Benefit-Risk Appraisal of Medicines

306 Pages·2009·1.77 MB·English

by  Filip Mussen

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
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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)