30
PHARMACOVIGILANCE Second Edition Editors RONALD D. MANN ELIZABETH B. ANDREWS
PHARMACOVIGILANCE
Second Edition
Editors
RONALD D. MANN
ELIZABETH B. ANDREWS
PHARMACOVIGILANCE
PHARMACOVIGILANCE
Second Edition
Editors
RONALD D. MANN
ELIZABETH B. ANDREWS
Copyright © 2007 John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester,West Sussex PO19 8SQ, England
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Library of Congress Cataloging in Publication Data
Pharmacovigilance / edited by Ronald D. Mann, Elizabeth Andrews. — 2nd ed.p. ; cm.
ISBN-13: 978-0-470-01803-3 (alk. paper)ISBN-10: 0-470-01803-8 (alk. paper)1. Pharmacoepidemiology. I. Mann, Ronald D. (Ronald David), 1928– II. Andrews, Elizabeth B.[DNLM: 1. Pharmaceutical Preparations—adverse effects. 2. Drug Toxicity—classification.3. Pharmacoepidemiology—methods. 4. Product Surveillance, Postmarketing QZ 42 P5375 2006]RM302.5.P545 2006363.19′463—dc22 2006036640
Anniversary Logo Design : Richard J. Pacifico
British Library Cataloguing in Publication Data
A catalogue record for this book is available from the British Library
ISBN 978-0-470-01803-3
Typeset in 10/12pt Times by Integra Software Services Pvt. Ltd, Pondicherry, IndiaPrinted and bound in Great Britain by Antony Rowe Ltd, Chippenham, WiltshireThis book is printed on acid-free paper responsibly manufactured from sustainable forestry inwhich at least two trees are planted for each one used for paper production.
Contents
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii
PART I. THE BASIS OF PHARMACOVIGILANCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Ronald D. Mann and Elizabeth B. Andrews
2. Legal Basis – EU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Nicholas Macfarlane, Paul Brown, Caroline Moore, Claire Taylor,Uwe Froehlich, Tanja Barton, Olivier Banchereau and Paola La Licata
3. Legal Basis – United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25Jayne P. Bultena
4. Ethical Oversight, Consent and Confidentiality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35Donna A. Boswell and Elizabeth B. Andrews
5. Pharmacovigilance-Related Topics at the Level of the International Conference onHarmonisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51Priya Bahri and Panos Tsintis
6. Periodic Safety Update Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63Patrice Verpillat and Mondher Toumi
7. Non-Clinical Safety Evaluation and Adverse Events in Phase I Trials . . . . . . . . . . . . . . . . . . . . . . . . . 75Patricia M. Reed, Stuart J. Mair and Stephen Freestone
8. Mechanisms of Adverse Drug Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85Munir Pirmohamed and B. Kevin Park
9. Micturin and Torsades de Pointes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105Richard N. Wild
10. Withdrawal of Terodiline: A Tale of Two Toxicities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109Rashmi R. Shah
11. Nomifensine and Haemolytic Anaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137Peter D. Stonier and J. Guy Edwards
vi CONTENTS
PART II. SIGNAL GENERATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
12. WHO Programme – Global Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151I. Ralph Edwards and Cecilia Biriell
13. Medical Dictionary for Regulatory Activities (MedDRA®) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167Elliot Brown
14. Regulatory Pharmacovigilance in the EU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185Priya Bahri, Panos Tsintis and Patrick C. Waller
15. Spontaneous Reporting – UK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199Sarah Davis, Bridget King and June M. Raine
16. Spontaneous Reporting – France . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217Nicholas Moore, Carmen Kreft-Jais and Alban Dhanani
17. Spontaneous Reporting in Germany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227Ulrich Hagemann and Norbert Paeschke
18. Spontaneous Reporting – United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237David J. Graham, Syed R. Ahmad and Toni Piazza-Hepp
19. Statistical Methods of Signal Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249Stephen Evans
20. Statistical Methods of Evaluating Pharmacovigilance Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257Bernard Bégaud
21. Data Mining in Pharmacovigilance: A View from the UppsalaMonitoring Centre . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265I. Ralph Edwards, Marie Lindquist, Andrew Bate and G. Niklas Norén
22. Pharmacovigilance in the Netherlands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277Kees van Grootheest and Eugene van Puijenbroek
23. CIOMS Working Groups and their Contribution to Pharmacovigilance . . . . . . . . . . . . . . . . . . . . . . 287Sue Roden and Trevor Gibbs
24. PEM in the UK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307Saad A.W. Shakir
25. PEM in New Zealand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317Mira Harrison-Woolrych and David M. Coulter
26. MEMO in the United Kingdom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333Douglas Steinke, Josie M.M. Evans and Thomas M. Macdonald
27. The General Practice Research Database: Now and the Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341John Parkinson, Sarah Davis and Tjeerd Van Staa
28. Overview of North American Databases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349Brian L. Strom and Judith L. Kinman
29. Other Databases in Europe for the Analytic Evaluation of Drug Effects . . . . . . . . . . . . . . . . . . . . . . . 361Miriam C.J.M. Sturkenboom
30. Surveillance for Medical Devices – USA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375Thomas P. Gross
31. Pharmacovigilance and Risk Management in Japan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387Kiyoshi Kubota and Hiroko Koyama
PART III. PHARMACOVIGILANCE AND SELECTED SYSTEM ORGAN CLASSES . . . . . . . . . . . . . . . 395
32. Dermatological ADRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397Laurence Allanore-Valeyrie and Jean-Claude Roujeau
CONTENTS vii
33. Gastrointestinal ADRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407John R. Wood and Graham A. Pipkin
34. Haematological ADRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419Peter J. Carey
35. Hepatic ADRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429Guruprasad P. Aithal and Christopher P. Day
36. Ocular Side Effects of Prescription Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445F.W. Fraunfelder
37. Drug Safety in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455Christina D. Chambers and Elizabeth B. Andrews
38. Renal Adverse Drug Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467Gert A. Verpooten
39. Anaesthetic Adverse Drug Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475Anita Holdcroft
40. Pharmacovigilance in Pediatrics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497Solomon Iyasu and M. Dianne Murphy
41. The Cardiovascular Spectrum of Adverse DrugReactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507Judith Hsia, Jinping Mo, Laura Burleson and Annlouise R. Assaf
42. Drugs and the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515Una Martin and Jamie J. Coleman
PART IV. KEY CURRENT TOPICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533
43. US Activities in Risk Management of PharmaceuticalProducts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535Jonca Bull
44. Risk Management – a European Regulatory View . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553June M. Raine
45. The Efficacy and Safety of Selective Serotonin Reuptake Inhibitorsfor the Treatment of Depression in Children and Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559Julie Magno Zito and Daniel J. Safer
46. Pharmacoepidemiology of Hormone Therapy: An Evolving Picture . . . . . . . . . . . . . . . . . . . . . . . . . . . 571Annlouise R. Assaf, Laura E. Burleson and Joann E. Manson
47. NSAIDs – COX-2 Inhibitors – Risks and Benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583K. Arnold Chan and S. Christopher Jones
48. Introduction to Pharmionics: The Vagaries in Ambulatory Patients’ Adherenceto Prescribed Drug Dosing Regimens, and Some of TheirClinical and Economic Consequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603John Urquhart and Bernard Vrijens
PART V. LESSONS AND DIRECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619
49. Teaching and Learning Pharmacovigilance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621Frank May
49b. Practical Experience in Teaching Pharmacovigilance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633Stephen Evans
viii CONTENTS
50. Fatal Medication Errors and Adverse Drug Reactions – Coroners’ Inquestsand Other Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635R.E. Ferner, S.E. McDowell and A.K. Cotter
51. Pharmacogenetics and the Genetic Basis of ADRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647Penelope K. Manasco
52. Keynote Clinical Lessons from Pharmacovigilance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667David H. Lawson and Keith Beard
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 677
Contributors
SYED R. AHMAD, MB, BS, MPH Office of Drug Safety, Center for Drug Evaluation and Research,US Food and Drug Administration, Rockville, MD, USA.
