Table of Contents
Table of Contents
This edition first published 2012, © 2012 by John Wiley & Sons, Ltd.
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Library of Congress Cataloging-in-Publication Data
Pharmacoepidemiology / edited by Brian L. Strom, Stephen E. Kimmel, Sean Hennessy. – 5th ed.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-0-470-65475-0 (hard cover : alk. paper)
ISBN-10: 0-470-65475-9 (hard cover : alk. paper)
ISBN: 978-1-119-95991-5 (epdf)
ISBN: 978-1-119-95992-2 (epub)
ISBN: 978-1-119-95993-9 (mobi)
1. Pharmacoepidemiology. 2. Pharmacology. I. Strom, Brian L. II. Kimmel, Stephen E. III. Hennessy, Sean.
[DNLM: 1. Pharmacoepidemiology–methods. QZ 42]
RM302.5.P53 2012
615'.7042–dc23
2011019285
A catalogue record for this book is available from the British Library.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.
List of Contributors
Trisha Acri
Assistant Professor
Department of Family and Community Medicine
Temple University School of Medicine
Philadelphia, PA
USA
Susan E. Andrade
Senior Research Associate and Research Associate Professor
Meyers Primary Care Institute
and
University of Massachusetts Medical School
Worcester, MA
USA
Elizabeth Andrews
Vice President
Pharmacoepidemiology and Risk Management
Research Triangle Institute Health Solutions
Research Triangle Park, NC
USA
Peter Arlett
Head
Pharmacovigilance and Risk Management
European Medicines Agency
London, UK
Jerry Avorn
Chief Division of Pharmacoepidemiology and Pharmacoeconomics
Brigham and Women’s Hospital
and
Professor of Medicine
Harvard Medical School
Boston, MA
USA
Jeffrey S. Barrett
Director
Laboratory for Applied Pharmacokinetics and Pharmacodynamics
Director
Pediatric Pharmacology Research Unit
The Children’s Hospital of Philadelphia
Research Professor, Pediatrics
Kinetic Modeling and Simulation (KMAS) Core Director
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
USA
David W. Bates
Chief
General Medicine Division
Brigham and Women’s Hospital
and
Professor of Medicine
Harvard Medical School
Boston, MA
USA
Ulf Bergman
Professor, Senior Medical Officer
Division of Clinical Pharmacology
Department of Laboratory Medicine
Karolinska Institute
WHO Collaborating Centre for Drug Utilization Research and Clinical Pharmacological Services
and
Centre for Pharmacoepidemiology
Karolinska University Hospital-Huddinge
Stockholm, Sweden
Jesse A. Berlin
Vice President
Department of Epidemiology
Johnson & Johnson Pharmaceutical Research and Development
Titusville, NJ
USA
Stella Blackburn
EMA Risk Management Development and Scientific Lead
European Medicines Agency
London, UK
Susan J. Blalock
Associate Professor
Division of Pharmaceutical Outcomes and Policy
Eshelman School of Pharmacy
University of North Carolina at Chapel Hill
Chapel Hill, NC
USA
Denise Boudreau
Scientific Investigator
Group Health Research Institute
Seattle, WA
USA
Arthur Caplan
Director
Center for Bioethics
Professor of Medical Ethics
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
USA
M. Soledad Cepeda
Director Department of Epidemiology
Johnson & Johnson Pharmaceutical Research and Development
Titusville, NJ
USA
Robert T. Chen
HIV Vaccine and Special Studies Team Leader
Division of HIV/AIDS Prevention
Centers for Disease Control and Prevention
Atlanta, GA
USA
Patricia F. Coogan
Associate Professor of Epidemiology Slone Epidemiology Center
Boston University
Boston, MA
USA
Francesca Cunningham
Director Center for Medication Safety and Program Manager Outcomes Research PBM Services
Department of Veterans Affairs
Center for Medication Safety
Hines, IL
USA
Gerald J. Dal Pan
Director
Office of Surveillance and Epidemiology
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MA
USA
Gregory W. Daniel
Vice President Government and Academic Research
Healthcore
Alexandria, VA
USA
Hassy Dattani
Research Director
Cegedim Strategic Data Medical Research Ltd
London, UK
Robert L. Davis
Director of Research
Center for Health Research—Southeast
Kaiser Permanente Georgia
Atlanta, GA
USA
Nancy A. Dreyer
Chief of Scientific Affairs
Outcome Sciences Inc.
