Factors and situations influencing the value of patient preference studies along the medical product lifecycle: a literature review

Teaser

This

study

can

inform

different

stakeholders

on

how

to

conduct,

assess,

and

use

patient

preference

studies

and

on

when

to

include

patient

preference

studies

in

development

plans.

Factors

and

situations

influencing

the

value

of

patient

preference

studies

along

the

medical

product

lifecycle:

a

literature

review

Eline

van

Overbeeke

,

Chiara

Whichello

,

Rosanne

Janssens

,

Jorien

Veldwijk

,

Irina

Cleemput

,

Steven

Simoens

,

Juhaeri

Juhaeri

,

Bennett

Levitan

,

Jürgen

Kübler

,

Esther

de

Bekker-Grob

and

Isabelle

Huys

1_{ClinicalPharmacologyandPharmacotherapy,UniversityofLeuven,Herestraat49Box521,3000Leuven,} Belgium

2_{ErasmusSchoolofHealthPolicy&Management(ESHPM)andErasmusChoiceModellingCentre(ECMC),} ErasmusUniversityRotterdam,P.O.Box1738,3000DRRotterdam,TheNetherlands

3_{BelgianHealthCareKnowledgeCentre(KCE),Kruidtuinlaan55,1000Brussels,Belgium} 4_{Sanofi,55CorporateDrive,Bridgewater,NJ08807,USA}

5_{JanssenResearch&Development,1125Trenton-HarbourtonRoad,P.O.Box200,Titusville,NJ08560,USA} 6_{QuantitativeScientificConsulting,Europabadstr.8,35041Marburg,Germany}

Industry,

regulators,

health

technology

assessment

(HTA)

bodies,

and

payers

are

exploring

the

use

of

patient

preferences

in

their

decision-making

processes.

In

general,

experience

in

conducting

and

assessing

patient

preference

studies

is

limited.

Here,

we

performed

a

systematic

literature

search

and

review

to

identify

factors

and

situations

influencing

the

value

of

patient

preference

studies,

as

well

as

applications

throughout

the

medical

product

lifecyle.

Factors

and

situations

identified

in

113

publications

related

to

the

organization,

design,

and

conduct

of

studies,

and

to

communication

and

use

of

results.

Although

current

use

of

patient

preferences

is

limited,

we

identified

possible

applications

in

discovery,

clinical

development,

marketing

authorization,

HTA,

and

postmarketing

phases.

Introduction

Theimportanceofincorporatingpatientneedsandperspectivesintodecisionmaking through-outthelifecyclesofdrugsandmedicaldevices,forthepurposeofthisstudycollectivelycalledthe medicalproductlifecycle(MPLC),isreceivingincreasingrecognition[1–4].Recognitionofthe valueofpatients’perspectiveshasledtoashiftindrugdevelopmentandassessments,fromonly lookingatclinicaloutcomes totakingintoaccountthejudgementsofpatientsonhowthese outcomesaffecttheirlives.Thisshiftoriginatesfromthenotionthatpatientsshouldbeatthe

Reviews

FOUNDA

TION

REVIEW

ElinevanOverbeekeisa PhDstudentatthe UniversityofLeuven (Belgium),andhasworked onthePatientPreferences inBenefit-Risk Assessmentsduringthe DrugLifeCycle(PREFER) projectoftheInnovative

MedicinesInitiative(IMI)sinceOctober2016.Before herPhD,shewasawardedherMastersinbiomedical sciencesattheUniversityofLeuvenandgained experienceinmedicalaffairsinthepharmaceutical industry.Elineconsidersitimportantthatthevoiceof patientsislistenedtothroughoutthemedicalproduct lifecycleandfocuseshercurrentworkonhowto improvetheimplementationofpatientpreferencesin assessmentsthroughoutthislifecycle.

ChiaraWhichelloisa PhDstudentatErasmus UniversityRotterdam,and iscurrentlyalsoworking ontheIMIPREFERproject. Chiarawasawardedboth anMScinglobalhealthand anMAinanthropology& sociologyfromthe

UniversityofGlasgow.Hercurrentresearchinterests includetheappraisalofpatientpreferenceelicitation andexplorationmethodsandtheadvancementof patient-focuseddrugdevelopment.

IsabelleHuysisthe deputycoordinatorofthe PREFERprojectfromthe IMIPREFERproject.She hasaPhDin pharmaceuticalsciences fromtheUniversityof Leuven(Belgium)and carriedoutpostdoctoral

researchattheirLawFacultyonpatentsand biomedicalinventions.Since2010,shehasbeena full-timeprofessorinregulatorysciencesattheFacultyof PharmaceuticalSciencesandamemberoftheCenter forIT&IntellectualPropertyITlaw(CiTiP).Shehas alsobeenanadvisorforEuropeanprojects, intellectualpropertyofficerandregionaldevelopment officerintheR&DDepartmentoftheUniversityof Leuven.

Correspondingauthor.vanOverbeeke,E. (eline.vanoverbeeke@kuleuven.be) z_{Jointfirstauthors.}

1359-6446/ã2018TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).

centeroftheMPLC,becausetheyaretheonesnotonlygainingthe benefits,butalsobeingexposedtotherisks[5].

One option to better understand the patient perspective is throughexploringandelicitingpatientpreferences(see Glos-sary).TheUSFoodandDrugAdministration(FDA)referstopatient preferences by defining patient preference information as ‘qualitativeorquantitativeassessmentsoftherelativedesirability or acceptability to patients of specified alternatives or choices amongoutcomesorotherattributesthatdifferamong alterna-tivehealthinterventions’[4].Patientpreferencescanbeobtained throughtheuseofdifferentexploration(qualitative)and elicita-tion(quantitative)methods[6].Preferenceexploration meth-odscanbedefinedasqualitativemethodsthatcollectdescriptive datathroughparticipantorphenomenonobservation,and exam-ining the subjectiveexperiencesand decisions madeby partici-pants.Examplesofpreferenceexplorationmethodsinclude semi-structuredinterviewsandfocusgroups.Preferenceelicitation methods can be defined as quantitative methods collecting quantifiable data that can bereported throughstatistical infer-ences or analysis. Examples of preference elicitation methods include discrete choiceexperiments(DCE), analyticalhierarchy process(AHP),and standard gamble.Althoughmethodscanbe classifiedasexplorationorelicitationmethods,theycanalsobe classifiedasstructured-weighting,health-stateutility, stated-pref-erence,orrevealed-preferencemethods,asdescribedinthe Medi-cal Device Innovation Consortium (MDIC) Patient Centered Benefit-RiskProjectreport[3,7].

