Tài liệu Andrew j. fletcher, lionel d. edwards, anthony w. fox, peter d. stonier practice and principles of pharmaceutical medicine wiley (2002)

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 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 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 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): [email protected] Visit our Home Page on: http://www.wiley.co.uk or http://www.wiley.com All Rights Reserved. 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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) Contents About the Editors . . . . . . . . . . . . . . . . . . . . . . . . ix 8 Good Clinical Practices . . . . . . . . . . . . . . . 69 Wendy Bohaychuk and Graham Ball 9 Quality Assurance, Quality Control and Audit . . . . . . . . . . . . . . . . . . . . . . . . . . 85 Donna Cullen 10 Phase I: The First Opportunity for Extrapolation from Animal Data to Human Experience . . . . . . . . . . . . . . . . 95 Stephen Curry, Dennis McCarthy, Heleen H. DeCory Matthew Marler and Johan Gabrielsson List of Contributors . . . . . . . . . . . . . . . . . . . . . . xi Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii Section I: Overview of Pharmaceutical Medicine 1 Pharmaceutical Medicine as a Medical Speciality . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Michael D. Young 2 What Pharmaceutical Medicine Is and Who Does It . . . . . . . . . . . . . . . . . . . . . . . . 13 W. Wardell and Susan Toland and Anthony W. Fox 11 Competency-based Training System for Clinical Research Staff . . . . . . . . . . . . . . . 17 Jay D. Miller Phase II and Phase III Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 Anthony W. Fox 12 Phase IV Drug Development: Post-marketing Studies . . . . . . . . . . . . . . 133 Lisa R. Johnson-Pratt 13 Over-the-counter Medicines Paul Starkey 3 Section II: Drug Discovery and Development Introduction . . . . . . . . . . . . . . . . . . . . . . . . 30 Lionel D. Edwards and Anthony W. Fox 4 Drug Discovery: Design and Serendipity . . . . . . . . . . . . . . . . . . . . . . . . . 31 Leslie J. Molony 5 Pharmaceutics . . . . . . . . . . . . . . . . . . . . . . 45 Anthony W. Fox 6 Non-clinical Toxicology Frederick Reno 7 Informed Consent . . . . . . . . . . . . . . . . . . . . 65 Anthony W. Fox Section III: . . . . . . . . . . 141 Special Populations Introduction . . . . . . . . . . . . . . . . . . . . . . . 154 Lionel D. Edwards 14 Drug Research in Older Patients Lionel D. Edwards 15 Drug Development Research in Women . . . . . . . . . . . . . . . . . . . . . . . . . 165 Lionel D. Edwards 16 Clinical Research in Children . . . . . . . . . 183 Lionel D. Edwards . . . . . . . . . . . . . . 55 . . . . . . 157 vi CONTENTS Section IV: Applied Aspects of Drug Development 26 Emergency and Compassionate-use INDs and Accelerated NDA or ANDA ApprovalsÐProcedures, Benefits and Pitfalls . . . . . . . . . . . . . . . . . . . . . . . . 299 Anthony W. Fox 27 Japanese Regulations Etienne Labbe 28 The Development of Human Medicines Control in Europe from Classical Times to the Year 2000 . . . . . . . . . . . . . . 325 John Griffin 29 Ethnic Issues in Drug Registration . . . . 347 Lionel D. Edwards, J.M. Husson A. Kumagai, E. LabbeÂ, C. Naito, M. Papaluca, S. Walker, R. Williams M. Weintraub and H. Yasurhara Introduction . . . . . . . . . . . . . . . . . . . . . . . 190 Anthony W. Fox 17 Biotechnology Products and Their Development . . . . . . . . . . . . . . . . . . . . . . 191 David Shapiro and Anthony W. Fox 18 Orphan Drugs . . . . . . . . . . . . . . . . . . . . . 203 Bert Spilker 19 Pharmacoeconomics: Economic and Humanistic Outcomes . . . . . . . . . . . 211 Raymond J. Townsend, Jane T. Osterhaus and J. Gregory Boyer 20 Pharmacoepidemiology and the Pharmaceutical Physician . . . . . . . . . . . 223 Hugh Tilson 21 Statistical Principles and Their Application in Biopharmaceutical Research . . . . . . . . . . . . . . . . . . . . . . . . . . 231 Dan Anbar . . . . . . . . . . . . . . . 307 Section VI: Medical Services Introduction . . . . . . . . . . . . . . . . . . . . . . . 364 Anthony W. Fox 30 An Introduction to Medical Affairs . . . . 365 Gill Price 22 Data Management . . . . . . . . . . . . . . . . . 259 T.Y. Lee and Michael Minor 31 Drug Labeling . . . . . . . . . . . . . . . . . . . . . 371 Anthony W. Fox 23 Patient Compliance . . . . . . . . . . . . . . . . . 269 Jean-Michel MeÂtry 32 24 Complementary Medicines . . . . . . . . . . . 281 Anthony W. Fox Organizing and Planning Local, Regional, National and International Meetings and Conferences . . . . . . . . . . . 375 Zofia E. Dziewanowska, Linda Packard and Lionel D. Edwards 33 Drug Surveillance . . . . . . . . . . . . . . . . . . 379 Howard J. Dreskin and Win M. Castle 34 Disease ManagementÐWhat Does It Mean? . . . . . . . . . . . . . . . . . . . . . . . . . . 389 Roy Lilley Section V: Drug Registration Introduction . . . . . . . . . . . . . . . . . . . . . . . 288 Anthony W. Fox 25 United States Regulations William Kennedy . . . . . . . . . . . 289 CONTENTS 35 Publishing Clinical Studies . . . . . . . . . . . 403 Anthony W. Fox Section VII: Legal and Ethical Aspects Introduction . . . . . . . . . . . . . . . . . . . . . . . 414 Sara Croft and Tim Pratt 36 Pharmaceutical Product Liability Han W. Choi and Howard B. Yeon 37 Patents . . . . . . . . . . . . . . . . . . . . . . . . . . . 431 Gabriel Lopez 38 Fraud and Misconduct in Clinical Research . . . . . . . . . . . . . . . . . . . 441 Frank Wells Section VIII: 39 . . . . . 421 Business Aspects The Multinational Corporations: Cultural Challenges, the Legal/Regulatory Framework and the Medico-commercial Environment . . . . . . . . . . . . . . . . . . . . . . . 453 R. Drucker and R. Graham Hughes vii 40 Outsourcing Clinical Drug Development Activities to Contract Research Organizations (CROs): Critical Success Factors . . . . . . . . . . . . . 461 John R. Vogel 41 The Third World . . . . . . . . . . . . . . . . . . . 483 Gamal Hammad 42 Financial Aspects of Clinical Trials . . . . 501 R. Graham Hughes and N. Turner 43 The Impact of Managed Care on the US Pharmaceutical Industry . . . . . . . 513 Robert Chaponis, Christine Hanson-Divers and Marilyn J. Wells AppendixÐUseful Internet Links . . . . . . . . . . 