Cover

Contents

ANTHONY W. FOX

MICHAEL D. YOUNG & PETER D. STONIER

PETER MARKS & SHEILA GWIZDAK

RONALD R. COBB & LESLIE J. MOLONY

ROBERT SANDS & DOUGLAS ROY

ANTHONY W. FOX

FREDERICK RENO

ANTHONY W. FOX

STEPHEN H. CURRY, HELEN H. DECORY, & JOHAN GABRIELSSON

ANTHONY W. FOX

LISA R. JOHNSON-PRATT

BARRY MISKIN

LIONEL D. EDWARDS

RITA HATTEMER-APOSTEL

PAUL STARKEY

LIONEL D. EDWARDS

LIONEL D. EDWARDS

LIONEL D. EDWARDS

LIONEL D. EDWARDS, J-M. HUSSON, E. LABBÉ, C. NAITO, M. PAPALUCA AMATI, S. WALKER, R.L., WILLIAMS, & H. YASURHARA

ANTHONY W. FOX

ANTHONY W. FOX & ANNE-RUTH VAN TROOSTENBURG

BERT SPILKER

BRUCE H. MORIMOTO & ANTHONY W. FOX

DAVID A. SHAPIRO & ANTHONY W. FOX

DANIEL C. MALONE, EDWARD P. ARMSTRONG, & MIRZA I. RAHMAN

RAYMOND J. TOWNSEND, JANE T. OSTERHAUS, & J. GREGORY BOYER

HUGH H. TILSON

DAN ANBAR

T.Y. LEE, MICHAEL MINOR, & LIONEL D. EDWARDS

DR. JEAN-MICHEL MÉTRY

ANTHONY W. FOX

GABRIEL LOPEZ & THOMAS HOXIE

ANTHONY W. FOX

WILLIAM KENNEDY & LIONEL D EDWARDS

ANTHONY W. FOX

JOHN P. GRIFFIN

A-R. VAN TROOSTENBURG & G. TABUSSO

ETIENNE LABBÉ

EDDA FREIDANK-MUESCHENBORN & ANJA KÖNIG

YAN YAN LI STARKEY

DARSHAN KULKARNI

GREGORY P. GEBA

ANTHONY W. FOX

MIRZA I. RAHMAN & ROBBERT P. VAN MANEN

ANTHONY W. FOX

ANTHONY W. FOX

ZOFIA DZIEWANOWSKA & LINDA PACKARD

RONALD D. MANN

KATIE P.J. WOOD

ANDREW J. FLETCHER

SARAH CROFT

JANE BARRETT

R. DRUCKER & R. GRAHAM HUGHES

JONATHAN BELSEY

HAN W. CHOI & JAE HONG LEE

GABRIEL LOPEZ

JOHN R. VOGEL

ROBERT J. CHAPONIS, CHRISTINE HANSON-DIVERS, & MARILYN J. WELLS

Title

Contributors

Anbar, Dan
DANA Pharmaceutical Consulting, Inc., NJ, USA Email:

Armstrong, Edward
Pharmacy Practice and Science, College of Pharmacy, University of Arizona, USA

Barrett, Jane
Gawsworth, Cheshire, UK Email:

Belsey, Jonathan
JB Medical Ltd, Sudbury, Suffolk, UK Email:

Boyer, J. Gregory
Accreditation Council for Pharmacy Education, Chicago, ILL, USA

Chaponis, Robert J.
Novartis, Parsippany, NJ, USA Email:

Choi, Han W.
Oracle Investment Management, Inc., Greenwich, CT, USA Email:

Cobb, Ronald R.
RiverWood BioConsulting Inc., Gainesville, FL, USA Email:

Croft, Sarah
Shook, Hardy and Bacon International LLP, London, UK Email:

Curry, Stephen, H.
University of Rochester, Rochester, NY, USA Email:

DeCory, Helen H.
Bausch and Lomb Inc.,Rochester, NY, USA

Drucker, R.
Technomark Life Sciences LLP, Durham, NC, USA

Dziewanowska, Zofia
New Drug Associates, Inc., La Jolla, CA, USA Email:

Fletcher, Andrew J.
Temple University School of Pharmacy, PHARM-QA/RA, Philadelphia, PA, USA Email:

Freidank-Mueschenborn, Edda
Bungalowsiedlung 1 B, D-17406 Rankwitz, Germany

Gabrielsson, Johan
AstraZeneca AB, Gothenburg, Sweden

Geba, Gregory P.
Clinical Development, MedImmune, LLC, Gaithersburg, MD Email:

Griffin, John P.
Asklepieion Consultancy Ltd, Welwyn, Hertfordshire, UK Email:

Sheila Gwizdak
Pfizer Inc., New London, CT, USA

Hanson-Divers, Christine
AstraZeneca, Cary, NC, USA

Hattemer-Apostel, Rita
Verdandi AG, 8049 Zurich, Switzerland Email:

Hoxie, Thomas
Hoxie & Associates LLC, Millburn, NJ, USA

Husson, Jean-Marc
Paris, France

Hughes, R. Graham
Consultant in Pharmaceutical Development, Merlimont, France

Johnson-Pratt, Lisa R.
Bryn Mawr, PA, USA Email:

Kennedy, William

König, Anja
Engelhard Arzneimittel AG, Niederdorfelden, Germany

Kulkarni, Darshan
The Kulkarni Law Firm, Philadelphia, PA, USA Email:

Labbé, Etienne
UCB S.A., Brussels, Belgium

Lee, Jae Hong
Morrison & Foerster LLP, San Diego, CA, USA Email:

Lee, T.Y.
Clinical Development and Asian Ventures, Kendle International Inc.,Cincinnati, OH, USA

Lopez, Gabriel
Basking Ridge, NJ, USA Email:

Malone, Daniel
Pharmacy Practice and Science, College of Pharmacy, University of Arizona, USA

van Manen, Robbert
Health Economics and Clinical Outcomes Research, Medical Affairs, Centocor Inc., Horsham, PA, USA

Mann, Ronald
University of Southampton, Hants, UK Email:

Marks, Peter
Pfizer Limited, Sandwich, Kent, UK Email:

Métry, Jean-Michel (Deceased)

Minor, Michael
Clinical Development and Asian Ventures, Kendle International Inc., Cincinnati, OH, USA

Miskin, Barry
Department of Surgery, Nova Southeastern University, College of Osteopathic Medicine, Fort Lauderdale – Davie, Florida, USA Email:

Molony, Leslie J.
Transgeneron Therapeutics, Inc., Gainesville, FL, USA Email:

Morimoto, Bruce H.
Allon Therapeutics Inc., Redwood City, CA, USA Email:

Naito, C.
Teikyo University, Tokyo, Japan

Osterhaus, Jane T.
Wasatch Health Outcomes, Park City, UT, USA Email:

Packard, Linda
American Academy of Pharmaceutical Physicians, Research Triangle Park, NC, USA

Papaluca Amati, Marisa
European Agency for the Evaluation of Medicinal Products, London, UK

Rahman, Mirza I.
Health Economics and Reimbursement, Evidence Based Medicine, Ortho-Clinical Diagnostics, Inc., Rochester, NY, USA Email:

Reno, Fred (retired)
Merritt Island, FL, USA

Roy, Douglas
Division of Pathway Medicine, Medical School, University of Edinburgh, Edinburgh, UK

Sands, Robert
Sanofi-aventis, Cambridge, MA, USA Email:

Shapiro, David A.
Intercept Pharmaceuticals, San Diego, CA, USA Email:

Spilker, Bert
Bert Spilker Associates, Bethesda, MD, USA Email:

Starkey, Paul W.
Merck Consumer Care, Whitehouse Station, NJ, USA Email:

Starkey, Yan Yan Li
GlaxoSmithKline Consumer Healthcare, Parsippany, NJ, USA Email:

Tabusso, Giuliana
Milan, Italy Email:

Tilson, Hugh H.
School of Public Health, University of North Carolina, Chapel Hill, NC, USA Email:

Townsend, Raymond J.
Elan Pharmaceuticals, San Diego, CA, USA Email:

van Troostenburg, Anne-Ruth
Takeda Group R&D, London, UK Email:

Vogel, John
John R. Vogel Associates Inc., Kihei, HI, USA Email:

Walker, Stuart
Centre for Medicines Research, International Institute for Regulatory Science, London UK Email:

Wells, Marilyn J.
East Stroudsburg University, East Stroudsburg, PA, USA

Williams, Roger L.
US Pharmacopia, Rockville, MD, USA

Wood, Katie P.J.
Foster City, CA, USA Email:

Yasurhara, H.
Teikyo University, Tokyo, Japan

Young, Michael
MDY Associates, Philadelphia, PA, USA Email:

Preface to the First Edition

Pharmaceutical medicine is a relatively new, but rapidly growing, academic discipline. As these trends continue into the 21st century, pharmaceutical physicians are increasingly regarding consultancy work and contract research organization (CRO) affiliation as good career opportunities, and now recognize the need for continuing education and training in this broad spectrum discipline.

As editors, we would like to thank our contributors for their expertise, their dedication, and their vision. We would like to thank and acknowledge the work and counsel of our colleague Robert Bell, MD, PhC, 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, Ltd, 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

Preface to the Second Edition

Since the first edition of this book, pharmaceutical medicine has only become more diverse and has also become widely accepted as a recognized medical specialty, for example, with its first graduates of specialist training in the United Kingdom, to add to those of Switzerland and Mexico. This has been accompanied by pharmaceutical medicine’s rapid progress toward specialty recognition within the European Community, and many changes in the pharmaceutical environment. So, we have taken this book further with this second edition. There are new chapters on European regulations, risk management, the Middle East, Asia, and other topical subjects in pharmaceutical medicine. Those chapters that did appear in the first edition have all been brought up to date.

But this book is for all those working in pharmaceutical medicine, regardless of their degrees, titles, or affiliations. Although it comprehensively covers the internationally harmonized syllabus for the Diplomas in Pharmaceutical Medicine that are awarded in Belgium, Switzerland, and the United Kingdom, this book will also usefully serve those teaching other types of certificates and (usually Master’s) degrees in this field, as well as being a vade mecum for those who are not undertaking academic courses.

We would again like to thank the team at John Wiley and Sons, Ltd, Chichester (UK). Hannah Bradley got this second edition started, but then went off on a tour around the world; the editors strenuously deny that they are the reason why. Lucy Sayer and Juliet Booker have since piloted the ship to the dock-side, successfully cajoling us into getting this edition done before its second decade. Not least, we would like to thank you, the reader, for your continued support and suggestions. So here is our second edition, it is more than a simple update, and it is even less US-centric than before.

Lionel Edwards
Andrew Fletcher
Tony Fox
Peter Stonier

Preface to the Third Edition

Pharmaceutical medicine is now practiced by people with a wider range of backgrounds than ever before. Clinical trials now demand the skills of ethicists, clinical pharmacologists, dental surgeons, medical practitioners, nurses, psychologists, regulators, and many others who will have attended diverse types of graduate and medical schools. This book is for all of them.

Pharmaceutical medicine is a discipline that is also spreading geographically. Not only are clinical trials now being conducted on a global scale, but also academic rigor in pharmaceutical medicine is being pursued in more and more countries. For example, we anticipate that during the currency of this edition the Diploma in Pharmaceutical Medicine, which began in the United Kingdom, either has already been or will have become established in Belgium, India, Mexico, South Africa, and Switzerland. In addition, there are well-established Master of Science degrees, covering much of the same syllabus, in most of the developed world. We have aimed this textbook to support all these academic endeavors.

Like the discipline itself, perseverance with our particular brand of editing has spread geographically during this third edition. We began with Lucy Sayer, who was bravely willing to take us on, yet again, from Portsmouth, UK. Then, one previously unpublished consequence of the merger of John Wiley and Sons with Blackwell Publishing was that Adam Gilbert, Robyn Lyons, and Gill Whitley accepted the awkward role of joining an ongoing project, while blissfully unaware of the cantankerous editors that came with it. But pressure is load divided by the area receiving it, and our load now is borne across a broad arc extending from Oxford, via London, to Normandy. We hope that this spreading of the load has reduced the megaPascals that we have created.