Stakeholders,includingthepharmaceuticalandmedicaldevice industry, regulatory authorities, HTAbodies, payers, clinicians, academia,andpatientorganizations,generallyagreethatthereis value in using patient preferences to inform assessments and

decision making [1,3,4,8–13]. In addition, patients themselves haveexpressedinterestindecision-makingprocesses[14].Patient preferencesarefoundtoprovideadditionalinformationon medi-cal products, such as insights into the relative importance of clinical outcomes and safetyissues, and to help in transparent communicationregardingthe incorporationofpatientviewsin regulatorydecisionmaking[1,3,15,16].Moreover,theycanleadto morerelevant,well-informed,transparent,publicallytrusted,and patient-centricdecisions[3,13,17,18].InHTAspecifically,patient preferencesarebelievedtoprovideahealthconditionperspective andtoimprovetheusefulness,appropriateness,andacceptability oftheassessments[2,8,19,20].Also,considerationofpatient pre-ferences in clinical trial design can lead to a lower burden for patientsparticipatingin thetrial,and couldresultinimproved recruitment,retention,andcomplianceofpatients.Moreover,it couldleadtomorereal-worldclinicaloutcomesifpreferencesof patients are considered during the establishment of treatment arms[4,21–25].

EuropeanandUSindustry,regulators,HTAbodies,andpayers are currently exploring the use of patient preferences in their processesanddecisionmaking.However,ingeneral,these stake-holdershavelimitedexperienceinconductingandassessingthese studies. Moreover, they are generally notfamiliar with factors influencing the value of these studies,the situationsin which these studies are most valuable, and possible applications of patientpreferencesin theirprocessesanddecision making[26– 28].

Byperformingasystematicliteraturesearchandreview(seeSP.I intheSupplementalinformationonline)focusedonthecurrent measurementanduseofpatientpreferencesinEuropeandtheUS, hereweprovideanoverviewoffactorsandsituationsthat influ-encethevalueofpatientpreferencestudies.Wealsoinvestigated applications ofpatient preferences in assessmentsand decision makingalongtheMPLC.

Overview

of

applications

of

patient

preferences

along

the

medical

product

lifecycle

Atotalof113publicationswereincludedintheliteraturereview (see SP.II in the Supplemental information online). Before we explore the factors and situations that influence the value of patient preference studies in assessments and decision making alongthe MPLC, firstwe give a shortoverviewof howpatient preferences can be used in MPLC phases. Several publications describedthatpatientpreferencescanbeusedineveryphaseof theMPLC,fromdiscoveryuntilpostmarketing[3,29].Here,we describe the applications of patient preferences following the structureof the MPLC (Fig. 1). An overview of the availability ofguidelines andframeworkson theuse ofpatient preferences throughoutthesephasesisgiveninTable1.Currently,the Inno-vativeMedicinesInitiative (IMI) PatientPreferencesin Benefit– RiskAssessmentsduringtheDrug LifeCycle(PREFER)project is workingonprovidingrecommendationsonhowpatient prefer-encescaninformdecisionmakingthroughouttheMPLC[9].

Discovery

Patient preferences are used in the discovery of new medical products [30,31]. They can inform ideation and prototyping. Duringideation,the elicitation of patientpreferences canhelp

GLOSSARY

Attributefeatureoftheproductunderinvestigation(e.g. price)[126]

Externalvaliditythedegreetowhichitiswarrantedto generalizeresultstoothercontexts

Internalvaliditytheextenttowhichacausalconclusion basedonastudyiswarranted.Suchwarrantisconstitutedby theextenttowhichastudyminimizessystemic error(or ‘bias’)

Levelvalueoftheattribute(e.g.,US$10)[126]

Patientpreferences(patientpreferenceinformation) qualitativeorquantitativeassessmentsoftherelative desirabilityoracceptabilitytopatientsofspecified alternativesorchoicesamongoutcomesorotherattributes thatdifferamongalternativehealthinterventions[4]

Preferenceelicitationmethodquantitativemethods collectingquantifiabledatathatcanbereportedthrough statisticalinferencesoranalysis

Preferenceexplorationmethodqualitativemethodsthat collectdescriptivedatathroughparticipantorphenomenon observation,examiningthesubjectiveexperiencesand decisionsmadebyparticipants

Preference-sensitivesituationpreference-sensitive decisionsarethoseinwhichtherearemultiplediagnosticor treatmentoptions,andthedecisionwhichoptiontopursue dependsupontheparticularpreferencesofthe decision-maker[3] 2 www.drugdiscoverytoday.com Reviews
FOUNDA TION REVIEW

toidentifyunmetmedicalneeds,alsoreferredtoasunmet health-care needs. For instance, this is demonstrated by the patient preference study on fragile X syndrome (FXS) by Cross et al.