529 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531 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 Editors ANDREW J. FLETCHER, MB, BChir, (Cantab), MS (Columbia), FFPM, DipPharmMedRCP, is Senior Assistant Editor of The Merck Manuals, Merck & Co. Inc. and 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, then joined Merck, first in the international division after graduating in business from Columbia University, New York City, he joined the Merck Manual as Assistant Editor. He teaches pharmaceutical medicine, bioethics, and medical and scientific writing at Temple University's School of Pharmacy. He is a founder member and ex-trustee of the American Academy of Pharmaceutical Physicians. LIONEL D. EDWARDS, MB, BS, LRCP, MRCS, Dip RCOG and FFPM., is President of Pharma Pro Plus Inc., a drug development consulting company and Director Medical Affairs Novartis USA. Previously, he was Vice President of Clinical Research at Bio-Technology Pharmaceutical Corporation, a small Biotech firm making a profit with operations in the US and International marketplaces. Prior to this he worked at Noven, Inc., a small Skin Patch Technology firm with large internationally licensed partnersÐCiba and Rhone Poulenc Rorer. He was Assistant Vice-President, International Clinical Research at Hoffman-La Roche, and Senior Director of Schering-Plough International Research, and Director of US Domestic Gastrointestinal, Hormonal and OTC Research Departments. Dr. Edwards has been involved in all aspects of clinical trials over the years on many different research drug devices in 10 therapeutic areas. He served as Chairman of the PMA Special Population committee for 5 years, also he was on the Institute of Medicine Committee for Research in Women, sponsored by the NIH. He served on the efficacy subcommittee Topic 5 (Acceptability of Foreign Clinical Data) of the International Committee on Harmonization (ICH). He is a Fellow of the Faculty of Pharmaceutical Medicine and an Adjunct Professor at Temple University Graduate School of Pharmacology. He has taught `Drug Development' for PERI for over ten years and is on the teaching faculty of the National Association of Physicians. He is a founder member of the American Academy of Pharmaceutical Physicians. ANTHONY (`Tony') W. FOX, BSc, MBBS, FFPM, MD (Lond), DipPharmMedRCP, CBiol, FIBiol, is President of EBD Group, San Diego. From The Royal London Hospital, after general clinical training he was Rotary International Fellow at Emory University (Atlanta), and CIBAGeigy Fellow at Harvard. Industrial positions at Procter and Gamble and Glaxo came next. He was then Vice-President of a small pharmaceutical company. Among many societies, Tony is Charter Member, Trustee, and Education VP of the American Academy of Pharmaceutical Physicians. Publications span several areas of pharmaceutical medicine, e.g., regulation, pharmacology, clinical trials, pharmacovigilance, analgesics, migraine, genotoxicology, and metabolism. He has four patents, and five journals use his reviews. PETER D. STONIER, BA, BSc, PhD, MBChB, MRCPsych, FRCP, FRCPE, FFPM has 24 years experience in pharmaceutical medicine. He was Medical and Board Director of the UK Hoechst Group of companies until he became a consultant in 2000. He is immediate past-President of the Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians UK. Formerly he was President of the International Federation of Associations of Pharmaceutical Physicians and Chairman of the British Association of Pharmaceutical Physicians. He is Visiting Professor in x ABOUT THE EDITORS pharmaceutical medicine at Kings College, London and at the University of Surrey, which under his direction introduced the first MSc degree in Pharmaceutical Medicine in 1993. His publications include edited works in human psychopharmacology, clinical research, medical marketing and careers in the pharmaceutical industry. He is a graduate of Manchester Medical School, qualifying in 1974, following a BSc degree in physiology and a PhD in protein chemistry. 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 Contributors Anbar, Dan Millennium Biostatistics Inc., Bound Brook, NJ, USA Bohaychuk, Wendy Good Clinical Research Practices Consultants, Lakehurst, Ontario, Canada Hanson Divers, Christine US Scientific Initiatives and Customer Support, Health Economics and Outcomes Research, AstraZeneca, Apex, NC, USA Hammad, G. Watford, UK Boyer, Gregory J. Pharmacia Corporation, Stokie, Illinois, USA Hughes, Graham R. Services, London, UK Castle, Win M. PA, USA Husson, J.M. Paris, France Glaxo Smithkline, Philadelphia, Chaponis, Robert J. Global Medical Affairs, Pharmacia Corporation, Peapack, NJ, USA Choi, Han W. Croft, Sara London, UK Shook, Hardy and Bacon, MNP Cullen, Donna Auditrial, Fairlawn, NJ, USA Curry, Stephen H. President Stephen H. Curry, Consulting, Professor of Pharmacology and Physiology, University of Rochester, NY, USA DeCory, Heleen H. chester, USA Astra Arcus USA Inc., Ro- Dreskin, Howard J. delphia, PA, USA Drucker, R. London, UK Glaxo SmithKline Phila- Technomark Consulting Services, Dziewanowska, Zofia Edwards, Lionel D. La Jolla, CA, USA Novartis, East Hanover, USA Fox, Anthony W. EBD Group Inc, 6120 Paseo del Norte, Suites 52±L2, Carlsbad CA 92009, USA Gabrielsson, Johan Pharmacokinetics and Pharmacodynamics Section, AstraZeneca R+D Sodertalie, Sweden Graham, Ball Good Clinical Research Practices Consultants, Lakehurst, Ontario, Canada Griffin, John P. Quartermans, Welwyn, UK Johnson-Pratt, Lisa R. Wales, PA, USA Technomark Consulting Merck & Co. Inc., North Kennedy, William Consultant Delaware, USA former V.P. Regulation Affairs Labbe, Etienne Lee, T.Y. Sanofi-Synthelabo, Paris, France ACER/EXCEL Inc., USA Lilley, Roy Independent Health Analyst, former NHS Trust Chairman, Camberley, Surrey, UK Linda, Packaid La Jolla, CA, USA Lopez, Gabriel Basking Ridge, NJ, USA Marler, Matthew ter, USA Astra Arcus USA Inc., Roches- McCarthy, Dennis J. Drug Metabolism and Pharmacokinetics, AstraZeneca Pharmaceuticals LP, Wilmington, Delaware, USA MeÂtry, Jean-Michel land Miller, Jay D. fornia, USA Minor, Michael AARDEX Ltd, Zug, Switzer- Amgen Inc., Thousand Oaks, CaliACER/EXCEL Inc., USA Molony, Leslie J. Biotechnology Business Strategies, Pleasant Hill, CA, USA Naito, C. Teikyo University, Japan Ostechaus, Jane T. Wasateh Health Outcomes, Park City, Utah, USA xii LIST OF CONTRIBUTORS Papaluca, Amati M. EMEA, London, UK Pratt, Timothy Shook, Hardy and Bacon LLP, Kansas City, USA Price, Gill