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PHARMACOVIGILANCE

Edited by

RONALD D. MANN

ELIZABETH B. ANDREWS

Innodata0470852976.jpg

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PHARMACOVIGILANCE


PHARMACOVIGILANCE

Edited by

RONALD D. MANN

ELIZABETH B. ANDREWS


Copyright # 2002 by John Wiley & Sons Ltd,Baffins Lane, Chichester,West Sussex PO19 1UD, England

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Contents

List of Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii

Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xix

PART I. BASIS OF PHARMACOVIGILANCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Ronald D. Mann and Elizabeth B. Andrews

2. Legal Basis—EU. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Nicholas Macfarlane, Gabrielle Turner, Caroline Moore, Christoph Hiltl, Paule Drouault-Gardratand Paolo Ricci

3. Legal Basis—US . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Robert P. Brady and Mark D. Learn

4. Ethical Oversight, Consent, and Confidentiality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37Donna A. Boswell and Elizabeth B. Andrews

5. Pre-clinical Safety Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51Norma Kellett, Stuart J. Mair and Walter S. Nimmo

6. Metabolic Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57Munir Pirmohamed and B. Kevin Park

7. Drugs and the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77Una Martin and Charles George

8. Natural History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97Paul E. Stang

9. Responding to Signals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105Patrick C. Waller and Peter Arlett

10. Micturin and Torsades de Pointes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129Richard N. Wild

11. Withdrawal of Terodiline: A Tale of Two Toxicities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135Rashmi R. Shah

12. Nomifensine and Haemolytic Anaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155Peter D. Stonier and J. Guy Edwards


PART II. SIGNAL GENERATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

13. WHO Programme—Global Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169I. Ralph Edwards and Sten Olsson

14. Regulatory Pharmacovigilance in the EU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183Patrick C. Waller and Priya Bahri

15. Spontaneous Reporting—UK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195Sarah Davis and June M. Raine

16. Spontaneous Reporting—France . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209Nicholas Moore, Carmen Kreft-Jais and Alban Dahnani

17. Spontaneous Reporting—USA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219David J. Graham, Syed R. Ahmad and Toni Piazza-Hepp

18. Algorithms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229John A. Clark

19. Overview—Spontaneous Signalling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247John A. Clark, Stephen L. Klincewicz and Paul E. Stang

20. Statistical Methods of Signal Detection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273Stephen Evans

21. Statistical Methods of Evaluating Pharmacovigilance Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281Bernard Bégaud

22. Data Mining . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291I. Ralph Edwards, Marie Lindquist, Andrew Bate and Roland Orre

23. Epidemiology of Adverse Events Associated with Epilepsy and Use of Lamotrigine . . . . . . . . . . . 301Patricia Tennis

24. Pharmacovigilance in the Netherlands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309A.C. van Grootheest and E.P. van Puijenbroek

25. CIOMS Working Groups and their Contribution to Pharmacovigilance . . . . . . . . . . . . . . . . . . . . . 317Sue Roden

26. PEM in the UK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333Saad A.W. Shakir

27. PEM in New Zealand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345David M. Coulter

28. MEMO in the UK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363Douglas Steinke, Josie M.M. Evans and Thomas M. Macdonald

29. GPRD in the UK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373Louise Wood

30. Overview of North American Databases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379Brian L. Strom and Judith L. Kinman

31. Pharmacovigilance in the HMO Research Network . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391Richard Platt et al.

32. Other databases in Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399Miriam C.J.M. Sturkenboom

33. Surveillance for Medical Devices—USA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411Thomas P. Gross and Larry G. Kessler

vi CONTENTS


PART III. PHARMACOVIGILANCE AND SELECTED SYSTEM ORGAN CLASSES . . . . . . . 423

34. Dermatological ADRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425Laurence Valeyrie and Jean-Claude Roujeau

35. Gastrointestinal ADRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435John R. Wood and Graham A. Pipkin

36. Haematological ADRs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449Sarah Davis and Ronald D. Mann

37. Hepatic Adverse Drug Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459Guruprasad P. Aithal and Christopher P. Day

38. Ocular ADRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475F.W. Fraunfelder and F.T. Fraunfelder

39. Drug Safety in Pregnancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483Christina D. Chambers and Elizabeth B. Andrews

40. ADRs and Drug Safety 1999–2000 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491Pauline Curel and Rosie Stather

PART IV. LESSONS AND DIRECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503

41. Teaching Pharmacovigilance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505Ronald Meyboom, Sten Olsson and Margaret Thorogood

42. Medical Errors and Lessons from Drug-Related Deaths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509Richard E. Ferner and R.M. Whittington

43. Pharmacogenetics and the Genetic Basis of ADRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515Penelope K. Manasco, Patricia Rieser, Gaile Renegar and Michael Mosteller

44. Keynote Clinical Lessons from Pharmacovigilance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535David H. Lawson

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545

CONTENTS vii

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Contributors

SYED R. AHMAD, MB, BS, MPH Medical Epidemiologist, Division of Drug Risk Evaluation, Office ofDrug Safety, Center for Drug Evaluation and Research, US Food andDrug Administration, 5600 Fishers Lane, HFD-400, Rm 15B-32, Rock-

ville, MD 20857, USA, [email protected]

GURUPRASAD P. AITHAL, MD,MRCP, PhD

Consultant Hepatobiliary Physician, Queen’s Medical Centre, UniversityHospital, D Floor, South Block, Nottingham NG7 2UH, UK,

[email protected]

SUSAN E. ANDRADE, ScD Senior Research Associate, Meyers Primary Care Institute, FallonHealthcare System, and University of Massachusetts, Worcester, MA01605, USA, [email protected]

ELIZABETH B. ANDREWS, MPH,PhD

Vice President, RTI Health Solutions, Research Triangle Institute, 3040Cornwallis Road, PO Box 12194, Research Triangle Park, NC 27709-2194,USA, Adjunct Associate Professor, School of Public Health and School

of Pharmacy, University of North Carolina at Chapel Hill, NC, USA,[email protected]

PETER ARLETT, BSc, MBBS, MRCP Senior Medical Assessor and CPMP Delegate, Post-Licensing Division,Medicines Control Agency, Market Towers, 1 Nine Elms Lane, London

