaks, Cali-Fox, Anthony W. EBD Group Inc, 6120 Paseo fornia, USAdel Norte, Suites 52±L2, Carlsbad CA 92009, USA Minor, Michael ACER/EXCEL Inc., USAGabrielsson, Johan Pharmacokinetics and Phar-macodynamics Section, AstraZeneca R+D Soderta- Molony, Leslie J. Biotechnology Business Strat-lie, Sweden egies, Pleasant Hill, CA, USAGraham, Ball Good Clinical Research Practices Naito, C. Teikyo University, JapanConsultants, Lakehurst, Ontario, Canada Ostechaus, Jane T. Wasateh Health Outcomes,Griffin, John P. Quartermans, Welwyn, UK Park City, Utah, USA
  10. 10. xii LIST OF CONTRIBUTORSPapaluca, Amati M. EMEA, London, UK Turner, Nadia AstraZeneca, Macclesfield, Chesh- ire, UKPratt, Timothy Shook, Hardy and Bacon LLP,Kansas City, USA Vogel, John R. John R. Vogel Associates, Kihei, HI, USAPrice, Gill VP MedImmune Inc., USA Walker, S. Centre of Medicine Research, Carshal-Reno, Frederick Merritt Island, FL, USA ton, UKSpilker, Bert Pharmaceutical Research and Wardell, William Wardell Associates Inter-Manufacturers of America, 1100 fifteenth street national LLC, Princeton, NJ, USANW, Washington DC 20005, USA Wells, Frank Medicolegal Investigations Ltd, Ips-Starkey, Paul Former Vice President Smithkline wich, UKBeecham Consumer Healthcare, Morris Plains, NJ,USA Wells, Marilyn J. Department of Health, Physical Education, and Recreation, Hampton University,Shapiro, David Scripps Clinic, La Jolla, CA, USA Virginia, USATilson, Hugh H. University of North Carolina Williams, R. US Pharmacopia, Rockville, USASchool of Public Health, Chapel Hill, NC, USA Yasurhara, H. Teikyo University, JapanToland, Susan Wardell Associates International,LLC Princeton, NJ, USA Yeon, Howard B.Townsend, Raymond J. Wasatch Health Out- Young, Michael D. Strategic Healthcare Develop-comes, Park city, Utah, USA ment, Wayne, PA, USA
  11. 11. Principles and Practice of Pharmaceutical Medicine Edited by Andrew J Fletcher, Lionel D Edwards, Anthony W Fox, Peter Stonier Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-98655-0 (Hardback); 0-470-84629-1 (Electronic) PrefacePharmaceutical medicine is a relatively new, As editors, we would like to thank our contribu-but rapidly growing, academic discipline in the tors for their expertise, their dedication, and theirUSA. The American Academy of Pharmaceutical vision. We would like to thank and acknowledgePhysicians (AAPP) was founded in 1993 and the work and counsel of our colleague Robert Bell,hosted, in 1999, a meeting of the International MD, MRPharmS, who helped us greatly during theFederation of Associations of Pharmaceutical early part of this project. We would also like toPhysicians (IFAPP). The birth of AAPP coincided thank and acknowledge the enormous help, en-with many ongoing changes in the pharmaceutical couragement, and patience of the team at Johnindustry in the USA, as health care delivery began Wiley & Sons, Inc., UK, with whom we haveto move more towards managed care, and large worked closely over these past few years, amongcorporations began to amalgamate and downsize. whom we have particularly stressed (!) MichaelAs these trends continue into the 21st century, Davis, Deborah Reece, Hannah Bradley, Lewispharmaceutical physicians are increasingly regard- Derrick, and Hilary Rowe.ing consultancy work and contract research organ- Lastly, we would like to thank our families, andization (CRO) affiliation as good career oppor- friends, who have withstood the frequent telephonetunities, and now recognize the need for continuing calls, e-mails, and meetings, often late into theeducation and training in this broad spectrum dis- night. Indeed, to all who made this project possible,cipline. both authors and non-authors, we thank you. We This textbook, which represents a collaborative are certain that this specialty, and our patients,effort of international experts, is dedicated to the even though we may help them vicariously, willmore than 3,500 pharmaceutical physicians and all benefit because of your contributions.the other professionals working in the US pharma-ceutical industry and allied fields. It is also Andrew Fletcherintended to be useful for those outside the USA Lionel Edwardsbecause the basic tenets of the specialty have, for a Tony Foxlong time, become global. Peter Stonier
  12. 12. Principles and Practice of Pharmaceutical Medicine Edited by Andrew J Fletcher, Lionel D Edwards, Anthony W Fox, Peter Stonier Copyright # 2002 John Wiley & Sons, Ltd ISBNs: 0-471-98655-0 (Hardback); 0-470-84629-1 (Electronic) Indexabbreviated new drug application safety data 316 biopharmaceutical research 231±47 (ANDA) 304±5 antibodies 195 biotechnology 441accelerated approvals 302±5 antisense drugs 196±7 biotechnology companies 191acute toxicity animal studies 58 anxiety neurosis 174 biotechnology industryadditives 355 archiving 79±80 impact 10adeno-associated viruses 197 area under the concentration time curve patents 200±1adenosine deaminase (ADA) 198 (AUC) 47, 48, 60, 63, 101, 351 biotechnology products 191±201adverse drug experiences (ADEs) Armitage technique 126 classes 193±8 handling 25±6 arthritis 161 clinical trials issues 193±8adverse drug reactions (ADRs) 367, ascending dose-ranging cohort definition 191 371, 374, 381, 382, 384, 386 design 123 ethical issues 199 database 387 aspirin 158 industry statistics 200 in children 386 Association of British Pharmaceutical informed consent 200 reporting 337±8, 387, 492 Industries (ABPI) 335, 420, 445 manufacturing issues 193adverse events (AEs) 74, 77, 384 ATP 41 regulatory considerations 192, 199 gender differences 174 audiovisual presentations 410±11 safety issues 198±9 reporting, ethnic effects 356±7 audit document 263, 266 sales by market segment 200age differences 355 audit result 267 types 191agency