Stephens' Detection of New Adverse Drug Reactions, Fifth Edition

752 Pages·2003·3.91 MB·English

Stephens’ Detection of
New Adverse Drug Reactions
Fifth Edition
Stephens’DetectionofNewAdverseDrugReactions,FifthEdition.
EditedbyJohnTalbotandPatrickWaller
Copyright2004JohnWiley&Sons,Ltd.ISBN:0-470-84552-X
Stephens’ Detection of
New Adverse Drug Reactions
Fifth Edition
Edited by
John Talbot
Director,GlobalDrugSafety,AstraZenecaR&DCharnwood,Loughborough,
Leicestershire,UK
Patrick Waller
ConsultantinPharmacovigilanceandPharmacoepidemiology,Southampton,UK
Copyright#2004 JohnWiley&SonsLtd,TheAtrium,SourthernGate,Chichester,
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Contents
Foreword xi
Preface xiii
ListofContributors xv
1 Introduction 1
M.D.B.Stephens
Mercury 1
Introductiontopharmacovigilance 1
Thehistoryofpharmacovigilance 3
Under-reportingofadversedrugreactions 10
Incidenceofadversedrugreactions 17
Thefinancialcostofadversedrugreactions 30
Preventabilityofadversedrugreactions 35
Risk–benefitratio 35
Thechangingriskswithnewdrugs 44
Expressionofrisk 47
Theriskswearepreparedtotake 52
Definitions 57
Classificationofadversedrugreactions 58
Adversereactionprofile 60
Adverseeventsinapatient’slife 61
Symptomsinhealthypersons 62
Adversereactionstoplacebo 63
Infectiousnessofadversedrugreactions 67
Herbalmedicines 69
Somefinalfoodforthought 70
References 71
Furtherreading 88
2 AdverseDrugReactionsandInteractions:Mechanisms,RiskFactors,
Detection,ManagementandPrevention 92
P.Routledge
Introduction 92
Classificationofadversedrugreactions 92
RiskfactorsfortypeAadversereactions 93
RiskfactorsfortypeBadversereactions 101
Detectionofadversedrugreactions 106
Stephens’DetectionofNewAdverseDrugReactionsFifthEditioneditedbyJohnTalbotandPatrickWaller
#2004JohnWiley&Sons,Ltd ISBN:047084552X
vi CONTENTS
Managementofadversedrugreactions 108
Preventionofadversedrugreactions 109
Druginteractions 111
Conclusions 122
References 122
3 ToxicologyandAdverseDrugReactions 128
D.J.Snodin
Introduction 128
Toxicitytesting 128
Drugdevelopment 137
Datainterpretationandriskassessment 144
Adversedrugreactionsdetectedafterauthorization 150
Examplesoftoxicologicalinvestigationofadversedrugreactions 157
Conclusions 159
Acknowledgements 159
References 159
4 ClinicalTrials:CollectionofSafetyDataandEstablishingthe
AdverseDrugReactionProfile 167
J.C.C.Talbot,M.D.B.Stephens
Introduction 167
Adverseevents 168
Finalanalysisofdata 229
Inadequatereportingofsafetydatafromclinicaltrials 231
Conclusions 232
Futureaspirations 233
Acknowledgements 233
References 233
5 ClinicalLaboratorySafetyDatainDrugStudies 244
A.Craig
Introduction 244
Factorsthatinfluenceinterpretationofclinicallaboratorydata 245
Samplecollectionprocedure 252
Analyticalvariation 255
Referenceranges 256
Intra-individualbiologicalvariation 259
Safetytestingindrugdevelopment 261
Testselection 289
Exclusioncriteriaand‘paniclevels’ 290
Harmonizationofdatafromdifferentlaboratories 292
Dataanalysisandpresentation 294
Conclusion 298
References 298
CONTENTS vii
6 Statistics:AnalysisandPresentationofSafetyData 301
S.J.W.Evans
Introductionandbackground 301
Analysisandpresentationofdatafromtrials 305
Measuresthattaketimeintoaccount 308
Statisticaltestsutilizingtimesincestartoftreatment 310
Combiningdatafromseveraltrials:meta-analysis 312
Analysisandpresentationofdatafromobservationalstudies 312
Useofstatisticalmethodsforsignaldetectionwithspontaneousreports 316