[32], described in the report of Selig [3,4,30]. Selig described howstakeholderssoughttogetabetterunderstandingofunmet needsinFXS.Caregiverpreferenceswerequantifiedforsix treat-mentoutcomes.Caregiversfoundtheabilityofpatientstocontrol theirpsychological,gestural,andverbalbehaviortobethemost importanttreatmentoutcome.Crossetal.[32]statedthatthese resultswouldhavethe potentialtoinformfuturedrug develop-mentinFXS[30].Inadditiontoidentifyingunmetmedicalneeds, theycanleadtoa betterunderstandingofthe disease,personal

experiencesofpatientswiththedisease,andtheacceptabilityof benefitsandrisks[3,4,30,33].Patientpreferencescanevenbeused toinformthedesignofthetargetproductprofile,ensuringthat patient needs aremet [34].During prototyping,patient prefer-encescaninformadaptionofthedesignofthemedicalproduct

[3,4,11].

Preclinical

development

Almostnoevidencewasfoundonapplicationsofpatient prefer-ences in preclinical development. Patient preference were sug-gested to ensure that the patient needs are addressed by the medical productin design validation duringpreclinical testing

Discovery _developPre clinica_mentl _developClinica_mentl _authoMarke_rizationting _markePost-_ting

Ideation

Medical need assessment Disease familiarization Target product profile design Prototyping

Product design adaptation Product design validation

Clinical trial design PRO identification

Inclusion and exclusion criteria development

Treatment arm selection Acceptable uncertainty level calculation

Information and communication to patients

Benefit-risk assessment

Patient trade-off understanding Subpopulation identification Benefit-risk weighing Product design validation

Benefit-risk assessment

Patient trade-off understanding Subpopulation identification Benefit-risk weighing Early access

Labelling optimization

Economic evaluation

Cost-effectiveness analysis Cost-benefit analysis Cost-utility analysis PRO identification Subpopulation identification Outcomes weighing QALY estimation

Product acceptance Extensions of indications Post-marketing assessments

Risk weighing Product innovation HTA &

reimbursement

Drug Discovery Today

FIGURE1

Applicationsofpatientpreferencesalongthemedicalproductlifecycle(MPLC).ApplicationsofpatientpreferencesweremappedalongthephasesoftheMPLC. ApplicationswereidentifiedforallphasesoftheMPLC.StagesoftheMPLCandtheirorganizationwereidentifiedastheyemergedfromtheliterature. Abbreviations:HTA,HealthTechnologyAssessment;PRO,patient-relevantoutcomes;QALY,quality-adjustedlifeyear.

TABLE 1

AvailabilityofguidanceontheuseofpatientpreferencesalongtheMPLCa

PhaseofMPLC Availabilityofguidance Refs

Discovery Lackofguidancereported [98]

Preclinicaldevelopment Noguidanceidentified Clinicaldevelopment Noguidanceidentified

Marketingauthorization PatientPreferenceInformation–VoluntarySubmission,ReviewinPremarketApprovalApplications,Humanitarian DeviceExemptionApplications,andDeNovoRequests,andInclusioninDecisionSummariesandDeviceLabeling: GuidanceforIndustry,FoodandDrugAdministrationStaff,andOtherStakeholders.USDepartmentofHealthand HumanServices,FDA,CenterforDevicesandRadiologicalHealthandCenterforBiologicsEvaluationandResearch

[4]

MDICPatient-CenteredBenefit–RiskProjectReport:AFrameworkforIncorporatingInformationonPatientPreferences regardingBenefitandRiskintoRegulatoryAssessmentsofNewMedicalTechnology

[3] ICHHarmonizedGuideline:RevisionofM4EGuidelineonEnhancingtheFormatandStructureofBenefit-Risk

InformationinICH

[127]

HTAandreimbursement Klemeetal.:PatientperspectiveinhealthtechnologyassessmentofpharmaceuticalsinFinland [107] Kievitetal.:Takingpatientheterogeneityandpreferencesintoaccountinhealthtechnologyassessments [20]

Lackofguidancereported [10,128]

Postmarketing Noguidanceidentified

a

Abbreviations:ICH,InternationalCouncilforHarmonizationofTechnicalRequirementsforPharmaceuticalsforHumanUse.

www.drugdiscoverytoday.com 3

Reviews

FOUNDA

TION

[3].Noliterature wasretrieveddemonstrating the actualuseof patientpreferencesduringpreclinicaldevelopment.

Clinical

development

Patientpreferencescanbeelicitedduringclinicaldevelopmentto informclinicaltrialdesign,productdesignvalidation,and benefit-–riskassessment[3].Patientpreferencesarecurrentlytakeninto accountinclinicaltrialdesign[3,4,11,30],duringwhichpatient preferencescanbeusedtoidentifypatient-relevantoutcomesthat caninformtheselectionofclinicalendpoints[4,22,35–37].Also, patient preferences can inform the development of reasonable inclusion andexclusioncriteria. Moreover,they canbeusedto defineexperimentalorcontroltreatmentarmsindoubly random-izedpreferencetrial(DRPT)designs.InDRPTdesigns,theeffectof preferencesonclinicaloutcomescanbeanalyzed[24,25,38–44]. Patient preferences can alsobe used in clinical trial designsto calculatetheacceptablelevelofuncertainty(significanceleveland power) in clinical trials [45,46] and to inform development of informationthatwillbeprovidedtopatientsduringclinicaltrials, includingbackgroundinformationandstudyresults[23].

Marketing

authorization

The useofpatientpreferencesinregulatory marketingauthorization was discussed in 46out of 113 (41%) publications. Regulatory authoritiessuchastheFDA[4]andtheEuropeanMedicinesAgency (EMA)[1]arecurrentlyexploringtheuseofpatientpreferences[11– 13].However,theydonotrequirethesubmissionofpatient pre-ferences[16].TheFDAacceptsthesubmissionofpatientpreference informationinapprovalapplicationsformedicaldeviceseitheras supportingevidenceorforinformationalpurposes[4,47].