GURUPRASAD P. AITHAL, MD,MRCP, PhD
Queen’s Medical Centre University Hospital, Nottingham, UK,[email protected].
LAURENCE ALLANORE-VALEYRIE Service de Dermatologie, Hôpital Henri Mondor, Université ParisXII, Créteil, France, [email protected].
ELIZABETH B. ANDREWS, MPH, PhD RTI Health Solutions, Research Triangle Institute, ResearchTriangle Park, NC, USA, and School of Public Health and Schoolof Pharmacy, University of North Carolina at Chapel Hill, NC,USA, [email protected].
ANNLOUISE R. ASSAF Pfizer, Inc. New London, CT, USA, [email protected].
PRIYA BAHRI, PhD European Medicines Agency, 7 Westferry Circus, London, UK,[email protected].
OLIVIER BANCHEREAU Lovells, Paris, France.
TANJA BARTON Lovells, Munich, Germany.
ANDREW BATE, MA Uppsala Monitoring Centre, Stora Torget 3, Uppsala, Sweden,[email protected].
KEITH BEARD Department of Medicine of the Elderly, Victoria Infirmary,Glasgow, UK.
BERNARD BÉGAUD, MD Département de Pharmacologie Clinique – Unité dePharmaco-épidémiologie, ARME-Pharmacovigilance, UniversitéVictor Segalen, Bordeaux, France, [email protected].
CECILIA BIRIELL Uppsala Monitoring Centre, Uppsala, Sweden.
DONNA A. BOSWELL, JD, PhD Hogan & Hartson, L.L.P., Washington, DC, USA, [email protected].
x CONTRIBUTORS
ELLIOT BROWN Elliot Brown Consulting, Barnet, UK, [email protected].
PAUL BROWN Lovells, Atlantic House, 50 Holborn Viaduct, London, UK,[email protected].
JONCA BULL Acting Deputy Director, Office of Drug Safety, US Foodand Drug Administration, Rockville, MD, USA, [email protected].
JAYNE P. BULTENA Hogan & Hartson L.L.P., Washington, DC, USA, [email protected].
LAURA E. BURLESON Pfizer, Inc. New London, CT, USA.
PETER J. CAREY Sunderland Royal Hospital, Sunderland, UK, [email protected].
CHRISTINA D. CHAMBERS, MPH, PhD Department of Pediatrics and Family and PreventiveMedicine, University of California at San Diego, CA, USA,[email protected].
K. ARNOLD CHAN, MD, ScD Harvard School of Public Health, Boston, MA, USA, and DrugSafety, Waltham, MA, USA, [email protected].
JAMIE J. COLEMAN The Division of Medical Sciences, Medical School, Universityof Birmingham, Edgbaston, Birmingham, UK.
A.K. COTTER HM Coroner for Birmingham and Solihull Districts, Coroner’sCourt, Newton Street, Birmingham, UK.
DAVID M. COULTER, MB, ChB (NZ),DTM&H (Sydney)
Former Director, Intensive Medicines Monitoring Programmeand Research Associate Professor, Department of Preventive andSocial Medicine, University of Otago, Dunedin, New Zealand,[email protected].
SARAH DAVIS, BSc (Hons), PhD Vigilance and Risk Management of Medicines, Medicines andHealthcare products Regulatory Agency, London, UK.
CHRISTOPHER P. DAY, FRCP, MD, PhD Centre for Liver Research, The Medical School, FramlingtonPlace, Newcastle upon Tyne, UK.
ALBAN DHANANI Agence Française de Sécurité Sanitaire des Produits de Santé(AFSSAPS), St-Denis, France.
J. GUY EDWARDS, MB, BCh,FRCPsych, DPM
Khon Kaen University, Khon Kaen and Prince of SongklaUniversity, Hat Yai, Thailand.
I. RALPH EDWARDS, MB, ChB, FRCP,FRACP
Uppsala Monitoring Centre, Stora Torget 3, Uppsala, Sweden,[email protected].
JOSIE M.M. EVANS, MA (Oxon), MPH,PhD
Medicines Monitoring Unit, University of Dundee, NinewellsHospital and Medical School, Dundee, UK.
STEPHEN EVANS, BA, MSc, CStat,FRCP (Ed)
London School of Hygiene and Tropical Medicine, London, UK,[email protected].
CONTRIBUTORS xi
R.E. FERNER, MD, MSc, FRCP West Midlands Centre for Adverse Drug Reactions, City Hospital,Birmingham, UK, [email protected].
F.W. FRAUNFELDER, MD Casey Eye Institute, Oregon Health & Science University, Portland, OR,USA, [email protected].
STEPHEN FREESTONE Charles River Laboratories Clinical Services, Edinburgh, UK.
UWE FROEHLICH Lovells, Munich, Germany.
TREVOR GIBBS G1axoSmithKline Research & Development Ltd, Greenford, Middlesex,UK.
DAVID J. GRAHAM Office of Drug Safety, Center for Drug Evaluation and Research, US Foodand Drug Administration, Rockville, MD, USA, [email protected].
KEES VAN GROOTHEEST Netherlands Pharmacovigilance Centre Lareb, Goudsbloemvallei, MH ‘s-Hertogenbosch, The Netherlands, [email protected].
THOMAS P. GROSS, MD, MPH Division of Postmarket Surveillance, Office of Surveillance and Biomet-rics, Center for Devices and Radiological Health, US Food and DrugAdministration, Rockville, MD, USA, [email protected].
ULRICH HAGEMANN Federal Institute for Drugs and Medical Devices, Bonn, Germany,[email protected].
MIRA HARRISON-WOOLRYCH Intensive Medicines Monitoring Programme, Department of Preventiveand Social Medicine, University of Otago, Dunedin, New Zealand,[email protected].