Cambridge, MA
USA
Antoine C. El Khoury
Leader, Outcomes Research
Global Health Outcomes
Merck & co., Inc
West Point, PA
USA
Chris Feudtner
Associate Professor
Department of Pediatrics
The Children’s Hospital of Philadelphia
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
USA
Brian T. Fisher
Assistant Professor of Pediatrics
Center for Pediatric Clinical Effectiveness
The Children’s Hospital of Philadelphia
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
USA
Cristin Palumbo Freeman
Research Project Manager
Center for Clinical Epidemiology and Biostatistics
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
USA
Nicolle M. Gatto
Senior Director
Epidemiology Worldwide Safety Strategy
Pfizer Inc.
New York, NY
USA
Joel M. Gelfand
Medical Director, Clinical Studies Unit
Assistant Professor of Dermatology and Epidemiology
Senior Scholar, Center for Clinical Epidemiology and Biostatistics
Departments of Dermatology and Biostatistics and Epidemiology
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
USA
Kate Gelperin
Medical Officer
Division of Epidemiology
Office of Surveillance and Epidemiology
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MD
USA
Jason M. Glanz
Epidemiologist
Institute for Health Research
Kaiser Permanente Colorado
Department of Epidemiology Colorado School of Public Health
Denver, CO
USA
Henry A. Glick
Professor of Medicine
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
USA
Robert Gross
Associate Professor of Medicine and Epidemiology
Center for Clinical Epidemiology and Biostatistics
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
USA
Thomas Gross
Deputy Director
Office of Surveillance and Biometrics
Center for Devices and Radiological Health
US Food and Drug Administration
Silver Spring, MD
USA
Gordon H. Guyatt
Professor
Department of Clinical Epidemiology and Biostatistics
McMaster University
Health Sciences Center
and
Department of Medicine
St Joseph’s Hospital
Hamilton
Ontario, Canada
Katherine Haffenreffer
Project Administrator
Harvard Pilgrim Health Care Institute
and
Department of Population Medicine
Harvard Medical School
Boston, MA
USA
Sean Hennessy
Associate Professor of Epidemiology and of Pharmacology
Senior Scholar, Center for Clinical Epidemiology and Biostatistics
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
USA
Ron M.C. Herings
Director
PHARMO Institute
Utrecht The Netherlands
and
Associate Professor of Pharmacoepidemiology
Department of Health Policy and Management
Erasmus University Rotterdam
Rotterdam, The Netherlands
Roman Jaeschke
Professor
Department of Clinical Epidemiology and Biostatistics
McMaster University
Health Sciences Center
and
Professor
Department of Medicine
St Joseph’s Hospital
Hamilton
Ontario, Canada
Bradley C. Johnston
Assistant Professor
Department of Clinical Epidemiology and Biostatistics
McMaster University
Health Sciences Center
Hamilton
Ontario, Canada
Judith K. Jones
President and CEO
The Degge Group Ltd
Arlington, VA
USA
and
Adjunct Professor and Lecturer
University of Michigan School of Public Health Summer Program
Georgetown University
Washington, DC
USA
Jason Karlawish
Professor of Medicine
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
USA
Claudia Karwoski
Director
Division of Risk Management
Office of Surveillance and Epidemiology
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MA
USA
David W. Kaufman
Associate Director
Slone Epidemiology Center at Boston University
and
Professor of Epidemiology
Boston University School of Public Health
Boston, MA
USA
Aaron S. Kesselheim
Assistant Professor of Medicine
Division of Pharmacoepidemiology and Pharmacoeconomics
Department of Medicine
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
USA
Carin J. Kim
Mathematical Statistician
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, MD
USA
Stephen E. Kimmel
Professor of Medicine and Epidemiology
Senior Scholar, Center for Clinical Epidemiology and Biostatistics
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
USA
Karel Kostev
Senior Research Analyst
Centre of Excellence Patient Data
IMS Health GmbH & Co OHG
Frankfurt/Main, Germany
Martin Kulldorff
Professor, Biostatistician
Department of Population Medicine
Harvard Medical School and Harvard Pilgrim Health Care Institute
Boston, MA
USA
Sinéad M. Langan
National Institute for Health Research Clinician Scientist and Honorary Consultant Dermatologist
London School of Hygiene and Tropical Medicine
and St John’s Institute of Dermatology
London, UK
Ebbing Lautenbach
Professor of Medicine and Epidemiology
Senior Scholar, Center for Clinical Epidemiology and Biostatistics
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
USA
Deborah Layton
Principal Research Fellow Honorary Senior Lecturer Portsmouth University
Drug Safety Research Unit academic contact for collaborative programme MSc in Pharmacovigilance
Portsmouth University
Portsmouth, UK
David Lee
Director
Technical Strategy and Quality
Center for Pharmaceutical Management
Management Sciences for Health, Inc.