Patientpreferencescanbeusedatthemarketingauthorization stageinbenefit–riskassessment,assessmentforearlyaccess[11], andforoptimizinglabelingthatwillinformpatientsonbenefits and risks[3,4].Use ofpatientpreferencesin benefit–risk assess-menthasgivenrisetopatient-centeredbenefit–risk(PCBR) assess-ments [48,49]. Several initiatives areworking on incorporating patientpreferencesinbenefit–riskassessments,suchastheMDIC PatientCenteredBenefit-RiskProject,IMIPREFER,andtheFDA’s CenterforDevicesandRadiologicalHealth(CDRH)Patient Pref-erence Initiative[9,50].Inbenefit–riskassessments,patient pre-ferences canprovideinformationon maximumacceptablerisk, minimumacceptablebenefit,netclinicalbenefit,quality-adjusted timewithoutsymptomsandtoxicity,andrelativevalue-adjusted numberneededtotreatthroughmultiple-criteriadecision analy-sis,benefit–less-riskanalysis,theGailassessment,andprobabilistic simulationmethods[49,51–56].Theseassessmentsareinformed bypatientpreferencesthroughunderstandingthetrade-offsthat patients make between benefits and risks [36]. Moreover, the results ofpatientpreference studiescannotonlyshowa range of preferences, but also be usedto identify subpopulations for whom the benefits outweigh the risks [3,4,16,52,57]. Finally, patient preferences canhelp to weighthe benefits and risks in benefit–riskassessmentsbasedontherelativeimportanceof out-comes,benefits,andrisksforthepatients[51,58].

Health

technology

assessment

&

reimbursement

Althoughdifferentpublicationsdescribedthatpatientpreferences caninform reimbursementdecisionsduringtheHTAand

reim-bursementstage[3,59–62],Dirksenetal. [63]reportedthat not muchevidenceisavailableontheactualuseofpatientpreferences inreimbursementdecisionmakingandthatmultiplecountriesdo notconsiderpatientpreferencesasanexplicitprioritization crite-rion.TheuseofpatientpreferencesinHTAwasdiscussedby49out of113(43%) publications.Although cases havebeen described whereHTAbodiesarereluctanttowardsconsideringpatient pre-ferencesintheirassessments,EuropeanandUSHTAbodiesand payershaveincreasinglyshowninterestinusing patient prefer-encesintheirassessments(Table2)[2,8,10,11,31,64–67].

Twelvepublicationsspecificallymentionedtheuse ofpatient preferencesineconomicevaluations,includingcost-effectiveness, cost–benefit, and cost–utility analyses [60,61,68–77]. In these analyses, patient preferences can inform the identification of patient-relevantoutcomes,and theidentification of subpopula-tionsforwhomthebenefitsoutweightherisks[20,52,61,75].In addition,patientpreferencescanhelptoweighoutcomes accord-ing to their relative importance to patients [20,61,75,78].This could be done by incorporating patient preferences and other evidence into a multicriteria decision analysis [52,55]. Lastly, Bewtraetal.[76]describedthattheutilityvaluesresultingfrom patientpreferencestudiescanbeusedasquality-of-lifeweightsin thecalculationofquality-adjustedlifeyears(QALYs).QALYsand EuroQolfivedimensions (EQ-5D)utilitiesarefrequentlyusedin HTA,buttheirclassicalusehasbeencriticizedbysome,because they only cover benefit for generic quality-of-life dimensions ratherthanforallfactorsthatimportanttopatients[73,79,80].

Post

marketing

Although some applications of patient preferences described abovemightalsobeapplicabletothepostmarketingphase,some additionalpostmarketing-specificapplicationswereidentifiedin theMDICreport[3]andtheFDAguidance[4].Duringthe post-marketingphase,patientpreferencescouldinformproduct accep-tance by patients, extensions of indications, postmarketing assessmentsthroughriskweighing,andproductinnovation[3,4].

Factors

and

situations

influencing

the

value

of

patient

preference

studies

Manyfactorsandsituationswereidentifiedthatcaninfluencethe valueofpatientpreferencestudies(Fig.2) [18,81].Factorswere definedbytheresearchersasafactorinfluencethatoccursduring theorganization,design,conduct,orcommunicationofresultsof thestudyandthatcontributeto,oraffect,thevalueofresultsfrom

TABLE2

MainUSandEuropeanHTAbodiesandpayersinterestedin patientpreferencesa

Country Organization

Belgium BelgianHealthCareKnowledgeCentre(KCE)

England NationalInstituteforHealthandCareExcellence(NICE) Finland FinnishMedicinesAgency(Fimea)

France HighAuthorityofHealth(HAS)

Germany InstituteforQualityandEfficiencyinHealthCare(IQWiG) Scotland ScottishMedicinesConsortium(SMC)

TheNetherlands CareInstituteNetherlands(CVZ)

USA CentersforMedicare&MedicaidServices(CMS) a BasedonRefs[19,29,61,62,65,66,78,81,129]. 4 www.drugdiscoverytoday.com Reviews
FOUNDA TION REVIEW

patient preferencestudies.Situationswere definedasa circum-stanceorconditionthatoccursduringtheuseofresultsandthat contributesto,oraffectsthevalueof,resultsfrompatient prefer-ence studies. Situations were considered to be external to the preferencestudy and notcontrollable by the researcher. These factorsandsituationsaredescribedbelowfollowingthedifferent stagesandstepsofapatientpreferencestudy.Althoughthereare alternativewaystodescribethestagesofpatientpreferencestudies andthedifferentstepsthattheyencompass,weidentifiedsteps and their organization asthey emergedfrom the literature, in additionto theorganizationalcontext(see SP.IIIinthe supple-mentalinformationonline).Stagesincludedstudydesign,study conduct,andcommunicationanduseoftheresults.

Organizational

context

Multipleorganizationalfactorswereidentifiedthatdeterminethe valueofpatientpreferencestudies,asdiscussedbelow.

Expertise

Clinical,medicalproductdevelopment,patient,methodological, andstatisticalexpertiseoftheconductingpartieswillhave con-siderableimpactonwhetherandhowapreferencestudyis per-formed [2,3,12,28,30,50,82,83]. Partnerships between industry, academia,andpatientorganizationscanbeestablishedtoacquire theneededexpertise[28],butagreementsonsharingandusingthe data need to be established [28,30]. Expertise must be shared betweenparties to ensure appropriate conduct by trained staff andcommonunderstanding[4,28,30].