ANITA HOLDCROFT, MB, ChB,MD, FRCA
Reader in Anaesthesia and Honorary Consultant Anaesthetist, Depart-ment of Anaesthesia, Pain Medicine and Intensive Care, ImperialCollege London and Chelsea and Westminster Hospital, London, UK,[email protected].
JUDITH HSIA, MD George Washington University Medical Center, Washington, DC,USA.
SOLOMON IYASU, MD, MPH Director, Division of Surveillance, Research and CommunicationSupport, Office of Surveillance and Epidemiology, Center forDrug Evaluation and Research, US Food and Drug Administration,[email protected].
CHRISTOPHER JONES Office of Generic Drugs, Division of Bioequivalence, US Food and DrugAdministration, Silverspring, MD, USA.
LARRY G. KESSLER, ScD Office of Surveillance and Biometrics, Center for Devices and Radiolog-ical Health, US Food and Drug Administration, Rockville, MD, USA.
BRIDGET KING Vigilance and Risk Management of Medicines, Medicines and Healthcareproducts Regulatory Agency, London, UK.
JUDITH L. KINMAN, MA Center for Clinical Epidemiology and Biostatistics, University ofPennsylvania School of Medicine, Philadelphia, PA, USA.
xii CONTRIBUTORS
HIROKO KOYAMA Senior Leader of Drug Safety Evaluation Department, ChugaiPharmaceutical Co., Ltd., Chuo-ku, Tokyo, Japan, [email protected].
CARMEN KREFT-JAIS, MD Agence Française de Sécurité Sanitaire des Produits de Santé (AFSS-APS), St-Denis, France.
KIYOSHI KUBOTA, MD, PhD Associate Professor, Department of Pharmacoepidemiology, Faculty ofmedicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan, [email protected].
DAVID H. LAWSON, CBE, MD,FRCP
Department of Clinical Pharmacology, Royal Infirmary, Glasgow, UK,[email protected].
PAOLA LA LICATA Lovells, Rome, Italy.
MARIE LINDQUIST, MSc Pharm Uppsala Monitoring Centre, Stora Torget 3, Uppsala, Sweden.
THOMAS M. MACDONALD, BSc,MD, FRCP, FESC
Medicines Monitoring Unit, University of Dundee, Ninewells Hospitaland Medical School, Dundee, UK, [email protected].
NICHOLAS MACFARLANE, BA Lovells, Atlantic House, 50 Holborn Viaduct, London, UK, [email protected].
STUART J. MAIR, MBChB,DRCOG, DCPSA
Charles River Laboratories Clinical Services, Edinburgh, UK,[email protected].
PENELOPE K. MANASCO, MD PharmaVigilant, Boston, MA, USA, [email protected].
RONALD D. MANN, MD, FRCP,FRCGP, FFPM, FISPE, Hon.Member ISoP
University of Southampton; Waterlooville, Hampshire, PO8 9BT UK,[email protected].
JOANN E. MANSON Brigham and Women’s Hospital, Harvard Medical School, MA, USA.
UNA MARTIN, BSc, PhD, FRCPI The Division of Medical Sciences, Medical School, University ofBirmingham, Edgbaston, Birmingham, UK, [email protected].
FRANK MAY Harvard Medical School, Division of Pharmacoepidemiology and Phar-macoeconomics, Brigham & Women’s Hospital, Boston, MA, USA,[email protected].
S.E. MCDOWELL West Midlands Centre for Adverse Drug Reaction Reporting, CityHospital, Birmingham, UK.
JINPING MO Pfizer Inc., New York, NY, USA.
CAROLINE MOORE, BA (Oxon) Lovells, London, UK.
NICHOLAS MOORE, MD, PhD,FRCP (Ed), FISPE
Department of Pharmacology, Université Victor Segalen, Bordeaux,France, [email protected].
M. DIANNE MURPHY, MD, FAAP Director, Office Pediatric Therapeutics, Office of the Commissioner,US Food and Drug Administration, [email protected].
G. NIKLAS NORÉN Uppsala Monitoring Centre, Stora Torget 3, Uppsala, Sweden.
CONTRIBUTORS xiii
NORBERT PAESCHKE Federal Institute for Drugs and Medical Devices, Bonn, Germany,[email protected].
B. KEVIN PARK, BSc (Hons), PhD,Hon MRCP
The Department of Pharmacology and Therapeutics, The Universityof Liverpool, Liverpool, UK.
JOHN PARKINSON GPRD Group, Medicines and Healthcare Products RegulatoryAgency, London, UK.
TONI PIAZZA-HEPP, PharmD Office of Drug Safety, Center for Drug Evaluation and Research, USFood and Drug Administration, Rockville, MD, USA.
GRAHAM A. PIPKIN, BSc (Hons) GlaxoSmithKline Research and Development, Stockley Park,Middlesex, UK.
MUNIR PIRMOHAMED, PhD,FRCP, FRCP (Ed)
The Department of Pharmacology and Therapeutics, The Universityof Liverpool, Liverpool, UK, [email protected].
EUGENE VAN PUIJENBROEK, MD,PhD
Netherlands Pharmacovigilance Centre Lareb, Goudsbloemvallei,MH ‘s-Hertogenbosch, The Netherlands.
JUNE M. RAINE, MA, MSc, FRCP(Ed)
Vigilance and Risk Management of Medicines and Healthcare prod-ucts Regulatory Agency, London, UK, [email protected].
PATRICIA M. REED Charles River Laboratories Clinical Services, Edinburgh, UK.
SUE RODEN, BSc, MSc, MRPS G1axoSmithKline Research & Development Ltd, Greenford, Middle-sex, UK, [email protected], [email protected].
JEAN-CLAUDE ROUJEAU, MD Service de Dermatologie, Hôpital Henri Mondor, Université ParisXII, Créteil, France, [email protected].
DANIEL J. SAFER Associate Professor of Psychiatry and Pediatrics, Johns HopkinsMedical Institutions, Baltimore, MD, USA.
RASHMI R. SHAH, BSc, MBBS,MD, FRCP, FFPM
Pharmaceutical Consultant, Gerrards Cross (Bucks) SL9 7JA,Formerly Senior Clinical Assessor at Medicines and Health-care products Regulatory Agency, London, United Kingdom, [email protected].
SAAD A.W. SHAKIR, FRCP (Glas &Ed), FFPM, MRCGP
Drug Safety Research Unit, Southampton, UK, [email protected].
DOUGLAS STEINKE, BSc (Pharm),MSc, PhD
Primary Care Information Group, Information and Statistics Division,Edinburgh, UK.
PETER D. STONIER, PhD,MRCPsych, FRCP, FFPM
Medical Director, Amdipharm Plc, Regency House, MilesGray Road, Basildon, Essex, UK, [email protected],[email protected].
BRIAN L. STROM, MD, MPH Center for Clinical Epidemiology and Biostatistics, Universityof Pennsylvania School of Medicine, Philadelphia, PA, USA,[email protected].
