Stephens' Detection and Evaluation of Adverse Drug Reactions: Principles and Practice, Sixth Edition

737 Pages·2011·7.04 MB·English

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Stephens’ Detection and Evaluation
of Adverse Drug Reactions
Principles and Practice
Sixth Edition
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JWST093-FM JWST093-Talbot September12,2011 14:22 PrinterName:YettoCome
Stephens’ Detection and
Evaluation of Adverse
Drug Reactions
Principles and Practice
Sixth Edition
Edited by
John Talbot
SeniorLecturer,UniversityofHertfordshire,UK
Formerly,Director,PatientSafety,AstraZenecaR&D
Jeffrey K. Aronson
ReaderinClinicalPharmacology,DepartmentofPrimaryHealthCare,
UniversityofOxford,UK
A John Wiley & Sons, Ltd., Publication
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Stephens’detectionandevaluationofadversedrugreactions:principlesandpractice/editedbyJohnTalbot,
JeffreyK.Aronson.–6thed.
p.;cm.
title:Stephens’detectionandevaluationofadversedrugreactions:principlesandpractice
Rev.ed.of:Stephens’detectionofnewadversedrugreactions/editedbyJohnTalbot,PatrickWaller.5thed.c2004
Includesbibliographicalreferencesandindex.
ISBN978-0-470-98634-9(cloth)–ISBN978-0-470-97504-6(ePDF) 1.Drugs–Sideeffects. 2.Drugs–Toxicology.
3.Drugs–Sideeffects–Handbooks,manuals,etc. I.Talbot,J.C.C. II.Aronson,J.K. III.Stephens,M.D.B.,1930–
IV.Stephens’detectionofnewadversedrugreactions. V.Title:Detectionandevaluationofadversedrugreactions.
[DNLM: 1.DrugTherapy–adverseeffects. 2.AdverseDrugReactionReportingSystems. 3.Pharmaceutical
Preparations–adverseeffects. 4.ProductSurveillance,Postmarketing.QZ42]
RM302.5.S742011
615(cid:2).7042–dc23
2011020998
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Contents
Foreword xi
PrefacetotheSixthEdition xiii
ListofContributors xv
Acknowledgements xvii
1 AdverseDrugReactions:History,Terminology,Classification,
Causality,Frequency,Preventability 1
JeffreyK.Aronson
1.1 Introduction 1
1.2 Definingpharmacovigilance 1
1.3 Themodernhistoryofpharmacovigilance 3
1.4 Terminologyanddefinitionsinpharmacovigilance 6
1.5 Medicationerrors 25
1.6 Pharmacologicalclassificationofadversedrugreactions 32
1.7 Druginteractions 53
1.8 Reportingsuspectedadversedrugreactions 59
1.9 Causalityassessment 64
1.10 Frequenciesofadversedrugreactions 69
1.11 Riskperceptionandadversedrugreactions 77
1.12 Classeffectsofdrugs 78
1.13 Unlicensedindications,off-labeluses,andorphandrugs 80
1.14 Preventingadversedrugreactions 84
1.15 Publishingaccountsofadversedrugreactions 95
References 101
2 PharmacogeneticsofAdverseDrugReactions 121
SudeepP.PushpakomandMunirPirmohamed
2.1 Introduction 121
2.2 Historicalreview 121
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vi CONTENTS
2.3 Sourcesofgeneticvariability 122
2.4 Roleofpharmacogeneticfactorsindrugpharmacokinetics 123
2.5 Roleofpharmacogeneticfactorsindrugpharmacodynamics 133
2.6 Theroleofpharmacogeneticsinpharmaceuticalcompanies 139
2.7 Theimpactofpharmacogeneticsonregulatoryagencies 141
2.8 Theimpactofpharmacogeneticsonclinicalpractice 143
2.9 Conclusions 145
References 145
3 ToxicologyandAdverseDrugReactions 157
D.J.SnodinandA.Suitters
3.1 Introduction 157
3.2 Toxicitytesting 157
3.3 Drugdiscoveryanddevelopment 168
3.4 Datainterpretationandriskassessment 174
3.5 Adversedrugreactionsdetectedaftermarketingauthorization 186
3.6 ExamplesoftoxicologicalinvestigationofADRs 199
3.7 Conclusions 200
Acknowledgements 201
