Benefit-Risk Appraisal of Medicines PDF
Preview Benefit-Risk Appraisal of Medicines
Benefit-Risk Appraisal of Medicines Benefit-Risk Appraisal of Medicines A systematic approach to decision-making Filip Mussen, Johnson&JohnsonPharmaceuticalResearchandDevelopment, Beerse,Belgium Sam Salek, CardiffUniversity,Cardiff,UK Stuart Walker, CMRInternationalInstituteforRegulatoryScience,London,UK AJohn Wiley & Sons, Ltd., Publication Thiseditionfirstpublished2009,(cid:2)2009JohnWiley&Sons,Ltd Wiley-BlackwellisanimprintofJohnWiley&Sons,formedbythemergerofWiley’sglobalScientific,Technicaland MedicalbusinesswithBlackwellPublishing. Registeredoffice:JohnWiley&SonsLtd,TheAtrium,SouthernGate,Chichester,WestSussex,PO198SQ,UK OtherEditorialOffices: 9600GarsingtonRoad,Oxford,OX42DQ,UK 111RiverStreet,Hoboken,NJ07030-5774,USA Fordetailsofourglobaleditorialoffices,forcustomerservicesandforinformationabouthowtoapplyforpermissionto reusethecopyrightmaterialinthisbookpleaseseeourwebsiteatwww.wiley.com/wiley-blackwell TherightoftheauthortobeidentifiedastheauthorofthisworkhasbeenassertedinaccordancewiththeCopyright, DesignsandPatentsAct1988. Allrightsreserved.Nopartofthispublicationmaybereproduced,storedinaretrievalsystem,ortransmitted,inanyform orbyanymeans,electronic,mechanical,photocopying,recordingorotherwise,exceptaspermittedbytheUKCopyright, DesignsandPatentsAct1988,withoutthepriorpermissionofthepublisher. Wileyalsopublishesitsbooksinavarietyofelectronicformats.Somecontentthatappearsinprintmaynotbeavailablein electronicbooks. 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Thecontentsofthisworkareintendedtofurthergeneralscientificresearch,understanding,anddiscussiononlyandarenot intendedandshouldnotberelieduponasrecommendingorpromotingaspecificmethod,diagnosis,ortreatmentby physiciansforanyparticularpatient.Thepublisherandtheauthormakenorepresentationsorwarrantieswithrespecttothe accuracyorcompletenessofthecontentsofthisworkandspecificallydisclaimallwarranties,includingwithoutlimitation anyimpliedwarrantiesoffitnessforaparticularpurpose.Inviewofongoingresearch,equipmentmodifications,changesin governmentalregulations,andtheconstantflowofinformationrelatingtotheuseofmedicines,equipment,anddevices,the readerisurgedtoreviewandevaluatetheinformationprovidedinthepackageinsertorinstructionsforeachmedicine, equipment,ordevicefor,amongotherthings,anychangesintheinstructionsorindicationofusageandforaddedwarnings andprecautions.Readersshouldconsultwithaspecialistwhereappropriate.ThefactthatanorganizationorWebsiteis referredtointhisworkasacitationand/orapotentialsourceoffurtherinformationdoesnotmeanthattheauthororthe publisherendorsestheinformationtheorganizationorWebsitemayprovideorrecommendationsitmaymake.Further, readersshouldbeawarethatInternetWebsiteslistedinthisworkmayhavechangedordisappearedbetweenwhenthiswork waswrittenandwhenitisread.Nowarrantymaybecreatedorextendedbyanypromotionalstatementsforthiswork. Neitherthepublishernortheauthorshallbeliableforanydamagesarisingherefrom. LibraryofCongressCataloguing-in-PublicationData Salek,Sam. Benefit-riskappraisalofmedicines:asystematicapproachtodecisionmaking/ SamSalek,StuartR.Walker,FilipMussen. p. ; cm. Includesbibliographicalreferencesandindex. ISBN978-0-470-06085-8(cloth) 1. Drugs—Testing. 2. Pharmaceuticalpolicy—Decisionmaking. I. Walker,StuartR.,1944– II. Mussen,Filip. III. Title. [DNLM:1. DrugEvaluation—standards. 2. DecisionSupportTechniques. 