MIRIAM C.J.M. STURKENBOOM,PhD, MSc, PharmD
Pharmacoepidemiology Unit, Department of Epidemiology&Biostatistics and Medical Informatics, Erasmus University
xiv CONTRIBUTORS
Medical Centre, Rotterdam, The Netherlands, and InternationalPharmaco-epidemiology and Pharmaco-economics ResearchCentre (IPPRC sas), Desio (MI), Italy, [email protected].
CLAIRE TAYLOR Lovells, London, UK.
MONDHER TOUMI H. Lundbeck A/S, Copenhagen, Denmark.
PANOS TSINTIS European Medicines Agency, 7 Westferry Circus, London, UK.
JOHN URQUHART, MD, FRCPE, FRSE Chief Scientist, AARDEX Ltd, Zug, Switzerland; Departmentof Biopharmaceutical Sciences, Center for Drug DevelopmentScience, University of California San Francisco Medical Center,CA, USA, [email protected].
TJEERD VAN STAA GPRD Group, Medicines and Healthcare Products RegulatoryAgency, London, UK.
PATRICE VERPILLAT, MD, PhD Pharmacoepidemiologist, Section Leader Pharmacoepidemio-logy, Department of Special Projects, Corporate Economics& Pricing Division, Lundbeck SAS, Paris, France,[email protected].
GERT A. VERPOOTEN Department of Nephrology-Hypertension, Antwerp UniversityHospital, Antwerp, Belgium, [email protected].
BERNARD VRIJENS Pharmionic Systems Ltd and AARDEX Statistical ResearchCentre, Visé, Belgium; Department of Biostatistics and MedicalInformatics, University of Liège, Belgium.
PATRICK C. WALLER, MD, FRCP (Ed),FFPM, MPH
Consultant in Pharmacoepidemiology, Southampton, UK.
RICHARD N. WILD, MB, ChB, DCH,FFPM, FRCP (Ed)
Arakis Ltd, Saffron Walden, United Kingdom, [email protected].
JOHN R. WOOD, MB, BSc, PhD Wood and Mills Limited, Fulmer, Buckinghamshire, UK.
JULIE MAGNO ZITO, PhD Associate Professor of Pharmacy & Psychiatry, Departmentof Pharmaceutical Health Services Research, University ofMaryland, Baltimore, MD, USA, [email protected].
Preface
Pharmacovigilance is the study of the safety ofmarketed drugs examined under the practical condi-tions of clinical use in what are usually large popula-tions. Safety cannot, however, be considered except inrelation to the efficacy of the drug, whether it is usedin healthy or sick people, the pharmaceutical qualityof the drug, the nature and seriousness of any sideeffects and the degree to which these can be treated,the threat posed by the disease that is treated withthe drug and the rest of the complex of issues thatcomprise holistic patient care.
Much has happened in the world of pharmacovigi-lance since the first edition of this book was publishedin 2002. The legal basis of the subject in Europehas changed materially, the PSUR (Periodic SafetyUpdate Report) has come to be recognized as a majormeans of undertaking a comprehensive re-assessmentof the balance of safety and efficacy of the drug,the use of the MedDRA dictionary has become moreestablished, the growth of regional monitoring centreshas been found increasingly useful in the UK andespecially in France, adverse drug reaction monitor-ing has been strengthened in Germany, the struc-ture of the regulatory body in the UK has beenrevised, and there has been considerable emphasis onpharmacovigilance planning and the development ofrisk minimization action plans. There has been greaterscrutiny of drug safety policy in the US than ever before,within the regulatory agency itself, by congress, andby committees of the Institute of Medicine.
There have also been reassessments of the placeof some major drugs and drug classes in thera-
peutics. Drugs have been withdrawn or their usagemodified due to prolongation of the QTc intervaland the threat of torsades de pointes, the place ofthe SSRIs (selective serotonin reuptake inhibitors) inyoung people has been much modified, the long-term use of HRT (hormone replacement therapy)has been restricted and among the non-steroidalanti-inflammatory agents the cardiovascular safety oflong-term usage of the COX-2 (cyclo-oxygenase-2)inhibitors has been challenged.
All of these changes call attention to the need foryet more rigorous and proactive pharmacovigilance.The changes also highlight the need for greater trans-parency of the pharmacovigilance process to assurethe public that regulators, health professionals, phar-maceutical companies and academics are continuallyreviewing risks and benefits of medicines in theirfullest context.
These events have necessitated a second edition ofthis book which is now divided into five parts, thus:
1. The basis of pharmacovigilance2. Signal generation3. Pharmacovigilance and selected system–organ
classes4. Key current topics5. Lessons and directions.
It is interesting that the latter section ends with animportant chapter on pharmacogenetics – a road,along with the growth of the use of organized
xvi PREFACE
databases, that many of us feel will provide much ofthe progress of the future.
The editors wish to express their considerableappreciation of the support received from Mrs LucySayer of Wiley and Mrs Juliet Booker who hasassisted her. Professor Mann wishes to acknowledge
the very extensive help he has received from hispersonal assistant, Mrs Susan Jerome.
Ronald D. MannElizabeth B. Andrews
27 April 2006
Foreword
When I wrote the foreword to the first edition of thisbook in 2002, I little thought that I would be invited torepeat the exercise a mere four years later. The earlypublication of the second edition of a book such as thisis an important event, signalling that the contents ofthe first edition have met with professional approval,have fulfilled an informational need and, as sciencemoves on, the topics discussed need to be revisited.
So what of moment has occurred in the field of phar-macovigilance in the past four years? I would high-light four developments which to me seem significant.
First, from a regulatory standpoint, the fallout fromthe withdrawal of rofecoxib (Vioxx) by the manufac-turers in September 2004 has cast the longest shadow.Regulatory agencies worldwide were forced to exam-ine their approach to the safety of marketed medicines.The timely implementation in November 2005 of thenew EU pharmaceutical directives into national legis-lation gave fresh emphasis to the importance of riskmanagement strategies and risk minimisation plans fornewly approved medicines. How these plans shouldbe implemented and monitored remains the subject ofintense debate in the light of earlier and largely unsuc-cessful attempts by regulators to encourage effectivepostmarketing surveillance by the sponsors of newmedicines. Among the issues up for discussion is whoshould pay for studies which have been agreed andwhat penalties should be exacted for non-compliance.
Second, from a scientific standpoint, the contri-butions of the ‘omics’ to pharmacovigilance haveperhaps been less than many had hoped for. Thetranslation of the principles of pharmacogenomics tothe practice of personalised medicine in the clinicremains an elusive goal, with the notable exception ofoncology where long-standing genetic research is now
beginning to pay rich dividends. Innovations in diag-nostic tests are an essential precursor to the success-ful adoption of personalised medicine and, again,intensive work in oncology illustrates the importanceof this. The widespread development of safer andmore effective medicines underpinned by pharmaco-genetic principles remains tantalisingly distant in spiteof our increasing knowledge base in the understand-ing of genetic polymorphisms of drug-metabolisingenzymes, drug transporters and of receptors mediatingdrug response.
