Stephens' Detection and Evaluation of Adverse Drug Reactions: Principles and Practice, Sixth Edition PDF
Preview Stephens' Detection and Evaluation of Adverse Drug Reactions: Principles and Practice, Sixth Edition
P1:TIX/XYZ P2:ABC JWST093-FM JWST093-Talbot September12,2011 14:22 PrinterName:YettoCome Stephens’ Detection and Evaluation of Adverse Drug Reactions Principles and Practice Sixth Edition P1:TIX/XYZ P2:ABC 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 P1:TIX/XYZ P2:ABC JWST093-FM JWST093-Talbot September12,2011 14:22 PrinterName:YettoCome Thiseditionfirstpublished2012 ©2012byJohnWiley&Sons,Ltd. Wiley-BlackwellisanimprintofJohnWiley&Sons,formedbythemergerofWiley’sglobalScientific,TechnicalandMedicalbusiness withBlackwellPublishing. 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ThedocumentAppendix2GuidelinesandaChecklistforReportingSuspectedAdverseDrugReactionsAnecdotallyinJournalscreated byJeffreyK.Aronsonmaybefreelycopiedfornon-commercialpurposes,andmaybeincludedinotherpublicationswithouttheconsent oftheauthorsorthepublisher. Designationsusedbycompaniestodistinguishtheirproductsareoftenclaimedastrademarks.Allbrandnamesandproductnamesused inthisbookaretradenames,servicemarks,trademarksorregisteredtrademarksoftheirrespectiveowners.Thepublisherisnot associatedwithanyproductorvendormentionedinthisbook.Thispublicationisdesignedtoprovideaccurateandauthoritative informationinregardtothesubjectmattercovered.Itissoldontheunderstandingthatthepublisherisnotengagedinrendering professionalservices.Ifprofessionaladviceorotherexpertassistanceisrequired,theservicesofacompetentprofessionalshouldbe sought. 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Theauthorsandpublishershavemadeeveryefforttocontactallthecopyrightholderstoobtaintheirpermissiontoreproducecopyright material.However,ifanyhavebeeninadvertentlyoverlooked,thepublisherwillbepleasedtomakethenecessaryarrangementsatthe firstopportunity. LibraryofCongressCataloging-in-PublicationData 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 AcataloguerecordforthisbookisavailablefromtheBritishLibrary. Thisbookispublishedinthefollowingelectronicformats:ePDF9780470975046;WileyOnlineLibrary9780470975053; ePub9781119952107;Mobi9781119952114 Typesetin10/12ptTimesbyAptaraInc.,NewDelhi,India FirstImpression2012 P1:TIX/XYZ P2:ABC JWST093-FM JWST093-Talbot September12,2011 14:22 PrinterName:YettoCome 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 P1:TIX/XYZ P2:ABC JWST093-FM JWST093-Talbot September12,2011 14:22 PrinterName:YettoCome 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 P1:TIX/XYZ P2:ABC JWST093-FM JWST093-Talbot September12,2011 14:22 PrinterName:YettoCome 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 P1:TIX/XYZ P2:ABC JWST093-FM JWST093-Talbot September12,2011 14:22 PrinterName:YettoCome viii CONTENTS 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 P1:TIX/XYZ P2:ABC JWST093-FM JWST093-Talbot September12,2011 14:22 PrinterName:YettoCome 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 P1:TIX/XYZ P2:ABC JWST093-Foreword JWST093-Talbot September14,2011 11:18 PrinterName:YettoCome 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. P1:TIX/XYZ P2:ABC JWST093-Foreword JWST093-Talbot September14,2011 11:18 PrinterName:YettoCome 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
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