SW8 5NQ, UK, [email protected]

PRIYA BAHRI, PhD Scientific Administrator, Sector Pharmacovigilance and Post-Authorisa-tion Safety and Efficacy of Human Medicines, European Agency for theEvaluation of Medicinal Products (EMEA), 7 Westferry Circus, London

E14, 4HB, UK, [email protected]

ANDREW BATE, MA Programme Leader, Signal Research Methodology, Uppsala MonitoringCentre, Stora Torget 3, 753 20 Uppsala, Sweden, andrew.bate@who-

umc.org

BERNARD BÉGAUD, MD Professor of Pharmacology, Départment de Pharmacologie Clinique—Unité de Pharmaco-épidémiologie, ARME-Pharmacovigilance, UniversitéVictor Segalen, 33076 Bordeaux, France, [email protected]

bordeaux2.fr

DONNA A. BOSWELL, JD, PhD Partner, Hogan & Hartson, L.L.P., Columbia Square, 555 ThirteenthStreet, NW, Washington, DC 20004-1109, USA, [email protected]


ROBERT P. BRADY, Esq. Partner, Hogan & Hartson, L.L.P., Columbia Square, 555 ThirteenthStreet, NW, Washington, DC 20004-1109, USA, [email protected]

CHRISTINA D. CHAMBERS, MPH,

PhD

Assistant Professor of Pediatrics, Department of Pediatrics, UCSD

Medical Center MC8446, 200 W Arbor Drive, San Diego, CA 92103,USA, [email protected]

K. ARNOLD CHAN, MD, ScD Assistant Professor, Department of Epidemiology, Harvard School ofPublic Health, Boston, MA 02215, USA, [email protected]

JOHN A. CLARK, MD, MSPH Vice President, Safety Services, Galt Associates, Inc., 21240 Ridgetop

Circle, Ste 140, Sterling, VA 20166, USA, [email protected]

DAVID M. COULTER, MB, ChB(NZ), DTM&H (Sydney)

Head, Centre for Adverse Drug Reactions Monitoring, Director,Intensive Medicines Monitoring Programme, Department of Preventive

and Social Medicine, University of Otago, PO Box 913, Dunedin, NewZealand, [email protected]

PAULINE CUREL, MPS Team Leader, Drug Information Pharmacists, Clineanswers, ClearCentre, Smales Farm Office Park, PO Box 33-1548, Takapuna, Auckland1332, New Zealand, [email protected]

ALBAN DAHNANI, PharmD Assistant to the Head of the Pharmacovigilance Unit, Agence Françoisede Sécurité Sanitaire des Produits de Santé (AFSSAPS), 143=147 BdAnatole, France 93 285 St Denis, France, [email protected]

ROBERT L. DAVIS, MD, MPH Associate Professor, Department of Pediatrics and Epidemiology,University of Washington, and Group Health Cooperative Center forHealth Studies, Seattle, WA 98101, USA, [email protected]

SARAH DAVIS, BSc (Hons), PhD Scientific Assessor, Pharmacovigilance Group, Post-Licensing Division,Medicines Control Agency, Market Towers, 1 Nine Elms Lane, LondonSW8 5NQ, UK, [email protected]

CHRISTOPHER P. DAY, FRCP, MD,PhD

Professor of Liver Medicine and Honorary Consultant Hepatologist,Centre for Liver Research, The Medical School, Framlington Place,

Newcastle upon Tyne NE2 4HH, UK, [email protected]

FRANK DESTEFANO, MD, PhD Project Director, Vaccine Safety Datalink, National ImmunizationProgram, Centers for Disease Control and Prevention, Atlanta, GA

30333, USA, [email protected]

PAULE DROUAULT-GARDRAT,LL.M, CEIPI, Avocat

Pharmacist, Lovells, 37 Avenue Pierre-1er-De Serbie, 75008 Paris, France,[email protected]

J. GUY EDWARDS, MB, BCh,FRCPsych, DPM

Visiting Professor, Khon Kaen University, Khon Kaen and Prince ofSongkla University, Hat Yai, Thailand

I. RALPH EDWARDS, MB, ChB,FRCP, FRACP

Director, Uppsala Monitoring Centre, Stora Torget 3, 753 20 UppsalaSweden, [email protected]

JOSIE M. M. EVANS, MA (Oxon)

MPH, PhD

Lecturer in Epidemiology, Department of Epidemiology and Public

Health, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK,[email protected]

STEPHEN EVANS, BA, MSc, CStat,FRCP (Ed)

Professor of Pharmacoepidemiology, Medical Statistics Unit, TheLondon School of Hygiene and Tropical Medicine, Keppel Street,London WC1E 7HT, UK, [email protected]

x CONTRIBUTORS


RICHARD E. FERNER, MD, MSc,FRCP

Director, West Midlands Centre for Adverse Drug Reaction Reporting,City Hospital, Birmingham B18 7QH, UK, [email protected]

JONATHAN A. FINKELSTEIN, MD,MPH

Associate Professor, Department of Ambulatory Care and Prevention andof Pediatrics, Harvard Medical School and Harvard Pilgrim Health Care,

Boston, MA 02215, USA, [email protected]

F. T. FRAUNFELDER, MD Professor of Ophthalmology, Casey Eye Institute, Oregon Health SciencesUniversity, 3375 SW Terwilliger Blvd, Portland, OR 97035, USA,

[email protected]

F. W. FRAUNFELDER, MD Assistant Professor, Cornea and External and Disease Director of theNational Registry of Drug-Induced Ocular Side Effects, Casey EyeInstitute, Oregon Health Sciences University, 3375 SW Terwilliger Blvd,

Portland, OR 97035, USA, [email protected]

SIR CHARLES GEORGE, BSc, MD,FRCP

Medical Director, British Heart Foundation, 14 Fitzhardinge Street,London W1H 6DH, UK, [email protected]

ALAN S. GO, MD, MPH Physician Scientist, Division of Research, Kaiser Foundation ResearchInstitute, Oakland, CA 94611, USA

MICHAEL J. GOODMAN, PhD Senior Research Investigator, HealthPartners Research Foundation,Minneapolis, MN 55440, USA, [email protected]