Pharmacoepidemiology is a third area worthy ofcomment and here I would highlight one study whichprovided new evidence of the clinical and economicimportance of adverse drug reactions. Pirmohamedand colleagues (2004) reviewed some 18 820 patientsadmitted to two large general hospitals over a six-month period. 1225 patients (or 6.5% of the popula-tion) were admitted as a direct result of an adversedrug reaction. The overall fatality rate of these patientswas 0.15% with a projected annual cost to the NHSof adverse drug reactions, based on these figures, of£466 million. Studies such as this give a clear indica-tion of the clinical and economic burden that adversedrug reactions place on health-care systems.
A fourth area where the pace of debate has acceler-ated is the role of patients in all aspects of medicinesregulation, including pharmacovigilance. For manyyears, patients were regarded as the passive recipientsof medicines prescribed by health-care profession-als, mainly doctors. This is no longer the case, andthe sponsors of new drugs, regulators and prescribersignore the views of patients at their peril. The public’sassessment of the risk–benefit balance of a medicinemay differ markedly from that of the industry or the
xviii FOREWORD
regulator and attention must be paid to these views.The greater involvement of patients is an importantand positive move. Implicit in this is the need toprovide higher quality and clearer information onmedicines for both prescribers and the public. Thisprocess has been set in train, but has some way to goand deserves further encouragement.
My foreword in 2002 expressed the wish that pharma-covigilance should focus more on extending knowledgeon drug safety and less on finding evidence of harm,andfurther,moreworkonoutcomemeasures (includingsurrogate markers and biomarkers) was needed. These
remain worthy aspirations and it will be interesting tosee the progress which is made when the third editionof this valuable book comes to be written.
Alasdair Breckenridge
REFERENCE
Pirmohamed M, James S, Meakin S, et al. (2004) Adversedrug reactions as a cause of admission to hospital:Prospective analysis of 18 820 patients. BMJ, 329: 15–19.
Part I
THE BASIS OF PHARMACOVIGILANCE
1
IntroductionRONALD D. MANNUniversity of Southampton, Waterlooville, Hampshire, PO8 9BT, UK
ELIZABETH B. ANDREWSRTI Health Solutions, Research Triangle Institute, Research Triangle Park, NC, USA, and School of Public Health andSchool of Pharmacy, University of North Carolina at Chapel Hill, NC, USA
‘Not all hazards can be known before a drug ismarketed’.
Committee on Safety of Drugs, Annual Report 1969,1970.
Pharmacovigilance – the study of the safety ofmarketed drugs under the practical conditions of clin-ical use in large communities – involves the para-dox that what is probably the most highly regulatedindustry in the world is, from time to time, forcedto remove approved and licensed products from themarket because of clinical toxicity. Why is such closeregulation not effective in preventing the withdrawalof licensed products? The question has been with usfrom the very early days of the 1960s and remainswith us today, and its consideration tells us a greatdeal about pharmacovigilance.
The greatest of all drug disasters was the thalido-mide tragedy of 1961–62. Thalidomide had beenintroduced, and welcomed, as a safe and effectivehypnotic and anti-emetic. It rapidly became popularfor the treatment of nausea and vomiting in earlypregnancy. Tragically, the drug proved to be a potenthuman teratogen that caused major birth defects in anestimated 10 000 children in the countries in which
it was widely used in pregnant women. Figure 1.1shows a child with thalidomide-induced amelia of theupper limbs and phocomelia of the lower limbs fittedwith the kind of prostheses available at that time. Thestory of this disaster has been reviewed elsewhere(Mann, 1984).
The thalidomide disaster led, in Europe and else-where, to the establishment of the drug regulatorymechanisms of today. These mechanisms require thatnew drugs shall be licensed by well-established regu-latory authorities before being introduced into clini-cal use. This, it might be thought, would have mademedicines safe – or, at least, acceptably safe. ButTable 1.1 summarizes a list of 39 licensed medicineswithdrawn, after marketing, for drug safety reasonssince the mid-1970s in the United Kingdom.
Why should the highly regulated pharmaceuticalindustry need, or be compelled, to withdraw licensedmedicines for drug safety reasons? Why do theseproblems of licensed products being found toxiccontinue despite the accumulated experience of morethan 45 years since the thalidomide tragedy?
Partly, the problem is one of numbers. For example,the median number of patients contributing data to
Pharmacovigilance: Second Edition Editors: Ronald D. Mann and Elizabeth B. Andrews© 2007 John Wiley & Sons, Ltd
4 PHARMACOVIGILANCE
Figure 1.1. Child with thalidomide-induced deformities of the upper and lower limbs fitted with pneumatic prostheses.
the clinical safety section of new drug licensingapplications in the United Kingdom is only justover 1500 (Rawlins and Jefferys, 1991). Increasingregulatory demands for additional information beforeapproval have presumably increased the averagenumbers of patients in applications, especially for newchemical entities; nevertheless, the numbers remainfar too small to detect uncommon or rare adverse drugreactions (ADRs), even if these are serious.
The size of the licensing applications for impor-tant new drugs cannot be materially increased withoutdelaying the marketing of new drugs to an extentdamaging to diseased patients. Thus, because of thisproblem with numbers, drug safety depends verylargely on the surveillance of medicines once theyhave been marketed.
A second reason for difficulty is that the kindsof patients who receive licensed medicines are very
INTRODUCTION 5
Table 1.1. Drugs withdrawn in the United Kingdom by the marketing authorization holder or suspended or revokedby the Licensing Authority.