3. Models,Theoretical. 4. RiskAssessment. QV771S163b2009] RM301.27.S252009 6150.1901—dc22 2009019338 AcataloguerecordforthisbookisavailablefromtheBritishLibrary. ISBN:978-0-470-06085-8 Setin10.5/13ptTimesbyIntegraSoftwareServicesPvt.Ltd.,Pondicherry,India PrintedinGreatBritainbyAntonyRoweLtd.,Chippenham,Wiltshire Firstimpression—2009 Contents Foreword vii Preface ix 1 ConceptandScopeofBenefit–RiskEvaluationofMedicines 1 1.1 Historicalbackground 1 1.2 Theregulatorysystemsforassessingmedicines 3 1.3 Benefit–riskassessment:definitions 4 1.4 Viewsandperceptionsofbenefitsandrisksofmedicines 6 1.5 Stagesandconceptsinbenefit–riskassessment 11 1.6 Benefit–riskassessment:thecurrentregulatoryenvironment 19 1.7 Benefit–riskassessmentinotherdisciplines 19 1.8 Specificmethodsandmodelsforbenefit–riskassessment 21 1.9 Discussionswithstakeholdersontheconceptsandmodelsforbenefit–risk evaluation 30 2 CriteriaforaBenefit–RiskModel:aConceptualFramework 31 2.1 Introduction 31 2.2 Regulatoryguidelinesonbenefitandriskcriteria 32 2.3 Identification,definitionandrationaleofrelevantbenefitandriskcriteria 35 2.4 Verificationofthelistofbenefitandriskcriteriabymeansofasurvey 59 3 ReviewoftheCurrentBenefit–RiskAssessmentModels 63 3.1 Background 63 3.2 Evaluationoftheexistingbenefit–riskassessmentmodels 65 3.3 Reviewofmodelsinsingleclinicaltrialsandforspecificmedicines 86 3.4 Conclusion 93 3.5 Newermodels 96 4 DefiningaSystematicApproachtoDecisionMaking 99 4.1 Introduction 99 4.2 Objectivesandfeaturesoftheidealmodelforbenefit–riskassessment 100 4.3 Theuseofdecision-analysistechniquesforthedevelopmentofthenew model 101 vi CONTENTS 5 DevelopmentandApplicationofaBenefit–RiskAssessment ModelBasedonMulti-CriteriaDecisionAnalysis 111 5.1 Introduction 111 5.2 Conceptualizationofthenewmodel 111 5.3 Reasonsforusingdecisionanalysistechniquesinthenewmodel 113 5.4 TheuseofMCDAinthenewmodel 114 5.5 Developmentofthenewmodel 116 5.6 Applicabilityofthenewmodel 133 5.7 Summary 148 5.8 ReviewoftheMCDAmodel 149 6 AFutureFrameworkforBenefit–RiskAppraisalofMedicines 151 6.1 Background 151 6.2 Developmentofabenefit–riskframeworkforregulatoryreviewofnew medicines 151 6.3 Prerequisitesofabenefit–riskframeworkfortheregistrationofanew medicine 161 6.4 Currentstatusofbenefit–riskassessmentamongcompaniesandagencies 164 6.5 Constructingabenefit–riskframework 172 6.6 Conclusion 184 Appendices Appendix1 SummaryReportsoftheCMRInternationalInstitutefor RegulatoryScienceMarch2004andJune2005Workshops onBenefit–Risk 185 Appendix2 OfficeofHealthEconomicsBriefing:Challengesand OpportunitiesforImprovingBenefit–riskAssessmentof PharmaceuticalsfromanEconomicPerspective–JamesCross andLouisGarrison(August2008) 207 Appendix3 ReflectionPaperonBenefit–riskAssessmentMethodsinthe ContextoftheEvaluationofMarketingAuthorisationApplications ofMedicinalProductsforHumanUse–CommitteeforMedicinal ProductsforHumanUse(March2008) 233 Appendix4 Commentarieson‘AQuantitativeApproachtoBenefit–risk AssessmentofMedicines’Pharmacoepidemiologyand DrugSafety,2007,16 251 Appendix5 ForumonBenefit:RiskDecisionAnalysis–Summaryof DiscussionsandRecommendations–MHRA(September2008) 261 References 271 Index 285 Foreword Balancingbenefitsandrisksformsanintegralpartofeverydaylife–personal,financial and professional; yet there is little agreement as to how this can be measured and expressed. Take two clinical scenarios. First, a medicine has the potential