VP MedImmune Inc., USA Reno, Frederick Merritt Island, FL, USA Spilker, Bert Pharmaceutical Research and Manufacturers of America, 1100 fifteenth street NW, Washington DC 20005, USA Starkey, Paul Former Vice President Smithkline Beecham Consumer Healthcare, Morris Plains, NJ, USA Shapiro, David Scripps Clinic, La Jolla, CA, USA Tilson, Hugh H. University of North Carolina School of Public Health, Chapel Hill, NC, USA Toland, Susan Wardell Associates International, LLC Princeton, NJ, USA Townsend, Raymond J. Wasatch Health Outcomes, Park city, Utah, USA Turner, Nadia ire, UK AstraZeneca, Macclesfield, Chesh- Vogel, John R. HI, USA John R. Vogel Associates, Kihei, Walker, S. Centre of Medicine Research, Carshalton, UK Wardell, William Wardell Associates national LLC, Princeton, NJ, USA Wells, Frank wich, UK Inter- Medicolegal Investigations Ltd, Ips- Wells, Marilyn J. Department of Health, Physical Education, and Recreation, Hampton University, Virginia, USA Williams, R. US Pharmacopia, Rockville, USA Yasurhara, H. Teikyo University, Japan Yeon, Howard B. Young, Michael D. Strategic Healthcare Development, Wayne, PA, USA 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) Preface Pharmaceutical medicine is a relatively new, but rapidly growing, academic discipline in the USA. The American Academy of Pharmaceutical Physicians (AAPP) was founded in 1993 and hosted, in 1999, a meeting of the International Federation of Associations of Pharmaceutical Physicians (IFAPP). The birth of AAPP coincided with many ongoing changes in the pharmaceutical industry in the USA, as health care delivery began to move more towards managed care, and large corporations began to amalgamate and downsize. 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. This textbook, which represents a collaborative effort of international experts, is dedicated to the more than 3,500 pharmaceutical physicians and all the other professionals working in the US pharmaceutical industry and allied fields. It is also intended to be useful for those outside the USA because the basic tenets of the specialty have, for a long time, become global. 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 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) Index abbreviated new drug application (ANDA) 304±5 accelerated approvals 302±5 acute toxicity animal studies 58 additives 355 adeno-associated viruses 197 adenosine deaminase (ADA) 198 adverse drug experiences (ADEs) handling 25±6 adverse drug reactions (ADRs) 367, 371, 374, 381, 382, 384, 386 database 387 in children 386 reporting 337±8, 387, 492 adverse events (AEs) 74, 77, 384 gender differences 174 reporting, ethnic effects 356±7 age differences 355 agency laws Middle East 493 aging population impact on society 157±8 agonist±antagonists 105 Agouron Pharmaceuticals, Inc. 42 AIDS 4, 183, 197, 357 AIDS-associated infective retinitis 52 AIDS Coalition to Unleash Power (ACTUP) 5 alcohol effects 354 allometric scaling 101±2, 104 Alzheimer's disease 158, 161±2, 525 American Academy of Pharmaceutical Physicians 13, 15 American College of Epidemiology (ACE) 226 American Heart Association 166 analgesic effect-time data 108 analysis of variance model (ANOVA) 242 angina in women 166 angiotensin-converting enzyme (ACE) inhibitors 167, 193, 386 animal±human extrapolation 95±115 animal pharmacokinetics 316±17 animal pharmacology 316 animal species 57 animal studies 121 acute toxicity 58 in vitro and in vivo 96 prediction to humans in vivo 101± 4 safety data 316 antibodies 195 antisense drugs 196±7 anxiety neurosis 174 archiving 79±80 area under the concentration time curve (AUC) 47, 48, 60, 63, 101, 351 Armitage technique 126 arthritis 161 ascending dose-ranging cohort design 123 aspirin 158 Association of British Pharmaceutical Industries (ABPI) 335, 420, 445 ATP 41 audiovisual presentations 410±11 audit document 263, 266 audit result 267 audit sheet 263, 266 audit summary 263 audits 90±2 future trends 92±3 autonomy concept 65 B. subtilis 34 Bacille Calmet±Guerrin vaccine (BCG) 196 baseline burden of illness 215±16 basic chemical or structural research 6 Bayesian trial designs 129±30 Bendectin 444 benefit±risk analysis 131±2 benefit±risk evaluation 383 benzocaine 50 benzodiazepines 111, 174 bias 236±7, 239 concepts 118 defences against 119 in clinical trials 118 sources 124 binders 47 binomial model 241 bioequivalence studies 48 biologic licence application (BLA) 19, 20, 25, 27, 28 biological products 457 history 191 Biological Standards Act 1975 334 biological therapeutics 43 biomolecular technology 8 biopharmaceutical research 231±47 biotechnology 441 biotechnology companies 191 biotechnology industry impact 10 patents 200±1 biotechnology products 191±201 classes 193±8 clinical trials issues 193±8 definition 191 ethical issues 199 industry statistics 200 informed consent 200 manufacturing issues 193 regulatory considerations 192, 199 safety issues 198±9 sales by market segment 200 types 191 vs. conventional drug products 192 Black Cohosh 283 blastocyst 170 blinding (or masking) 81, 236±7 blocking 239 blood pressure 161 British Association for Lung Research 49 British Association of Pharmaceutical Physicians (BrAPP) 13 British Medical Association (BMA) 332 British Pharmacopoeia 332 Budapest Treaty on the International Recognition of the Deposit of Micro-organisms for the Purposes of Patent Procedure 439 budgets see financial aspects Bugbane 283 bulking agents 47 C. elegans 34 calcitonin gene-related peptide (CGRP) 194 calendar displays 272 Cancer Act 1939 333 cancers childhood 183 Candida albicans 51 carcinogenicity studies 62±3 cardiac fatigue 357 532 case-control study designs 224 case report data and databases 26 case report forms see CRFs causality 233 assessment 385 determination 384 CBER (Center for Biologicals Evaluation and Research) 290, 297, 457 CDER (Center for Drug Evalutaiton and Research) 297±8, 457 cell-based assays 41 cell products 199 cellular mechanisms of disease 32 center effect 249±50 Center for Biologics Evaluations and Research see CBER Center for Disease Control and Prevention (CDC) 161 Central and Eatern Europe (CEE) 459 central nervous system drugs 174 Central Pharmaceutical Affairs Council (CPAC) 309 Centre for Medicines Research (CMR) 353, 358 chemical diversity 42 chemical libraries 39 childbearing population 177±8 children ADRs in 386 clinical research 183±8 pharmacokinetic studies 