laws audit sheet 263, 266 vs. conventional drug products Middle East 493 audit summary 263 192aging population audits 90±2 Black Cohosh 283 impact on society 157±8 future trends 92±3 blastocyst 170agonist±antagonists 105 autonomy concept 65 blinding (or masking) 81, 236±7Agouron Pharmaceuticals, Inc. 42 blocking 239AIDS 4, 183, 197, 357 B. subtilis 34 blood pressure 161AIDS-associated infective retinitis 52 Bacille Calmet±Guerrin vaccine British Association for LungAIDS Coalition to Unleash Power (BCG) 196 Research 49 (ACTUP) 5 baseline burden of illness 215±16 British Association of Pharmaceuticalalcohol effects 354 basic chemical or structural research 6 Physicians (BrAPP) 13allometric scaling 101±2, 104 Bayesian trial designs 129±30 British Medical Association (BMA)Alzheimers disease 158, 161±2, 525 Bendectin 444 332American Academy of Pharmaceutical benefit±risk analysis 131±2 British Pharmacopoeia 332 Physicians 13, 15 benefit±risk evaluation 383 Budapest Treaty on the InternationalAmerican College of Epidemiology benzocaine 50 Recognition of the Deposit of (ACE) 226 benzodiazepines 111, 174 Micro-organisms for the PurposesAmerican Heart Association 166 bias 236±7, 239 of Patent Procedure 439analgesic effect-time data 108 concepts 118 budgets see financial aspectsanalysis of variance model defences against 119 Bugbane 283 (ANOVA) 242 in clinical trials 118 bulking agents 47angina in women 166 sources 124angiotensin-converting enzyme (ACE) binders 47 C. elegans 34 inhibitors 167, 193, 386 binomial model 241 calcitonin gene-related peptideanimal±human extrapolation 95±115 bioequivalence studies 48 (CGRP) 194animal pharmacokinetics 316±17 biologic licence application (BLA) 19, calendar displays 272animal pharmacology 316 20, 25, 27, 28 Cancer Act 1939 333animal species 57 biological products 457 cancersanimal studies 121 history 191 childhood 183 acute toxicity 58 Biological Standards Act 1975 334 Candida albicans 51 in vitro and in vivo 96 biological therapeutics 43 carcinogenicity studies 62±3 prediction to humans in vivo 101± 4 biomolecular technology 8 cardiac fatigue 357
  13. 13. 532 INDEXcase-control study designs 224 clinical protocols see protocols competency-based trainingcase report data and databases 26 clinical research program 17±28case report forms see CRFs competencies associated with 23±6 competitor intelligence (CI) 369±76causality 233 competencies associated with information source available 370 assessment 385 planning 19 complementary medicines 281±6 determination 384 GCP-compliant 69±70 commonly used 282±5CBER (Center for Biologicals standards 443 miscellaneous 285 Evaluation and Research) 290, 297, clinical research and development plans regulatory aspects 285 457 (CRDPs) 19, 22 terminology 281±2CDER (Center for Drug Evalutaiton clinical research fraud 443 complementary therapies 282 and Research) 297±8, 457 clinical studies adverse effects 285cell-based assays 41 design 19±20 compliance see patient compliancecell products 199 reports 27±8 composite hypothesis 232cellular mechanisms of disease 32 setting up 70±2 computer-assisted design (CAD) ofcenter effect 249±50 sites 71±2 drugs 42±3Center for Biologics Evaluations and clinical trial certificate (CTC) 336, 344 computer-assisted NDAs Research see CBER clinical trials (CANDAs) 63, 169, 298Center for Disease Control and analysis 256±7 conferences Prevention (CDC) 161 basic designs and factors suited and organization and planning 377±80Central and Eatern Europe (CEE) unsuited 123 confidence 245±7 459 controls on conduct 336 confidence intervals 245±7central nervous system drugs 174 enrolment criteria 382 confidence level 246Central Pharmaceutical Affairs Council exemption (CTX) 95, 336, 344, 458, confidence limits 246 (CPAC) 309 460 confirmatory experiments 231Centre for Medicines Research historical 119±20 consent forms 448 (CMR) 353, 358 limitations 120±1 Consumer Protection Act of 1987 424chemical diversity 42 monitoring 24 contemporaneous independentchemical libraries 39 regulations 317±18 treatment allocation 126±7childbearing population 177±8 regulatory governance of 121 contract investigational sites (CISs) 461,children reporting 256±7 462 ADRs in 386 sample size 381±2 contract law 416±18, 423, 424 clinical research 183±8 see also financial aspects; publishing contract research organizations pharmacokinetic studies 186 clinical trials (CROs) 91±2, 463±84 pharmacological action of drugs 386 clinicians contributory negligence 426 see also pediactric studies role in industry 14 ±15 controlled clinical trial (CCT) 235±9China see Peoples Republic of China Clostridium welchii 333 controlling factors in adoption of newchlordiazepoxide 173 clotting factors 109±10 therapeutic agents 5Chondroitin 283±4 vitamin K-dependent 110 copyright 433chronic lymphocytic leukemias 199 Cochrane Collaboration 281 in publishing clinical trials 412±13chronic toxicity studies 61 Code of Federal Regulations (CFR) 457 corporate culture 456±7chronology diagrams 272 codes of practice 420 cost-containment strategies 525cimetidine 203 cogenital abnormalities 167 cost-effectiveness 369Cimicifuga racemosa 283 Color Additives Amendments 86 cost-to-benefit consideration 4CIOMS I 382±3 combinatorial chemistry 39, 40, 43 costs see financial aspectsCIOMS II 382±3 Commission for Health Improvement coumadin 158CIOMS IV 383 (CHImp) 392 Council for International Organizationscivil law 416±18 Committee for Orphan Medical of Medical Sciencesclass A drugs 339 Products (COMP) 209±10 (CIOMS) 382±3class B drugs 339 Committee for Proprietary Medicinal Cox II inhibitors 161class C drugs 339 Products (CPMP) 209, 340, 341, CRFs 24, 25, 71, 256, 259clinical competencies 18±23 345, 458 cover sheet 262clinical data coordinator (CDC) 260 common technical document (CTD) 345 design of format and content 21±2clinical development 6, 317 communication to prescribers and image review process 262clinical development plan 55±6, 121 patients 388 managing 26clinical investigators comparative superiority trials 134 preparation 260 identification and selection 22±3 compassionate use 301±2 criminal law 416 sources 23 competencies associated with clinical crisis management 9clinical±legal interface 137 research 23±6 critical research organizations see CROsclinical/marketing interface 138 competency-based education and CROsclinical outcomes 212, 213 training system (CBETS) 17±18 capability 471