Patientcenteredness

Patientcenterednessofpatientpreferencestudiesisanimportant factorfor success.The FDAguidance[4] statesthat thepatient

should be‘the centralfocus ofthe study’.Patients and patient representatives canparticipatein thestudy designto guarantee comprehensibilityoftheinformationandquestionsprovidedto patients,toimproverecruitment,andtoensurecorrect interpre-tationandcommunicationofresults[4,16,28].

Goodpractices

Followinggoodresearchpractices,similartoGoodClinical Prac-tices [84] and Good Pharmacoepidemiology Practices [85],will ensureacorrectdesignandconductofthestudyandthevalueof the results [30,86]. However, patient preference study-specific guidanceisoftenlacking(Table3).Differentinitiativesare work-ing on addressingmethodological issues and providing recom-mendationsand guidanceonthedesignandconductofpatient preferencestudies(Table4).

Ethics

Compliancewithethicsrequirementsassociatedwithquestioning patientsisnecessaryinsettingupapatientpreferencestudy,and different measures have to be taken to meet these ethics requirements

[14,60].Thisprocessistimeconsuming.Obtainingethicsand/or institutionalreviewboard(IRB)approvalwhenquestioningpatients canespeciallybechallengingforindustry,andwillnotalwaysgive directaccesstopatientsandtheirdata[31,83].Postmusetal.[16]

describedthattheydidnotcollectdemographicandclinicaldatain theirpatientpreferencestudytoavoidthecomplexityofdata pro-tection,butstatedthatnothavingthesedatalimitedtheiranalysis.

Financialresources

Conducting patient preference studies comes with a financial burdenthatcandifferamongmethods.BudgetsofUS$100000– 400000(s90000tos370000)havebeenquotedforquantitative patientpreferencestudies[2,3,12,30,31,50,82,83,87].

Organization Design Research question Sample definition Method selection Instrument design Conduct Participant recruitment Piloting and data collection Analysis and interpretation Expertise

Patient centeredness Good practices Ethics

Financial resources Study duration Timing along MPLC

Patient vs other preferences Clarity Ensuring representativeness Ability to participate Sample size Ethics

Match to research question Match to MPLC stage Validity of the method

Capturing demographics and clinical baseline data Attribute development Cognitive burden Patient education Question framing Appeal of the instrument

Ensuring representativeness Ethics

Testing validity and reliability Protocol compliance

Robustness Preference heterogeneity Tailoring of communication Presentation of results Situations Communication and use of results

Patient population characteristics Product characteristics Familiarity of assessors Attitudes of assessors New competitors Communication to patients

Drug Discovery Today

FIGURE2

Factorsandsituationsinfluencingthevalueofpatientpreferencestudies.Factorsandsituationsweremappedalongtheorganization,design,conduct,and communicationanduseofresultsofpatientpreferencestudies.Stagesandstepsofpatientpreferencestudiesandtheirorganizationwereidentifiedasthey emergedfromtheliterature.Abbreviations:MPLC,medicalproductlifecycle.

www.drugdiscoverytoday.com 5

Reviews

FOUNDA

TION

Studyduration

The conduct of a patient preference study is time-consuming, ranging from 6 months to 2 years in complex cases

[2,12,30,82,83].Therecruitmentofpatientscanparticularlytake moretimethanisanticipated[82,83].

TimingalongMPLC

Itisnotclearwhenpatientpreferencestudiesshouldbeconducted because the submission of patient preferences is currently not requiredbyregulatoryauthoritiesandHTAbodiesand/orpayers, butcanbeacceptedassupportingevidenceinasubmissiondossier

[3,4,50,55]. Currently, the study sponsor themselves needs to decide whether information on patient preferences is needed andtoassesswhenandhowtobestcollectit[3].

Patient

preference

study

design

Ifpatientpreferencesareelicitedinwell-designedand well-con-ductedpatientpreferencestudies,patientpreferencesare consid-ered to be valid scientific evidence that can be valuable in informingdecisionmaking[4].Thus,thedesignphaseofapatient preferencestudyisacrucialphase.Inadequatedesignwill nega-tivelyinfluencethevalueofthestudyandmakeitunlikelythat outcomes will be considered by decision makers [12]. Design factorsthatcouldinfluencethevalueofthestudy arediscussed belowperstepinthedesignprocess(Fig.2).

Research

question

Theformulationoftheresearchquestionwillinfluencethevalue ofthe studyandchoiceofpreferenceelicitation,orexploration method, because the applicabilityof measuring patient prefer-encesdependsontheresearchquestionbeingasked[3,30]:

Patientversusotherpreferences

Decision making might notbe sensitive to patient preferences whenpreferencesofotherstakeholders,suchasthegeneralpublic orclinicians,orotherevidence,arefoundtobemoreimportant thanthoseofthepatient[3].Thismightbeparticularlyimportant whensettingupastudytoinformHTAbecausesome reimburse-mentdecision-makersmightwishtotakethepreferencesofthe generalpublic,asahealthcarepayer,intoaccount[55,63,88].

Sample

definition

Besidesobtainingethicsand/orIRBapprovalandaccesstopatients asdescribedabove,additionalfactorscaninfluencethe valueof patientpreferencestudiesduringsampledefinition:

Clarity

Clearlydefiningthepatient samplewillensureinclusionofthe right patients and value of results. Setting up inclusion and exclusioncriteriacansafeguardacleardefinitionofthepatient sample[3].

Ensuringrepresentativeness

Ensuringheterogeneityinthepatientsamplewillresultin gener-alizableresultsthatarerepresentativeofthepreferencesofthefull patientpopulationforwhichthemedicalproductisintendedtobe launched [3,4,21,30,36,50,89,90].Generalizability ofthe results mightbelimitedbecauseoftheeligibilitycriteriaofthesample, especiallywhenpatientpreferencestudiesareperformed along-sideclinicaltrials[39,72,89,91–96].