Arlington, VA
USA
Jacques LeLorier
Professor
Department of Medicine
Department of Pharmacology
Université de Montréal
CHUM/Centre de Researche Hôpital Hôtel-Dieu de Montréal, Montreal,
Quebec, Canada
Samuel M. Lesko
Medical Director and Director of Research
Northeast Regional Cancer Institute
Scranton, PA
USA
and
Adjunct Professor of Public Health Sciences
Pennsylvania State University College of Medicine
Hershey, PA
USA
and
Adjunct Professor of Basic Sciences
The Commonwealth Medical College
Scranton, PA
USA
Hubert G. Leufkens
Professor
Department of Pharmacoepidemiology and Clinical Pharmacotherapy
Utrecht Institute for Pharmaceutical Sciences
Utrecht University
Utrecht, The Netherlands
Mitchell Levine
Professor Department of Clinical Epidemiology & Biostatistics, Department of Medicine McMaster University
Centre for Evaluation of Medicines
Hamilton
Ontario, Canada
Peter K. Lindenauer
Director
Center for Quality of Care Research
Baystate Medical Center
Springfield
and Associate Professor
Department of Medicine
Tufts University School of Medicine
Boston, MA
USA
Marie Lindquist
Director
Uppsala Monitoring Centre
WHO Collaborating Centre for International Drug Monitoring
Uppsala, Sweden
Darren R. Linkin
Assistant Professor of Medicine
Associate Scholar, Center for Clinical Epidemiology and Biostatistics
Perelman School of Medicine at the University of Pennsylvania
and
Philadelphia VA Medical Center
Philadelphia, PA
USA
Helene Levens Lipton
Professor of Pharmacy and Health Policy
Schools of Medicine and Pharmacy
University of California at San Francisco
San Francisco, CA
USA
Sumit R. Majumdar
Professor of Medicine
Department of Medicine
Faculty of Medicine and Dentistry
University of Alberta
Edmonton
Alberta, Canada
Danica Marinac-Dabic
Director
Division of Epidemiology
Office of Surveillance and Biometrics
Center for Devices and Radiological Health
US Food and Drug Administration
Silver Spring, MD
USA
the late Kenneth L. Melmon
Stanford University School of Medicine
Stanford, CA
USA
Colleen J. Metge
Associate Professor (Senior Scholar)
Faculty of Pharmacy
University of Manitoba
Winnipeg
Manitoba, Canada
Allen A. Mitchell
Director
Slone Epidemiology Center at Boston University
and
Professor of Epidemiology and Pediatrics
Boston University Schools of Public Health and Medicine
Boston, MA
USA
Jingping Mo
Senior Director
Epidemiology, Worldwide Safety Strategy
Pfizer Inc.