  14. 14. INDEX 533 choice of contract 512±13 diagnostic procedures 243 drug assessment process compatibility 473 diazepam 51, 173 role of 361 critical success steps 466±83 diet 355 drug case studies 353±4 early warnings 483 diethylstilbestrol (DES) 429±30 drug clearance financial aspects 509±13 diets elementary aspects 96±7 financial stability 511±12 high-or low-fat 355 prediction of human 97±9 frequent causes of problems 465±6 differential diagnosis 143 drug constituents 45±6 identifying problems 483 direct-to-consumer advertising (DTCA) drug delivery targeting 46 instructions to bidders 474 ±5 campaigns 256, 523 drug development 7 leveraging experience 473±4 disaster recovery plan 266±7 epidemiology 226±7 modern view 464 disclaimers 425±6 legal/regulatory framework 457±61 obtaining and comparing bids 510±11 disease procedures 315±20 pharmaceutical industry views 463±4 cellular mechanisms of 32 process 18 prequalifying 473 in vivo models of 36 regulations, Japan 311 proposals from 474 ±9 disease management (DM) 391±406 regulations governing 19 responsibilities 481 areas on concern 393±4 role of 361 roles 464, 481 benefits to health service specific guidelines 315 selection criteria 471±4 providers 396±7 drug differences strategies for using 464 benefits to patients 395±7 influences on 354±5 traditional view 463±4 benefits to pharmaceutical drug discovery 7 see also sponsor±CRO companies 397 allometric approaches 102±4cross-over experiments 239 company requirements 404±5 design and serendipity 31±44cross-over studies 124 ±5 contractual framework 392 process 38cultural challenges 455±7 definition 391, 392 project design 31cultural responsiveness 457 effectiveness 398±9 drug evaluation 4CYP2C19 351 guidelines and protocols 392 drug formulations 45±52, 56CYP2D6 351 implementation in practice 402±4 choice 46cytokines 32±3, 195±6 ineffectiveness 399±400 pediatric studies 186cytomegalovirus retinitis 197 key issues 403 safety and efficacy trials 136 overview 391±3 drug holidays 273±4Dalcon shield 9 patient perspectives 404 Drug Information Association (DIA) 18data analysis 254±6 politics and history 393±4 drug interactions 137data collection 119 prospective companies 404 adverse 158 statisticians role 256 relationship with pharmaceutical potential for 382 with integrity 78 industry 394±5 drug labeling 373±6, 386data confidence 217 staffing 403 European Union (EU) 376data creation flow chart 261 disease-modifying drugs (DMDs) 31 investigational drugs 25data entry 262 disproving liability 169 Japan 373±4data integrity assurance 78±9 Dixon up±down technique 125 USA 374±5data management 259±67 DNA 33, 35±6, 52, 195, 197, 351 drug licensing 227±9 project material 259 DNA viruses 197 drug managementdata package 359±60 donezil 161 training 9data process status 263 dosage drug metabolism 60data processing 260±6 pediatric studies 185±6 drug monitoring see drug surveillance;data provision dosage formulations 136, 137 safety monitoring pediatric studies 185 dosage selection drug registration 227±9data validity 217 OTC 144 ethnic issues in 349±63database release memorandum 266, 267 dose determination 57 future 362database update 262 dose-response date 359 medical practice 355±6datasets 263 dose±response relationship 254 subjective factors 355±8Debendox 444 dose ranges terminology, diagnosis and otherdecision-making 4, 211, 213±14 gender differences 172 subjective factors 357±8Declaration of Helsinki 65, 86 dose size 121 drug requirementsDedrick plot 104 double-blind 237, 241 non-clinical studies 57demographics double-dummy method 237 drug research in older patients 157±64 elderly population 157 double entry 262 regulatory response 159Department of Health, Education and Downs syndrome 167 drug risk as epidemiologic problem Welfare (DHEW) 86±7 downsizing 388 225depression 161, 174 drop-outs 254±5 drug safety 9developed countries 157 drug accountability management 25 drug screening flowchart 39
  15. 15. 534 INDEXdrug screening process 41±2 essential hypertension 353 243, 289±94, 298, 299, 358, 368, 370,drug surveillance 381±9 ethical issues 72±3 371, 374, 419, 420, 445, 457, 460 see also safety monitoring biotechnology products 199 audits 90±2drug utilization drug research in older background 85±7 elderly population 158 populations 158±9 economic considerations 294 restrictions 521 pediatric studies 187 meetings with 296drugs see investigational drugs; publishing clinical trials 407 organizational aspects 294±5 investigational new drug ethics committee 56, 72±5 FDA Modernization Act application (IND) and specific financial aspects 507 (FDAMA) 184 drugs ethnic differences fee-for-service (FFS) health insuranceDurham±Humphrey pharmacokinetics/ policies 515±18 Amendment 1951 86, 370 pharmacodynamics 351±2 fees see financial aspects prescribing differences 352 female population see gender differences;E. coli 34 ethnic effects womenECU50u 105, 106 adverse event reporting fertility testing 170ECG 122 (ADRs) 356±7 fetal damage liabilities 178ECHO model 213 ethnic factors financial aspects 503±14economic outcomes 213 and population extrapolation 