186 pharmacological action of drugs 386 see also pediactric studies China see People's Republic of China chlordiazepoxide 173 Chondroitin 283±4 chronic lymphocytic leukemias 199 chronic toxicity studies 61 chronology diagrams 272 cimetidine 203 Cimicifuga racemosa 283 CIOMS I 382±3 CIOMS II 382±3 CIOMS IV 383 civil law 416±18 class A drugs 339 class B drugs 339 class C drugs 339 clinical competencies 18±23 clinical data coordinator (CDC) 260 clinical development 6, 317 clinical development plan 55±6, 121 clinical investigators identification and selection 22±3 sources 23 clinical±legal interface 137 clinical/marketing interface 138 clinical outcomes 212, 213 INDEX clinical protocols see protocols clinical research competencies associated with 23±6 competencies associated with planning 19 GCP-compliant 69±70 standards 443 clinical research and development plans (CRDPs) 19, 22 clinical research fraud 443 clinical studies design 19±20 reports 27±8 setting up 70±2 sites 71±2 clinical trial certificate (CTC) 336, 344 clinical trials analysis 256±7 basic designs and factors suited and unsuited 123 controls on conduct 336 enrolment criteria 382 exemption (CTX) 95, 336, 344, 458, 460 historical 119±20 limitations 120±1 monitoring 24 regulations 317±18 regulatory governance of 121 reporting 256±7 sample size 381±2 see also financial aspects; publishing clinical trials clinicians role in industry 14 ±15 Clostridium welchii 333 clotting factors 109±10 vitamin K-dependent 110 Cochrane Collaboration 281 Code of Federal Regulations (CFR) 457 codes of practice 420 cogenital abnormalities 167 Color Additives Amendments 86 combinatorial chemistry 39, 40, 43 Commission for Health Improvement (CHImp) 392 Committee for Orphan Medical Products (COMP) 209±10 Committee for Proprietary Medicinal Products (CPMP) 209, 340, 341, 345, 458 common technical document (CTD) 345 communication to prescribers and patients 388 comparative superiority trials 134 compassionate use 301±2 competencies associated with clinical research 23±6 competency-based education and training system (CBETS) 17±18 competency-based training program 17±28 competitor intelligence (CI) 369±76 information source available 370 complementary medicines 281±6 commonly used 282±5 miscellaneous 285 regulatory aspects 285 terminology 281±2 complementary therapies 282 adverse effects 285 compliance see patient compliance composite hypothesis 232 computer-assisted design (CAD) of drugs 42±3 computer-assisted NDAs (CANDAs) 63, 169, 298 conferences organization and planning 377±80 confidence 245±7 confidence intervals 245±7 confidence level 246 confidence limits 246 confirmatory experiments 231 consent forms 448 Consumer Protection Act of 1987 424 contemporaneous independent treatment allocation 126±7 contract investigational sites (CISs) 461, 462 contract law 416±18, 423, 424 contract research organizations (CROs) 91±2, 463±84 contributory negligence 426 controlled clinical trial (CCT) 235±9 controlling factors in adoption of new therapeutic agents 5 copyright 433 in publishing clinical trials 412±13 corporate culture 456±7 cost-containment strategies 525 cost-effectiveness 369 cost-to-benefit consideration 4 costs see financial aspects coumadin 158 Council for International Organizations of Medical Sciences (CIOMS) 382±3 Cox II inhibitors 161 CRFs 24, 25, 71, 256, 259 cover sheet 262 design of format and content 21±2 image review process 262 managing 26 preparation 260 criminal law 416 crisis management 9 critical research organizations see CROs CROs capability 471 INDEX choice of contract 512±13 compatibility 473 critical success steps 466±83 early warnings 483 financial aspects 509±13 financial stability 511±12 frequent causes of problems 465±6 identifying problems 483 instructions to bidders 474 ±5 leveraging experience 473±4 modern view 464 obtaining and comparing bids 510±11 pharmaceutical industry views 463±4 prequalifying 473 proposals from 474 ±9 responsibilities 481 roles 464, 481 selection criteria 471±4 strategies for using 464 traditional view 463±4 see also sponsor±CRO cross-over experiments 239 cross-over studies 124 ±5 cultural challenges 455±7 cultural responsiveness 457 CYP2C19 351 CYP2D6 351 cytokines 32±3, 195±6 cytomegalovirus retinitis 197 Dalcon shield 9 data analysis 254±6 data collection 119 statistician's role 256 with integrity 78 data confidence 217 data creation flow chart 261 data entry 262 data integrity assurance 78±9 data management 259±67 project material 259 data package 359±60 data process status 263 data processing 260±6 data provision pediatric studies 185 data validity 217 database release memorandum 266, 267 database update 262 datasets 263 Debendox 444 decision-making 4, 211, 213±14 Declaration of Helsinki 65, 86 Dedrick plot 104 demographics elderly population 157 Department of Health, Education and Welfare (DHEW) 86±7 depression 161, 174 developed countries 157 diagnostic procedures 243 diazepam 51, 173 diet 355 diethylstilbestrol (DES) 429±30 diets high-or low-fat 355 differential diagnosis 143 direct-to-consumer advertising (DTCA) campaigns 256, 523 disaster recovery plan 266±7 disclaimers 425±6 disease cellular mechanisms of 32 in vivo models of 36 disease management (DM) 391±406 areas on concern 393±4 benefits to health service providers 396±7 benefits to patients 395±7 benefits to pharmaceutical companies 397 company requirements 404±5 contractual framework 392 definition 391, 392 effectiveness 398±9 guidelines and protocols 392 implementation in practice 402±4 ineffectiveness 399±400 key issues 403 overview 391±3 patient perspectives 404 politics and history 393±4 prospective companies 404 relationship with pharmaceutical industry 394±5 staffing 403 disease-modifying drugs (DMDs) 31 disproving liability 169 Dixon up±down technique 125 DNA 33, 35±6, 52, 195, 197, 351 DNA viruses 197 donezil 161 dosage pediatric studies 185±6 dosage formulations 136, 137 dosage selection OTC 144 dose determination 57 dose-response date 359 dose±response relationship 254 dose ranges gender differences 172 dose size 121 double-blind 237, 241 double-dummy method 237 double entry 262 Down's syndrome 167 downsizing 388 drop-outs 254±5 drug accountability management 25 533 drug assessment process role of 361 drug case studies 353±4 drug clearance elementary aspects 96±7 prediction of human 97±9 drug constituents 45±6 drug delivery targeting 46 drug