DAVID J. GRAHAM, MD, MPH Associate Director for Science and Medicine, Office of Drug Safety,Centre for Drug Evaluation and Research, US Food and Drug

Administration, 5600 Fishers Lane, HFD-400, Rm 15B-32, RockvilleMD 20857, USA, [email protected]

A. C. VAN GROOTHEEST, MD Director, Netherlands Pharmacovigilance Centre Lareb, Goudsbloemvallei 7, 5273 MH’s-Hertogenbosch, The Netherlands, ac.vangrootheest@

lareb.nl

THOMAS GROSS, MD, MPH Director, Division of Postmarket Surveillance, Office of Surveillance andBiometrics, Center for Devices and Radiological Health, US Food andDrug Administration, 1350 Piccard Drive, Room 300P, Rockville, MD

20850, USA, [email protected]

JERRY H. GURWITZ, MD The Dr John Meyers Professor of Primary Care Medicine, University ofMassachusetts Medical School and Executive Director, Meyers PrimaryCare Institute, Fallon Healthcare System, and University of Massachu-

setts Medical School, Worcester, MA 01605, USA

CHRISTOPH HILTL, Dr.jur. Partner, Lovells Boesebeck Droste, Marstallstrasse 8, 80539 Munchen,Germany, [email protected]

NORMA KELLETT, BSc, MBChB,

MRCGP, FFPM

Director Clinical Services, Inveresk Research, Tranent EH33 2NE, UK,

[email protected]

LARRY G. KESSLER, ScD Office Director, Office of Surveillance and Biometrics, Centre for Devicesand Radiological Health, US Food and Drug Administration, 1350Piccard Drive, Rockville MD 20850, USA [email protected]

JUDITH L. KINMAN, MA Project Manager, Center for Clinical Epidemiology and Biostatistics,University of Pennsylvania School of Medicine, 824 Blockley Hall,423 Guardian Drive, Philadelphia, PA 19104-6021, USA, jkinman@

CONTRIBUTORS xi


cceb.med.upenn.edu, Regional Managing Editor, Pharmacoepidemi-ology and Drug Safety

STEPHEN L. KLINCEWICZ, DO,MPH, JD

Global Safety Officer, Drug Safety and Surveillance, Johnson andJohnson Pharmaceutical Research and Development LLC, 1125 Tren-

ton-Harbourtown Road, Titusville, NJ 08560-0200, USA, [email protected]

CARMEN KREFT-JAIS, MD Head, Pharmacovigilance Unit, Agence Française de Sécurité Sanitairedes Produits de Santé (AFSSAPS), 143=147 Bd Anatole France, 93 285 StDenis, France, [email protected]

PAOLA LA LICATA, JD Lawyer, Lovells, Via Dei Due Marcelli 66, 00187 Roma, Italy,

[email protected]

DAVID H. LAWSON, CBE, MD,

FRCP

Head of Department of Clinical Pharmacology, Royal Infirmary,

Glasgow, UK, [email protected]

MARK D. LEARN, Esq. Associate, Hogan & Hartson, L.L.P., Columbia Square, 555 ThirteenthStreet, NW,Washington, DC 20004-1109, USA,[email protected]

MARIE LINDQUIST, MSc Pharm Head of Data Management & Research, General Manager, UppsalaMonitoring Centre, Stora Torget 3, 753 20 Uppsala, Sweden,[email protected]

THOMAS M. MACDONALD, BSc,

MD, FRCP, FESC

Professor of Clinical Pharmacology and Pharmacoepidemiology, Director,

MEdicines MOnitoring Unit (MEMO), Department of Clinical Pharma-cology and Therapeutics, University of Dundee, Ninewells Hospital andMedical School, Dundee DD1 9SY, UK, [email protected]

NICHOLAS MACFARLANE, BA Partner, Lovells, 65 Holborn Viaduct, London EC1A 2DY, UK, nicholas.

[email protected]

STUART J. MAIR, MBChB, DRCOG,

DCPSA

Medical Advisor, Inveresk Research, Tranent EH33 2NE, UK,

[email protected]

PENELOPE K. MANASCO, MD Chief Medical Officer, First Genetic Trust, 3 Parkway North Center Suite150N, Deerfield, IL 60015, USA, [email protected]

RONALD D. MANN, MD, FRCP,FRCGP, FFPM

Professor Emeritus, University of Southampton, UK, and 42 HazletonWay, Waterlooville, Hampshire PO8 9BT, UK, [email protected]

UNA MARTIN, BSc, PhD, FRCPI Senior Lecturer in Clinical Pharmacology, Division of Medical Sciences,

The University of Birmingham, Queen Elizabeth Hospital, Edgbaston,Birmingham B15 2TH, UK, [email protected]

BRIAN C. MARTINSON, PhD Research Investigator, HealthPartners Research Foundation, Minne-apolis, MN 55440, USA, [email protected]

RONALD MEYBOOM, MD, PhD Medical Adviser, Uppsala Monitoring Centre, Stora Torget 3, 753 20Uppsala, Sweden, [email protected]

CAROLINE MOORE, BA (Oxon) Barrister, Lovells, 65 Holborn Viaduct, London EC1A 2DY, UK,

[email protected]

NICHOLAS MOORE, MD, PhD Professor of Clinical Pharmacology, Département de Pharmacologie,Université Victor Segalen—CHU de Bordeaux, 33076 Bordeaux cedex,France, [email protected]

xii CONTRIBUTORS


MICHAEL MOSTELLER, MS, PhD Statistical Geneticist, Population Genetics, Genetics Research, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA,[email protected]

WALTER S. NIMMO, BSc, MD,

FRCP, FRCA, FANZCA, FFPM,FRSE

Chief Executive, Inveresk Research, Tranent EH33 2NE, UK, walter.