Abilitytoparticipate

Inthefollowingpatientpopulations,itmightbemoredifficultto measurepreferencesanditmightbenecessarytopaymoreattention tothedesignoftheexplorationorelicitationinstrument:(i)low readinglevelorvisiondifficulties;(ii)notabletouseapencilora computer mouse; (iii) no access to the internet; (iv) physically disabled;(v)cognitiveimpairments;and(vi)pediatricpatient popu-lations[3,4,70,83,97].Ifpreferencescannotbeeliciteddirectlyfrom patientsthemselves,preferencescanbeelicitedfrominformal care-givers,includingparentsandfamilymembers[3,4,33].Parentscan beincluded to represent theirchildren and family membersto representolderrelatives[3,4,30,49,70,93,98].However,their pre-ferencesmightdifferfromthoseofthepatientsbecausetheymight notassignthesamevaluestovariousrisksandbenefits[4,99].

Samplesize

Duringthedesignphaseofpatientpreferencestudies,samplesize andpowercalculationscanbemadetoallowforstatisticalanalyses lateron[14,100].Ifsamplesizecalculationsdonottake heteroge-neityintoaccount,itmightbeimpossibletodosubpopulations analysis when results are available [89,90,93,95,97]. Required sample sizes differ among methods. For example, in general, smallersamplesarerequiredforswingweightingcomparedwith DCEs[87].

Method

selection

Manydifferenttypesofpreferenceexploration(qualitative)and elicitation(quantitative)methodsexistandcanbeusedinpatient

TABLE3

Availabilityofguidanceondesignandconductofpatient preferencestudiesa

Topic Availabilityofguidance Refs

Goodresearchpractices ISPORmethod-specificgood researchpractices

[4,78,103] Choiceofpreference

exploration/elicitationmethod

Lackofguidancereported [3,18,98] Selectionofattributes Lackofguidancereported [3] Whosepreferencesshouldbe

measured

Lackofguidancereported [3,60] Validityassessment Janssenetal.:Improvingthe

qualityofdiscrete-choice experimentsinhealth:howcan weassessvalidityandreliability?

[109]

Lackofguidancereported [3] a

Abbreviations:ISPOR,InternationalSocietyforPharmacoeconomicsandOutcomes Research.

TABLE4

Initiativesworkingonaddressingmethodologicalissuesand providingrecommendationsandguidanceonthedesignand conductofpatientpreferencestudies

Initiative Website

IMIPREFER www.imi-prefer.eu

InternationalSocietyfor

PharmacoeconomicsandOutcomes Research(ISPOR),PatientPreferences SpecialInterestGroup

www.ispor.org/sigs/

Stated-Preference-Methods.asp

InternationalAcademyofHealth PreferenceResearch(IAHPR)

http://iahpr.org InternationalHealthEconomicsAssociation

(iHEA),HealthPreferenceResearchSpecial InterestGroup www.healtheconomics.org/ page/HealthPreference 6 www.drugdiscoverytoday.com Reviews
FOUNDA TION REVIEW

preferencestudies[3,4,14,81].Factorsthatdeterminethevalueof patientpreferencestudiesarediscussedbelow.

Matchtoresearchquestion

Theoptimalmethodforpatientpreferenceelicitationor explora-tionwilldependonthestudyobjectiveandprimaryuseofresults, andcanbediscussedwiththestakeholdersaffectedby,or evalu-ating,the results inadvanceto increasethe valueofthe study

[4,12,18,81,101].Elicitationmethodscanquantifypersonal pre-ferences, are structured, have clearly defined data types, have limited response options, allow for statistical analysis, and are recommendedtobeusedwhenthe aimistoexplorepreference heterogeneityindifferentpatientprofiles[3,4,45,56].Exploration methods,suchasinterviewsandfocusgroups,arerecommended forconceptexplorationand gainingin-depthknowledgeofthe valueofmedicalproducts[3,10,18].Althoughitisimportantto matchthe methodtotheresearchquestion,thisspecificityand lackofstandardmeasuresisalsowhatmakesithardtocompare preferencestudiesacrossconditions,limitingtheirvalueforsome HTAagenciesorreimbursementdecision-makers[55].

MatchtoMPLCstage

Theappropriatechoiceofthemethoddependsonthephaseinthe MPLC.Duringdiscovery,interactiveexplorationmethods,suchas focusgroups,havebeendescribedasbeingparticularlyuseful[4]. Ininformingclinicaltrialdesign,bothexplorationandelicitation methods have been used [24,25,35–37,39,102]. For benefit–risk assessments,elicitationmethods,suchasDCEandAHP,aswellas explorationmethodscanbeuseful[12,53,59,103].InHTA, elici-tation methods that can examine willingness to pay are also describedasbeinguseful[59,60,69,70,81,104,105].However,until now, HTA has mainly focused on patient involvement using preferenceexplorationmethods[55,106,107].

Validityofthemethod

Giventhatparticipantresponsesmightdependonthepreference elicitation method used [105,108], weights or values obtained through different methods might not be comparable[82].Therefore, guidanceonwhichmethodstouseareofimportanttoensurethe valueofpatientpreferencestudiesindecisionmaking.Thereisalack ofguidanceonhowtoassessthevalidityofapatientpreference study[3](Box5).However,workisunderwayon approaches toassess thevalidityofpatientpreferencestudies.Forexample,Janssenetal.

[109]createdaconceptualmodelfortheassessmentofvalidityin DCEs.Themannerinwhichinternalvaliditycanbeensuredor assesseddependsonthemethodused.Tervonenetal.[87]compared swingweighting(SW)toDCEsandstatedthatinternalvalidityis automaticallyenforcedwithSWbecauseoftheexactnatureofthe collectedpreferences,whereastheinternalvalidityofDCEresults needstobeassessedmanually.Assessmentofexternalvalidityof stated-preferencemethods,requiringacomparisonbetweenstated and actualchoices, isdifficult to performbecause ofthe use of hypotheticalchoices[3,100].