359 charges 506EDU50u 125 classification of intrinsic and clinical trial medication 507EEG 110±11, 122 extrinsic 360 consultancy 507effect-compartment model 107, 109 pharmacologic implications 354 CROs 509±13effect-distribution model 107 potential sensitivity to 359 equipment costs 508efficacy 21, 105 ethnic issues in drug registration 349±63 ethics committees 507 OTC 143±4 future 362 external costs 503 stopping a clinical trial 129 medical practice 355±6 institutional review boardsEgypt subjective factors 355±8 (IRBs) 507 pharmaceutical market 493±4 terminology, diagnosis and other internal costs 508±10 private pharmaceutical subjective factors 357±8 investigator fees 503±5 companies 494 ethnic susceptibility 352±3 laboratory charges 506elderly population Europe meetings 508 clinical studies 162 Orphan Drug legislation 209±10 multinational trials 508 compliance in 162 European Agency for the Evaluation of patient fees 507 demographics 157 Medicines (EMEA) 344, 346, 347 Phase III project 509 disease issues 161 European Federation Pharmaceutical price ratios for common research drug utilization 158 Association (EFFPA) 353 procedures 504 informed consent 162 European Medicines Evaluation Agency printing and copying 508 investigative sites 163 (EMEA) 70, 341±2, 376, 419 regulatory fees 507 medication regimens 162 European Patent Convention (EPC) 438 relative costs by country 505 recruitment 163 European Patent Office (EPO) 438 relative costs by therapeutic area screening 163 European Union (EU) 335, 336, 346±7, 504elimination rate 96±7 458, 459 travel 506±7ELISA (enzyme-linked Directives 339±41, 418±19, 424 Fine Chemical Database 40 immunoabsorbent assay) 40±1 drug labeling 376 Fine Chemical Directory 42embryonic malformation 166 future clinical trial legislation 344 Food and Drug Administrationembryonic stem cells 35 evergreening process 9 Modernization ActEmergency INDs 299±301 evolutionary designs 125 (FDAMA) 293±4enzymes 195 expectedness 384 Food and Drug Administration. SeeEphedra spp. 284 expert reports 63±4 FDAepidemiology 223±4 exploratory experiments 231 Food and Drug Agency (FDA) 49 drug development 226±7 expressed sequence tags (ESTs) 34 Food and Drugs Act 1906 370 drug registration and licensing 227±9 extrapyramidal reactions 173 Food, Drug and Cosmetic Act 85, 184, methodologies 224 291±2, 370, 419epidermal growth factor (EGF) FACS 37 formulary enforcement policies receptor 32 falsifiability condition 231, 232 521epilepsy Far East formulary status 137 outcomes 216 pharmaceutical market 495 fraud 443±51equipoise concept 65 registration dossier compilation 498 animal research 448equivalence trials 135 trading with 498 British cases 444±5error analysis 259 FDA 19, 27, 47, 58, 67, 85, 134, 145±7, definition 444error probabilities 232±3 149, 150, 160, 175, 192, 206, 212, detection 446±7
  16. 16. INDEX 535 examples 444 Good Clinical Practice (GCP) 17, 19, human genomic map 44 historical aspects 443±5 69±84, 349, 367, 443, 445±6, 25, 314 human medicines control 327 investigation 446±7 basic tenets 69 centralized procedure 341±2 literature 446 compliant clinical research 69±70 classical times to end of 18th prevention 445±6 general regulatory framework 69±70 century 327 prosecution 447 implementation 70 decentralized or mutual recognition recent cases 448 investigator responsibilities 72 procedure 343 sources of international guidelines/ 19th and 20th century to Medicinesgall bladder disease 387 regulations 82±4 Act 1968 332±4gases 48±9 good laboratory practice (GLP) 55, 57, recommendations 333gastric emptying time 314 humanistic outcomes 213 women 172 good manufacturing practice Hypericum perforatum 283Gauchers disease 194, 195, 198 (GMP) 314 hypertension 161gender data 165 principles and guidelines 338±9 hypothesis 232gender data collection 178 standards 338 testing 243gender differences 166, 170 Good post-marketing Surveillance adverse events 174 Practive (GPMSP) 315 ibuprofen 173 dose ranges 172 Guidance E5 359 ICh guidelines 57, 59, 62, 250 in drug handling 172±4 Guide to Clinical Trials 18 Â IL-1a 33 metabolism 173±4 Guideline on Drug Development in the imipramine 173 pharmaceutical industry Elderly 159 immigration 158 practice 175±6 Guidelines for the Study and Evaluation of immune adjuvants 196 weight-for-height tables 172 Gender Differences in the Clinical impurities and stability 56±7 see also women Evaluation of Drugs 170 incidence of a disease 208gender-related research 174±6 indomethacin 158gene therapy 43, 197±8 HU2u blockers 358 Indonesia pharmacokinetics 198 Haemophilus influenzae 34 clinical trials 501gene therapy agents harmonization of data requirements 345 health centres 501 pharmacokinetic properties 193 headache pharmaceutical industry 501±2General Agreement on Tariffs and diagnosis 142 inflammatory bowel disease 50 Trades (GATT) 440 health economics 212 information systems (IS) 397±8General Consideration for the Clinical health maintenance organizations information technology (IT) 397±8, 403, Evaluation of Drugs 174 (HMO) 516 527±8General Considerations for Clinical network model 517 informed consent 65±7, 73, 121 Trials 458 staff model 517 benefit±risk assessment 131General Medical Council (GMC) 445, Health Maintenance Organizations biotechnology products 200 447, 448 (HMO) Act 1973 516 children 66 disciplinary powers 450±1 health outcomes 212 elderly population 162general pharmacovigilance 228 healthcare 212 emergency patients 67 see also pharmacovigilance healthcare budget 4 essential elements 65±6generalizability 239±40, 249±50 healthcare provision 4 ethical basis 65generic drugs 304±5 heart attack in women 166 pediatric studies 187 scandal 9 heart disease in women 166 principles for conducting 75genetic counseling 170 heart