Brand name (drug substance) Year action taken Major safety concerns
Secholex (polidexide) 1975 Safety concerns because of impuritiesEraldin (practolol) 1975 Oculomucocutaneous syndromeOpren (benoxaprofen) 1982 Hepatotoxicity, serious skin reactionsDevryl (clomacran phosphate) 1982 HepatotoxicityFlosint (indoprofen) 1982 Gastrointestinal toxicityZomax (zomepirac) 1983 AnaphylaxisOsmosin (indomethacin-modified release) 1983 Small intestine perforationsZelmid (zimeldine) 1983 NeurotoxicityFlenac (fenclofenac) 1984 Lyell’s syndromeMethrazone (feprazone) 1984 Serious skin reactions, multi-system toxicityAlthesin (alphaxolone plus alphadolone) 1984 AnaphylaxisPexid (perhexilene) 1985 Hepatotoxicity, neurotoxicitySuprol (suprofen) 1986 NephrotoxicityMerital (nomifensine) 1986 Haemolytic anaemiaUnicard (dilevalol) 1990 HepatotoxicityGlauline eye drops 0.6% (metipranolol) 1990 UveitisHalcion (triazolam) 1991 Psychiatric reactionsMicturin (terodiline) 1991 ArrhythmiasTeflox (temafloxacin) 1992 Multi-system toxicityCentoxin (nebacumab) 1993 MortalityRoxiam (remoxipride) 1994 Aplastic anaemiaVolital (pemolin) 1997 HepatotoxicityRomazin (troglitazone) 1997 HepatotoxicitySerdolect (sertindole) 1998 ArrhythmiasTasmar (tolcapone) 1998 HepatotoxicityPonderax (fenfluramine) 1998 Cardiac valvular diseaseAdifax (dexfenfluramine 1998 Cardiac valvular diseasePosicor (mibefradil) 1998 Drug interactionsTrovan (trovafloxacin) 1999 HepatotoxicityGrepafloxacin (Raxar) 1999 QT interval prolongationPrepulsid (cisapide) 2000 QT interval prolongationAlec (pumactant) 2000 Adverse comparative trial resultsDroleptan (droperidol) 2001 Increased cardiac risksLipobay (cerivastatin) 2001 RhabdomyolysisKava-Kava 2001 Liver toxicityAnorectic agents (amfepramone, phentermine) 2000 Heart valve disordersVioxx (rofecoxib) 2004 Increased cardiovascular event risksNon-proprietary (co-proxamol) 2005 Use in suicideBextra (valdecoxib) 2005 Stevens–Johnson syndrome
different from the kinds of volunteers and patientsin whom pre-marketing clinical trials are undertaken.The patients in formal clinical trials almost alwayshave only one disease being treated with one drug.The drug, once licensed, is likely to be used in anolder group of patients, many of whom will have morethan one disease and be treated by polypharmacy. Thedrug may also be used in paediatric patients, whoare generally excluded from initial clinical trials. The
formal clinical trials may be a better test of efficacythan they are of safety under the practical conditionsof everyday clinical usage.
A third problem is that doctors may be slow or inef-fective in detecting and reporting adverse drug effects.Many of the drugs summarized in Table 1.1 were inwidespread, long-term use before adverse reactionswere detected, and even now, hospital admissions dueto ADRs have shown an incidence of between 2.4%
6 PHARMACOVIGILANCE
and 3.6% of all admissions in Australia with simi-lar or greater figures in France and the United States(Pouyanne et al., 2000). Even physicians astute indetecting adverse drug effects are unlikely to identifyeffects of delayed onset.
A fourth reason for difficulty is that drugs are oftenwithdrawn from the market for what may be veryrare adverse effects – too infrequent by far to haveshown up in the pre-licensing studies – and we do notyet have effective means in place for monitoring totalpost-marketing safety experience. This situation maywell change as large comprehensive databases suchas the General Practice Research Database (GPRD)become more widely used for signal detection andevaluation. These databases record, in quite large andrepresentative populations, all usage of many specificmedicines and clinical outcomes and can be used tosystematically screen for and evaluate serious adverseevents. Because they contain comprehensive infor-mation on some important information, such as age,sex, dose and clinical events on all patients in therepresented population, they are systematic comparedwith spontaneous reporting systems. They may offer abetter chance of detecting long-latency adverse reac-tions, effects on growth and development and othersuch forms of adverse experience.
Some of the difficulties due to numbers, patientpopulations and so on were recognized quite early.The Committee on Safety of Drugs in the UnitedKingdom (established after the thalidomide disas-ter, originally under the chairmanship of Sir DerrickDunlop, to consider drug safety whilst the MedicinesAct of 1968 was being written) said – quiteremarkably – in its last report (for 1969 and 1970)that ‘no drug which is pharmacologically effective iswithout hazard. Furthermore, not all hazards can beknown before a drug is marketed’. This then has beenknown for over 35 years. Even so, many prescribersstill seem to think that licensed drugs are ‘safe’, andthey are surprised when a very small proportion oflicensed drugs have to be withdrawn because of unex-pected drug toxicity. Patients themselves may haveexpectations that licensed drugs are ‘completely safe’rather than having a safety profile that is acceptablysafe in the context of the expected benefit and natureof the underlying health condition.
The methodological problems have been longrecognized. The Committee on Safety of Medicines,
the successor in the United Kingdom to the DunlopCommittee, investigating this and related problems,established a Working Party on Adverse Reactions.This group, under the chairmanship of ProfessorDavid Grahame-Smith, published its second report inJuly 1985. The report supported the continuation ofmethods of spontaneous reporting by professionalsbut recommended that post-marketing surveillance(PMS) studies should be undertaken on ‘newly-marketed drugs intended for widespread long-termuse’; the report also mentioned record-linkage meth-ods and prescription-based methods of drug safetysurveillance as representing areas of possible progress(Mann, 1987).
Similar reviews and conclusions have emergedfrom the United States since the mid-1970s. A seriesof events in the United States recently created aresurgence of interest in drug safety evaluation andmanagement. The Prescription Drug User Fee Act(PDUFA) of 1992 provided additional resources atthe Food and Drug Administration (FDA) for drugreviews through user fees and established target time-lines for FDA reviews. The shorter approval timeslead to some medications being approved sooner inthe United States than that in Europe in contrast tothe pre-PDUFA experience. A few highly visible drugwithdrawals led to a perception that perhaps drugswere being approved too quickly. Lazarou, Pomeranzand Corey (1998) published the results of a meta-analysis that estimated that 106 000 fatal adverse reac-tions occurred in the United States in 1994. Thisand other articles (Wood, Stein and Woosley, 1998)stimulated considerable public, congressional andregulatory attention on reducing the societal burdenof drug reactions and medication errors (Institute ofMedicine, 1999; U.S. Food and Drug Administra-tion, 1999; United States General Accounting Office,2000). As a result, greater attention and resources arecurrently being devoted to signal generation and eval-uation by the FDA, industry and academic centres.Moreover, efforts are underway to develop better toolsto manage recognized risks through a variety of inter-ventions, such as communications with healthcareproviders and patients, restricted product distributionsystems and other mechanisms. Additional effort isbeing focused on measuring the success of these risk-management interventions. This new initiative repre-sents a fundamental shift in the safety paradigm in
INTRODUCTION 7
the United States and offers new challenges to phar-macovigilance professionals. In fact, the shift is notrestricted to the United States as both the FDA andthe EMEA in 2005 issued guidance documents forindustry on signal detection, evaluation, good pharma-covigilance practice and recommendations for manag-ing risks after the approval (EMEA, 2005; U.S. Foodand Drug Administration, 2005a–c).
We have long recognized then that the safety ofpatients depends not only on drug licensing by regu-latory bodies but also on post-marketing drug safetysurveillance, pharmacovigilance. It is also importantto note that the same post-marketing informationneeded to confirm new safety signals is also neededto refute signals and protect the ability of patientsto benefit from needed medicines that may be undersuspicion due to spurious signals.
DIAGNOSING ADVERSE DRUGREACTIONS
There are two types of adverse drug reactions. TypeA reactions are common, predictable, usually dose-dependent and appear as excessive manifestations ofthe normal pharmacology/toxicology of the drug; theyare seldom fatal. Type B reactions are uncommon,unpredictable, often independent of dose and usuallyrepresent abnormal manifestations of the drug’s phar-macology/toxicology; they involve relatively highrates of serious morbidity and mortality.