development 7 epidemiology 226±7 legal/regulatory framework 457±61 procedures 315±20 process 18 regulations, Japan 311 regulations governing 19 role of 361 specific guidelines 315 drug differences influences on 354±5 drug discovery 7 allometric approaches 102±4 design and serendipity 31±44 process 38 project design 31 drug evaluation 4 drug formulations 45±52, 56 choice 46 pediatric studies 186 safety and efficacy trials 136 drug holidays 273±4 Drug Information Association (DIA) 18 drug interactions 137 adverse 158 potential for 382 drug labeling 373±6, 386 European Union (EU) 376 investigational drugs 25 Japan 373±4 USA 374±5 drug licensing 227±9 drug management training 9 drug metabolism 60 drug monitoring see drug surveillance; safety monitoring drug registration 227±9 ethnic issues in 349±63 future 362 medical practice 355±6 subjective factors 355±8 terminology, diagnosis and other subjective factors 357±8 drug requirements non-clinical studies 57 drug research in older patients 157±64 regulatory response 159 drug risk as epidemiologic problem 225 drug safety 9 drug screening flowchart 39 534 drug screening process 41±2 drug surveillance 381±9 see also safety monitoring drug utilization elderly population 158 restrictions 521 drugs see investigational drugs; investigational new drug application (IND) and specific drugs Durham±Humphrey Amendment 1951 86, 370 E. coli 34 ECU50u 105, 106 ECG 122 ECHO model 213 economic outcomes 213 EDU50u 125 EEG 110±11, 122 effect-compartment model 107, 109 effect-distribution model 107 efficacy 21, 105 OTC 143±4 stopping a clinical trial 129 Egypt pharmaceutical market 493±4 private pharmaceutical companies 494 elderly population clinical studies 162 compliance in 162 demographics 157 disease issues 161 drug utilization 158 informed consent 162 investigative sites 163 medication regimens 162 recruitment 163 screening 163 elimination rate 96±7 ELISA (enzyme-linked immunoabsorbent assay) 40±1 embryonic malformation 166 embryonic stem cells 35 Emergency INDs 299±301 enzymes 195 Ephedra spp. 284 epidemiology 223±4 drug development 226±7 drug registration and licensing 227±9 methodologies 224 epidermal growth factor (EGF) receptor 32 epilepsy outcomes 216 equipoise concept 65 equivalence trials 135 error analysis 259 error probabilities 232±3 INDEX essential hypertension 353 ethical issues 72±3 biotechnology products 199 drug research in older populations 158±9 pediatric studies 187 publishing clinical trials 407 ethics committee 56, 72±5 financial aspects 507 ethnic differences pharmacokinetics/ pharmacodynamics 351±2 prescribing differences 352 ethnic effects adverse event reporting (ADRs) 356±7 ethnic factors and population extrapolation 359 classification of intrinsic and extrinsic 360 pharmacologic implications 354 potential sensitivity to 359 ethnic issues in drug registration 349±63 future 362 medical practice 355±6 subjective factors 355±8 terminology, diagnosis and other subjective factors 357±8 ethnic susceptibility 352±3 Europe Orphan Drug legislation 209±10 European Agency for the Evaluation of Medicines (EMEA) 344, 346, 347 European Federation Pharmaceutical Association (EFFPA) 353 European Medicines Evaluation Agency (EMEA) 70, 341±2, 376, 419 European Patent Convention (EPC) 438 European Patent Office (EPO) 438 European Union (EU) 335, 336, 346±7, 458, 459 Directives 339±41, 418±19, 424 drug labeling 376 future clinical trial legislation 344 evergreening process 9 evolutionary designs 125 expectedness 384 expert reports 63±4 exploratory experiments 231 expressed sequence tags (ESTs) 34 extrapyramidal reactions 173 FACS 37 falsifiability condition 231, 232 Far East pharmaceutical market 495 registration dossier compilation 498 trading with 498 FDA 19, 27, 47, 58, 67, 85, 134, 145±7, 149, 150, 160, 175, 192, 206, 212, 243, 289±94, 298, 299, 358, 368, 370, 371, 374, 419, 420, 445, 457, 460 audits 90±2 background 85±7 economic considerations 294 meetings with 296 organizational aspects 294±5 FDA Modernization Act (FDAMA) 184 fee-for-service (FFS) health insurance policies 515±18 fees see financial aspects female population see gender differences; women fertility testing 170 fetal damage liabilities 178 financial aspects 503±14 charges 506 clinical trial medication 507 consultancy 507 CROs 509±13 equipment costs 508 ethics committees 507 external costs 503 institutional review boards (IRBs) 507 internal costs 508±10 investigator fees 503±5 laboratory charges 506 meetings 508 multinational trials 508 patient fees 507 Phase III project 509 price ratios for common research procedures 504 printing and copying 508 regulatory fees 507 relative costs by country 505 relative costs by therapeutic area 504 travel 506±7 Fine Chemical Database 40 Fine Chemical Directory 42 Food and Drug Administration Modernization Act (FDAMA) 293±4 Food and Drug Administration. See FDA Food and Drug Agency (FDA) 49 Food and Drugs Act 1906 370 Food, Drug and Cosmetic Act 85, 184, 291±2, 370, 419 formulary enforcement policies 521 formulary status 137 fraud 443±51 animal research 448 British cases 444±5 definition 444 detection 446±7 INDEX examples 444 historical aspects 443±5 investigation 446±7 literature 446 prevention 445±6 prosecution 447 recent cases 448 gall bladder disease 387 gases 48±9 gastric emptying time women 172 Gaucher's disease 194, 195, 198 gender data 165 gender data collection 178 gender differences 166, 170 adverse events 174 dose ranges 172 in drug handling 172±4 metabolism 173±4 pharmaceutical industry practice 175±6 weight-for-height tables 172 see also women gender-related research 174±6 gene therapy 43, 197±8 pharmacokinetics 198 gene therapy agents pharmacokinetic properties 193 General Agreement on Tariffs and Trades (GATT) 440 General Consideration for the Clinical Evaluation of Drugs 174 General Considerations for Clinical Trials 458 General Medical Council (GMC) 445, 447, 448 disciplinary powers 450±1 general pharmacovigilance 228 see also pharmacovigilance generalizability 239±40, 249±50 generic drugs 304±5 scandal 9 genetic counseling 170 genetic susceptibility 352±3 genetic variation 351 genomics and new target identification 34±5 geriatric population see aging population; older patients Gingko biloba 283 ginseng 284 Glasgow Coma Score 67 global utilization of streptokinase and t-PA for occluded coronary arteries (GUSTO) 135 glomerular filtration rates (GFR) 185 