Pharmaceutical Medicine Guide

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
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


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Contents

About the Editors . . . . . . . . . . . . . . . . . . . . . . . . ix 8 Good Clinical Practices . . . . . . . . . . . . . . . 69
Wendy Bohaychuk and Graham Ball
List of Contributors . . . . . . . . . . . . . . . . . . . . . . xi
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii 9 Quality Assurance, Quality Control
and Audit . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Section I: Overview of Donna Cullen
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-Pratt
Section 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

vi CONTENTS

Section 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. Fox

17 Biotechnology Products and Their 27 Japanese Regulations . . . . . . . . . . . . . . . 307
Development . . . . . . . . . . . . . . . . . . . . . . 191 Â
Etienne Labbe
David Shapiro and
Anthony W. Fox 28 The Development of Human Medicines
Control in Europe from Classical
18 Orphan Drugs . . . . . . . . . . . . . . . . . . . . . 203 Times to the Year 2000 . . . . . . . . . . . . . . 325
Bert Spilker John Griffin

19 Pharmacoeconomics: Economic 29 Ethnic Issues in Drug Registration . . . . 347
and Humanistic Outcomes . . . . . . . . . . . 211 Lionel D. Edwards, J.M. Husson
Raymond J. Townsend, Jane Â
A. Kumagai, E. Labbe, C. Naito,
T. Osterhaus and M. Papaluca, S. Walker, R. Williams
J. Gregory Boyer M. Weintraub and H. Yasurhara

20 Pharmacoepidemiology and the
Pharmaceutical Physician . . . . . . . . . . . 223 Section VI: Medical Services
Hugh Tilson
Introduction . . . . . . . . . . . . . . . . . . . . . . . 364
21 Statistical Principles and Their Anthony W. Fox
Application in Biopharmaceutical
Research . . . . . . . . . . . . . . . . . . . . . . . . . . 231 30 An Introduction to Medical Affairs . . . . 365
Dan Anbar Gill Price
22 Data Management . . . . . . . . . . . . . . . . . 259 31 Drug Labeling . . . . . . . . . . . . . . . . . . . . . 371
T.Y. Lee and Michael Minor Anthony W. Fox
23 Patient Compliance . . . . . . . . . . . . . . . . . 269
32 Organizing and Planning Local,
Â
Jean-Michel Metry
Regional, National and International
Meetings and Conferences . . . . . . . . . . . 375
24 Complementary Medicines . . . . . . . . . . . 281
Zofia E. Dziewanowska,
Anthony W. Fox
Linda Packard and
Lionel D. Edwards

Section V: Drug Registration 33 Drug Surveillance . . . . . . . . . . . . . . . . . . 379
Howard J. Dreskin and
Introduction . . . . . . . . . . . . . . . . . . . . . . . 288 Win M. Castle
Anthony W. Fox
34 Disease ManagementÐWhat Does
25 United States Regulations . . . . . . . . . . . 289 It Mean? . . . . . . . . . . . . . . . . . . . . . . . . . . 389
William Kennedy Roy Lilley

CONTENTS vii

35 Publishing Clinical Studies . . . . . . . . . . . 403 40 Outsourcing Clinical Drug
Anthony W. Fox Development Activities to Contract
Research Organizations (CROs):
Critical Success Factors . . . . . . . . . . . . . 461
Section 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 . . . . 501
36 Pharmaceutical Product Liability . . . . . 421 R. Graham Hughes and
Han W. Choi and N. Turner
Howard B. Yeon
43 The Impact of Managed Care on
37 Patents . . . . . . . . . . . . . . . . . . . . . . . . . . . 431 the US Pharmaceutical Industry . . . . . . . 513
Gabriel Lopez Robert Chaponis,
Christine Hanson-Divers and
38 Fraud and Misconduct in Marilyn J. Wells
Clinical Research . . . . . . . . . . . . . . . . . . . 441
Frank Wells AppendixÐUseful Internet Links . . . . . . . . . . 529
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
Section VIII: Business Aspects
39 The Multinational Corporations: Cultural
Challenges, the Legal/Regulatory
Framework and the Medico-commercial
Environment . . . . . . . . . . . . . . . . . . . . . . . 453
R. Drucker and
R. Graham Hughes


About the Editors

ANDREW J. FLETCHER, MB, BChir, (Cantab), the efficacy subcommittee Topic 5 (Acceptability
MS (Columbia), FFPM, DipPharmMedRCP, is of Foreign Clinical Data) of the International
Senior 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 Pharmaceutical
Pharmaceutical 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 has
bridge University and St. Bartholomew's Hospital, taught `Drug Development' for PERI for over ten
London, briefly trained in Neurosurgery, joined years and is on the teaching faculty of the National
CIBA-GEIGY in the UK as Medical Advisor, Association of Physicians. He is a founder member
then 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 University's School of Pharmacy. He is a From The Royal London Hospital, after general
founder member and ex-trustee of the American clinical training he was Rotary International
Academy of Pharmaceutical Physicians. Fellow at Emory University (Atlanta), and CIBA-
Geigy Fellow at Harvard. Industrial positions at
LIONEL D. EDWARDS, MB, BS, LRCP, MRCS, Procter and Gamble and Glaxo came next. He was
Dip 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 Charter
and 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 pharmaceutical
small Biotech firm making a profit with operations medicine, e.g., regulation, pharmacology, clinical
in 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 four
Technology firm with large internationally licensed patents, and five journals use his reviews.
partnersÐCiba and Rhone Poulenc Rorer. He was
Assistant 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 years
of Schering-Plough International Research, and experience in pharmaceutical medicine. He was
Director of US Domestic Gastrointestinal, Hormo- Medical and Board Director of the UK Hoechst
nal and OTC Research Departments. Dr. Edwards Group of companies until he became a consultant
has 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 Royal
10 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 and
the 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