ADRs frequently mimic ordinary diseases and, ifthey are uncommon, may easily be overlooked. Theytend to affect the skin, haematopoietic system andlining of the gut (situations in which there is rapidcell multiplication) or the liver or kidneys (wheredrugs are detoxified and excreted). These special sitesare frequently involved in iatrogenic (doctor-induced),type B illnesses, such as toxic epidermal necrolysis,aplastic anaemia, pseudomembranous colitis, drug-induced hepatitis or nephritis.
A high index of suspicion is needed if ADRs are tobe successfully diagnosed. The clinician always has tothink: ‘Could this be drug-induced – is this an ADR’.The question is important, for withdrawal of the causeof an ADR is usually essential.
Iatrogenic ADRs are usually uncommon or rare,and this adds to the difficulty of diagnosis. Some are
avoidable, such as skin rashes in patients with glandu-lar fever given ampicillin. Some are accidental, suchas the non-iatrogenic disaster of an asthmatic given abeta-adrenergic blocking agent by another member ofthe family. It is a truism that the detection of commonor uncommon ADRs requires vigilance. Many of theknown serious ADRs have been recognized by astuteclinicians with a high level of awareness, and suchawareness is likely to be just as important, as newmethods of pharmacovigilance are developed as it hasbeen in the past.
Linked with this problem of diagnosing ADRs isthe problem of understanding them. Why does onepatient in 10 000 get some bizarre type B reaction,and the rest of this population not get it? Clearly,our increasing knowledge of clinical pharmacology,drug metabolism and genetics will contribute to ourunderstanding of these things, and these subjects areexplored in many of the chapters in this book.
CURRENT METHODS OFPHARMACOVIGILANCE
Pharmacoepidemiology is the study of the use of, andeffects of, drugs in large numbers of people. As theterm implies, this form of enquiry uses the methodsof epidemiology; it is concerned with all aspects ofthe benefit–risk ratio of drugs in populations. Phar-macovigilance is a branch of pharmacoepidemiologybut is restricted to the study, on an epidemiologicalscale, of drug events or adverse reactions.
‘Events’, in this context, are happenings recorded inthe patient’s notes during a period of drug monitor-ing; they may be because of the disease for which thedrug is being given, some other intercurrent disease orinfection, an adverse reaction to the drug being moni-toredor theactivityofadrugbeinggivenconcomitantly.They can also be because of drug–drug interactions.
Public health surveillance methods are used toidentify new signals of possible ADRs. Studies inpharmacoepidemiology are intended to be either‘hypothesis-generating’ or ‘hypothesis-testing’ or toshare these objectives. Hypothesis-generating studies,with a recently marketed drug, aim to detect unex-pected ADRs; hypothesis-testing studies aim to provewhether any suspicions that may have been raised arejustified.
8 PHARMACOVIGILANCE
HYPOTHESIS-GENERATING METHODS
Spontaneous ADR Reporting
Doctors (in some countries, other healthcare profes-sionals and patients as well) are provided with formsupon which they can notify a central authority of anysuspected ADRs that they detect. In the United King-dom, the ‘yellow card’ has been used for this purposesince 1964. Similar forms are provided in the FP10prescriptions pads, the British National Formulary andother sources. In the United States, the MedWatchform is used and is made broadly available to healthprofessionals to encourage reporting.
The great strength of spontaneous reporting is thatit operates for all drugs throughout the whole of theirlifetime; it is the only affordable method of detectingreally rare ADRs. The data may represent merely thesuspicions of the reporter, but they provide the opinionof a doctor or health professional attending a real-lifepatient. The main weaknesses are that there is grossunder-reporting, and the data provide a ‘numerator’(the number of reports of each suspected reaction)only. Nevertheless, the scheme is invaluable, and it isessential that health professionals should be providedwith the means of reporting their suspicions.
Spontaneous reporting has led to the identifica-tion and verification of many unexpected and seri-ous ADRs. These findings have resulted in manymarketed drugs being withdrawn or additional infor-mation being provided to guide safer use of theproduct.
A variety of formal epidemiological studies can beundertaken to generate or test hypotheses.
Prescription Event Monitoring
This monitoring, abbreviated as PEM, as conductedin the United Kingdom and New Zealand, representsa ‘hybrid’ method, combining aspects of public healthsurveillance and spontaneous reporting with aspectsof formal epidemiological studies. In the United King-dom, this important technique takes advantage ofmany features of the British National Health Service(NHS). Within the NHS, prescriptions written bygeneral practitioners are sent, once they have beendispensed, to a central Prescription Pricing Author-ity (PPA). The PPA provides confidential copies ofcertain prescriptions for newly introduced drugs that
are being monitored to the Drug Safety Research Unit(DSRU) at Southampton. Six or twelve months afterthe first prescription for an individual drug in an indi-vidual patient, the DSRU sends a ‘green form’ ques-tionnaire to the general practitioner who wrote theoriginal prescription. Changing requirements regard-ing confidentiality and the effect that these have hadon PEM are discussed in the appropriate chapter ofthis volume.
Thus, the prescriptions provide the ‘exposure data’showing which patients have been exposed to the drugbeing monitored, and the green forms provide the‘outcome data’ showing any events noted during theperiod of monitoring. Pregnancies, deaths or eventsof special interest can be followed up by contactbetween the DSRU and the prescribing doctor whoholds, within the NHS, the lifetime medical record ofall of his or her registered patients.
The great strengths of this method are that it providesa numerator (the number of reports) and a denom-inator (the number of patients exposed), both beingcollected over a precisely known period of observa-tion. Furthermore, nothing happens to interfere with thedoctor’s decision regarding which drug to prescribe foreach individual patient, and this avoids selection biases,which can make data interpretation difficult. The mainweakness of PEM is that only 50%–70% of the greenforms are returned, and the experience of the patientswhose forms are not returned may differ from thosereturned. In addition, because PEM limits follow-upto 6 or 12 months, it cannot identify events of longlatency. Thus, it is of great importance that doctorsshould continue to support the scheme by returningthose green forms that they receive.
So far, some 90 drugs have been studied by PEM,and the average number of patients included in eachstudy (the cohort size) has been over 10 000. Thisis a substantial achievement and a tribute to thegeneral practitioners who have participated. PEM inthe United Kingdom and a similar programme in NewZealand are unique in providing a monitored-releaseprogramme that can detect or help refute new signalsin the early life of a medicine.
Considerable interest centres around those patientswho produce major ADRs that are too rare tobe detected in cohorts of around 10 000 patients.How many of these patients have inborn errors ofmetabolism or other rarities that reflect features of the
INTRODUCTION 9
patient rather than the drug? We do not have adequatefacilities to investigate the genetic and metabolicfeatures of those patients who produce these very raretype B adverse reactions.