References 201
4 ClinicalTrials—CollectingSafetyDataandEstablishing
theAdverseDrugReactionsProfile 215
JohnTalbot,MarianneKeisu,andLarsSta˚hle
4.1 Introduction 215
4.2 Adverseevents 216
4.3 Clinicalstudiesandsafety 236
4.4 Theemergingsafetyprofile 267
4.5 Presentationofsafetydata 271
4.6 Conclusions 280
References 281
5 ClinicalLaboratorySafetyData 291
AlanCraig
5.1 Introduction 291
5.2 Factorsthatinfluencetheinterpretationofclinicallaboratorydata 294
5.3 Samplecollectionprocedure 300
5.4 Analyticalvariation 301
5.5 Referenceranges 304
5.6 Intra-individualbiologicalvariation 307
5.7 Detectingadverseeventsduringdrugdevelopment 309
5.8 Testselection 333
5.9 Exclusioncriteriaand“paniclevels” 335
5.10 Harmonizationofdatafromdifferentlaboratories 337
5.11 Dataanalysisandpresentation 339
5.12 Conclusions 344
5.13 Appendix 345
References 346
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CONTENTS vii
6 Statistics:AnalysisandPresentationofSafetyData 349
StephenJ.W.EvansandDorotheaNitsch
6.1 Introductionandbackground 349
6.2 Problemswithefficacytrialsfordetectingadversedrugreactions 352
6.3 Analysisandpresentationofdatafromtrials 355
6.4 Statisticalmeasuresoftheoccurrenceofadverseevents 356
6.5 Combiningdatafromseveraltrials—meta-analysis 364
6.6 Useofstatisticalmethodsforsignaldetectionfromspontaneousreports 365
6.7 Analysisandpresentationofdatafromobservationalstudies 373
6.8 Summaryandconclusions 384
Acknowledgements 385
References 386
7 ProactivePharmacovigilanceandRiskManagement 389
JuneRaine,LesleyWise,JohnTalbot,andJeffreyK.Aronson
7.1 Introduction 389
7.2 Riskmanagement—definitionandgeneralprinciples 390
7.3 Definingtheknowledgebase—thesafetyspecification 391
7.4 Extendingtheknowledgeofsafetyandcharacterizingrisk—the
pharmacovigilanceplan 394
7.5 Minimizingrisks 395
7.6 Specialchallengesforriskmanagement 397
7.7 Experiencewithriskevaluationandmitigationstrategies(REMS)intheUSA 398
7.8 Apossiblemethodforriskmanagementwhenanewadversereactionis
discoveredaftermarketing 399
7.9 Futurechallengesforriskmanagement 405
7.10 Conclusions 406
References 407
8 RegulatoryAspectsofPharmacovigilance 411
KristinaLeilaStruttandBarryDavidCharlesArnold
8.1 Introduction 411
8.2 Thestandardizationandharmonizationofsafetydatacollectionand
reporting:CIOMSandICH 412
8.3 TheEuropeanUnion 447
8.4 TheUK 481
8.5 France 483
8.6 Germany 485
8.7 USA 487
8.8 Japan 500
Acknowledgements 505
References 506
Usefulwebsites 509
9 LegalAspectsofPharmacovigilanceintheEuropeanUnion 511
ChristineH.Bendall
9.1 Introduction 511
9.2 ApplicationofEUlegislationinMemberStates 511
9.3 InterpretationofEUlaw 514
9.4 Relationshipbetweenlawandguidelines 515
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9.5 IssuesininterpretingEUpharmacovigilancelegislation 517
9.6 Legalresponsibilityforpharmacovigilanceactivities 519
9.7 Failurestomeetpharmacovigilancerequirements 522
9.8 Enforcementandsanctions 524
9.9 Europeanpowersandproceduresintheeventofaproductsafetyissue 528
9.10 Civilliability 534
9.11 Personaldataprivacy 537
9.12 Safetyinresearchproducts 538
References 541
10 DictionariesandCodinginPharmacovigilance 545
E.G.BrownandJ.E.Harrison
10.1 Introduction 545
10.2 Scopeofthischapter 546
10.3 Whatisadictionary? 546
10.4 Drugdictionaries 547
10.5 Diseaseclassifications 554
10.6 MedicalDictionaryforRegulatoryActivities,MedDRA(cid:2)R 557
10.7 CommonTerminologyCriteriaforAdverseEvents(CTCAE) 567
10.8 Definitionofadversereactionterms 567