x ABOUT THE EDITORS

pharmaceutical medicine at Kings College, marketing and careers in the pharmaceutical
London 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 BSc
degree in Pharmaceutical Medicine in 1993. His degree in physiology and a PhD in protein
publications include edited works in human psy- chemistry.
chopharmacology, clinical research, medical


List of Contributors

Anbar, Dan Millennium Biostatistics Inc., Bound Hanson Divers, Christine US Scientific Initiatives
Brook, NJ, USA and Customer Support, Health Economics and
Outcomes Research, AstraZeneca, Apex, NC, USA
Bohaychuk, Wendy Good Clinical Research Prac-
tices Consultants, Lakehurst, Ontario, Canada Hammad, G. Watford, UK
Boyer, Gregory J. Pharmacia Corporation, Stokie, Hughes, Graham R. Technomark Consulting
Illinois, USA Services, London, UK
Castle, Win M. Glaxo Smithkline, Philadelphia, Husson, J.M. Paris, France
PA, USA
Johnson-Pratt, Lisa R. Merck & Co. Inc., North
Chaponis, Robert J. Global Medical Affairs, Phar- Wales, PA, USA
macia Corporation, Peapack, NJ, USA
Kennedy, William Consultant Delaware, USA
Choi, Han W. former V.P. Regulation Affairs
Croft, Sara Shook, Hardy and Bacon, MNP Â
Labbe, Etienne Sanofi-Synthelabo, Paris, France
London, UK
Lee, T.Y. ACER/EXCEL Inc., USA
Cullen, Donna Auditrial, Fairlawn, NJ, USA
Lilley, Roy Independent Health Analyst, former
Curry, Stephen H. President Stephen H. Curry, NHS Trust Chairman, Camberley, Surrey, UK
Consulting, Professor of Pharmacology and Physi-
Linda, Packaid La Jolla, CA, USA
ology, University of Rochester, NY, USA
Lopez, Gabriel Basking Ridge, NJ, USA
DeCory, Heleen H. Astra Arcus USA Inc., Ro-
chester, USA Marler, Matthew Astra Arcus USA Inc., Roches-
Dreskin, Howard J. Glaxo SmithKline Phila- ter, USA
delphia, PA, USA McCarthy, Dennis J. Drug Metabolism and Phar-
Drucker, R. Technomark Consulting Services, macokinetics, AstraZeneca Pharmaceuticals LP,
London, UK Wilmington, Delaware, USA

Dziewanowska, Zofia La Jolla, CA, USA Â
Metry, Jean-Michel AARDEX Ltd, Zug, Switzer-
land
Edwards, Lionel D. Novartis, East Hanover, USA
Miller, Jay D. Amgen Inc., Thousand Oaks, Cali-
Fox, Anthony W. EBD Group Inc, 6120 Paseo fornia, USA
del Norte, Suites 52±L2, Carlsbad CA 92009, USA
Minor, Michael ACER/EXCEL Inc., USA
Gabrielsson, Johan Pharmacokinetics and Phar-
macodynamics Section, AstraZeneca R+D Soderta- Molony, Leslie J. Biotechnology Business Strat-
lie, Sweden egies, Pleasant Hill, CA, USA
Graham, Ball Good Clinical Research Practices Naito, C. Teikyo University, Japan
Consultants, Lakehurst, Ontario, Canada
Ostechaus, Jane T. Wasateh Health Outcomes,
Griffin, John P. Quartermans, Welwyn, UK Park City, Utah, USA

xii LIST OF CONTRIBUTORS

Papaluca, Amati M. EMEA, London, UK Turner, Nadia AstraZeneca, Macclesfield, Chesh-
ire, UK
Pratt, Timothy Shook, Hardy and Bacon LLP,
Kansas City, USA Vogel, John R. John R. Vogel Associates, Kihei,
HI, USA
Price, Gill VP MedImmune Inc., USA
Walker, S. Centre of Medicine Research, Carshal-
Reno, Frederick Merritt Island, FL, USA
ton, UK
Spilker, Bert Pharmaceutical Research and
Wardell, William Wardell Associates Inter-
Manufacturers of America, 1100 fifteenth street
national LLC, Princeton, NJ, USA
NW, Washington DC 20005, USA
Wells, Frank Medicolegal Investigations Ltd, Ips-
Starkey, Paul Former Vice President Smithkline
wich, UK
Beecham 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, USA
Tilson, Hugh H. University of North Carolina
Williams, R. US Pharmacopia, Rockville, USA
School of Public Health, Chapel Hill, NC, USA
Yasurhara, H. Teikyo University, Japan
Toland, 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