to cure cancer or successfully treat a severe infection without causing major adverse effects; second a medicine is used for the treatment of transient muscle aches but causes frequent skin rashes. In each of these instances the benefit–risk balance is obvious. But most therapeutic options are not so easy and more often concern marginal benefits and risks which are difficult to assess. In addition, the same experimental information on risks and benefits of a new medicine may be interpreted differently by the drug developer,theregulator,thehealthcareprofessionalandthepatient. None of this is new. The lexicon of risk has been inconclusively debated foryears anduseddifferentlybyvariousstakeholders.Whatislackingisasystematicapproach todecisionmakingandcommunication.Intherapeuticstheneedforsuchanapproach hasneverbeengreater.Aspowerfulnewmedicinesforhithertountreatablediseasesare produced, all concerned parties must decide whether their potential for benefit outweighs that for causing harm, and should be able to engage in a dialogue to expressthis. Such an assessment is not only made at the time of application for marketing authorization of a new product. At each stage of the development process, both preclinical and clinical, risk and benefit are continually balanced. As more evidence accrues as on the effectiveness and safety of a medicine when it is in widespread clinicaluse,thisbalancemaychangemarkedlyandrequireregulatoryaction,resulting ineitherallowingitsmoreextensiveusefornewindicationsorinlimitingitsusageto specifiedgroupsofpatients.Thelatterrepresentsaspecialproblemfortheregulator. Byrestrictingtheuseofanewmedicinetoagroupofpatientswho,forexample,may havealreadyfailedtreatmentwithothertherapeuticagentswhichmayhaveresultedin impairment of an already compromised immune system, the regulator may cause the balance to swing against its further successful use. Formal assessment of the benefit viii FOREWORD riskbalanceanditsclearcommunicationbyallpartiesinvolvedinthissituationwould facilitatemoreinformeddebate. But another party is assuming greater importance in the discussion surrounding benefit and risk. Approval by health technology assessors and reimbursers decides whether already financially pressed healthcare systems will allow a new drug to be widely used. Although such decisions are predominantly made on considerations of clinicalandcosteffectiveness,implicitintheseisanappreciationofriskandbenefit. The measurements used in health technology assessment differ from those of the developer and the regulator, but can be accommodated into various models, and theseconsiderationsarediscussedinthetextthatfollows. This book provides a review of how present concepts of benefit and risk in the assessment of medicines have developed and how these are interpreted in various countries by various stakeholders. It describes a framework in which various models canbeaccommodated,illustratingthesewithimportantworkedclinicalexamples.The authorshavecontributedtothisfieldformanyyearsandtheirideashavebeenrefined by workshops, discussions and debates reports of which are helpfully included as appendices to the book. This will not be the last word in a rapidly moving field but asanexpressionofthecurrentstateoftheart,ithasmuchtocommendit. ProfessorSirAlasdairBreckenridgeCBE ChairoftheMedicineHealthcareproducts RegulatoryAgency(MHRA)
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