10.9 Dictionariesusedinelectronichealthrecords 568
10.10 Useofdictionariesinstandardproductinformation 570
10.11 Conclusions 571
Acknowledgements 571
References 571
11 AdverseDrugReactions:SocietalConsiderations 573
NickyBritten
11.1 Introduction 573
11.2 Adversedrugreactionsatthepopulationlevel 574
11.3 ThesocialproductionofADRs 576
11.4 Trust 579
11.5 InformationaboutADRs 581
11.6 Conclusions 583
References 583
12 SafetyofBiotherapeutics 585
AndrewErdman,JamesNickas,andBentonBrown
12.1 Introduction 585
12.2 Propertiesofproteins 586
12.3 Classificationofbiotherapeutics 587
12.4 Monitoringforadverseeventsduetobiotherapeutics 589
12.5 Conclusions 598
References 598
13 VaccineSafetySurveillance 603
E.MillerandJ.Stowe
13.1 Introduction 603
13.2 Whatisspecialaboutvaccinesafetycomparedwithotherdrugs? 604
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CONTENTS ix
13.3 Pathogenesisofvaccinereactions 605
13.4 Criteriaforestablishingcausalityaftervaccine-relatedadverseevents 608
13.5 Pre-licensingevaluationofvaccinesafety 610
13.6 Objectivesofanidealpost-licensingvaccinesafetysurveillancesystem 611
13.7 Conclusions 620
References 620
14 AssessingtheSafetyofDrugsUsedinOncology 625
AnneKehely
14.1 Introduction 625
14.2 Factorstoconsiderwhenassessingthesafetyofdrugsusedinoncology 627
14.3 Sourcesofadverseeffectdata 632
14.4 Natureofthedata 634
14.5 Assessmentofadverseeffectsdatainoncology 635
14.6 Conclusions 641
References 642
15 AdverseDrugReactionsandPharmacovigilanceofHerbalMedicines 645
JoanneBarnes
15.1 Introduction 645
15.2 Herbalmedicines:definitionsanddescriptions 646
15.3 Characteristicsofherbalmedicines 647
15.4 Regulationofherbalmedicinesandpharmacovigilancerequirements 648
15.5 Accesstoanduseofherbalmedicines 655
15.6 Adversereactionsassociatedwithherbalmedicines 656
15.7 Methodsforpharmacovigilanceofherbalmedicines 666
15.8 Respondingtosafetyconcernsassociatedwithherbalmedicines 673
15.9 Thefutureforpharmacovigilanceofherbalmedicines 674
15.10 Conclusions 675
References 676
Appendix1 WebSitesRelevanttoPharmacovigilance—An
AnalysisofContents 685
CharlotteI.S.Barker,JohnTalbot,andJeffreyK.Aronson
A1.1 Introduction 685
A1.2 Tennationalpharmacovigilancewebsites 685
A1.3 Twelveinstitutionalwebsites 689
Acknowledgements 697
References 697
Appendix2 GuidelinesandaChecklistforReportingSuspected
AdverseDrugReactionsAnecdotallyinJournals 699
JeffreyK.Aronson
A2.1 Introduction 699
A2.2 Notesonthechecklist 700
A2.3 Conclusions 706
Note 706
References 706
Index 709
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Foreword
Despite the many therapeutic advances made possible by drug discovery over the decades,
experiencehasshownthatallactivepharmaceuticalshavethepotentialtocauseharm.Inthe
half-century which has now passed since the thalidomide disaster, much progress has been
made in developing the concepts and strategies to study the balance of benefits and harms,
which determines the clinical utility of a medicine. The scientific methods to do so have
become progressively more refined—in the laboratory, in the clinic, and in the population.
This book reviews in depth the impact that genetics and toxicology have had on our ability
to understand the mechanisms of drug toxicity; the contribution of the randomised control
trialtotheassessmentofbothbenefitandharm;andtheincreasingpowerofepidemiological
methodstodetectunanticipatedadverseeventsinthetreatedpopulation.