Summaryandconclusions 325
Acknowledgements 326
References 326
7 CausalityandCorrelationinPharmacovigilance 329
S.A.W.Shakir
Introductionandhistoricalbackground 329
Thenotionsofnecessaryandsufficientcauses 330
Factorstobeconsideredincausalityassessment 330
Methodsforcausalityassessment 333
Whentoassesscausality 336
Assessingcausalityfrommultipleinformationsources:theBradford-Hillcriteria 337
Conclusion 342
References 342
8 ManagingDrugSafetyIssueswithMarketedProducts 345
P.C.Waller,H.H.Tilson
Introduction 345
Identificationofdrugsafetyissues 346
Investigation 356
Evaluation 359
Action 361
Communicatingaboutdrugsafety 364
Beyondcommunication:riskmanagement 369
Managingtheprocess 371
Conclusion:somethoughtsonthefuture 372
References 373
9 RegulatoryAspectsofPharmacovigilance 375
B.D.C.Arnold
Introduction 375
CouncilforInternationalOrganizationsofMedicalSciences 375
TheInternationalConferenceonHarmonization 379
TheEuropeanUnion 399
TheUnitedKingdom 419
France 424
Germany 428
UnitedStatesofAmerica 432
viii CONTENTS
Japan 443
Acknowledgements 448
References 449
Bibliography 449
10 LegalAspectsofPharmacovigilance 453
C.Bendall
Introduction 453
Legalresponsibilityforpharmacovigilance 454
Interpretinglegalprovisions 458
TherelationshipbetweenEuropeanCommunitypharmacovigilancelegislationand
guidelines 460
Nationalimplementation 461
UncertaintiesinEuropeanCommunityprovisions 463
Thepotentialimpactofthe2001reviewofpharmaceuticallegislation 468
Europeanpowersandproceduresintheeventofaproductsafetyissue 469
ReferraltotheCommitteeforProprietaryMedicinalProducts 471
Failurestomeetadversedrugreactionreportingrequirements 478
Consequencesoffailuretomeetrequirements 481
Safetyinresearchproducts 487
Personaldataprivacy 490
Reference 491
11 OperationalAspectsoftheDrugSafetyFunctionwithina
PharmaceuticalCompany 493
J.Steiner
Introduction 493
Overviewofthecase-handlingprocess 493
Specificsofthecase-handlingprocess 494
Periodicsafetyupdates 499
Staffingmodelsforthecase-handlingprocess 504
Technologyandthecase-handlingprocess 508
Qualitycontrolandthecase-handlingprocess 513
Trainingandthecase-handlingprocess 520
Externalpartnersandthecase-handlingprocess 525
Casedistributiontoexternalpartiesotherthanregulatoryauthorities 527
Conclusion:visionforthefuture 531
Acknowledgement 531
References 531
Furtherreading 532
12 DictionariesandCodinginPharmacovigilance 533
E.Brown
Introduction 533
Scopeofthischapter 534
Drugdictionaries 534
Adversedrugreactiondictionaries 537
CONTENTS ix
Diseaseclassifications 538
Combinationterminology 545
Definitionofadversereactionterms 555
Conclusion 556
Acknowledgements 556
References 556
13 SafetyofBiotechnologyProducts 559
B.Brown,M.Westland
Introduction 559
Propertiesofproteins 560
Categoriesofproteintherapeuticagent 560
Safetymonitoringforproteintherapeuticagents 562
Off-labeluse 566
Conclusion 568
References 568
14 VaccineSafetySurveillance 571
E.Miller
Whatisspecialaboutvaccinesafetycomparedwithotherdrugs? 571
Pathogenesisofvaccinereactions 572
Criteriaforestablishingcausalityforvaccineadverseevents 575
Pre-licensureevaluationofvaccinesafety 577
Objectivesofanidealpost-licensurevaccinesafetysurveillancesystem 579
Passivepost-licensuresurveillancesystems 579
Activesurveillanceofadversevaccineevents 581
Controlledepidemiologicalstudiesofvaccinesafety 582
Ecologicalstudiesofvaccinesafety 585
Conclusions 587
References 587