New York, NY
USA
Yola Moride
Associate Professor
Faculty of Pharmacy
Université de Montréal
and
Researcher
Research Centre
University of Montreal Hospital Centre (CRCHUM)
Montreal, Canada
Sharon-Lise Normand
Professor of Health Care Policy (Biostatistics)
Department of Health Care Policy
Harvard Medical School
and
Professor
Department of Biostatistics
Harvard School of Public Health
Boston, MA
USA
Alexis Ogdie
Instructor in Medicine
Division of Rheumatology
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
USA
Julie R. Palmer
Professor of Epidemiology
Slone Epidemiology Center
Boston University
Boston, MA
USA
John Parkinson
Director
General Practice Research Database (GPRD)
Medicines and Healthcare products Regulatory Agency (MHRA)
London, UK
Pamala A. Pawloski
Research Investigator
HealthPartners Research Foundation
Bloomington, MN
USA
Lars Pedersen
Associate Professor of Clinical Epidemiology
Department of Clinical Epidemiology
Aarhus University Hospital
Aarhus, Denmark
Richard Platt
Professor and Chair
Department of Population Medicine, Harvard Medical School and
Executive Director
Harvard Pilgrim Health Care Institute
Boston, MA
USA
Daniel Polsky
Professor of Medicine
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
USA
Charles Poole
Associate Professor
Department of Epidemiology
Gillings School of Global Public Health
University of North Carolina
Chapel Hill, NC
USA
Judith A. Racoosin
Sentinel Initiative Scientific Lead
Office of Medical Policy
Center for Drug Evaluation and Research
Food and Drug Administration
Silver Spring, MD
USA
Marsha A. Raebel
Investigator
Institute for Health Research
Kaiser Permanente Colorado
and
Clinical Professor
School of Pharmacy
University of Colorado at Denver
Denver, CO
USA
Timothy R. Rebbeck
Professor of Epidemiology
Senior Scholar, Center for Clinical Epidemiology and Biostatistics
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
USA
Shelby D. Reed
Associate Professor in Medicine
Duke University
Durham, NC
USA
Robert F. Reynolds
Vice President
Epidemiology, Worldwide Safety Strategy
Pfizer Inc.
New York, NY
USA
Mary Elizabeth Ritchey
Associate Division Director
Food and Drug Administration
Center for Devices and Radiological Health
Silver Spring, MD
USA
Melissa A. Robb
Sentinel Initiative Program Director
Office of Medical Policy
Center for Drug Evaluation and Research
Food and Drug Administration
Silver Spring, MD
USA
Lynn Rosenberg
Professor of Epidemiology
Associate Director
Slone Epidemiology Center
Boston University
Boston, MA
USA
Rita Schinnar
Senior Research Project Manager and Analyst
Center for Clinical Epidemiology and Biostatistics
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
USA
Sebastian Schneeweiss
Associate Professor of Medicine and Epidemiology
Harvard Medical School
and
Vice Chief
Division of Pharmacoepidemiology
Department of Medicine
Brigham & Women’s Hospital
Boston, MA
USA
Kevin A. Schulman
Professor of Medicine and Gregory Mario and Jeremy Mario Professor of Business Administration
Duke University
Durham, NC
USA
Holger Schünemann
Professor and Chair
Department of Clinical Epidemiology and Biostatistics
McMaster University
Health Sciences Center
and
Professor
Department of Medicine
St Joseph’s Hospital
Hamilton
Ontario, Canada
Art Sedrakyan
Associate Professor
Director
Comparative Effectiveness Program at HSS and NYP
Weill Cornell Medical College
New York, NY
USA
John Seeger
Lecturer in Medicine
Brigham and Women’s Hospital/Harvard Medical School
Boston, MA
USA
Hanna M. Seidling
Head of Cooperation Unit Clinical Pharmacy
Department of Clinical Pharmacology and Pharmacoepidemiology
Cooperation Unit Clinical Pharmacy
University of Heidelberg
Heidelberg
Germany
Saad A.W. Shakir
Professor and Director
Drug Safety Research Unit
Southampton, UK
Rachel E. Sherman
Director, Office of Medical Policy
Center for Drug Evaluation and Research
Food and Drug Administration
Silver Spring, MD
USA
Betsy L. Sleath
Professor and Chair
Division of Pharmaceutical Outcomes and Policy
Eshelman School of Pharmacy
University of North Carolina at Chapel Hill
Chapel Hill, NC
USA
Rachel E. Sobel
Senior Director
Epidemiology
Worldwide Safety Strategy
Pfizer Inc.
New York, NY
USA
Stephen B. Soumerai
Professor of Population Medicine
Professor of Medicine and Director of the Drug Policy Research Group
Department of Population Medicine
Harvard Medical School and Harvard Pilgrim Health Care Institute
Boston, MA
USA
Brian L. Strom
George S. Pepper Professor of Public Health and Preventive Medicine
Professor of Biostatistics and Epidemiology, of Medicine, and of Pharmacology
Chair
Department of Biostatistics and Epidemiology
Director
Center for Clinical Epidemiology and Biostatistics
Vice Dean for Institutional Affairs
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
USA
Samy Suissa
James McGill Professor of Epidemiology, Biostatistics and Medicine
McGill University
and
Director
Centre for Clinical Epidemiology
Lady Davis Research Institute
Jewish General Hospital
Montreal
Quebec, Canada
Sengwee Toh
Assistant Professor
Department of Population Medicine
Harvard Medical School and Harvard Pilgrim Health Care Institute
Boston, MA
USA
Priscilla Velentgas
Director of Epidemiology
Outcome Sciences Inc.