[email protected]

STEN OLSSON, MSci, Pharm Head, External Affairs, Uppsala Monitoring Center, Stora Torget 3, 75320 Uppsala, Sweden, [email protected]

ROLAND ORRE, MSc Department of Mathematical Statistics, Stockholm University S-10691Stockholm, Sweden, [email protected]

B. KEVIN PARK, BSc (Hons), PhD,

Hon MRCP

Professor of Pharmacology, Department of Pharmacology and Thera-

peutics, The University of Liverpool, Ashton Street, Liverpool L69 3GE,UK, [email protected]

TONI PIAZZA-HEPP, PharmD Deputy Director, Division of Surveillance, Research and CommunicationSupport, Office of Drug Safety, Center for Drug Evaluation and

Research, US Food and Drug Administration, 5600 Fishers Lane,HFD-400, Rm 15B-32, Rockville, MD 20857, USA, [email protected]

GRAHAM A. PIPKIN, BSc (Hons) Communications Manager, GI, Neurology and GI GCS, GlaxoSmith-

Kline, Stockley Park West, Uxbridge, Middlesex UB11 1BU, UK,[email protected]

MUNIR PIRMOHAMED, PhD,FRCP, FRCP (Ed)

Professor of Clinical Pharmacology=Consultant Physician, Departmentof Pharmacology and Therapeutics, The University of Liverpool, AshtonStreet, Liverpool L69 3GE, UK, [email protected]

RICHARD PLATT, MD, MSc Professor of Ambulatory Care and Prevention, Harvard Medical School,Director of Research, Harvard Pilgrim Health Care, 133 BrooklineAvenue, 6th Floor, Boston MA 02215, USA, [email protected]

E. P. VAN PUIJENBROEK, MD, PhD Head, Science Department, Netherlands Pharmacovigilance CentreLareb, Goudsbloemvallei 7, 5273 MH’s-Hertogenbosch, The Nether-lands, [email protected]

MARSHA A. RAEBEL, PharmD Pharmacotherapy Research Manager, Kaiser Permanente Colorado, andAdjoint Associate Professor of Pharmacy, University of Colorado School

of Pharmacy, Denver, CO 80231, USA, [email protected]

JUNE M. RAINE, MA, MSc, FRCP(Ed)

Director, Post-Licensing Division, Medicines Control Agency, MarketTowers, 1 Nine Elms Lane, London SW8 5NQ, UK, [email protected]

GAILE RENEGAR, JD, RPh Director, Genetics Education and External Relations, Genetics Research,

GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709,USA, [email protected]

PAOLO RICCI, JD Partner, Lovells, Via Dei Due Marcelli 66, 00187 Roma, Italy,[email protected]

PATRICIA RIESER, BSN, RN, CFNP Consultant, Genetics Education and External Relations, GeneticsResearch, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park,NC 27709, USA, [email protected]

CONTRIBUTORS xiii


DOUGLAS ROBLIN, PhD Research Scientist, Kaiser Permanente Georgia, Atlanta, GA 30305,USA, [email protected]

SUSAN RODEN, BSc, MSc, MRPS Director, Global Pharmacovigilance and Risk Management, GCSP,GlaxoSmithKline Research and Development Ltd, Greenford Road,

Greenford, Middlesex UB6 0HE, UK, [email protected]

DENNIS ROSS-DEGNAN, ScD Associate Professor, Department of Ambulatory Care and Prevention,Harvard Medical School, and Harvard Pilgrim Health Care, Boston, MA02215, USA, [email protected]

JOHN-CLAUDE ROUJEAU, MD Assistant, Service de Dermatologie, Hôpital Henri Mondor, UniversitéParis XII, 94010 Créteil, France, [email protected]

RASHMI R. SHAH, BSc, MBBS, MD,

FRCP, FFPM

Senior Medical Officer, Medicines Control Agency, Market Towers,

1 Nine Elms Lane, Vauxhall, London SW8 5NQ, UK, [email protected]

SAAD A.W SHAKIR, FRCP (Glas &Ed), FFPM, MRCGP

Director, Drug Safety Research Unit, Bursledon Hall, Blundell Lane,Southampton SO31 1AA, UK, [email protected]

DAVID H. SMITH, RPh, PhD Investigator, Kaiser Permanente Center for Health Research, Portland,

OR 97227, USA, [email protected]

STEPHEN B. SOUMERAI, ScD Professor of Ambulatory Care and Prevention, Department of Ambula-tory Care and Prevention, Harvard Medical School and Director of Drug

Policy Research Group, Harvard Pilgrim Health Care, Boston, MA02215, USA, [email protected]

PAUL E. STANG, PhD Executive Vice-President, Galt Associates, Inc., 1744 DeKalb Pike, Suite175, Blue Bell, PA 19422-3352, USA, Adjunct Associate Professor of

Epidemiology, University of North Carolina School of Public Health,Chapel Hill, NC, USA, [email protected]

ROSIE STATHER, MA (Cantab) Editor, Drug Safety; Consulting Editor, Reactions Weekly, Adis Interna-tional Ltd, 41 Centorian Drive, Private Bag 65901, Mairangi Bay,

Auckland 10, New Zealand, [email protected]

DOUGLAS STEINKE, BSc (Pharm),MSc, PhD

Research Pharmacist, Primary Care Information Group, Information andStatistics Division, Room BO12, Trinity Park House, South Trinity Road,Edinburgh EH5 3SQ, UK, [email protected]

PETER D. STONIER, PhD,

MRCPsych, FRCP, FFPM

Medical Director, HPRU Medical Research Centre, University of Surrey,

Egerton Road, Guildford GU2 5XP, UK, [email protected]

BRIAN STROM, MD, MPH Director, Center for Clinical Epidemiology and Biostatistics, Universityof Pennsylvania School of Medicine, 824 Blockley Hall, 423 GuardianDrive, Philadelphia PA 19104-6021, USA, [email protected]

MIRIAM C.J.M. STURKENBOOMPHD, MSc, PharmD

Assistant Professor, Pharmaco-epidemiology Unit, Department ofEpidemiology and Biostatistics and Medical Informatics. ErasmusUniversity Medical Centre., PO Box 1738, 3000 DR Rotterdam, The

Netherlands; International Pharmacoepidemiology and Pharmaco-economics Research Centre (IPPRC), Via Mantova 11, 20033 Desio(MI), Italy, [email protected]

xiv CONTRIBUTORS


PATRICIA TENNIS, PhD Senior Director of Safety Epidemiology, Worldwide Epidemiology,GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709,USA, [email protected]