Other people deserve our thanks because this third edition would never have appeared without them. As before, these include Rob Bell MD, PhC and Andrew Fletcher MB BChir, MSc, DipPharmMedRCP, FFPM, both of whom were seminal to this project. Our families, too, are big indirect contributors.

But the reason that we have done this, now for the third time in a decade, is because of you, the reader, and through you, even if it is vicariously, foryourpatients.

Lionel Edwards
Tony Fox
Peter Stonier

About the Editors

Lionel D. Edwards, MB, BS, LRCP, MRCS, Dip COG, FFPM, is President of Pharma Pro Plus Inc., a drug development consulting company. Dr Edwards has been involved in all aspects of clinical trials for over 37 years on many different research drug and devices in 10 therapeutic areas. Previously, he was Senior Director at Novartis, a managing consultant at PA consulting, Vice President of Clinical Research at Bio-Technology Pharmaceutical Corporation, a small biotechnology firm operating both in the United States and internationally. Prior to this, he worked at Noven Inc., a small Skin Patch Technology firm with large International licensed partners: CIBA and Rhone Poulenc Rorer. He was Assistant Vice President, International Clinical Research at Hoffman-La Roche, Senior Director of Schering-Plough International Research, and Director of US Domestic Gastrointestinal, Hormonal, and OTC Research Departments. Dr Edwards chaired the PMA (PhRMA) Special Populations Committee, and also sat on the Institute of Medicine Committee for Research in Women, through the US National Institutes of Health. He also served on the Efficacy subcommittee Topic 5 (Acceptability of Foreign Clinical Data) for the International Committee on Harmonization (ICH) and contributed to the working paper on E Topic 1 (Research in Geriatric Patients). Dr Edwards is a Fellow of the Faculty of Pharmaceutical Medicine and an Adjunct Professor at Temple University Graduate School of Pharmacology. He has taught for the Pharmaceutical Education & Research Institute for over 12 years and was on the teaching faculty of the National Association of Physicians. He is a Founder member of the American Academy of Pharmaceutical Physicians now part of the Association of Clinical Research Professionals (ACRP). Dr Edwards has homes in New Jersey and Florida.

Anthony (“Tony”) W. Fox, BSc, MBBS, FFPM, FRCP, MD(Lond), DipPharmMedRCP, CBiol FIBiol is President of EBD Consulting, and one of four Managing Directors of FGK Representative Services (Munich, Germany and Zug, Switzerland). From The (now Royal) London Hospital, after general clinical training, he was Rotary International Fellow at Emory University (Atlanta, Georgia), and CIBA-Geigy Fellow at Harvard. Industrial positions with Procter and Gamble, Glaxo Inc (Research Triangle Park, North Carolina), and a small company called Cypros Pharmaceuticals (Carlsbad, California) came next. From time to time, he serves as Chief Medical Officer for small companies (currently Conatus Pharmaceuticals and Zogenix Inc., both in San Diego, California). Tony was a Charter Member, and sometime Vice-President and Trustee, of the American Academy of Pharmaceutical Physicians; he is also a founder, Secretary, and Treasurer of the Southern California Pharmaceutical Medicine Group. He is a liveryman guardant of the Society of Apothecaries of London, and is a voluntary Associate Clinical Professor at the University of California, San Diego. His publications span several areas of pharmaceutical medicine, including regulation, pharmacology, clinical trial methodology, pharmacovigilance, migraine, and analgesics, with occasional excursions into toxicology and human metabolism. He is a named inventor on several patents. Tony is currently one of the six editors of Int J Clin Pharmacol Ther, and the Consulting Editor for Pharmaceutical Medicine. Proud to be an Essex man (!), he researches the history of that county, and is a Fellow of the Royal Geographical Society, the Royal Numismatic Society, and the Royal Society for the Encouragement of Arts, Manufactures, and Commerce (FRSA).