Cambridge, MA
USA
Claudia Vellozzi
Deputy Director
Immunization Safety Office
Division of Healthcare Quality and Promotion
National Center for Emerging and Zoonotic Diseases
Centers for Disease Control and Prevention
Atlanta, GA
USA
Suzanne L. West
RTI Fellow and Senior Scientist
RTI International
Research Triangle Park
and
Department of Epidemiology
Gillings School of Global Public Health
University of North Carolina
Chapel Hill, NC
USA
Janet Woodcock
Director
Center for Drug Evaluation and Research
Food and Drug Administration
Silver Spring, MD
USA
Athena F. Zuppa
Associate Professor of Pediatrics, Anesthesia and Critical Care Medicine
Laboratory for Applied Pharmacokinetics and Pharmacodynamics
Children’s Hospital of Philadelphia
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
USA
Preface
“… If the whole materia medica, as now used, could be sunk to the bottom of the sea, it would be all the better for mankind, and all the worse for the fishes.”
Oliver Wendell Holmes, Medical Essays, Comments and Counter-Currents in Medical Science
The history of drug regulation in the United States is largely a history of political responses to epidemics of adverse drug reactions, each adverse reaction of sufficient public health importance to lead to political pressure for regulatory change.
The initial law, the Pure Food and Drug Act, was passed in 1906. It was a response to the excessive adulteration and misbranding of foods and drugs. The 1938 Food, Drug, and Cosmetic Act was passed in reaction to an epidemic of renal failure resulting from a brand of elixir of sulfanilamide formulated with diethylene glycol. The 1962 Kefauver–Harris Amendment to the Food, Drug, and Cosmetic Act was enacted in response to the infamous “thalidomide disaster,” in which children exposed to thalidomide in utero were born with phocomelia, that is with flippers instead of limbs. The resulting regulatory changes led, in part, to the accelerated development of the field of clinical pharmacology, which is the study of the effects of drugs in humans.
Subsequent decades continued to see an accelerating series of accusations about major adverse events possibly associated with drugs. Those discussed in the first edition of this book included liver disease caused by benoxaprofen, subacute myelo-optic-neuropathy (SMON) caused by clioquinol, the oculomucocutaneous syndrome caused by practolol, acute flank pain and renal failure caused by suprofen, liver disease caused by ticrynafen, and anaphylactoid reactions caused by zomepirac. Added in the second edition were cardiac arrhythmias from astemizole and terfenadine; hypertension, seizures, and strokes from postpartum use of bromocriptine; deaths from fenoterol; suicidal ideation from fluoxetine; hypoglycemia from human insulin; birth defects from isotretinoin; cancer from depot medroxyprogesterone; multiple illnesses from silicone breast implants; memory and other central nervous system disturbances from triazolam; and hemolytic anemia and other adverse reactions from temafloxacin. Further added in the third edition were liver toxicity from the combination of amoxicillin and clavulanic acid; liver toxicity from bromfenac; cancer and myocardial infarction from calcium channel blockers; cardiac arrhythmias with cisapride; primary pulmonary hypertension and cardiac valvular disease from dexfenfluramine and fenfluramine; gastrointestinal bleeding, postoperative bleeding, deaths, and many other adverse reactions associated with ketorolac; multiple drug interactions with mibefradil; thrombosis from newer oral contraceptives; myocardial infarction from sildenafil; seizures with tramadol; eosinophilia myalgia from tryptophan; anaphylactic reactions from vitamin K; and liver toxicity from troglitazone. Added in the fourth edition were ischemic colitis from alosetron; myocardial infarction from celecoxib, naproxen, and rofecoxib; rhabdomyolysis from cerivastatin; cardiac arrhythmias from grepafloxacin; stroke from phenylpropanolamine; bronchospasm from rapacuronium; and many others. New in this fifth edition are progressive multifocal leukoencephalopathy from natalizumab; hepatotoxicity from pemoline and from lumiracoxib; serious cardiovascular complications from rosiglitazone, tegaserod, sibutramine, rimonabant, valdecoxib, pergolide, and propoxyphene; fatal adverse reactions when used with alcohol from hydromorphone; and serious and sometimes fatal brain infections from efalizumab. Many of these resulted in drug withdrawals. Published data also suggest that adverse drug reactions could be as much as the fourth leading cause of death. These and other serious but uncommon drug effects have led to the development of new methods to study drug effects in large populations. Academic investigators, the pharmaceutical industry, regulatory agencies, and the legal profession have turned for these methods to the field of epidemiology, the study of the distribution and determinants of disease in populations.