Other Hypothesis-Generating Methods
Other systematic methods are used in signal gener-ation. In some cases, data being collected forgeneral public health surveillance, such as causeof death files, cancer registries and birth defectregistries are used to identify patterns of eventsthat might be associated with medication use. Otherprogrammes, such as case–control surveillance ofbirth defects, conducted by the Slone EpidemiologyCenter, screen for potential associations between birthdefects and prescription and over-the-counter medi-cations. Analytic methods that allow screening ofenormous amounts of data for patterns that mightdeviate from expected – data mining techniques –are being applied to spontaneous reporting databases,databases on potential drug abuse and diversion andlarge population-based health records.
HYPOTHESIS-TESTING METHODS
Case–Control and Case–Crossover Studies
Studies of this type compare cases with a disease withcontrols susceptible to the disease but free of it. Usingthis method, the research compares the exposure ratein the cases with the exposure rate in the controls,adjusting statistically for factors that may confoundthe association. As with any formal epidemiologicalor clinical study, great care has to be taken in thedesign. Special attention is needed in case definitionso that the cases truly represent the specific outcomeof interest (e.g. Stevens–Johnson syndrome and not allcases of rash). It is also important to select an appro-priate control group that represents the populationthat gave rise to the cases. Careful design can mini-mize the amount of bias in a study; adequate controlin the analysis is also important. Case–control stud-ies have provided a substantial body of evidence formajor drug safety questions. Two notable examplesare studies that demonstrated the association betweenaspirin and Reye’s syndrome (Hurwitz et al., 1987)
and the evaluation of diethylstilbestrol (DES) andvaginal cancer in the offspring of mothers who tookDES in pregnancy (Herbst et al., 1974, 1975). More-over, a case–control study established the protectiveeffects of prenatal vitamin supplementation on thedevelopment of neural tube defects (Werler, Shapiroand Mitchell, 1993). The final results of these studiespresent a measure of the risk of the outcome associ-ated with the exposure under study – expressed as theodds ratio. Only in very special circumstances can theabsolute risk be determined. Clearly, a fairly smallincrease in the risk of a common, serious condition(such as breast cancer) may be of far greater publichealth importance than a relatively large increase in asmall risk (such as primary hepatic carcinoma).
Case–control studies are more efficient than cohortstudies, because intensive data need only becollected on the cases and controls of interest. Case–control studies can often be nested within exist-ing cohort or large clinical trial studies. A nestedcase–control study affords the ability to quantify abso-lute risk while taking advantage of the inherent effi-ciency of the case–control design.
The case–crossover design is a design very usefulfor the evaluation of events with onset shortly aftertreatment initiation. In this design, cases, but notcontrols, are identified. A drug association is evalu-ated through comparing frequency of exposure at thetime of the event with frequency of exposure at adifferent time for the same individuals. This design isless subject to bias than case–control studies becauseindividuals serve as their own controls. As with case–control studies, unless the experience is nested withina larger cohort, it is not possible to estimate the abso-lute rate of events. For special circumstances, thecase–crossover design is a very powerful design inpharmacoepidemiology.
Cohort Studies
These studies involve a large body of patientsfollowed up for long enough to detect the outcome ofinterest. Cohort studies generally include an exposedand unexposed group, but there are also single-exposure, disease or general population follow-upstudies and registries. Studies must be designed tominimize potential biases. An advantage of the cohortstudy is its ability to quantify both an absolute risk
10 PHARMACOVIGILANCE
and a relative risk. Cohort studies can be conductedprospectively, but such studies are usually expensiveand time-consuming. Retrospective cohort studies canbe conducted within large existing databases, provid-ing the advantage of the cohort study design and theefficiencies inherent in studies using existing records.
Case–control studies are particularly useful toconfirm a safety signal relating to a rare event (lessthan 1/1000). Cohort studies are useful when theoutcome has not already been identified or whenmultiple outcomes are of interest. Both case–controland cohort studies can be conducted within large exist-ing databases, assuming the required information isavailable.
An example of current methodologies can be foundin the Medicines Evaluation and Monitoring Orga-nization (MEMO). MEMO achieves ‘record-linkage’by joining together general practitioner prescriptiondata (the exposure data) with hospital dischargesummaries (the outcome data). This activity takesplace in Tayside, Scotland, where (uniquely in theUnited Kingdom) all patients have a personal Commu-nity Health Number (CHNo), which is widely usedby NHS facilities of all types. Advantages includecompleteness, freedom from study-introduced biasin data collection and timely availability of datafor analysis. MEMO is an example of the types ofdatabases that have been established since the mid-1970s that utilize data collected for other purposes.These databases have been used to detect and quanti-tatively evaluate hypotheses regarding safety signals.
Data resources now exist in many countries, espe-cially in North America and western Europe. Someexamples of these data resources and application ofthese databases to answer important safety questionswill be described in further chapters.
Randomized Controlled Trials
In this method of study, a group of patients isdivided into two in strictly random order; one groupis then exposed and the other not exposed, so that theoutcomes can be compared. The method is of greatimportance because random assignment of treatmentremoves some of the biases possible in observationalstudies. It is, however, of only limited (but important)use as a pharmacoepidemiological tool because mostserious ADRs are relatively uncommon; randomized
controlled trials (RCTs) used in such contexts can,therefore, become unmanageably large and expen-sive. Large simple trials have become more commonover the last decade in evaluating safety and efficacyin special circumstances, such as vaccine develop-ment, hormone replacement therapy and treatmentsfor common cardiovascular conditions.
CONCLUSION
Current progress in pharmacovigilance is marked byincreasing use of databases and by attempts to makethe process more proactive and organized. Attemptsare being made to augment the spontaneous, randomnature of the generation of pharmacovigilance dataand to make the process more systematic and struc-tured. These changes are emphasized by the recentguidance documents for industry by both EMEAand FDA on pharmacovigilance planning and riskmanagement. This emphasis on planning a pharma-covigilance programme for a drug and trying thought-fully to minimize risk appears constructive and, tosome of us, long overdue. It is notable that the empha-sis on proactive safety planning is linked with anexpectation that the suspicions arising from sponta-neous reporting will rapidly be tested by formal phar-macoepidemiological studies conducted in organizedand validated databases or prospective studies.
It is in everyone’s interest to develop safe andeffective medicines and provide access to patients forwhom benefits will outweigh harms. Post-approvalsurprises, such as drug withdrawals, are not innocentof harm for the drug is precipitously denied to largenumbers of patients who found it safe and effective.There has been a coming together of academic, regu-latory and industrial interests across many countriesto produce the guidance documents mentioned aboveas well as good practice guidelines for the conduct ofpharmacopepidemiology studies (International Soci-ety for Pharmacoepidemiology, 2004).
REFERENCES
Herbst AL, Poskanzer DC, Robboy SJ et al. (1975) Prena-tal exposure to stilbestrol. A prospective comparisonof exposed female offspring with unexposed controls.N Engl J Med 292: 334–9.