failure 161 responsibility of parties to 67genetic susceptibility 352±3 height differences 355 substitute 67genetic variation 351 helium/oxygen mixtures 48 surrogate 66genomics and new target hepatic clearance unwritten 66 identification 34±5 comparison of predicted and written 65±6geriatric population see aging actual 99 inhalational toxicology 49 population; older patients equations 98 inhalers 49Gingko biloba 283 herpes simplex virus 1 (HSV1) 197 initial clinical studies 55ginseng 284 hexachlorophene toxicity 9 initial non-clinical considerations 56±7Glasgow Coma Score 67 Hill factor 106 initial proof of principle 56global utilization of streptokinase and HIV 196 injectates 51 t-PA for occluded coronary arteries homeopathic drugs 285 innovation in pharmaceutics 52 (GUSTO) 135 homeopathy 282 in situ studies 35glomerular filtration rates (GFR) 185 homogeneity 240 institutional review boards (IRBs) 56,glucosamine/chondroitin hormones 195 67, 89, 459, 461, 507 combinations 283±4 horseradish peroxidase (HRP) 41 pediatric studies 187Goldenthal guidelines 62 Human Genome Project 34 review 72±5
  17. 17. 536 INDEXintegrated summary 61, 63 drug labeling 373±4 multiple player influence 522±3integrated summary of efficacy regulations 307 population and demographics 524±5 (ISE) 257 Japanese health authorities 307±10 terminology 516integrated summary of safety (ISS) 257 Japanese pharmaceutical laws managed care organizationintellectual property rights 433±4 310±11 (MCO) 516±28intent-to-treat (ITT) analysis 255±6 types or models 516±17interference practice 440±1 Kaplan±Meier analysis 128 marketing approval application 343±4interim analysis 253±4 Kava 284 maximum outsourcing 465interim efficacy analyses 129 Kefauver±Harris Act 192 MCA 342International Clearing House for Birth Kefauver±Harris Drug Meat Inspection Act 290 Defects Monitoring 179 Amendements 1962 86, 184, 292, Med-DRA (Medical Dictionary forInternational Conference on 371 Regulatory Activities) 385 Harmonization (ICH) 13, 17, 55, Medicaid 158, 461, 522 57, 59, 62, 87, 159±60, 243, 250, 345, labeling see drug labeling medical affairs 367±72 349, 358, 383±4, 387, 458, 462, 463 labeling of investigational products 22, organization 367±71International Federation of Associations 25 overview 367 of Pharmaceutical Physicians laboratory charges 506 personnel 368 (IFAPP) 13±14 large, automated, multipurpose, phaseline 371international regulatory guidelines for population-based systems medical communications 368 safety pharmacology studies 61 (LAMPS) 225±7 medical culture 456, 457International Society for large, simple study 127±8 medical loss ratio (MLRs) 518±19 Pharmacoepidemiology (ISPE) last-observation-carried-forward medical science liaisons 367 226 method 255 Medicare 158, 461, 492, 522international treaties 437±40 law of contract see contract law Medicare Prospective Payment SystemInternet 4 law of tort 416±18 (PPS) 516interpretation of measurements 119 LDU50u 58 medications and devicesintranasal administration 50 legal framework for regulating control at study sites 80±1investigational drugs pharmaceutical products 418±20 management 80 labeling of 25 legal principles 416 overall accountability 81 packaging of 25 legal/regulatory framework for drug preparation 80investigational new drug application development 457±61 shipment 80 (IND) 48, 56, 87, 95, 128, 146, 292, licensing in 388 medicines 295±6, 419, 459, 460 licensing of new medicines 335±7 establishing differences among 208 see also emergency INDs; treatment licensing out 388 Medicines Act 1968 335, 336, 339, 344, INDs licensing requirements 130 418investigational products life-threatening diseases 302±4 medico-commercial environment 461±2 labeling of 22, 25 linear models 242 meetings packaging of 22 link-model 107±9 audiovisual presentations 410±11investigators linkage analysis 34 megatrials 135 choosing 138 lipophilic drugs 172 melatonin 46 fees 503±5 liposomes 197 menstrual cycle responsibilities 72 lithium 173 standardizing for 171 selection 71±2 log-in 260±2 Merck Index 46investigators brochure (IB) lubricants 47 meta-analysis 257 new clinical data 21 lyophilizates 51 metabolism preparation 20 differences in 386in vitro assay development 37±43 Malaysia gender differences 173±4 primary vs. secondary screens 37±9 product registration 499±500 methaqualone 173 technological considerations 37 trading with 498±500 metronidazole 50 throughput and assay cycles 40±1 managed care 515±29 Michaelis±Menten equation 106in vitro data collection 95 basic concepts 515 Middle East 492±5in vitro functional assays 95 cost containment strategies 520±2 agency laws 493in vitro/in vivo prediction 96±101 emerging trends 527±8 company registrationin vivo data 110 historical perspectives 515±18 requirements 494±5in vivo models of disease 36 impact on pharmaceutical pharmaceutical and healthcarein vivo studies 35 industry 519±27 market 492±3 impact on pharmaceutical product life migraine syndrome 118Japan cycle 526 minimization trials 125±7 clinical fees 506 key principles 518±19 misconduct 443±51 drug development regulations 311 market competition 523±4 missing data 255