As this edition goes to press, major new changes have been made in drug regulation and organization, largely in response to a series of accusations about myocardial infarction and stroke caused by analgesics, each detected in long-term prevention trials rather than in normal use of the drugs. For example, the pharmacoepidemiology group at the US Food and Drug Administration (FDA) is being doubled in size, FDA has been given new regulatory authority after drug marketing, and has also been charged with developing the Sentinel Initiative, a program to conduct medical product safety surveillance in a population to exceed 100 million. Further, the development since January 1, 2006 of Medicare Part D, a US federal program to subsidize prescription drugs for Medicare recipients, introduces to pharmacoepidemiology a new database with a stable population of 25 million, as well as the interest of what may be the largest health-care system in the world. These developments portend major changes for our field.
The joining of the fields of clinical pharmacology and epidemiology resulted in the development of a new field: pharmacoepidemiology, the study of the use of and the effects of drugs in large numbers of people. Pharmacoepidemiology applies the methods of epidemiology to the content area of clinical pharmacology. This new field became the science underlying postmarketing drug surveillance, studies of drug effects that are performed after a drug has been released to the market. In recent years, pharmacoepidemiology has expanded to include many other types of studies, as well.
The field of pharmacoepidemiology has grown enormously since the publication of the first edition of this book. The International Society of Pharmacoepidemiology (ISPE), an early idea when the first edition of this book was written, has grown into a major international scientific force, with over 1280 members from 52 countries, an extremely successful annual meeting attracting close to 1000 attendees, a large number of very active committees and scientific interest groups, and its own journal (Pharmacoepidemiology and Drug Safety). In addition, a number of established journals have targeted pharmacoepidemiology manuscripts as desirable. As new scientific developments occur within mainstream epidemiology, they are rapidly adopted, applied, and advanced within our field as well. We have also become institutionalized as a subfield within the field of clinical pharmacology, with a Pharmacoepidemiology Section within the American Society for Clinical Pharmacology and Therapeutics, recently reorganized into a Section on Drug Safety, and with pharmacoepidemiology a required part of the clinical pharmacology board examination.
Most of the major international pharmaceutical companies have founded dedicated units to organize and lead their efforts in pharmacoepidemiology, pharmacoeconomics, and quality-of-life studies. The continuing parade of drug safety crises continues to emphasize the need for the field, and some foresighted manufacturers have begun to perform “prophylactic” pharmacoepidemiology studies, to have data in hand and available when questions arise, rather than waiting to begin to collect data after a crisis has developed. Pharmacoepidemiologic data are now routinely used for regulatory decisions, and many governmental agencies have been developing and expanding their own pharmacoepidemiology programs. Risk management programs are now required by regulatory bodies with the marketing of new drugs, as a means of improving drugs’ benefit–risk balance, and manufacturers are scrambling to respond. Requirements that a drug be proven to be cost-effective have been added to national, local, and insurance health-care systems, either to justify reimbursement or even to justify drug availability. A number of schools of medicine, pharmacy, and public health have established research programs in pharmacoepidemiology, and a few of them have also established pharmacoepidemiology training programs in response to a desperate need for more pharmacoepidemiology manpower. Pharmacoepidemiologic research funding is now more plentiful, and even limited support for training is now available.