glucosamine/chondroitin combinations 283±4 Goldenthal guidelines 62 Good Clinical Practice (GCP) 17, 19, 69±84, 349, 367, 443, 445±6, 25, 314 basic tenets 69 compliant clinical research 69±70 general regulatory framework 69±70 implementation 70 investigator responsibilities 72 sources of international guidelines/ regulations 82±4 good laboratory practice (GLP) 55, 57, 314 good manufacturing practice (GMP) 314 principles and guidelines 338±9 standards 338 Good post-marketing Surveillance Practive (GPMSP) 315 Guidance E5 359 Guide to Clinical Trials 18 Guideline on Drug Development in the Elderly 159 Guidelines for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs 170 HU2u blockers 358 Haemophilus influenzae 34 harmonization of data requirements 345 headache diagnosis 142 health economics 212 health maintenance organizations (HMO) 516 network model 517 staff model 517 Health Maintenance Organizations (HMO) Act 1973 516 health outcomes 212 healthcare 212 healthcare budget 4 healthcare provision 4 heart attack in women 166 heart disease in women 166 heart failure 161 height differences 355 helium/oxygen mixtures 48 hepatic clearance comparison of predicted and actual 99 equations 98 herpes simplex virus 1 (HSV1) 197 hexachlorophene toxicity 9 Hill factor 106 HIV 196 homeopathic drugs 285 homeopathy 282 homogeneity 240 hormones 195 horseradish peroxidase (HRP) 41 Human Genome Project 34 535 human genomic map 44 human medicines control 327 centralized procedure 341±2 classical times to end of 18th century 327 decentralized or mutual recognition procedure 343 19th and 20th century to Medicines Act 1968 332±4 recommendations 333 humanistic outcomes 213 Hypericum perforatum 283 hypertension 161 hypothesis 232 testing 243 ibuprofen 173 ICh guidelines 57, 59, 62, 250 IL-1a 33 imipramine 173 immigration 158 immune adjuvants 196 impurities and stability 56±7 incidence of a disease 208 indomethacin 158 Indonesia clinical trials 501 health centres 501 pharmaceutical industry 501±2 inflammatory bowel disease 50 information systems (IS) 397±8 information technology (IT) 397±8, 403, 527±8 informed consent 65±7, 73, 121 benefit±risk assessment 131 biotechnology products 200 children 66 elderly population 162 emergency patients 67 essential elements 65±6 ethical basis 65 pediatric studies 187 principles for conducting 75 responsibility of parties to 67 substitute 67 surrogate 66 unwritten 66 written 65±6 inhalational toxicology 49 inhalers 49 initial clinical studies 55 initial non-clinical considerations 56±7 initial proof of principle 56 injectates 51 innovation in pharmaceutics 52 in situ studies 35 institutional review boards (IRBs) 56, 67, 89, 459, 461, 507 pediatric studies 187 review 72±5 536 integrated summary 61, 63 integrated summary of efficacy (ISE) 257 integrated summary of safety (ISS) 257 intellectual property rights 433±4 intent-to-treat (ITT) analysis 255±6 interference practice 440±1 interim analysis 253±4 interim efficacy analyses 129 International Clearing House for Birth Defects Monitoring 179 International Conference on Harmonization (ICH) 13, 17, 55, 57, 59, 62, 87, 159±60, 243, 250, 345, 349, 358, 383±4, 387, 458, 462, 463 International Federation of Associations of Pharmaceutical Physicians (IFAPP) 13±14 international regulatory guidelines for safety pharmacology studies 61 International Society for Pharmacoepidemiology (ISPE) 226 international treaties 437±40 Internet 4 interpretation of measurements 119 intranasal administration 50 investigational drugs labeling of 25 packaging of 25 investigational new drug application (IND) 48, 56, 87, 95, 128, 146, 292, 295±6, 419, 459, 460 see also emergency INDs; treatment INDs investigational products labeling of 22, 25 packaging of 22 investigators choosing 138 fees 503±5 responsibilities 72 selection 71±2 investigator's brochure (IB) new clinical data 21 preparation 20 in vitro assay development 37±43 primary vs. secondary screens 37±9 technological considerations 37 throughput and assay cycles 40±1 in vitro data collection 95 in vitro functional assays 95 in vitro/in vivo prediction 96±101 in vivo data 110 in vivo models of disease 36 in vivo studies 35 Japan clinical fees 506 drug development regulations 311 INDEX drug labeling 373±4 regulations 307 Japanese health authorities 307±10 Japanese pharmaceutical laws 310±11 Kaplan±Meier analysis 128 Kava 284 Kefauver±Harris Act 192 Kefauver±Harris Drug Amendements 1962 86, 184, 292, 371 labeling see drug labeling labeling of investigational products 22, 25 laboratory charges 506 large, automated, multipurpose, population-based systems (LAMPS) 225±7 large, simple study 127±8 last-observation-carried-forward method 255 law of contract see contract law law of tort 416±18 LDU50u 58 legal framework for regulating pharmaceutical products 418±20 legal principles 416 legal/regulatory framework for drug development 457±61 licensing in 388 licensing of new medicines 335±7 licensing out 388 licensing requirements 130 life-threatening diseases 302±4 linear models 242 link-model 107±9 linkage analysis 34 lipophilic drugs 172 liposomes 197 lithium 173 log-in 260±2 lubricants 47 lyophilizates 51 Malaysia product registration 499±500 trading with 498±500 managed care 515±29 basic concepts 515 cost containment strategies 520±2 emerging trends 527±8 historical perspectives 515±18 impact on pharmaceutical industry 519±27 impact on pharmaceutical product life cycle 526 key principles 518±19 market competition 523±4 multiple player influence 522±3 population and demographics 524±5 terminology 516 managed care organization (MCO) 516±28 types or models 516±17 marketing approval application 343±4 maximum outsourcing 465 MCA 342 Meat Inspection Act 290 Med-DRA (Medical Dictionary for Regulatory Activities) 385 Medicaid 158, 461, 522 medical affairs 367±72 organization 367±71 overview 367 personnel 368 phaseline 371 medical communications 368 medical culture 456, 457 medical loss ratio (MLRs) 518±19 medical science liaisons 367 Medicare 158, 461, 492, 522 Medicare Prospective Payment System (PPS) 516 medications and devices control at study sites 80±1 management 80 overall accountability 81 preparation 80 shipment 80 medicines establishing differences among 208 Medicines Act 1968 335, 336, 339, 344, 418 medico-commercial environment 461±2 meetings audiovisual presentations 410±11 megatrials 135 melatonin 46 menstrual cycle standardizing