Peter D. Stonier, BA, BSc, PhD, MBChB, MRCPsych, FRCP, FRCPE, FFPM has over 30 years experience in pharmaceutical medicine. He is a graduate of Manchester Medical school, qualifying in 1974, following a BSc degree in Physiology (University of Birmingham) and a PhD in protein chemistry (inborn errors of metabolism, University of Sheffield). He is a pharmaceutical physician and was Medical Adviser with the UK Hoechst Group of companies from 1977, serving as Medical Director and Board Director until 2000. He is Group Medical Director of the pharmaceutical company Amdipharm plc. Formerly he was President of the International Federation of Associations of Pharmaceutical Physicians (IFAPP) and Chairman of the British Association of Pharmaceutical Physicians (BrAPP). He is a founder Board member and Past President of the Faculty of Pharmaceutical Medicine (FPM), Royal Colleges of Physicians, UK, and is currently Director of Education & Training of the Faculty.

He is Visiting Professor in Pharmaceutical Medicine at King’s College London, School of Biomedical & Health Sciences. In 1993, while Visiting Professor in Pharmaceutical Medicine at the University of Surrey, the first Masters programme (MSc) in Pharmaceutical Medicine was introduced under his co-direction.

His publications include texts in pharmaceutical medicine and edited works in human psychopharmacology, clinical research and paediatric clinical research, medical marketing, and careers with the pharmaceutical industry. In 2002 he became Honorary Member of the Belgian College of Pharmaceutical Medicine. He is a member of the Council for Education in Pharmaceutical Medicine (CEPM/IFAPP). In 2006 he received the Lifetime Achievement Award of the Academy of Pharmaceutical Physicians and Investigators (APPI/ACRP) for distinguished contributions and leadership in the field of pharmaceutical medicine.

SECTION I

OVERVIEW OF PHARMACEUTICAL MEDICINE

CHAPTER 1

THE PRACTICE AND PRACTITIONERS OF PHARMACEUTICAL MEDICINE

Anthony W. Fox

EBD Group Inc., Carlsbad, CA, USA and Munich, Germany, and Skaggs SPPS, University of California, San Diego, USA

Pharmaceutical medicine is unquestionably a young specialty, formalized within the past forty years or so, and its diversity is probably greater than most medical specialties. It is also a specialty that is frequently misunderstood by those outside it.

The diversity of pharmaceutical medicine

Elements of what we regard today as pharmaceutical medicine have resided in the specialties of general and/or internal medicine for a long time. Some of these may be found in the chapters that follow, but obvious examples include Lind’s clinical trial (see the index) and Withering’s bit of pharmacognosy when he identified Digitalis purpurea as a treatment for what was then called dropsy. Moreover, every prescription written is a clinical trial of some sort, where n = 1, because human beings are anisogenetic.

Pharmaceutical medicine is also a discipline that overlaps with many others: Techniques shared with the fields of epidemiology and public health are obvious. Moreover, like orthopedics or dental surgery, there are borrowings from as far afield as the discipline of engineering (e.g., adaptive clinical trials designs, and some aspects of pharmaceutics). Ever since the need to demonstrate efficacy, tolerability, and purity in drug products (and their equivalents in diagnostics and devices), pharmaceutical medicine has been evidence-based. It is interesting that only lately have the more venerable medical specialties adopted an interest in evidence-based approaches to clinical practice, slowly catching up with pharmaceutical physicians!

The diversity of the practitioners

It is therefore unsurprising that the diverse discipline of pharmaceutical medicine is populated by people with varied educational backgrounds. There can be no doubt that clinical experience is always a good prelude to a career in pharmaceutical medicine. But this experience can be found among dental surgeons, medical practitioners, nurses, pharmacists, physical therapists, psychologists, and many other members of the allied health professions; satisfying careers in pharmaceutical medicine, and international distinction, are available to people with all these sorts of early training. For those with a lifelong thirst to learn on a cross-disciplinary basis, it is this breadth of intellectual interaction that forms one of the greatest attractors to the specialty.