Preface

Pharmaceutical 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 their
USA. The American Academy of Pharmaceutical vision. We would like to thank and acknowledge
Physicians (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 the
Federation of Associations of Pharmaceutical early part of this project. We would also like to
Physicians (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 John
industry in the USA, as health care delivery began Wiley & Sons, Inc., UK, with whom we have
to move more towards managed care, and large worked closely over these past few years, among
corporations began to amalgamate and downsize. whom we have particularly stressed (!) Michael
As these trends continue into the 21st century, Davis, Deborah Reece, Hannah Bradley, Lewis
pharmaceutical physicians are increasingly regard- Derrick, and Hilary Rowe.
ing consultancy work and contract research organ- Lastly, we would like to thank our families, and
ization (CRO) affiliation as good career oppor- friends, who have withstood the frequent telephone
tunities, and now recognize the need for continuing calls, e-mails, and meetings, often late into the
education 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, will
more 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 Fletcher
intended to be useful for those outside the USA Lionel Edwards
because the basic tenets of the specialty have, for a Tony Fox
long time, become global. Peter Stonier


Index

abbreviated new drug application safety data 316 biopharmaceutical research 231±47
(ANDA) 304±5 antibodies 195 biotechnology 441
accelerated approvals 302±5 antisense drugs 196±7 biotechnology companies 191
acute toxicity animal studies 58 anxiety neurosis 174 biotechnology industry
additives 355 archiving 79±80 impact 10
adeno-associated viruses 197 area under the concentration time curve patents 200±1
adenosine deaminase (ADA) 198 (AUC) 47, 48, 60, 63, 101, 351 biotechnology products 191±201
adverse drug experiences (ADEs) Armitage technique 126 classes 193±8
handling 25±6 arthritis 161 clinical trials issues 193±8
adverse 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 193
adverse 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 200
age differences 355 audit result 267 types 191
agency laws audit sheet 263, 266 vs. conventional drug products
Middle East 493 audit summary 263 192
aging population audits 90±2 Black Cohosh 283
impact on society 157±8 future trends 92±3 blastocyst 170
agonist±antagonists 105 autonomy concept 65 blinding (or masking) 81, 236±7
Agouron Pharmaceuticals, Inc. 42 blocking 239
AIDS 4, 183, 197, 357 B. subtilis 34 blood pressure 161
AIDS-associated infective retinitis 52 Bacille Calmet±Guerrin vaccine British Association for Lung
AIDS Coalition to Unleash Power (BCG) 196 Research 49
(ACTUP) 5 baseline burden of illness 215±16 British Association of Pharmaceutical
alcohol effects 354 basic chemical or structural research 6 Physicians (BrAPP) 13
allometric scaling 101±2, 104 Bayesian trial designs 129±30 British Medical Association (BMA)
Alzheimer's disease 158, 161±2, 525 Bendectin 444 332
American Academy of Pharmaceutical benefit±risk analysis 131±2 British Pharmacopoeia 332
Physicians 13, 15 benefit±risk evaluation 383 Budapest Treaty on the International
American College of Epidemiology benzocaine 50 Recognition of the Deposit of
(ACE) 226 benzodiazepines 111, 174 Micro-organisms for the Purposes
American Heart Association 166 bias 236±7, 239 of Patent Procedure 439
analgesic effect-time data 108 concepts 118 budgets see financial aspects
analysis of variance model defences against 119 Bugbane 283
(ANOVA) 242 in clinical trials 118 bulking agents 47
angina in women 166 sources 124
angiotensin-converting enzyme (ACE) binders 47 C. elegans 34
inhibitors 167, 193, 386 binomial model 241 calcitonin gene-related peptide
animal±human extrapolation 95±115 bioequivalence studies 48 (CGRP) 194
animal pharmacokinetics 316±17 biologic licence application (BLA) 19, calendar displays 272
animal pharmacology 316 20, 25, 27, 28 Cancer Act 1939 333
animal species 57 biological products 457 cancers
animal 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