for 171 Merck Index 46 meta-analysis 257 metabolism differences in 386 gender differences 173±4 methaqualone 173 metronidazole 50 Michaelis±Menten equation 106 Middle East 492±5 agency laws 493 company registration requirements 494±5 pharmaceutical and healthcare market 492±3 migraine syndrome 118 minimization trials 125±7 misconduct 443±51 missing data 255 INDEX Misuse of Drugs Regulations 1985 339±40 Misuse of Drugs Regulations Act 1971 339 model parameters 242 molecular modeling 40 molecular target identification 32±3 monitoring 73±6 objectives 77 More Secret Remedies 333 mRNA 34 multicenter trials 248±50 multinational corporations 455±62 languages 457 multiplicity 251±3 mutagenicity studies 59±60 mutagenicity testing 170 mutations 36 Mycoplasma genetalium 34 National Committee for Quality Assurance (NCQA) 519 National Heart and Lung Blood Institute (NHLBI) 163 National Health Insurance Drug Price List 322 National Institute for Clinical Excellence (NICE) 392 national reimbursement policies 357 nausea 150 nebulized drugs 49±50 negligence 417±18, 425 new biological entities (NBEs) 336 new chemical entities (NCEs) 42, 55, 159, 336 new drug applications (NDAs) 45, 63±4, 92, 117, 131, 175, 208, 214, 292, 296±7, 303, 304, 313, 460 content 320 new drug approval process 320±3 new medicines sponsors of 361 New Medicines in Women 177 new molecular entities (NMEs) 159, 184 new uses for old drugs 43 NHS and pharmaceutical companies 394±5 nitrous oxide/oxygen 48 noise and noise reduction 234, 243, 249 non-clinical summary documents 61 non-clinical toxicology 55±64 non-compliance see patient noncompliance Normal distribution 245 NSAIDS 158, 161, 358 null hypothesis 232 Nuremberg Code 86 Office of Research Integrity (ORI) 445 older patients drug research in 157±64 regulatory response 159 open-label trials 135 Oraflex 9 oral bioavailability elementary aspects 100 prediction 101 oral contraceptives 173, 177, 387 oral formulations optimal design features 47 oral suspensions 46±8 oral transmucosal administration 50 organ transplantation 199 orphan disease 203 Orphan Drug Act 203, 207±8, 293 unintended consequences 208 Orphan Drug legislation Asian countries 210 Europe 209±10 USA 209 orphan drugs 203, 312 benefits from development perspective 207 classification 204 defintion 203 development 206 development disincentives and obstacles 207 discovery 206 distribution 206 economic±medical interface 204±5 heterogeneous group 203 interested parties 205 marketing 206 marketing benefits in selling 206±7 principles 203±4 regulatory processes 204 specific sources of information 206 osteoarthritis 161 outcomes research 528 three-dimensional assessment 212±13 see also pharmacoeconomics and specific areas outsourcing 464±5 over-the-counter (OTC) 351 over-the-counter (OTC) medication 5, 141±51, 289 advertising and marketing 150±1 criteria for use 142 development cycle 145 dosage selection 144 efficacy 143±4 labeling 149±50 market 148 market support studies 150±1 marketing 145 pharmaceutical physician's role in 144±6 537 Phase IV studies 147 prescription-to-OTC switch 146±9 proposed labeling 148 safety evaluation 143 special study designs 149±50 specific clinical testing 145±6 tolerability 143 unique characteristics 144±6 over-the-counter (OTC) pharmaceuticals 3 oxazepam 173 oxygen/nitrous oxide 48 p-value 243±5 P450 cytochrome enzyme systems 351 packaging 51±2 of investigational drugs 25 of investigational products 22 package insert 322 Palmito caroliniensis 283 paraldehyde 50 parallel-group studies 122±3 Paris Convention for the Protection of Industrial Property 1883 437±8 Parkinson's disease 161 partial agonists 105 patent application 441±2 Patent Cooperation Treaty (PCT) 438±40, 442 international phase 439 national phase 439 patent protection 435 patentable subject matter 435±6 patents 433±42 biotechnology industry 200±1 criteria for obtaining 436±7 history 434±5 role of 434 patient compliance 269±79 actions to enhance 274±5 classification 273 common patterns 273 cost-effectiveness 277 definition 269±70 direct compliance evaluation 270 during clinical trials 270±2 full compliance 273 improving 275 in elderly population 162 indirect compliance evaluation 270 interactive packaging 276±7 methods of evaluating 270 monitoring with feedback 275 non-compliance 273 over-compliance 273 partial compliance 273 Phase I clinical studies 271 Phase II clinical studies 271 Phase III clinical studies 271±2 Phase IV clinical studies 272 538 patient compliance (cont.) potential players involved in real-time compliance 275±6 reports 272±3 standards for analyzing real-time compliance data 272 timing non-compliance 274 patient compliance/satisfaction 136±7 patient±consumers 4 patient fees 507±8 Patient Management Strategies 398 patient needs 5 patient non-compliance 254 patient package insert 138 patient participation 124 patient rights 4 payer±providers 4 pediatric studies 183±8 data provision 185 dosing 185±6 drug formulations 186 ethical concerns 187 final rules 184±5 informed consent 187 IRBs 187 physiological variations 185 placebo control 188 recruitment 186±7 toxicology 186 vulnerability 187 pentamidine 219 People's Republic of China 486±92 clinical trials 486±7 procedures 490±2 pharmaceutical joint ventures 487 requirements for authorization of clinical trials 487±90 peptides 194 performance metrics 481±2 perpherazine 351 pessary 51 Petasites hybridus 46 phantom fetus 167, 169 Pharmaceutical Affairs Bureau (PAB) 308±9 pharmaceutical benefit manager (PBM) 517, 518, 528 pharmaceutical companies 191 Pharmaceutical Education and Research Institute Inc. (PERI) 18 pharmaceutical industry basic cycle 6 individual or corporate responsibility 420±1 voluntary codes 420 Pharmaceutical Manufacturers' Association (PMA) 253 Commission on Drug Safety 368 pharmaceutical medicine coverage 3±5 INDEX definition 3 function 5 industrial roles 14±15 medical specialty 3±11, 13 role of 13 sub-specializations 14 pharmaceutical products legal framework for regulating 418±20 pharmaceutical research and development 525±6 Pharmaceutical Research and Manufacturers of America (PhRMA) 160, 183 pharmacoeconomic outcomes current and future uses 219±20 pharmacoeconomic research 528 pharmacoeconomic trials Phase IV 138 pharmacoeconomics 369 baseline burden of illness 215±16 economic and humanistic outcomes 211±21 in development programs 213±14 information demands 213 outcomes