MARGARET THOROGOOD, PhD Reader in Public Health and Preventative Medicine, Research DegreesDirector, Health Promotion Research Unit, Department of Public Health

and Policy, London School of Hygiene and Tropical Medicine, KeppelStreet, London WC1E 7HT, UK, [email protected]

GABRIELLE TURNER, LL.M Solicitor, Lovells, 65 Holborn Viaduct, London EC1A 2DY, UK,[email protected]

MARIANNE ULCICKAS-YOOD,DSc, MPH

Senior Epidemiologist, Henry Ford Health Systems, Detroit, MI 48202,USA, [email protected]

LAURENCE VALEYRIE, MD Chef de Clinique, Service de Dermatologie, Hôpital Bichat, 46 Ave HenriHuchard, 75877 Paris Cedex 18, France, [email protected]

PATRICK C. WALLER, MD, FRCP(Ed), FFPM, MPH

Post-Licensing Division, Medicines Control Agency, Market Towers, 1Nine Elms Lane, London SW8 5NQ, UK, [email protected]

R. M. WHITTINGTON Former HM Coroner for Birmingham and Solihull Districts, Coroner’s

Court, Newton Street, Birmingham B4 6NE, UK

RICHARD N. WILD, MB, ChB, DCH,

FFPM, FRCP (Ed)

Medical Director, Arakis Ltd, Chesterford Research Park, Little

Chesterford, Saffron Walden, Essex CB10 1XL, UK, [email protected]

JOHN R. WOOD, MB, BSc, PhD Managing Director, Wood and Mills Limited, The Mill House, Frame-wood Road, Fulmer, Bucks SL2 4QS, UK, [email protected]

LOUISE WOOD, BSc (Hons), PhD Director, GPRD Division, Medicines Control Agency, Room 15-103Market Towers, 1 Nine Elms Lane, Vauxhall, London SW8 5NQ, UK,[email protected]

CONTRIBUTORS xv

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Preface

The editors of this volume have looked uponpharmacovigilance as being the study of the safetyof marketed drugs under the practical conditionsof clinical usage in large communities. However,some aspects of this definition need qualification:safety cannot be considered apart from efficacy inmost situations. For example, an ineffective drugused in a serious and life-threatening disease wouldbe unsafe. Those individuals conducting pharma-covigilance are concerned not only with marketeddrugs but also with their pre-marketing data—butour working definition serves a practical purpose.

Spontaneous reporting of suspected adversedrug effects is central to pharmacovigilance—which is the systematic search for signals of drugtoxicity. When such a signal is detected it has to beverified, explored, and understood—realising thatthe drug may be acceptably safe if used byindividuals who are not at especially high risk byvirtue of genetic constitution, metabolism, or othercharacteristics that could alter individual risk.

Pharmacovigilance is conducted by a very largenumber of people concerned with protectingpopulations from serious unintended adverseconsequences of medication exposure. It is im-portant to recognise that most medications carrysome risk due to their pharmacologic properties orto other factors. The evaluation of risk must beconducted in the context of the patient benefitderived from treatment, the severity of the condi-tion being treated, and other objective andsubjective factors (such as the patient’s values).Each of the stakeholders—the patient, physician,pharmaceutical company, academic investigator,

government—may have a different perspective onthe same set of evidence. For example, a patientmay be willing to accept a high risk of side-effectsfor benefits of the treatment for a condition thatmight be considered trivial by others. A regulatoryagency may consider the burden of the same side-effects to be too high, given their view of the risk–benefit equation. A governmental or third-partypayer might see the issue from an even differentperspective, since a payer may not wish to bear thecost of the treatment or the cost of treating anadverse event. It is perhaps not surprising thateach group may take a different view of the sameevidence. In addition, each group may also beswayed by intense external pressures to take actionto protect specific interests, for example to protectthe public against potential harm or to protectagainst legal liability. These pressures may lead toearly decisions based on incomplete scientific data.

There have been mistakes and errors in the fieldof pharmacovigilance: some drugs have beenwithdrawn when the benefit to large numbers ofpatients has not been properly balanced againstthe harm done to very few highly susceptiblesubjects. Identifying the patients most susceptibleto risk and finding ways to channel medications tothe appropriate patients would have been morerational. It is always highly desirable to subject thesignal to the formal processes of pharmacoepide-miology (such as case–control, cohort, largesimple randomised trial, etc.) before taking grossaction on a weak or questionable signal. We haveto weigh benefit against risk and the benefit maybe to a large population affected by a serious

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disease and the risk may be to a small populationof susceptibles.

This book intends to help bring more rigorousconsiderations of scientific evidence to the varioussectors that face critical decisions about how to actin the face of incomplete information. Our hope isthat future decisions will be improved, and thatpublic policy decisions can be made more trans-parent in the process.

The tension between regulator (governmentoversight agencies) and regulated (pharmaceuticalindustry) that was apparent in earlier years mustbe viewed in a more complex environment inwhich additional sectors also have consideredopinions of the evidence, and possess stronginterests as well. All sectors must grapple withthe evidence and the pros and cons of decisionsand the consequences of these decisions. Thesubject is not easy and its participants arefrequently highly exposed. If this book is of anyhelp to those exposed to political pressure, mediapressure, their own indecision and anxieties, etc.,then it will have been worth the effort taken toproduce it.

The book falls into four parts: the basis ofpharmacovigilance, signal generation, pharmacov-igilance and the system–organ classes, and, finally,lessons and directions. We have eliminated someduplication but not all of it: people come at thesame thing from different directions and some-

times those different viewpoints need to bepreserved. Some subjects, for a variety of reasons,have been inadequately covered (signal generationin important countries and developing areas of theworld; dictionaries and MedDRA; pharmacovigi-lance as conducted by some of the big companies,other than those already reviewed; non-US med-ical devices legislation; renal, cardiovascular andrespiratory adverse drug reactions, etc.). Some ofthese subjects have been left for expansion in oursecond edition; some have been omitted this timeround because, for example, we do not intend tocover all the system–organ classes in each editionbut will choose different themes as time goes by.A large number of people are concerned with

pharmacovigilance but they are a very smallnumber compared with the populations that theyset out to protect. We hope that this volume will beof help to them and we thank our many authorsfor their contributions.The editors wish to express their considerable

appreciation to John and Celia Hall who took overthe management of the production of this book indifficult circumstances and whose contribution ismuch appreciated. Professor Mann also wishes toacknowledge the considerable support of hispersonal assistant, Mrs Susan Jerome.