  18. 18. INDEX 537Misuse of Drugs drug research in 157±64 Phase IV studies 147 Regulations 1985 339±40 regulatory response 159 prescription-to-OTC switch 146±9Misuse of Drugs Regulations open-label trials 135 proposed labeling 148 Act 1971 339 Oraflex 9 safety evaluation 143model parameters 242 oral bioavailability special study designs 149±50molecular modeling 40 elementary aspects 100 specific clinical testing 145±6molecular target identification 32±3 prediction 101 tolerability 143monitoring 73±6 oral contraceptives 173, 177, 387 unique characteristics 144±6 objectives 77 oral formulations over-the-counter (OTC)More Secret Remedies 333 optimal design features 47 pharmaceuticals 3mRNA 34 oral suspensions 46±8 oxazepam 173multicenter trials 248±50 oral transmucosal administration 50 oxygen/nitrous oxide 48multinational corporations 455±62 organ transplantation 199 languages 457 orphan disease 203 p-value 243±5multiplicity 251±3 Orphan Drug Act 203, 207±8, 293 P450 cytochrome enzyme systems 351mutagenicity studies 59±60 unintended consequences 208 packaging 51±2mutagenicity testing 170 Orphan Drug legislation of investigational drugs 25mutations 36 Asian countries 210 of investigational products 22Mycoplasma genetalium 34 Europe 209±10 package insert 322 USA 209 Palmito caroliniensis 283National Committee for Quality orphan drugs 203, 312 paraldehyde 50 Assurance (NCQA) 519 benefits from development parallel-group studies 122±3National Heart and Lung Blood perspective 207 Paris Convention for the Protection of Institute (NHLBI) 163 classification 204 Industrial Property 1883 437±8National Health Insurance Drug Price defintion 203 Parkinsons disease 161 List 322 development 206 partial agonists 105National Institute for Clinical Excellence development disincentives and patent application 441±2 (NICE) 392 obstacles 207 Patent Cooperation Treatynational reimbursement policies 357 discovery 206 (PCT) 438±40, 442nausea 150 distribution 206 international phase 439nebulized drugs 49±50 economic±medical interface 204±5 national phase 439negligence 417±18, 425 heterogeneous group 203 patent protection 435new biological entities (NBEs) 336 interested parties 205 patentable subject matter 435±6new chemical entities (NCEs) 42, 55, marketing 206 patents 433±42 159, 336 marketing benefits in selling 206±7 biotechnology industry 200±1new drug applications (NDAs) 45, 63±4, principles 203±4 criteria for obtaining 436±7 92, 117, 131, 175, 208, 214, 292, regulatory processes 204 history 434±5 296±7, 303, 304, 313, 460 specific sources of information 206 role of 434 content 320 osteoarthritis 161 patient compliance 269±79new drug approval process 320±3 outcomes actions to enhance 274±5new medicines research 528 classification 273 sponsors of 361 three-dimensional assessment common patterns 273New Medicines in Women 177 212±13 cost-effectiveness 277new molecular entities (NMEs) 159, 184 see also pharmacoeconomics and definition 269±70new uses for old drugs 43 specific areas direct compliance evaluation 270NHS and pharmaceutical outsourcing 464±5 during clinical trials 270±2 companies 394±5 over-the-counter (OTC) 351 full compliance 273nitrous oxide/oxygen 48 over-the-counter (OTC) medication 5, improving 275noise and noise reduction 234, 243, 249 141±51, 289 in elderly population 162non-clinical summary documents 61 advertising and marketing 150±1 indirect compliance evaluation 270non-clinical toxicology 55±64 criteria for use 142 interactive packaging 276±7non-compliance see patient non- development cycle 145 methods of evaluating 270 compliance dosage selection 144 monitoring with feedback 275Normal distribution 245 efficacy 143±4 non-compliance 273NSAIDS 158, 161, 358 labeling 149±50 over-compliance 273null hypothesis 232 market 148 partial compliance 273Nuremberg Code 86 market support studies 150±1 Phase I clinical studies 271 marketing 145 Phase II clinical studies 271Office of Research Integrity (ORI) 445 pharmaceutical physicians role Phase III clinical studies 271±2older patients in 144±6 Phase IV clinical studies 272
  19. 19. 538 INDEXpatient compliance (cont.) definition 3 patient compliance 271 potential players involved in real-time function 5 regulatory practice 350 compliance 275±6 industrial roles 14±15 representative female reports 272±3 medical specialty 3±11, 13 population 171±2 standards for analyzing real-time role of 13 toxicological support 57±61 compliance data 272 sub-specializations 14 women 171±2 timing non-compliance 274 pharmaceutical products Phase II clinical studies 56, 58, 112, 113,patient compliance/satisfaction 136±7 legal framework for 117±32, 458, 462patient±consumers 4 regulating 418±20 common designs 122patient fees 507±8 pharmaceutical research and industry practice 170Patient Management Strategies 398 development 525±6 objectives and prerequisites 121±5patient needs 5 Pharmaceutical Research and patient compliance 271patient non-compliance 254 Manufacturers of America pharmacoeconomics 214patient package insert 138 (PhRMA) 160, 183 regulatory practice 350patient participation 124 pharmacoeconomic outcomes small-scale 130patient rights 4 current and future uses 219±20 toxicological support 61±3payer±providers 4 pharmacoeconomic research 528 Phase III clincal studies 58, 117±32,pediatric studies 183±8 pharmacoeconomic trials 248±9, 354, 458, 462 data provision 185 Phase IV 138 Phase III clinical studies dosing 185±6 pharmacoeconomics 369 common designs 122 drug formulations 186 baseline burden of illness 215±16 financial aspects 509 ethical concerns 187 economic and humanistic patient compliance 271±2 final rules 184±5 outcomes 211±21 pharmacoeconomics 214 informed consent 187 in development programs 213±14 regulatory practice 350 IRBs 187 information demands 213 toxicological support 61±3 physiological variations 185 outcomes research 211±12 Phase IV clinical studies 117±39 placebo control 188 Phase II studies 214 goals and tactics 133 recruitment 186±7 Phase III studies 214 investigators 138 toxicology 186 reporting and publications 218±19 objectives 133 vulnerability 187 studies within clinical trials 216±18 OTC 147pentamidine 219 traditional clinical development patient compliance 272Peoples Republic of China 486±92 programme 214±15 pharmacoeconomic trials 138 clinical trials 486±7 pharmacoepidemiology 223±30 practical aspects and problems 