532 INDEX
case-control study designs 224 clinical protocols see protocols competency-based training
case report data and databases 26 clinical research program 17±28
case report forms see CRFs competencies associated with 23±6 competitor intelligence (CI) 369±76
causality 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±5
CBER (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±2
CDER (Center for Drug Evalutaiton clinical research fraud 443 complementary therapies 282
and Research) 297±8, 457 clinical studies adverse effects 285
cell-based assays 41 design 19±20 compliance see patient compliance
cell products 199 reports 27±8 composite hypothesis 232
cellular mechanisms of disease 32 setting up 70±2 computer-assisted design (CAD) of
center effect 249±50 sites 71±2 drugs 42±3
Center for Biologics Evaluations and clinical trial certificate (CTC) 336, 344 computer-assisted NDAs
Research see CBER clinical trials (CANDAs) 63, 169, 298
Center for Disease Control and analysis 256±7 conferences
Prevention (CDC) 161 basic designs and factors suited and organization and planning 377±80
Central and Eatern Europe (CEE) unsuited 123 confidence 245±7
459 controls on conduct 336 confidence intervals 245±7
central nervous system drugs 174 enrolment criteria 382 confidence level 246
Central Pharmaceutical Affairs Council exemption (CTX) 95, 336, 344, 458, confidence limits 246
(CPAC) 309 460 confirmatory experiments 231
Centre for Medicines Research historical 119±20 consent forms 448
(CMR) 353, 358 limitations 120±1 Consumer Protection Act of 1987 424
chemical diversity 42 monitoring 24 contemporaneous independent
chemical libraries 39 regulations 317±18 treatment allocation 126±7
childbearing 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±9
China see People's Republic of China Clostridium welchii 333 controlling factors in adoption of new
chlordiazepoxide 173 clotting factors 109±10 therapeutic agents 5
Chondroitin 283±4 vitamin K-dependent 110 copyright 433
chronic lymphocytic leukemias 199 Cochrane Collaboration 281 in publishing clinical trials 412±13
chronic toxicity studies 61 Code of Federal Regulations (CFR) 457 corporate culture 456±7
chronology diagrams 272 codes of practice 420 cost-containment strategies 525
cimetidine 203 cogenital abnormalities 167 cost-effectiveness 369
Cimicifuga racemosa 283 Color Additives Amendments 86 cost-to-benefit consideration 4
CIOMS I 382±3 combinatorial chemistry 39, 40, 43 costs see financial aspects
CIOMS II 382±3 Commission for Health Improvement coumadin 158
CIOMS IV 383 (CHImp) 392 Council for International Organizations
civil law 416±18 Committee for Orphan Medical of Medical Sciences
class A drugs 339 Products (COMP) 209±10 (CIOMS) 382±3
class B drugs 339 Committee for Proprietary Medicinal Cox II inhibitors 161
class C drugs 339 Products (CPMP) 209, 340, 341, CRFs 24, 25, 71, 256, 259
clinical competencies 18±23 345, 458 cover sheet 262
clinical data coordinator (CDC) 260 common technical document (CTD) 345 design of format and content 21±2
clinical development 6, 317 communication to prescribers and image review process 262
clinical development plan 55±6, 121 patients 388 managing 26
clinical 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 9
clinical±legal interface 137 research 23±6 critical research organizations see CROs
clinical/marketing interface 138 competency-based education and CROs
clinical outcomes 212, 213 training system (CBETS) 17±18 capability 471

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±4
cross-over experiments 239 company requirements 404±5 design and serendipity 31±44
cross-over studies 124 ±5 contractual framework 392 process 38
cultural challenges 455±7 definition 391, 392 project design 31
cultural responsiveness 457 effectiveness 398±9 drug evaluation 4
CYP2C19 351 guidelines and protocols 392 drug formulations 45±52, 56
CYP2D6 351 implementation in practice 402±4 choice 46
cytokines 32±3, 195±6 ineffectiveness 399±400 pediatric studies 186
cytomegalovirus retinitis 197 key issues 403 safety and efficacy trials 136
overview 391±3 drug holidays 273±4
Dalcon shield 9 patient perspectives 404 Drug Information Association (DIA) 18
data analysis 254±6 politics and history 393±4 drug interactions 137
data collection 119 prospective companies 404 adverse 158
statistician's role 256 relationship with pharmaceutical potential for 382
with integrity 78 industry 394±5 drug labeling 373±6, 386
data confidence 217 staffing 403 European Union (EU) 376
data creation flow chart 261 disease-modifying drugs (DMDs) 31 investigational drugs 25
data entry 262 disproving liability 169 Japan 373±4
data integrity assurance 78±9 Dixon up±down technique 125 USA 374±5
data management 259±67 DNA 33, 35±6, 52, 195, 197, 351 drug licensing 227±9
project material 259 DNA viruses 197 drug management
data package 359±60 donezil 161 training 9
data process status 263 dosage drug metabolism 60
data 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±9
data validity 217 OTC 144 ethnic issues in 349±63
database release memorandum 266, 267 dose determination 57 future 362
database update 262 dose-response date 359 medical practice 355±6
datasets 263 dose±response relationship 254 subjective factors 355±8
Debendox 444 dose ranges terminology, diagnosis and other
decision-making 4, 211, 213±14 gender differences 172 subjective factors 357±8
Declaration of Helsinki 65, 86 dose size 121 drug requirements
Dedrick plot 104 double-blind 237, 241 non-clinical studies 57
demographics double-dummy method 237 drug research in older patients 157±64
elderly population 157 double entry 262 regulatory response 159
Department of Health, Education and Down's syndrome 167 drug risk as epidemiologic problem
Welfare (DHEW) 86±7 downsizing 388 225
depression 161, 174 drop-outs 254±5 drug safety 9
developed countries 157 drug accountability management 25 drug screening flowchart 39