research 211±12 Phase II studies 214 Phase III studies 214 reporting and publications 218±19 studies within clinical trials 216±18 traditional clinical development programme 214±15 pharmacoepidemiology 223±30 definitions 226 future 229±30 training 229 pharmacognosy 42±3, 282 pharmacokinetic parameters 59, 243 pharmacokinetic properties 121 pharmacokinetic studies 60 children 186 pharmacokinetic/pharmacodynamic (PK/PD) model/computergenerated feedback 112 pharmacokinetic/pharmacodynamic (PK/PD) models 192, 198 pharmacokinetic/pharmocodynamic (PK/PD) models complex and time-dependent 106±10 elementary aspects 104±5 single-compartment timeindependent 105±6 pharmacophores 37±8 pharmacovigilance 228, 337±8, 371 and problems currently facing industry 387±8 postmarketing surveillance 492 Phase I clinical studies 56, 95±115, 117±32, 458, 462 industry practice 170 patient compliance 271 regulatory practice 350 representative female population 171±2 toxicological support 57±61 women 171±2 Phase II clinical studies 56, 58, 112, 113, 117±32, 458, 462 common designs 122 industry practice 170 objectives and prerequisites 121±5 patient compliance 271 pharmacoeconomics 214 regulatory practice 350 small-scale 130 toxicological support 61±3 Phase III clincal studies 58, 117±32, 248±9, 354, 458, 462 Phase III clinical studies common designs 122 financial aspects 509 patient compliance 271±2 pharmacoeconomics 214 regulatory practice 350 toxicological support 61±3 Phase IV clinical studies 117±39 goals and tactics 133 investigators 138 objectives 133 OTC 147 patient compliance 272 pharmacoeconomic trials 138 practical aspects and problems 134 safety surveillance 136 searching for new indications 136 tactical aspects 137±8 types 133±5 Philippines clinical trials 500±1 health care and pharmaceuticals 500 regulatory affairs and registration 500 Phiso-Hex (hexachlorophene) 9 phocomelia 387 Physicians' Desk Reference 386 physicochemical properties 46, 48 physiological substance models 109 physiological systems 35 pivotal clinical trials 130 placebo comparisons 194 placebo control pediatric studies 188 placebo effect 237, 241 placebo treatment 123 plasma concentration 107 plasma determination 57 plasma kinetics 107 plasma protein binding 100 Pneumocystis carinii pneumonia 219 population demographics 350 population derivation 265 INDEX population extrapolation and ethnic factors 359 population inclusion and exclusion criteria 239±41 populations and subpopulations 386 postapproval activities 323±5 post-marketing adverse drug experiences (AE) 370 post-marketing approval medical affairs 7 post-marketing safety surveillance 370±1 post-marketing studies 133±9 post-marketing surveillance studies 228 postmarketing surveillance organization 323±4 postural hypotension 357 potency 105 potential sensitivity to ethnic factors 359 precision 245±7 preclinical research and development 6 preclinical studies 316 preferred provider organization (PPO) 517 pregnancy 167±70, 177, 387 clinical studies 168±9 contraindications 386 registries 228±9 prescribing differences ethnic differences 352 Prescription Drug Users Fee Act (PDUFA) 293 prescription drugs 4, 5 prescription-event monitoring (PEM) 228 Prescription Medicines Code of Practice Authority (PMCPA) 420 Prescription Only Medicines List (POM) 339 press releases 412 prestudy visits 23 prevalence of a disease 208 prion-mediated disease 196 probability 231, 234, 239 proctitis 50 product defects 425 product labeling see drug labeling product liability 137, 423±30 international issues 426±7 landmark cases 427±30 legal defenses 425±6 principles of law 423±5 product licence application (PLA) 117 product licences 45 Product Licences of Right (PLRs) 337 product life cycles 526±7 pro-glidant 47 project setup 260 project team formation 260 propranolol 173 Proprietary Association of Great Britain 335 proprietary medicinal products controls of 340±4 prospective cohort epidemiologic studies 224 protein chemistry 8 protein pump inhibitor 358 proteins recombinant vs. natural 41 prothrombin complex activity (PCA) 109±10 protocols 21, 71, 121, 256, 259 design and preparation 20 elements 20 pseudoephidrine 158 publishing clinical trials 407±14 audiovisual presentations at academic meetings 410±11 CD-ROM vs. textbook 411 classic components in peer-reviewed journal 409±10 copyright 412±13 desirability of, and biases in 408±9 electronic facsimiles 411 electronic journals 412 ethics 407 isolated abstracts 410 newer forms 411±12 posters 410 Pure Food and Drug Act (PFDA) 290±1 539 quality assurance 87±8 imported drugs and medical devices (GMPI) 314 sampling 259 quality control 88±90 rules 259 quality of life (QOL) 217, 218 quality protocols 21 quality standards 313±14 quantitative interaction 249 quantitative structure±activity relationships (QSARs) 42 query resolution 262 quinidine 158 definition 203 prevalence 203 RAS 32 receptor/ligand assays 40 receptor science 8 receptors 32 sensitivity 353 recruitment pediatric studies 186±7 rectal administration 50 ±1 re-evaluation system 324 ±5 re-examination system 324 regulatory compliance 425 regulatory development 6 regulatory governance clinical trials 121 drug development 19 regulatory issues biotechnology products 192, 199 regulatory processes orphan drugs 204 regulatory strategy 56 renal perfusion 185 repeated-dose toxicity studies 58±9 reporting clinical research 27±8 clinical trials 256±7 criteria 384 patient compliance 272±3 reproduction studies 62 request for proposal (RFP) 465, 474 research fraud 443 resource allocations worksheet 475±9 retroviruses 197 review of products on the market pre-1971 337 review process 321±2 Revised Policy on Inclusion of Women of Childbearing Potential in Clinical Trials 175 Reye's syndrome 9 rheumatoid arthritis 161 routes of sale and supply 339±40 Royal College of Physicians (RCP) 11, 13, 445 Rx-to-OTC switch 146±8 R&D 10 expenditure 7, 8 process 6 racial groups definitions 351 random error 242 randomization 81, 129, 235±7, 239 randomized blocks 236 randomized control trial (RCT) 217 randomized controlled clinical trial (RCCT) 241 rare diseases case reports 130 Saccharomyces cervisiae 34 safety assessment 57 safety committees 124 safety evaluation 55 OTC 143 safety events reporting and recording 76±8 safety issues 9, 25 biotechnology products 198±9 stopping a clinical trial 128±9 safety measures 240 safety monitoring 381 postmarketing 381±2