134 procedures 490±2 definitions 226 safety surveillance 136 pharmaceutical joint ventures 487 future 229±30 searching for new indications 136 requirements for authorization of training 229 tactical aspects 137±8 clinical trials 487±90 pharmacognosy 42±3, 282 types 133±5peptides 194 pharmacokinetic parameters 59, 243 Philippinesperformance metrics 481±2 pharmacokinetic properties 121 clinical trials 500±1perpherazine 351 pharmacokinetic studies 60 health care and pharmaceuticals 500pessary 51 children 186 regulatory affairs and registration 500Petasites hybridus 46 pharmacokinetic/pharmacodynamic Phiso-Hex (hexachlorophene) 9phantom fetus 167, 169 (PK/PD) model/computer- phocomelia 387Pharmaceutical Affairs Bureau generated feedback 112 Physicians Desk Reference 386 (PAB) 308±9 pharmacokinetic/pharmacodynamic physicochemical properties 46, 48pharmaceutical benefit manager (PK/PD) models 192, 198 physiological substance models 109 (PBM) 517, 518, 528 pharmacokinetic/pharmocodynamic physiological systems 35pharmaceutical companies 191 (PK/PD) models pivotal clinical trials 130Pharmaceutical Education and Research complex and time-dependent 106±10 placebo comparisons 194 Institute Inc. (PERI) 18 elementary aspects 104±5 placebo controlpharmaceutical industry single-compartment time- pediatric studies 188 basic cycle 6 independent 105±6 placebo effect 237, 241 individual or corporate pharmacophores 37±8 placebo treatment 123 responsibility 420±1 pharmacovigilance 228, 337±8, 371 plasma concentration 107 voluntary codes 420 and problems currently facing plasma determination 57Pharmaceutical Manufacturers industry 387±8 plasma kinetics 107 Association (PMA) 253 postmarketing surveillance 492 plasma protein binding 100 Commission on Drug Safety 368 Phase I clinical studies 56, 95±115, Pneumocystis carinii pneumonia 219pharmaceutical medicine 117±32, 458, 462 population demographics 350 coverage 3±5 industry practice 170 population derivation 265
  20. 20. INDEX 539population extrapolation and ethnic Proprietary Association of Great definition 203 factors 359 Britain 335 prevalence 203population inclusion and exclusion proprietary medicinal products RAS 32 criteria 239±41 controls of 340±4 receptor/ligand assays 40populations and subpopulations 386 prospective cohort epidemiologic receptor science 8postapproval activities 323±5 studies 224 receptors 32post-marketing adverse drug experiences protein chemistry 8 sensitivity 353 (AE) 370 protein pump inhibitor 358 recruitmentpost-marketing approval medical proteins pediatric studies 186±7 affairs 7 recombinant vs. natural 41 rectal administration 50 ±1post-marketing safety prothrombin complex activity re-evaluation system 324 ±5 surveillance 370±1 (PCA) 109±10 re-examination system 324post-marketing studies 133±9 protocols 21, 71, 121, 256, 259 regulatory compliance 425post-marketing surveillance studies 228 design and preparation 20 regulatory development 6postmarketing surveillance elements 20 regulatory governance organization 323±4 pseudoephidrine 158 clinical trials 121postural hypotension 357 publishing clinical trials 407±14 drug development 19potency 105 audiovisual presentations at academic regulatory issuespotential sensitivity to ethnic factors 359 meetings 410±11 biotechnology products 192, 199precision 245±7 CD-ROM vs. textbook 411 regulatory processespreclinical research and development 6 classic components in peer-reviewed orphan drugs 204preclinical studies 316 journal 409±10 regulatory strategy 56preferred provider organization copyright 412±13 renal perfusion 185 (PPO) 517 desirability of, and biases in 408±9 repeated-dose toxicity studies 58±9pregnancy 167±70, 177, 387 electronic facsimiles 411 reporting clinical studies 168±9 electronic journals 412 clinical research 27±8 contraindications 386 ethics 407 clinical trials 256±7 registries 228±9 isolated abstracts 410 criteria 384prescribing differences newer forms 411±12 patient compliance 272±3 ethnic differences 352 posters 410 reproduction studies 62Prescription Drug Users Fee Act Pure Food and Drug Act (PFDA) 290±1 request for proposal (RFP) 465, 474 (PDUFA) 293 research fraud 443prescription drugs 4, 5 quality assurance 87±8 resource allocations worksheet 475±9prescription-event monitoring imported drugs and medical devices retroviruses 197 (PEM) 228 (GMPI) 314 review of products on the marketPrescription Medicines Code of Practice sampling 259 pre-1971 337 Authority (PMCPA) 420 quality control 88±90 review process 321±2Prescription Only Medicines List rules 259 Revised Policy on Inclusion of Women of (POM) 339 quality of life (QOL) 217, 218 Childbearing Potential in Clinicalpress releases 412 quality protocols 21 Trials 175prestudy visits 23 quality standards 313±14 Reyes syndrome 9prevalence of a disease 208 quantitative interaction 249 rheumatoid arthritis 161prion-mediated disease 196 quantitative structure±activity routes of sale and supply 339±40probability 231, 234, 239 relationships (QSARs) 42 Royal College of Physicians (RCP) 11,proctitis 50 query resolution 262 13, 445product defects 425 quinidine 158 Rx-to-OTC switch 146±8product labeling see drug labelingproduct liability 137, 423±30 R&D 10 Saccharomyces cervisiae 34 international issues 426±7 expenditure 7, 8 safety assessment 57 landmark cases 427±30 process 6 safety committees 124 legal defenses 425±6 racial groups safety evaluation 55 principles of law 423±5 definitions 351 OTC 143product licence application (PLA) 117 random error 242 safety eventsproduct licences 45 randomization 81, 129, 235±7, 239 reporting and recording 76±8Product Licences of Right (PLRs) 337 randomized blocks 236 safety issues 9, 25product life cycles 526±7 randomized control trial (RCT) 217 biotechnology products 198±9pro-glidant 47 randomized controlled clinical trial stopping a clinical trial 128±9project setup 260 (RCCT) 241 safety measures 240project team formation 260 rare diseases safety monitoring 381propranolol 173 case reports 130 postmarketing 381±2