534 INDEX
drug 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±2
drug utilization drug research in older background 85±7
elderly population 158 populations 158±9 economic considerations 294
restrictions 521 pediatric studies 187 meetings with 296
drugs 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 insurance
Durham±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 women
ECU50u 105, 106 adverse event reporting fertility testing 170
ECG 122 (ADRs) 356±7 fetal damage liabilities 178
ECHO model 213 ethnic factors financial aspects 503±14
economic outcomes 213 and population extrapolation 359 charges 506
EDU50u 125 classification of intrinsic and clinical trial medication 507
EEG 110±11, 122 extrinsic 360 consultancy 507
effect-compartment model 107, 109 pharmacologic implications 354 CROs 509±13
effect-distribution model 107 potential sensitivity to 359 equipment costs 508
efficacy 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 boards
Egypt 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 506
elderly 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, 504
elimination rate 96±7 458, 459 travel 506±7
ELISA (enzyme-linked Directives 339±41, 418±19, 424 Fine Chemical Database 40
immunoabsorbent assay) 40±1 drug labeling 376 Fine Chemical Directory 42
embryonic malformation 166 future clinical trial legislation 344 Food and Drug Administration
embryonic stem cells 35 evergreening process 9 Modernization Act
Emergency INDs 299±301 evolutionary designs 125 (FDAMA) 293±4
enzymes 195 expectedness 384 Food and Drug Administration. See
Ephedra spp. 284 expert reports 63±4 FDA
epidemiology 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, 419
epidermal growth factor (EGF) FACS 37 formulary enforcement policies
receptor 32 falsifiability condition 231, 232 521
epilepsy Far East formulary status 137
outcomes 216 pharmaceutical market 495 fraud 443±51
equipoise concept 65 registration dossier compilation 498 animal research 448
equivalence trials 135 trading with 498 British cases 444±5
error analysis 259 FDA 19, 27, 47, 58, 67, 85, 134, 145±7, definition 444
error probabilities 232±3 149, 150, 160, 175, 192, 206, 212, detection 446±7

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 Medicines
gall bladder disease 387 regulations 82±4 Act 1968 332±4
gases 48±9 good laboratory practice (GLP) 55, 57, recommendations 333
gastric emptying time 314 humanistic outcomes 213
women 172 good manufacturing practice Hypericum perforatum 283
Gaucher's disease 194, 195, 198 (GMP) 314 hypertension 161
gender data 165 principles and guidelines 338±9 hypothesis 232
gender data collection 178 standards 338 testing 243
gender 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 208
gender-related research 174±6 indomethacin 158
gene therapy 43, 197±8 HU2u blockers 358 Indonesia
pharmacokinetics 198 Haemophilus influenzae 34 clinical trials 501
gene therapy agents harmonization of data requirements 345 health centres 501
pharmacokinetic properties 193 headache pharmaceutical industry 501±2
General Agreement on Tariffs and diagnosis 142 inflammatory bowel disease 50
Trades (GATT) 440 health economics 212 information systems (IS) 397±8
General Consideration for the Clinical health maintenance organizations information technology (IT) 397±8, 403,
Evaluation of Drugs 174 (HMO) 516 527±8
General Considerations for Clinical network model 517 informed consent 65±7, 73, 121
Trials 458 staff model 517 benefit±risk assessment 131
General 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 162
general pharmacovigilance 228 healthcare 212 emergency patients 67
see also pharmacovigilance healthcare budget 4 essential elements 65±6
generalizability 239±40, 249±50 healthcare provision 4 ethical basis 65
generic drugs 304±5 heart attack in women 166 pediatric studies 187
scandal 9 heart disease in women 166 principles for conducting 75
genetic counseling 170 heart failure 161 responsibility of parties to 67
genetic susceptibility 352±3 height differences 355 substitute 67
genetic variation 351 helium/oxygen mixtures 48 surrogate 66
genomics and new target hepatic clearance unwritten 66
identification 34±5 comparison of predicted and written 65±6
geriatric population see aging actual 99 inhalational toxicology 49
population; older patients equations 98 inhalers 49
Gingko biloba 283 herpes simplex virus 1 (HSV1) 197 initial clinical studies 55
ginseng 284 hexachlorophene toxicity 9 initial non-clinical considerations 56±7
Glasgow Coma Score 67 Hill factor 106 initial proof of principle 56
global 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 35
glomerular 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 187
Goldenthal guidelines 62 Human Genome Project 34 review 72±5