15 EthicalIssuesinDrugSafety 591
M.D.B.Stephens
Introduction 591
Ethicsinclinicaltrials 591
Ethicsandthepharmaceuticalindustry 608
Conclusions 636
References 637
Furtherreading 647
16 AModelfortheFutureConductofPharmacovigilance 649
P.C.Waller,S.J.W.Evans
Introduction 649
Proposedmodel 649
Descriptionofmodelcomponents 650
Conclusions 665
x CONTENTS
Acknowledgements 666
References 666
AppendixI 667
AppendixII 705
Bibliography 709
Index 721
Foreword
When does a book become a classic? The fact that Stephens’ Detection of New Adverse
Drug Reactions is now in its fifth edition speaks volumes for its value to a multiplicity of
readers.Thescienceofpharmacovigilancehasgrowninbreadthanddepthovertheeighteen
years of the book’s existence and the present edition shows not only how the scope of the
fieldhasincreased,withchaptersonthesafetyofbiotechnologyproductsandvaccinesafety
surveillance, but also how the operating techniques of statistical analysis, legal aspects and
ethicalissuesnowformimportantareasfordebateinthefieldofdrugsafety.
The history of drug safety is a roll call of the practice of medicine and of the science of
pharmacology and toxicology which underpin it. Even the nomenclature of adverse drug
reactions has evolved as we understand more of the underlying scientific basis. Nowhere is
this better illustrated than in the area of drug interactions. Two examples serve to illustrate
this. The broad division into pharmacokinetic and pharmacodynamic interactions has been
further complicated by new understanding of how cellular transporter mechanisms are
utilisedtotransferdrugsacrosstissueboundariesinthegut,liver,kidneyandbrain,andhow
thisnowformsthebasisofanewsetofwaysinwhichonedrugcanalterthedispositionand
response to another. Secondly, as our knowledge of the human genome has evolved, the
scienceofpharamacogenomicshasincreasedourabilitytoselectpatientswhowillrespond
to specific drugs, and this response may be beneficial or adverse. Again, such information
mustbefactoredintoourappreciationofthebasisofdruginteractions.
As well as considering how we have reached our present position in considering adverse
drug reactions, this book looks to the future. The chapter by Patrick Waller and Stephen
Evans is particularly important in this respect, showing how the prediction of drug safety
will form the future of pharmacovigilance, whereas in the past this depended more on the
demonstration of harm. Medicinal chemists who design drug molecules appreciate the
toxicity potential of various chemical groupings in a molecule, and are increasingly able to
design out the offending entity without impairing efficacy. The clinical pharmacologist and
the drug regulator, always aiming to reconcile possible risk with benefit, appreciate how
criticalisappropriatedoseselectioninachievingthisbalance.Theclinicianwillalwaysplay
an important role by his careful documentation and reporting of patient harm on systems
such as the Yellow Card. Such spontaneous reporting systems will always serve the public
health by creating signals of drug safety which can be augmented and further analysed in
othermoresophisticatedways.
Theconceptofbalancingriskwithbenefit,athemetowhichthebookcorrectlyrepeatedly
returns,remainsthebedrockofdrugtherapy.Itisnotanideawhicheither thepublicor the
Stephens’DetectionofNewAdverseDrugReactionsFifthEditioneditedbyJohnTalbotandPatrickWaller
#2004JohnWiley&Sons,Ltd ISBN:047084552X