Instrument

design

Depending on the objectiveof a patient preference study, the preferenceexplorationorelicitationinstrumentcanbedesigned toexploreorelicitpreferencesforhealthstates,treatment attri-butes,ortreatmentalternatives[81].Different factorsrelatedto thedesignoftheinstrumentinfluencethevalueofthestudy,as discussedbelow.

Capturingdemographicsandclinicalbaselinedata

Collectingdemographicandclinicaldataisimportantifsubgroup analysisisplannedtobeperformed[16].

Attributedevelopment

Attributescouldbeidentifiedthroughpatient andcaregiver in-volvement, via a combinationof literature reviews, interviews, andmeta-analysesofclinicaldata,andpossiblyviatrialeconomic evaluations[49,73,89,110].Identifyingattributesandtheirlevels thatarerelevantanddonotoverlapisnecessarytoproduceresults thatcanbeusedtoassesstrade-offs[4,16,49].Whenthereal-life attributesandlevelsarenotsufficientlydifferentanddooverlap, hypothetical choices can be included. This inclusion is often mentioned as a limitation, because hypothetical choices can reflectbenefitandriskprofilesotherthanoftheactualtherapies that willbeapproved[3,36,91,93,96].The numberofattributes thatcanbeincludedintheinstrumentdiffersamongmethods.For example,DCEshave been arguedto notallowthe inclusionof many attributes and, thus, their applicability to contexts with manyattributesislimited[87].

Cognitiveburden

Cognitiveburdenvariesamongmethods,andminimizationofthis burdenwillassurethevalueoftheresults[4,87].Inpatient prefer-enceelicitationstudies,thecognitiveburdenforparticipantscanbe highbecause oftheuse ofhypotheticalchoices andthelarge number and representation of questions, attributes, and levels

[3,4,14,52,59,82,83,89,91,111]. Exploration methods, including interviewsandfocusgroupdiscussions,havealowcognitiveburden for participants [61]. The patient population should be able to performthe method-specifictasksandunderstandthequestions torealizeresultsthatcanbeusedtoassessmeaningfultrade-offs

[3,4,16,49,83,112].Surveyadministrationviainterviewsor work-shopsinsteadofonlineadministrationcouldprovidesupportto patientsinunderstandingthequestions[87,112].

Patienteducation

Theextenttowhichpatientsareinformedonthebenefitsandrisks ofthemedicalproductwhenparticipatinginapatientpreference study isadeterminingfactor forthe valueoftheresults[4,16]. Effective communication on benefits, risk, uncertainties, and probabilities [30] can overcome cognitive burden [96] through the use ofappropriatenumeric, verbal,and graphic representa-tions[4,52,82].Effectivecommunicationisespeciallyimportant when the instrument is designed on a self-administered basis

[4,30]. The amount of, and how, information is provided to patients on the disease, risks, and benefits can influence their preferences and the validity of the study

[24,30,63,83,98,110,11–115].Indescribingoutcomestopatients, Hockleyetal.[83]recommenddefiningthenameoftheoutcome, thedescription,recurrence,duration,andwhethertheoutcomeis treatable.Althoughnofurtherguidanceonpatienteducationin patient preference studieswas found, othersources that might provide information on how to educate patients include the guidance of the FDA on communicating benefits and risks

[116],theIMIEUPATI project[117],andthecriteriaforjudging thequalityofpatientdecisionaidsfromtheInternationalPatient DecisionAidStandards(IPDAS)[118].

Questionframing

Whenelicitingpatientpreferences,theframingofthequestions caninfluencepreferencesandthevalidityofthestudy[119,120].

www.drugdiscoverytoday.com 7

Reviews

FOUNDA

TION

Bowlingetal.[119]statedthat‘patients’perceptionsofriskand preferencesfortreatmentaredifficulttomeasurebecauseofthe largeinfluenceofquestionframingandpresentationeffects (posi-tive/negativequestionwordingbiases)’.Inaddition,Howardetal.

[120] demonstratedin a DCE study that attribute framing can influencepatientpreferences.

Appealoftheinstrument

The selection of a method and design of the instrument can dependonhowengagingtheinstrument istoprevent dropout. Minimaldropoutcanbeachievedwhentheinstrumentis engag-ingthroughinclusionofengagingstimuliandexclusionof com-plexformatsanddifficulttoanswerquestions[3,83].

Patient

preference

study

conduct

Relevantfactorsinfluencingthevalueofthestudyandrelatedto thestudyconductarediscussedbelow,basedoneachstepofstudy conduct(Fig.2).

Participant

recruitment

Besides obtaining ethics and/or IRB approval and access to patients,asdescribedabove,anotherfactorrelatedtothe recruit-mentofparticipantsthatwillinfluencethevalueofthestudyis representativeness.Obtainingarepresentative sampleofthe pa-tient population is a recruitment challenge for many patient preference studies [2,100]. Sample bias can be caused by over-inclusion ofmotivatedpatients, forexamplebecause ofthe re-cruitment of patients via a sole patient organization

[16,36,49,78,93,121].However,evenin caseofsamplebias,the resultsofpatientpreferencestudiesmightstillbemeaningfulfor subpopulations[16].

Piloting

and

data

collection

Testingvalidityandreliability

Performingpilotstudiesbeforethemaindatacollectionisdone will allow testing of validity and reliability of the preference methodandinstrument[78,83].

Protocolcompliance

Duringdatacollection,compliancewiththeprotocolisacrucial determinantofthevalidityandreliabilityoftheresults[4,30].