536 INDEX
integrated summary 61, 63 drug labeling 373±4 multiple player influence 522±3
integrated summary of efficacy regulations 307 population and demographics 524±5
(ISE) 257 Japanese health authorities 307±10 terminology 516
integrated summary of safety (ISS) 257 Japanese pharmaceutical laws managed care organization
intellectual property rights 433±4 310±11 (MCO) 516±28
intent-to-treat (ITT) analysis 255±6 types or models 516±17
interference practice 440±1 Kaplan±Meier analysis 128 marketing approval application 343±4
interim analysis 253±4 Kava 284 maximum outsourcing 465
interim efficacy analyses 129 Kefauver±Harris Act 192 MCA 342
International Clearing House for Birth Kefauver±Harris Drug Meat Inspection Act 290
Defects Monitoring 179 Amendements 1962 86, 184, 292, Med-DRA (Medical Dictionary for
International 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±71
International Federation of Associations 25 overview 367
of Pharmaceutical Physicians laboratory charges 506 personnel 368
(IFAPP) 13±14 large, automated, multipurpose, phaseline 371
international regulatory guidelines for population-based systems medical communications 368
safety pharmacology studies 61 (LAMPS) 225±7 medical culture 456, 457
International 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, 522
international treaties 437±40 law of contract see contract law Medicare Prospective Payment System
Internet 4 law of tort 416±18 (PPS) 516
interpretation of measurements 119 LDU50u 58 medications and devices
intranasal administration 50 legal framework for regulating control at study sites 80±1
investigational 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 80
investigational 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 130 418
investigational 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±11
investigators 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 46
investigator's brochure (IB) lubricants 47 meta-analysis 257
new clinical data 21 lyophilizates 51 metabolism
preparation 20 differences in 386
in 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 106
in vitro data collection 95 basic concepts 515 Middle East 492±5
in vitro functional assays 95 cost containment strategies 520±2 agency laws 493
in vitro/in vivo prediction 96±101 emerging trends 527±8 company registration
in vivo data 110 historical perspectives 515±18 requirements 494±5
in vivo models of disease 36 impact on pharmaceutical pharmaceutical and healthcare
in vivo studies 35 industry 519±27 market 492±3
impact on pharmaceutical product life migraine syndrome 118
Japan 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

INDEX 537
Misuse of Drugs drug research in 157±64 Phase IV studies 147
Regulations 1985 339±40 regulatory response 159 prescription-to-OTC switch 146±9
Misuse of Drugs Regulations open-label trials 135 proposed labeling 148
Act 1971 339 Oraflex 9 safety evaluation 143
model parameters 242 oral bioavailability special study designs 149±50
molecular modeling 40 elementary aspects 100 specific clinical testing 145±6
molecular target identification 32±3 prediction 101 tolerability 143
monitoring 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 3
mRNA 34 oral suspensions 46±8 oxazepam 173
multicenter trials 248±50 oral transmucosal administration 50 oxygen/nitrous oxide 48
multinational corporations 455±62 organ transplantation 199
languages 457 orphan disease 203 p-value 243±5
multiplicity 251±3 Orphan Drug Act 203, 207±8, 293 P450 cytochrome enzyme systems 351
mutagenicity studies 59±60 unintended consequences 208 packaging 51±2
mutagenicity testing 170 Orphan Drug legislation of investigational drugs 25
mutations 36 Asian countries 210 of investigational products 22
Mycoplasma genetalium 34 Europe 209±10 package insert 322
USA 209 Palmito caroliniensis 283
National Committee for Quality orphan drugs 203, 312 paraldehyde 50
Assurance (NCQA) 519 benefits from development parallel-group studies 122±3
National Heart and Lung Blood perspective 207 Paris Convention for the Protection of
Institute (NHLBI) 163 classification 204 Industrial Property 1883 437±8
National Health Insurance Drug Price defintion 203 Parkinson's disease 161
List 322 development 206 partial agonists 105
National Institute for Clinical Excellence development disincentives and patent application 441±2
(NICE) 392 obstacles 207 Patent Cooperation Treaty
national reimbursement policies 357 discovery 206 (PCT) 438±40, 442
nausea 150 distribution 206 international phase 439
nebulized drugs 49±50 economic±medical interface 204±5 national phase 439
negligence 417±18, 425 heterogeneous group 203 patent protection 435
new biological entities (NBEs) 336 interested parties 205 patentable subject matter 435±6
new chemical entities (NCEs) 42, 55, marketing 206 patents 433±42
159, 336 marketing benefits in selling 206±7 biotechnology industry 200±1
new 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±79
new drug approval process 320±3 outcomes actions to enhance 274±5
new medicines research 528 classification 273
sponsors of 361 three-dimensional assessment common patterns 273
New Medicines in Women 177 212±13 cost-effectiveness 277
new molecular entities (NMEs) 159, 184 see also pharmacoeconomics and definition 269±70
new uses for old drugs 43 specific areas direct compliance evaluation 270
NHS and pharmaceutical outsourcing 464±5 during clinical trials 270±2
companies 394±5 over-the-counter (OTC) 351 full compliance 273
nitrous oxide/oxygen 48 over-the-counter (OTC) medication 5, improving 275
noise and noise reduction 234, 243, 249 141±51, 289 in elderly population 162
non-clinical summary documents 61 advertising and marketing 150±1 indirect compliance evaluation 270
non-clinical toxicology 55±64 criteria for use 142 interactive packaging 276±7
non-compliance see patient non- development cycle 145 methods of evaluating 270
compliance dosage selection 144 monitoring with feedback 275
Normal distribution 245 efficacy 143±4 non-compliance 273
NSAIDS 158, 161, 358 labeling 149±50 over-compliance 273
null hypothesis 232 market 148 partial compliance 273
Nuremberg Code 86 market support studies 150±1 Phase I clinical studies 271
marketing 145 Phase II clinical studies 271
Office of Research Integrity (ORI) 445 pharmaceutical physician's role Phase III clinical studies 271±2
older patients in 144±6 Phase IV clinical studies 272