As a generalization, one difference between pharmaceutical medicine and other medical specialties is the sizes of the teams that one works within. General practitioners, for example, probably work with six (or so) other types of professional (perhaps nurses, health visitors, administrators, their hospital colleagues, social workers, and, doubtless from time to time, the judiciary). Radiologists might add radiographers and physicists to this list and delete health visitors and social workers. But in comparison, the following list of nouns comprises pharmaceutical medicine, all of which have their own specialists (in no particular order): ethics, chemistry, pharmacology, computational modeling, pharmaceutics, project planning, toxicology, regulatory affairs, logistics, quality control engineering, biostatistics, pharmacogenomics, clinical trials, politics, economics, public relations, teaching, pharmacovigilance, marketing, finance, pharmacokinetics, technical writing, data automation, actuarial analysis, pharmacoeconomics, information science, publishing, public health, international aid and development, intellectual property, and other forms of law; and this is not an exhaustive list. Conversance, if not advanced capability, with these specialists should be an early goal of any career in pharmaceutical medicine.

Surely, there is no other industry where as many diverse professionals all have the sick patient as their ultimate concern?

Problem-solving in the pharmaceutical enterprise is often by teamwork. For physicians and pharmacists, the greatest difference between this specialty and all others is the value placed on their versatility and adaptability. Moreover, these specialists must learn that in pharmaceutical medicine they are unlikely to be as dominant in decision-making as in ordinary clinical practice. Knowing when to lead, when to follow, and when to get out of the way, rather than presuming a leadership role in all situations, will always be valued.

Organizations and educational systems

There is no need to embark on international disputes about who got where first. For more than thirty years, most countries in the developed world have had one or more national societies or academies devoted to the specialty of pharmaceutical medicine. All hold education and training as central to their mission, whereas some societies engage in the regulatory or political debates over particular issues.

In the European Economic Area (the European Union plus Iceland, Norway, and Lichtenstein) together with Switzerland, pharmaceutical medicine is becoming recognized as a specialty deserving of its own program of specialist training with accredited certification, through a Certificate of Completion of Training (CCT) or equivalent. To date, the United Kingdom, Ireland, Belgium and Switzerland are European countries that have formally recognized the specialty of pharmaceutical medicine.

These higher qualifications are attained after obtaining a more general knowledge base for the specialty. The latter has been examined by the Royal Colleges of Physicians (RCP) in the United Kingdom for more than thirty years and its Diploma in Pharmaceutical Medicine (DipPharmMedRCP) qualifies the holder as a Member of the Faculty of Pharmaceutical Medicine (MFPM) within those colleges. The Belgian Academy of Pharmaceutical Medicine and the Basel, Switzerland-based European Centre for Pharmaceutical Medicine (ECPM) with three associated Universities (EUCOR) have diplomas that are recognized reciprocally with the DipPharmMedRCP. Mexico has also recognized the specialty of pharmaceutical medicine. Progress towards an analogous goal (“Board certification”) is being made in North America. The international compatibility and recognition of these qualifications would seem essential in a world where drug development is being increasingly globalized, drug regulation has become increasingly harmonized, and many employment opportunities are in companies that are now international conglomerates.

This is not to say, however, that qualifications in pharmaceutical medicine are uniquely enabling to the practitioner. All of the long list of sub-specializations mentioned above have their own diplomas and degrees. Human resources departments have to be well-informed about the diversity of formal recognitions held by the many specialists who can contribute to the work of the industry and its regulators.

Finally, in pursuit of evidence for all the optimism above, it should be noted that in the year 2000, in the (then) American Academy of Pharmaceutical Physicians (AAPP), more than 90% of members indicated satisfaction with their choice of specialty. This was unlike the results of similar surveys conducted within other medical sub-specialties. What is now the Academy of Pharmaceutical Physicians and Investigators (APPI), and the Association of Clinical Research Professionals (ACRP) thrive, and have transatlantic activities.

Further reading

Smethurst D. Pharmaceutical medicine: making the leap. Student BMJ 2004; 12 :45–58.

Stonier PD (ed.). Careers with the Pharmaceutical Industry. John Wiley & Sons Ltd: Chichester UK, 2003, second edition. ISBN 0-470-84328-4.

Useful websites include: and (both accessed April 20, 2010).