Ronald D. MannElizabeth B. Andrews

xviii PREFACE


Foreword

My introduction to the world of drug toxicitytook place in 1965 when a patient attending ourHypertension Clinic at Hammersmith Hospital inLondon donated blood for transfusion andproblems in cross matching the blood samplewere encountered. This was found to be due to apositive direct Coombs’ test (DCT). The hyper-tensive patient in question was being treated with�-methyldopa, which at that time was one of themost widely used antihypertensive drugs in theworld and had been so for several years. When apossible connection between �-methyldopa and apositive DCT was postulated, initial hilarity andscepticism were rapidly replaced by curiosity andinterest when blood samples from a further 202patients treated with the same drug revealed 40(20%) patients with the same haematologicalabnormality, while none of a control group of76 hypertensive patients on other forms oftherapy demonstrated a positive DCT. This ledto a series of investigations to document theclinical epidemiology of the adverse effect and toinvestigate the underlying immunological ab-normality. We learned several lessons from thisepisode. The first was that careful observationand high clinical suspicion are of crucial impor-tance in order to identify a drug toxicity problem.The second lesson was that even though a drughas been on the market for several years and iswidely used, unusual adverse reactions may stillbe identified, stressing the importance of con-tinuing watchfulness. The term ‘‘post-marketingdrug surveillance’’ had not been introducedin 1965.

The history of drug safety, pre- and post-thalidomide, has been documented many times.In many respects, this history parallels the devel-opment of what we now call rational, or evidence-based, therapeutics. One of the editors of thisbook, Ronald Mann, elsewhere describes how theUnited Kingdom in 1914 was on the point ofadopting a drug regulatory system very akin tothat which we have today. This occurred becausearound the turn of the last century there waswidespread public concern and professional scepti-cism about the therapeutic value and the safety ofpatent medicines which were widely promoted andused. In 1909 the British Medical Associationpublished a booklet entitled Secret Remediesdetailing the excesses and shortcomings of thesemedicines; this proved to be a best seller which wasreprinted several times in quick succession. Suchwas the level of public anxiety caused by thispublication that a Parliamentary Select Committeewas established to examine the whole topic ofpatent medicines. The Committee, which tookevidence over three years, pulled no punches ininterviewing the purveyors of these products, andits final report recommended in considerable detailhow the public should be protected from thefrequently unjustifiable and often fraudulentclaims of the manufacturers of proprietary medi-cines. These recommendations included the crea-tion of a Commission whose role was to overseedrug quality, safety and efficacy, drug advertisingshould be controlled and the Ministry of Healthshould regulate the field. The publication of thereport of the Select Committee on 4 August 1914


was totally overshadowed by force majeure,namely the outbreak of the First World War,and the report sat gathering dust on the Ministry’sshelves with no action being taken. As RonaldMann succinctly states, ‘‘It is not altogetherfanciful to look on the children of the thalidomidedisaster as late and unwilling victims of WorldWar One.’’

Post thalidomide there was a worldwide realisa-tion that the introduction of new therapies and thecontinuing use of existing therapies had to beregulated based on sound scientific principles. Aspart of this, systems for doctors to report adversereactions to drugs were set up; in the UnitedKingdom a yellow card was used to file thereports. But by the 1980s there was an increasingrealisation that all was not well with the methodsavailable to assess adverse drug reactions, andwhile spontaneous reporting using yellow cards ortheir like continued to make a valuable contribu-tion to drug safety, other methods had to bedevised to help attribute adverse effects to specificdrugs. It was suggested that the methodologybeing pioneered by epidemiologists might make acontribution to study the response of the popula-tion to both the adverse and beneficial effects ofdrugs, thus obtaining a better assessment of riskand benefit. In particular, prospective and retro-spective cohort studies, case–control studies, andlinked data bases might help unravel the problemsof drug safety surveillance. Thus, pharmacoepide-miology arose as a new discipline. The limitationsof applying the techniques of the epidemiologist todrug surveillance are, of course, widely appre-ciated. The clinical data used can rarely be asrobust as those from the laboratory and theintroduction of bias is a constant risk. Further-more, the pharmacology of the drugs used and thepathophysiology of the diseases involved have tobe understood.

In general, scientists involved in drug safetyhave espoused the adoption of the principles ofpharmacoepidemiology into pharmacovigilancewith enthusiasm. However, from time to time,post-marketing safety surveillance studies fallbelow the required standards, usually due to poortrial design or the total lack of a comparatorgroup. If sound principles are not followed, then

such studies are worthless in scientific terms andmake no meaningful contribution to pharmacov-igilance.The concept of balancing risk and benefit is now

firmly embedded in modern drug treatment.Doctors, patients and the public are familiar withthe concept of iatrogenic disease. Large-scalerandomised control trials (a particular exampleof a prospective cohort study) are particularlyvaluable in defining the balance of risk and benefitand few modern medicines are introduced withoutbeing subjected to this form of analysis. Oneweakness of this approach is that risks and benefitsusually have different end points. For example, atrial of an angiotensin converting enzyme inhibitorto investigate the beneficial reduction of stroke,heart failure or myocardial infarction in patientswith hypertension has to be balanced againstincreasing the incidence of cough and rash. Formaldecision analysis is one way of dealing with issueslike this, but medicine is often uncomfortable withthis approach. Another problem is that in anyclinical trial there may be a cohort of patients whomay show great benefit, but the overall risk–benefit balance of the trial may be negative. Unlessone can clearly define the population who willshow a beneficial response, perhaps using phar-macogenetic methodology, a drug may be dis-carded by a developer or rejected by a regulatoryauthority.No branch of science stands still. It either makes