538 INDEX
patient 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, 462
patient±consumers 4 regulating 418±20 common designs 122
patient fees 507±8 pharmaceutical research and industry practice 170
Patient Management Strategies 398 development 525±6 objectives and prerequisites 121±5
patient needs 5 Pharmaceutical Research and patient compliance 271
patient non-compliance 254 Manufacturers of America pharmacoeconomics 214
patient package insert 138 (PhRMA) 160, 183 regulatory practice 350
patient participation 124 pharmacoeconomic outcomes small-scale 130
patient rights 4 current and future uses 219±20 toxicological support 61±3
payer±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 147
pentamidine 219 traditional clinical development patient compliance 272
People's 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±5
peptides 194 pharmacokinetic parameters 59, 243 Philippines
performance metrics 481±2 pharmacokinetic properties 121 clinical trials 500±1
perpherazine 351 pharmacokinetic studies 60 health care and pharmaceuticals 500
pessary 51 children 186 regulatory affairs and registration 500
Petasites hybridus 46 pharmacokinetic/pharmacodynamic Phiso-Hex (hexachlorophene) 9
phantom fetus 167, 169 (PK/PD) model/computer- phocomelia 387
Pharmaceutical Affairs Bureau generated feedback 112 Physicians' Desk Reference 386
(PAB) 308±9 pharmacokinetic/pharmacodynamic physicochemical properties 46, 48
pharmaceutical benefit manager (PK/PD) models 192, 198 physiological substance models 109
(PBM) 517, 518, 528 pharmacokinetic/pharmocodynamic physiological systems 35
pharmaceutical companies 191 (PK/PD) models pivotal clinical trials 130
Pharmaceutical Education and Research complex and time-dependent 106±10 placebo comparisons 194
Institute Inc. (PERI) 18 elementary aspects 104±5 placebo control
pharmaceutical 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 57
Pharmaceutical 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 219
pharmaceutical medicine 117±32, 458, 462 population demographics 350
coverage 3±5 industry practice 170 population derivation 265

INDEX 539
population extrapolation and ethnic Proprietary Association of Great definition 203
factors 359 Britain 335 prevalence 203
population inclusion and exclusion proprietary medicinal products RAS 32
criteria 239±41 controls of 340±4 receptor/ligand assays 40
populations and subpopulations 386 prospective cohort epidemiologic receptor science 8
postapproval activities 323±5 studies 224 receptors 32
post-marketing adverse drug experiences protein chemistry 8 sensitivity 353
(AE) 370 protein pump inhibitor 358 recruitment
post-marketing approval medical proteins pediatric studies 186±7
affairs 7 recombinant vs. natural 41 rectal administration 50 ±1
post-marketing safety prothrombin complex activity re-evaluation system 324 ±5
surveillance 370±1 (PCA) 109±10 re-examination system 324
post-marketing studies 133±9 protocols 21, 71, 121, 256, 259 regulatory compliance 425
post-marketing surveillance studies 228 design and preparation 20 regulatory development 6
postmarketing surveillance elements 20 regulatory governance
organization 323±4 pseudoephidrine 158 clinical trials 121
postural hypotension 357 publishing clinical trials 407±14 drug development 19
potency 105 audiovisual presentations at academic regulatory issues
potential sensitivity to ethnic factors 359 meetings 410±11 biotechnology products 192, 199
precision 245±7 CD-ROM vs. textbook 411 regulatory processes
preclinical research and development 6 classic components in peer-reviewed orphan drugs 204
preclinical studies 316 journal 409±10 regulatory strategy 56
preferred provider organization copyright 412±13 renal perfusion 185
(PPO) 517 desirability of, and biases in 408±9 repeated-dose toxicity studies 58±9
pregnancy 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 384
prescribing differences newer forms 411±12 patient compliance 272±3
ethnic differences 352 posters 410 reproduction studies 62
Prescription Drug Users Fee Act Pure Food and Drug Act (PFDA) 290±1 request for proposal (RFP) 465, 474
(PDUFA) 293 research fraud 443
prescription drugs 4, 5 quality assurance 87±8 resource allocations worksheet 475±9
prescription-event monitoring imported drugs and medical devices retroviruses 197
(PEM) 228 (GMPI) 314 review of products on the market
Prescription Medicines Code of Practice sampling 259 pre-1971 337
Authority (PMCPA) 420 quality control 88±90 review process 321±2
Prescription Only Medicines List rules 259 Revised Policy on Inclusion of Women of
(POM) 339 quality of life (QOL) 217, 218 Childbearing Potential in Clinical
press releases 412 quality protocols 21 Trials 175
prestudy visits 23 quality standards 313±14 Reye's syndrome 9
prevalence of a disease 208 quantitative interaction 249 rheumatoid arthritis 161
prion-mediated disease 196 quantitative structure±activity routes of sale and supply 339±40
probability 231, 234, 239 relationships (QSARs) 42 Royal College of Physicians (RCP) 11,
proctitis 50 query resolution 262 13, 445
product defects 425 quinidine 158 Rx-to-OTC switch 146±8
product labeling see drug labeling
product 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 143
product licence application (PLA) 117 random error 242 safety events
product licences 45 randomization 81, 129, 235±7, 239 reporting and recording 76±8
Product Licences of Right (PLRs) 337 randomized blocks 236 safety issues 9, 25
product life cycles 526±7 randomized control trial (RCT) 217 biotechnology products 198±9
pro-glidant 47 randomized controlled clinical trial stopping a clinical trial 128±9
project setup 260 (RCCT) 241 safety measures 240
project team formation 260 rare diseases safety monitoring 381
propranolol 173 case reports 130 postmarketing 381±2