Alliedwiththese scientific developments has been an expansion of theregulatory system
for pharmaceuticals in all developed countries. Two concepts have been particularly fruitful
in recent years. The first is that there needs to be a continuous review of the benefit–harm
relationshipforanypharmaceuticalasitpassesalongthetrajectoryfromdiscoverytolong-
establisheduse.Asnewknowledgeaccumulates,actionmaybeneededtorevisethetermsof
market authorization and to communicate significant new information to prescribers and to
patients.Thesecondistheshiftfromreactivetoproactivepharmacovigilance.Thelegaland
regulatoryunderpinningsforsuchashiftareclearlydescribedhere,notablytheprinciplesof
riskassessment,pharmacovigilanceplans,andriskmanagementstrategiestobespecifiedat
thetimeofmarketauthorization.
That is not to say that spontaneous reporting of suspected adverse drug reactions has
lessened in importance. The limitations of spontaneous reporting have long been known:
under-reporting,lackofprecisedenominatorinformation,andpreferentialreportingofclini-
cally‘unusual’eventswithashorttemporalrelationshiptodrugexposure.Yetsuchreporting,
byhealth-careprofessionalsandincreasinglybypatientsthemselves,hasanessentialrolein
providingsignalstobeassessedmorerigorouslyfromotherdatasources.Thisbookdescribes
manyrecentadvancesinthecapture,aggregation,analysis,andassessmentofspontaneousre-
portingdata.Theever-expandinguseofinformationtechnologyinclinicalsettings,capability
tomovelargequantitiesofdatabytheinternet,andtheuseofadvancedstatisticaltechniques
to‘mine’datahaveallcontributed.Althoughastutespontaneousreportinghasgenerallybeen
thoughtofasameans todeepenourunderstanding ofthehumanpharmacology ofthedrug
molecule,itcanalsoservetodetectqualityfailuresinthepharmaceuticalsupplychain,aswas
recentlyseenwiththecontaminationofheparinwithover-sulphatedchondroitinsulphate.
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xii FOREWORD
Thedetectionandevaluationofadversedrugreactionsispre-eminentlyamultidisciplinary
enterpriseandoneinwhichindustry,academia,regulatoryauthorities,andcliniciansallhave
key roles to play. The pace of change since the last edition seven years ago has been truly
remarkable. It has been driven by developments in science and by lessons learned from
individual drugs that have revealed adverse effects in the course of widespread population
use.Theaimofaproactivepharmacovigilancestrategymustbetoensurethatsucheffectsare
detected,assessed,andrespondedtoappropriately,withtheminimumofdelay.
Three particularly challenging areas of pharmacovigilance are dealt with in depth in this
volume. Vaccines areperennially controversial,despitetheirhugepositiveimpactonpublic
health,forcomplexreasonswhichareexamined.Drugsusedincancertherapyfrequentlylie
attheoppositeendofthebenefit–harmcontinuum.Herbalmedicinesareusedbyasubstantial
minorityofthepopulation,havealimitedevidencebaseonsafety,yetcanonoccasionsgive
risetolife-threateningtoxicityanddruginteractions.
Perhaps the greatest challenge we face is the transfer of new knowledge about individual
medicinesintoclinicalpractice.Heretootheimpactoftheinternetinrecentyearshasbeen
profound. It will undoubtedly increase further, offering as it does the essential elements of
fast dissemination, accessibility and search function, which printed media cannot match.
When important new benefit–harm information becomes available, from whatever source, a
regulatoryagencyshouldbeabletomakethatavailableonitswebsitewithinhoursratherthan
days.Ideallytheinformationshouldbetailoredseparatelytomeettheneedsofthreegroups
of users: prescribers, patients and specialists in the field. The Appendix examining national
and institutional pharmacovigilance web sites in a systematic way is a valuable addition to
thisvolume.
Communication is a key factor in pharmacovigilance. As it becomes increasingly multi-
disciplinary, from genetics and toxicology to statistics and law, we risk the Tower of Babel
problem:specialistsengagedonajointenterprisebeingunabletounderstandeachothers’lan-
guage.Stephens’DetectionandEvaluationofAdverseDrugReactionswillgreatlymitigate
thatrisk,tothebenefitofpatients.
SirKentWoods
Chiefexecutive
MedicinesandHealthcareproductsRegulatoryAgency
London,UK