significant advances or sinks back and becomesirrelevant, and pharmacovigilance is no exception.Looking to the future, perhaps we should be lessfocused on finding evidence of harm and moreinterested in extending our knowledge of safety. Aspecification of what is known about a medicine atthe time of licensing should form the basis of whatis required to extend understanding of its safety asit is introduced into the community. Risk–benefitdecisions in clinical practice and drug regulationare often complex, but other disciplines have alsostruggled with these problems and medicine shouldbe more prepared to adopt techniques such asformal decision analysis to improve its decisionmaking. Outcome measures should be classified ona hierarchical basis; hard end points such asmortality and morbidity are not always available

xx FOREWORD


and imaginative work on surrogate end points ofdrug safety should be encouraged and validated.As in all branches of medicine, the systematic auditof the processes involved and the outcomesmeasured should be mandatory and should formthe basis of the milestones to be set for thedevelopment of the medicine once it becomeswidely used. Finally, on perhaps a more mundanelevel, increasing emphasis should be placed on theprovision of comprehensive, and at the same timecomprehensible, information on the medicine forthe prescriber and the patient. One currently seesan unfortunate tendency for such documentationto become more legalistic and less user friendly.Unless the house physician prescribing for apatient at 3 a.m. has easy access to the essentialinformation he requires, or a patient can under-stand why he is taking a medicine and what the

outcomes are likely to be, all the work that hasgone into the development of the drug is valueless.A new approach to providing relevant informationon medicines is urgently needed, but sadly thissometimes seems to become more distant as thepractice of medicine becomes more complex.

I know of no book with a remit as extensive asthis. As the editors say in their preface, repetitionsare bound to occur and omissions (some of whichthey have already defined) are inevitable. Thebook is a tour de force and is a great tribute to thedriving energy, enthusiasm and professionalism ofRonald Mann and Elizabeth Andrews, and I amextremely proud to be associated with it.

Alasdair BreckenridgeChairman of the Committee

on Safety of Medicines

FOREWORD xxi

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Part I

BASIS OF PHARMACOVIGILANCE

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1

IntroductionRONALD D. MANN

Waterlooville, Hampshire, UK

ELIZABETH B. ANDREWSRTI Health Solutions, Research Triangle Institute, Research Triangle Park, NC, USA, and School of Public Health

and School of Pharmacy, University of North Carolina at Chapel Hill, NC, USA

‘‘Not all hazards can be known before a drug ismarketed.’’

Pharmacovigilance—the study of the safety ofmarketed drugs under the practical conditions ofclinical usage in large communities—involves aparadox. The nature of the paradox is bestexplained by glancing back to the very early 1960sand then looking at contemporary experience.

The greatest of all drug disasters was thethalidomide tragedy of 1961–1962. Thalidomidehad been introduced, and welcomed, as a safeand effective hypnotic and anti-emetic. It rapidlybecame popular for the treatment of nausea andvomiting in early pregnancy. Tragically, the drugproved to be a potent human teratogen thatcaused major birth defects in an estimated 10 000children in the countries in which it was widelyused in pregnant women. Figure 1.1 shows such achild fitted with the kind of prostheses available atthat time. The story of this disaster has beenreviewed elsewhere (Mann, 1984).

The thalidomide disaster led to the establish-ment of the drug regulatory mechanisms of today.These mechanisms require that new drugs shall be

licensed by the well-established regulatory autho-rities before being introduced into clinical usage.This, it might be thought, would have mademedicines safe—or, at least, acceptably safe. ButTable 1.1 shows a list of over 30 licensedmedicines withdrawn, after marketing, and fordrug safety reasons, over the last 25 years in theUnited Kingdom.

What is the explanation for the paradox that thehighly regulated pharmaceutical industry shouldneed, or be compelled, to withdraw licensedmedicines for drug safety reasons? Why do thesewithdrawals continue despite the accumulatedexperience of more than 40 years since thethalidomide tragedy?

Partly, the problem is one of numbers. To takebut one example: the median number of patientscontributing data to the clinical safety section ofnew drug licensing applications in the UnitedKingdom is only just over 1500 (Rawlins andJefferys, 1991). Increasing regulatory demands foradditional information prior to approval havepresumably increased the average numbers ofpatients in applications, especially for new chemi-cal entities. Nevertheless, the numbers remain far

Pharmacovigilance. Edited by R.D. Mann and E.B. Andrews# 2002 John Wiley & Sons, Ltd


too small to detect uncommon or rare adversedrug reactions, even if these are serious.

The size of the licensing applications forimportant new drugs cannot be materially in-creased without delaying the marketing of newdrugs to an extent damaging to diseased patients.Thus, drug safety depends very largely on thesurveillance of medicines once they have beenmarketed.

A second reason for difficulty is that the kindsof patients who receive licensed medicines are verydifferent from the kinds of volunteers and patientsin whom pre-marketing clinical trials are under-taken. The patients in formal clinical trials almostalways have only one disease being treated withone drug. The drug, once licensed, is likely to beused in an older group of patients, many of whomwill have more than one disease and be treated bymeans of polypharmacy. The formal clinical trialsmay be a better test of efficacy than they are ofsafety under the practical conditions of everydayclinical usage.

A third problem is that doctors may be slow orineffective in detecting and reporting adverse drugeffects. Many of the drugs shown in Table 1.1

were in wide-spread, long-term use before adversereactions were detected and, even now, hospitaladmissions due to adverse drug reactions haveshown an incidence of between 2.4% and 3.6% ofall admissions in Australia with similar or greaterfigures in France and the United States (Pouyanneet al., 2000). Even physicians astute in detectingadverse drug effects are unlikely to identify effectsof delayed onset.

An underlying reason 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 justdo not have effective means in place for monitor-ing total post-marketing safety experience. Themethodological problem is fundamental and itsrecognition widespread amongst those who havedevoted long periods to the issue of drug safetymonitoring.

Some of these difficulties were recognized fromquite early on. The Committee on Safety of Drugsin the United Kingdom (established after thethalidomide disaster, originally under the chair-manship of Sir Derrick Dunlop, to consider drugsafety whilst the Medicines Act of 1968 was beingwritten) said—quite remarkably—in its last re-port (for 1969 and 1970) that ‘‘no drug which ispharmacologically effective is without hazard.Furthermore, not all hazards can be known beforea drug is marketed.’’ This then has been known forover 30 years. Even so, many prescribers still seemto think that licensed drugs are ‘‘safe’’—andthey are surprised when a very small proportionof licensed drugs have to be withdrawn due tounexpected drug toxicity. And patients themselvesmay have expectations that licensed drugs are‘‘completely safe’’ rather than having a safetyprofile that is acceptably safe in the context of theexpected benefit and nature of the underlyinghealth condition.