540 INDEX
safety parameters 21 special study designs study specifications 466±71
safety pharmacology 60 OTC 149±50 importance of accuracy 466
international regulatory guidelines specialized designs 128 preparation 471
61 spironolactone 161 worksheet 466±71
safety reports sponsor roles and responsibilities study subjects
preparing 27 479 information to be provided 75±6
safety studies 360 sponsor±CRO subgroups 238
safety surveillance communication/decision-making subspecializations in pharmaceutical
Phase IV clinical trials 136 model 482 medicine 14
St John's Wort 283 end-of-study meeting 483 summary basis of approval (SBA) 323
salt content 355 periodic oversight meetings 482±3 summary of product characteristics
SAM-e 284 problems 465±6 (SPC) 346
sample size 247±8 relationship 479±83 suppositories 50
Saudi Arabia study initiation meeting 482 surveillances studies
healthcare structure 493 sponsors of new medicines 361 postmarketing 386±7
Saw Palmetto 283 spontaneous case reports 384±5 syrups 46±8
scan process 260±2 spontaneously arising phenotypic Systolic Hypertension in the Elderly
schedule 1 339 models 36 Person (SHEP) 163
schedule 2 339 SRC 32
schedule 3 339 stability and impurities 56±7 tablets 46±8
schedule 4 339 stability studies 316 tactical outsourcing 464
schedule 5 340 stability testing 52 target identification 38
Scientific 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±7
scientific experiment 231 standard error (SE) 243 teratogenic issues 167±9
scientific meetings standard error of the mean (SEM) 235 teratogenicity 167
organization and planning 377±80 Standard Normal distribution 245 testing 170
scientific method 231 standard operating procedures teratology studies 62
scintillation proximity assay (SPA) 40 (SOPs) 87 test statistic 243
Secret Remedies 332 statistical bias 236±7 Thailand
seed protection 433 statistical inference 243±7 health care and pharmaceutical
selection bias 236±7 statistical method 231±2 industry 496±7
selection 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, 444
self-medication 141±2 statistical principles 231±47 theophylline 50
sequential analysis study design 126 statistical test 232±3 therapeutic coverage 272±3
sequential cohort designs 123 statistical trial design 248±54 therapeutic index 143
serious adverse event (SAE) overdesign 248 Therapeutic Substances Act
procedures 24 statistics 118±19 (TSA) 333±4
serious diseases 302±4 status reporting 263 Third World 158, 485±502
signal 234 stopping a clinical trial overview 485
signal-to-noise ratio 234, 240±1 efficacy issues 129 three-dimensional outcome
signal transduction enzymes 41 safety issues 128±9 assessment 212±13
significance level 233 strata 238 time course of effect 105
simple hypothesis 232 strategic outsourcing 465 tissue products 199
Singapore 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, 424
skewed dosing 274 structure±activity relationship (SAR) 8, toxic shock syndrome 9
skipped dosing 274 42 toxicokinetic assays 57
societal culture 455±7 Student's t-distribution 244 toxicokinetic data 60
societal development 6 Studies in Support of Special Populations: toxicokinetics 59
socioeconomic influences 357 Geriatrics 159 toxicological coverage 121±2
source data verification 78±9 study closure 26 toxicological support
South 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±61
special populations 137 study documentation 23±4 toxicological testing 46
special studies 63 study initiation 23±4 toxicology

INDEX 541
non-clinical 55±64 Orphan Drug legislation 209 Waxman±Hatch Amendment 293
pediatric studies 186 regulations 289±98 weight differences 355
trade secrets 433 weight-for-height tables for males and
trademarks 433 vaccines 196 females 172
training 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 designs
training program program 214±15 124
competency-based 17±28 variability women
transdermal drugs 50 source of 233±5 disease presentatons 166±7
transgenic technology 35±6 variables measured before and after drug drug development research
treatment-by-center interaction 249 (or placebo) administration 119 165±81
Treatment INDs 301±2 variance 234 drug research subjects 176
treatment withdrawal study designs 128 Venereal Disease Act 1917 333 gastric emptying time 172
Trichomonas 51 vitamin K-dependent clotting in clinical studies 56
Tylenol 9 factors 110 Phase I studies 171±2
type A and B reactions 384±5 volumes of distribution representative population 167, 177
type 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 Property
uncertainty vulnerability Organization (WIPO) 438, 439
source of 233±5 pediatric studies 187 Written Opinion 439
uncertainty conditions 231±2
unmet clinical needs 31 wafers 46±8 Zollinger±Ellison syndrome 203
USA warfarin 109, 158 Zomax 9
drug labeling 374±5 warranty 424±5


Section I
Overview of Pharmaceutical Medicine

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