In the United States, drug utilization review programs are required, by law, of each of the 50 state Medicaid programs, and have been implemented as well in many managed care organizations. Now, years later however, the utility of drug utilization review programs is being questioned. In addition, the Joint Commission on Accreditation of Health Care Organizations now requires that every hospital in the country have an adverse drug reaction monitoring program and a drug use evaluation program, turning every hospital into a mini-pharmacoepidemiology laboratory. Stimulated in part by the interests of the World Health Organization and the Rockefeller Foundation, there is even substantial interest in pharmacoepidemiology in the developing world. Yet, throughout the world, the increased concern by the public about privacy has made pharmacoepidemiologic research much more difficult.
In the first edition, the goal was to help introduce this new field to the scientific world. The explosion in interest in the field, the rapid scientific progress that has been made, and the unexpected sales of the first edition led to the second edition. The continued maturation of what used to be a new field, the marked increase in sales of the second edition over the first, and the many requests from people all over the world, led to the third edition. Thereafter, much in the field has changed, and the fourth edition was prepared. We also prepared a textbook version, which has been widely used. Now, six years after the fourth edition, the field continues to rapidly change, so it is time for a new edition. For this edition as well, we now include two co-editors who have both shared the work and contributed many important new ideas.
In the process, most chapters in the new edition have been thoroughly revised. Ten new chapters have been added, along with many new authors. With some reorganization of some sections and careful pruning of old chapters, the net size has been kept the same.
As in earlier editions, Part I of this book provides background information on what is included in the field of pharmacoepidemiology, a description of the study designs it uses, a description of its unique problem—the requirement for very large sample sizes—and a discussion about when one would want to perform a pharmacoepidemiology study. Also included is a chapter providing basic principles of clinical pharmacology. Part II presents a series of discussions on the need for the field, the contributions it can make, and some of its problems, from the perspectives of academia, industry, regulatory agencies, and the law. Part III describes the systems that have been developed to perform pharmacoepidemiologic studies, and how each approaches the problem of gathering large sample sizes of study subjects in a cost-effective manner. We no longer attempt to include all the databases in the field, as they have continued to multiply. Instead, in this edition we have combined databases into categories, rather than dedicating a separate chapter to each database. Part IV describes selected special opportunities for the application of pharmacoepidemiology to address major issues of importance. These are of particular interest as the field continues to turn its attention to questions beyond just those of adverse drug reactions. Part V presents state-of-the-art discussions of some particular methodologic issues that have arisen in the field. Finally, Part VI provides our personal speculations about the future of the field. Our expectation is that Parts I, II, III, and VI of this book will be of greatest interest to those new to the field. In contrast, Parts III, IV, V, and VI should be of greatest interest to those with some background, who want a more in-depth view of the field.
This book is not intended as a textbook of adverse drug reactions, that is a compilation of drug-induced problems organized either by drug or by problem. Nor is it intended primarily as a textbook for use in introductory pharmacoepidemiology courses (for which Textbook of Pharmacoepidemiology may be more appropriate). Rather, it is intended to elucidate the methods of investigating adverse drug reactions, as well as other questions of drug effects. It is also not intended as a textbook of clinical pharmacology, organized by disease or by drug, or a textbook of epidemiology, but rather a text describing the overlap between the two fields.
It is our hope that this book can serve both as a useful introduction to pharmacoepidemiology and a reference source for the growing number of people interested in this field, in academia, in regulatory agencies, in industry, and in the law. It will also hopefully be useful as a reference text for the numerous courses now underway in this field. We have been excited by the rapid progress and growth that our field has seen, and delighted that this book has played a small role in assisting this. With this new edition, it will document the major changes the field has seen. In the process, we hope is that it can continue to serve to assist the field in its development.