The methodological problems have been longrecognized. The Committee on Safety of Medi-cines, the successor in the United Kingdom to theDunlop Committee, investigating this and relatedproblems, established a Working Party on AdverseReactions. This group, under the chairmanshipof Professor David Grahame-Smith, published itssecond report in July 1985. The report supported

Figure 1.1. Child with thalidomide-induced deformitiesof upper and lower limbs fitted with pneumaticprostheses.

4 PHARMACOVIGILANCE


continuation of methods of spontaneous reportingby professionals but recommended that post-marketing surveillance (PMS) studies should beundertaken on ‘‘newly-marketed drugs intendedfor widespread long-term use’’; the report alsomentioned record-linkage methods and prescrip-tion-based methods of drug safety surveillance asrepresenting areas of possible progress (see Mann,1987).

Similar reviews and conclusions have emergedfrom the United States over the last 30 years. Aseries of events in the United States recentlycreated a resurgence of interest in drug safetyevaluation and management. The PrescriptionDrug User Fee Act (PDUFA) of 1992 providedadditional resources at the Food and Drug

Administration (FDA) for drug reviews throughuser fees, and established target timelines for FDAreviews. The shorter approval times lead to somemedications being approved sooner in the UnitedStates than in Europe, in contrast to the pre-PDUFA experience. A few highly visible drugwithdrawals led to a perception that perhapsdrugs were being approved too quickly. In 1998,Lazarou et al. published the results of a meta-analysis that estimated that 106 000 fatal adversereactions occurred in the United States in 1994(Lazarou et al., 1998). This and other papers(Wood et al., 1998) stimulated considerablepublic, Congressional, and regulatory attentionon reducing the societal burden of drug reactionsand medication errors (FDA, 1999; Institute of

Table 1.1. Drugs withdrawn in the United Kingdom by the marketing authorization holder or suspended or revoked bythe Licensing Authority.

Brand name (drug substance) Year action taken Major safety concerns

Secholex (polidexide) 1975 Safety concerns due to 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 instestine 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, neruotoxicitySuprol (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 prolongationPrepulsid (cisapide) 2000 QT prolongation

INTRODUCTION 5


Medicine, 1999; US General Accounting Office,2000). As a result, greater attention and resourcesare currently being devoted to signal generationand evaluation by the FDA, industry, andacademic centers. Moreover, efforts are underwayto develop better tools to manage recognized risks,through a variety of interventions, such as com-munications with healthcare providers and pa-tients, restricted product distribution systems, andother mechanisms. Additional effort is beingfocused on measuring the success of these riskmanagement interventions. This new initiativerepresents a fundamental shift in the safetyparadigm in the United States, and offers newchallenges to pharmacovigilance professionals.

We have long recognized then that the safety ofpatients depends not only drug licensing byregulatory bodies but also on post-marketing drugsafety surveillance, pharmacovigilance. It is alsoimportant to note that the same post-marketinginformation needed to confirm new safety signalsis also needed to refute signals and protectpatients’ ability to benefit from needed medicinesthat may be under suspicion due to spurioussignals.

DIAGNOSING ADVERSE DRUGREACTIONS (ADRS)

There are two types of adverse drug reactions(ADRs). Type A are common, predictable, usuallydose-dependent and appear as excessive manifes-tations of the normal pharmacology=toxicologyof the drug; they are seldom fatal. Type B areuncommon, unpredictable, often independent ofdose and usually represent abnormal manifesta-tions of the drug’s pharmacology=toxicology; theyinvolve relatively high rates of serious morbidityand mortality.

ADRs frequently mimic ordinary diseases and,if they are uncommon, may easily be overlooked.They tend to affect the skin, haematopoieticsystem and lining of the gut (situations in whichthere is rapid cell multiplication) or the liver orkidneys (where drugs are detoxified and excreted).These special sites are frequently involved iniatrogenic (doctor-induced), type B illnesses, such

as toxic epidermal necrolysis, aplastic anaemia,pseudomembranous colitis, drug-induced hepatitisor nephritis.

A high index of suspicion is needed if ADRs areto be successfully diagnosed. The clinician alwayshas to think: ‘‘Could this be drug-induced—is thisan ADR?’’ The question is important, for with-drawal of the cause of an ADR is usually essential.

Iatrogenic ADRs are usually uncommon orrare—and this adds to the difficulty of diagnosis.Some are avoidable, such as skin rashes in patientswith glandular fever given ampicillin. Some areaccidental, such as the non-iatrogenic disaster ofan asthmatic given a beta-adrenergic blockingagent by another member of the family. It is atruism that the detection of common or uncom-mon ADRs requires vigilance. Many of the knownserious ADRs have been recognized by astuteclinicians with a high level of awareness—andsuch awareness is likely to be just as important, asnew methods of pharmacovigilance are developed,as it has been in the past.

Linked with this problem of diagnosing ADRsis the problem of understanding them. Why doesone patient in 10 000 get some bizarre Type Breaction—and the rest of this cohort not get it?Clearly our increasing knowledge of clinicalpharmacology, drug metabolism and genetics willcontribute to our understanding of these things—and these subjects are explored in many of thechapters in this book.

CURRENT METHODS OFPHARMACOVIGILANCE

Pharmacoepidemiology is the study of the use of,and effects of, drugs in large numbers of people.As the term implies, this form of enquiry uses themethods of epidemiology; it is concerned withall aspects of the benefit–risk ratio of drugs inpopulations. Pharmacovigilance is a branch ofpharmacoepidemiology but is restricted to thestudy, on an epidemiological scale, of drug eventsor ADRs.

‘‘Events’’, in this context, are happeningsrecorded in the patient’s notes during a period ofdrug monitoring; they may be due to the disease

6 PHARMACOVIGILANCE

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