  21. 21. 540 INDEXsafety parameters 21 special study designs study specifications 466±71safety pharmacology 60 OTC 149±50 importance of accuracy 466 international regulatory guidelines specialized designs 128 preparation 471 61 spironolactone 161 worksheet 466±71safety reports sponsor roles and responsibilities study subjects preparing 27 479 information to be provided 75±6safety studies 360 sponsor±CRO subgroups 238safety surveillance communication/decision-making subspecializations in pharmaceutical Phase IV clinical trials 136 model 482 medicine 14St Johns Wort 283 end-of-study meeting 483 summary basis of approval (SBA) 323salt content 355 periodic oversight meetings 482±3 summary of product characteristicsSAM-e 284 problems 465±6 (SPC) 346sample size 247±8 relationship 479±83 suppositories 50Saudi Arabia study initiation meeting 482 surveillances studies healthcare structure 493 sponsors of new medicines 361 postmarketing 386±7Saw Palmetto 283 spontaneous case reports 384±5 syrups 46±8scan process 260±2 spontaneously arising phenotypic Systolic Hypertension in the Elderlyschedule 1 339 models 36 Person (SHEP) 163schedule 2 339 SRC 32schedule 3 339 stability and impurities 56±7 tablets 46±8schedule 4 339 stability studies 316 tactical outsourcing 464schedule 5 340 stability testing 52 target identification 38Scientific Committee on Medicinal standard deviation 242 methods 33±5 Products and Medical standard deviation (SD) 235, 237±8, molecular 32±3 Devices 344±5 243, 247, 248 target validation 36±7scientific experiment 231 standard error (SE) 243 teratogenic issues 167±9scientific meetings standard error of the mean (SEM) 235 teratogenicity 167 organization and planning 377±80 Standard Normal distribution 245 testing 170scientific method 231 standard operating procedures teratology studies 62scintillation proximity assay (SPA) 40 (SOPs) 87 test statistic 243Secret Remedies 332 statistical bias 236±7 Thailandseed protection 433 statistical inference 243±7 health care and pharmaceuticalselection bias 236±7 statistical method 231±2 industry 496±7selection of subjects 240±1 statistical model 241±3 thalidomide 56, 62, 167, 334±5, 371, 387,self-diagnosis 142 statistical power 232±3 427±9, 444self-medication 141±2 statistical principles 231±47 theophylline 50sequential analysis study design 126 statistical test 232±3 therapeutic coverage 272±3sequential cohort designs 123 statistical trial design 248±54 therapeutic index 143serious adverse event (SAE) overdesign 248 Therapeutic Substances Act procedures 24 statistics 118±19 (TSA) 333±4serious diseases 302±4 status reporting 263 Third World 158, 485±502signal 234 stopping a clinical trial overview 485signal-to-noise ratio 234, 240±1 efficacy issues 129 three-dimensional outcomesignal transduction enzymes 41 safety issues 128±9 assessment 212±13significance level 233 strata 238 time course of effect 105simple hypothesis 232 strategic outsourcing 465 tissue products 199Singapore stratification 127, 171, 237±9 TNF 32±3 health care and pharmaceutical strict liability 418, 423±4 topical drugs 50 industry 497±8 stroke 161 tort law 423, 424skewed dosing 274 structure±activity relationship (SAR) 8, toxic shock syndrome 9skipped dosing 274 42 toxicokinetic assays 57societal culture 455±7 Students t-distribution 244 toxicokinetic data 60societal development 6 Studies in Support of Special Populations: toxicokinetics 59socioeconomic influences 357 Geriatrics 159 toxicological coverage 121±2source data verification 78±9 study closure 26 toxicological supportSouth Korea study design Phase II and Phase III studies 61±3 health care and overdesign 248 pre-IND and Phase I clinical pharmaceuticals 495±6 sample size 247±8 studies 57±61special populations 137 study documentation 23±4 toxicological testing 46special studies 63 study initiation 23±4 toxicology
  22. 22. INDEX 541 non-clinical 55±64 Orphan Drug legislation 209 Waxman±Hatch Amendment 293 pediatric studies 186 regulations 289±98 weight differences 355trade secrets 433 weight-for-height tables for males andtrademarks 433 vaccines 196 females 172training vaginal administration 51 wellness management 400±2 drug management 9 validation 119 wholesale dealers licences 339 pharmacoepidemiology 229 value-added clinical development within-patient dose titration designstraining program program 214±15 124 competency-based 17±28 variability womentransdermal drugs 50 source of 233±5 disease presentatons 166±7transgenic technology 35±6 variables measured before and after drug drug development researchtreatment-by-center interaction 249 (or placebo) administration 119 165±81Treatment INDs 301±2 variance 234 drug research subjects 176treatment withdrawal study designs 128 Venereal Disease Act 1917 333 gastric emptying time 172Trichomonas 51 vitamin K-dependent clotting in clinical studies 56Tylenol 9 factors 110 Phase I studies 171±2type A and B reactions 384±5 volumes of distribution representative population 167, 177type I and II errors 118, 232, 233, 242, elementary concepts 100 response to medications 166 244 prediction of human 100 see also gender differences volunteer studies 171 World Intellectual Propertyuncertainty vulnerability Organization (WIPO) 438, 439 source of 233±5 pediatric studies 187 Written Opinion 439uncertainty conditions 231±2unmet clinical needs 31 wafers 46±8 Zollinger±Ellison syndrome 203USA warfarin 109, 158 Zomax 9 drug labeling 374±5 warranty 424±5

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