Brian L. Strom
Stephen E. Kimmel
Sean Hennessy
Philadelphia
Acknowledgements
There are many individuals and institutions to whom we owe thanks for their contributions to our efforts in preparing this book. Over the years, our pharmacoepidemiology work has been supported mostly by grants, contracts, and cooperative agreements from the US government, especially multiple different branches of the National Institutes of Health, the Agency for Healthcare Research and Quality, Food and Drug Administration, and the Department of Veterans Affairs. Other funders of our work include the American Cancer Society, the American College of Cardiology, the American College of Clinical Pharmacy Foundation, the Asia Foundation, the Charles A. Dana Foundation, the Joint Commission on Prescription Drug Use, the Pennsylvania Department of Health, the Rockefeller Foundation, the Andrew W. Mellon Foundation, and the International Clinical Epidemiology Network, Inc. We have also benefitted from project grants from Aetna, Alza Corporation, Amgen, AstraZeneca, Bayer Corporation, Bayer Consumer Care, Berlex Laboratories, Boran Pharmaceuticals, Bristol-Myers Squibb, the Burroughs Wellcome Company, Ciba-Geigy Corporation, COR Therapeutics Inc., GlaxoSmithKline, Glaxo-SmithKline Beecham, Glaxo Wellcome, Health Information Designs, Inc., Hoechst-Roussel Pharmaceuticals, Hoffman-La Roche, Inc., Integrated Therapeutics, Inc., a subsidiary of Schering-Plough Corporation, International Formula Council, Key Pharmaceuticals Inc., Marion Merrell Dow, Inc., McNeil Consumer Products, McNeil Pharmaceuticals, Mead Johnson Pharmaceuticals, Merck and Company, Novartis Pharmaceuticals Corp., Pfizer Inc, Pharming, PharMark Inc., A.H. Robins Company, Rowell Laboratories, Sandoz Pharmaceuticals, Schering Corporation, Searle Pharmaceutical, Shire, Smith Kline and French Laboratories, Sterling Winthrop Inc., Syntex, Inc., Takeda Pharmaceuticals North America, the Upjohn Company, and Wyeth-Ayerst Research. In addition, generous support to our pharmacoepidemiology training program has been provided by Abbott Laboratories, Alza Corporation, Amgen, Aventis Pharmaceuticals, Inc., Berlex Laboratories, Inc., Ciba-Geigy Corporation, Genentech, Inc., Hoechst-Marion-Roussel, Inc., Hoffman LaRoche, Integrated Therapeutics Group, Inc., Johnson and Johnson, Mary E Groff Charitable Trust, Merck and Company, Inc., McNeil Consumer Product Company, McNeil Consumer Healthcare, Novartis Pharmaceuticals Corporation, , Pfizer Inc., Sanofi Aventis, Sanofi Pasteur, SmithKline Beecham Pharmaceuticals, Whitehall-Robins Healthcare, and Wyeth-Ayerst Research. Finally, we would like to thank the University of Pennsylvania. While none of this support was specifically intended to support the development of this book, without this assistance, we would not have been able to support our careers in pharmacoepidemiology. Finally, we would like to thank our publisher, John Wiley & Sons, Ltd., for their assistance and insights, both in support of this book, and in support of the field’s journal, Pharmacoepidemiology and Drug Safety.
Rita Schinnar’s contributions to this book were immeasurable, encompassing both the role of Managing Editor and reviewing all of the chapters, editing them thoughtfully and posing substantive questions and issues for the authors to address. She also co-authored one chapter and assisted BLS with researching topics to update his other chapters. Catherine Vallejo assisted with early arrangements to contact the authors. Finally, Anne Saint John provided superb help in preparing both the manuscripts for my chapters and all of the other chapters for submission to Wiley.
BLS would like to thank Steve Kimmel and Sean Hennessy for joining him as co-editors in this edition. These are two very special and talented men. It has been BLS’s pleasure to help to train them, now too many years ago, help them cultivate their own careers, and see them blossom into star pharmacoepidemiologists in their own right, now extremely effective and successful. It is a wonderful to be able to share with them this book, which has been an important part of BLS’s life and career.
BLS would also like to thank his parents for the support and education that were critical to his being able to be successful in his career. BLS would also like to thank Paul D. Stolley, M.D., M.P.H. and the late Kenneth L. Melmon, M.D., for their direction, guidance, and inspiration in the formative years of his career. He would like to thank his trainees, from whom he learns at least as much as he teaches. Last, but certainly not least, BLS would like to thank his family—Lani, Shayna, and Jordi—for accepting the time demands of the book, for tolerating his endless hours working at home on it, and for their ever present love and support.
SEK expresses his sincere gratitude to BLS for his almost 20 years as a mentor and colleague and for the chance to work on this book, to his parents for providing the foundation for all of his work, and to his family—Alison, David, Benjamin, and Jonathan—for all their support, patience, and willingness to engage in “no talking time” in the study while Dad worked.
SH also thanks BLS, his long-time friend and career mentor, and all of his students, mentees, and collaborators. Finally, he thanks his parents; and his family—Kristin, Landis, and Bridget—for their love and support.