Analysis

and

interpretation

Robustness

When the robustness of the analysis is ensured, results of the analysiswilllead toappropriate interpretation[4,30].However, thevalueoftheanalysiscanbereducedifthedesignofthestudy wasnotwellsetup[82].Inquantitativepatientpreferencestudies, statisticalanalysiscanbe performed,resulting inestimates and uncertainties(confidenceintervalsorstandarderrors),whichcan createavaluemodel[4,16,33].Asensitivityanalysiscanbe per-formed to assess the importance of the different valuesin the model[4,33]. Itmight benecessaryto use advanced regression techniquesinquantitativepatientpreferencestudies,suchasthe mixed logit model [89,93]. For qualitative patient preference studies,statisticalanalysisisnotappropriate[92].

Preferenceheterogeneity

Giventhatindividualpreferencesaremeasuredinpatient prefer-ence studies, it is possible that there are differences between patients in how they perceive and weigh the attributes

[4,50,60,95,122].Some patients might accepthigher risks fora certainbenefitthanotherpatients[3,4,50].Thedetectionofthese differencescouldnotonlyrevealpopulation-levelpreferencesfor themedicalproduct,butmightalsoleadtotheidentificationof subpopulationstoleratingtherisks[3,4,50,52,62].Usingstatistical analysistoolsthatallowfordetectionofvariationanddistribution ofpreferences,forexamplelatentclassanalysis,makessubgroup analysis possible [48,78,89,123]. However, the number of sub-groups that can be evaluated is limited [48]. Allowing for the identificationofsubpopulationsforwhomthebenefitsoutweigh the risks will increase the value of the study for benefit–risk assessmentsandHTA[3,4,16,20,52,57].

Communication

and

use

of

the

results

from

patient

preference

studies

Theresultsofpatientpreferencesstudiescanbecommunicatedto, andusedby,differentstakeholdersindecisionmakingduringthe MPLC.Besidesthecommunicationofresultstostakeholdersfor useindecisionmaking,resultscanalsobecommunicatedbackto patients. However, the communication of results to patients should bedone in a different manner thancommunication to assessors. During the use of the results, stakeholders’ attitudes towardtheuseofpatientpreferences,butalsoclinicalandmarket situationscaninfluencethevalueofpatientpreferencesstudies.

Factors

arising

in

communication

of

results

Tailoringofcommunication

Results of patient preference studies can inform many stake-holders,includingindustry,regulators,HTAbodies,payers, phy-sicians, patient organizations, and patients. However, these stakeholdershavedifferentneedsand,therefore,tailoringofthe language,format,andvenueofthestudyresultstothestakeholder groupcanenhancethe valueoftheresultsto thestakeholders. Patient organizations can participate in the communication of resultstopatientstoensurecomprehensibilityofthedisseminated results[28].

Presentationofresults

Visualizingresultscanpreventtheirmisinterpretation,andcanbe achievedthroughtheuseoftables,forestplots,andbarcharts[82].

Situations

influencing

the

value

of

patient

preference

studies

Patientpopulationcharacteristics

Patientpreferencesmightbeespeciallyusefulinapopulationwith unmetmedicalneedsorinrarediseases[3,4,49].However,ifthe medicalproductis developedfor anunmet medicalneed with severesymptomsandhighmortality,oriftheoutcomesof treat-mentwiththemedicalproductaremorefavorablethanthe out-comesofthediseasetreatedwithbest-availablecare,itmightbe lessvaluabletoelicitpatientpreferences[3].

Productcharacteristics

Thecharacteristicsoftheinvestigationalproductandits alterna-tivesinfluencethevalueofpatientpreferencesindecisionmaking

[3,4,50].Patient preferences can beuseful for decision making when: (i) it concerns a self-use medical product; (ii) there are significantbenefitsandriskscomparedwithalternatives;(iii)there aredifferentalternativeswithdifferentprofiles (preference-sen-sitivesituations);(iv)theimportanceofthebenefitsandrisksis similar(uncertainbenefit–riskprofiles);(v)benefitsandharmsdo

8 www.drugdiscoverytoday.com Reviews
FOUNDA TION REVIEW

not occur simultaneously; (vi) technologies new to a certain disease areaare used;(vii) riskscan beidentified forwhich no benefitcancompensate;and(viii)clinicalexperiencesand end-points are subjective [3,4,45,50,89,105,110]. When approval is likelybecauseofimportantbenefitsandnonsevererisksorbecause of superiority compared with alternatives, patient preferences mightbecomelessvaluable[3].

Familiarityofassessors

Elicitingpatient preferencesmightbeespeciallyvaluable in pa-tient populations with which regulators are not familiar [50]. Whensponsorsandregulatorsknowthediseaseareaand technol-ogieswell,patientpreferencesbecomelessvaluable[3].In addi-tion, the value of elicited quantitative patient preferences for decisionmakingcanbelimitedbyunfamiliaritywithpreference methodsamongassessorsinterpretingtheresults[82,98].

Attitudesofassessors

Thereisnoconsensusontheroleofpatientpreferencesindecision making along the MPLC. A consensus on this role might be difficulttoachievebecauseofdistrustinthe useofpatient pre-ferencesresultingfromthefalseimpressionthatpreferencescan onlybeusedasaverages,fearthatpatientpreferenceswillreplace existingclinicalevidence,barriersto‘culturalchange’,thelackof consensus on the definition of patient preferences, and disap-pointmentrisk(i.e.,thepossibilitythatpatientpreferencestudies mightyieldunexpectedresults;e.g.,somepatientsmightnotwant to accept the risks of a new product)

[1,3,4,12,30,31,36,47,50,63,64,66,70,81–83,98,124,125].

Newcompetitors

Ifnewtreatmentoptionsbecomeavailable,orifnewbenefitsand risks areidentified, the results ofpreviously performedpatient preferencestudiesmightnolongerbevalidandmightneedtobe reconducted[82].

Concluding

remarks

Althoughlimitedevidencewasfoundontheactualuseofpatient preferences in decision making, they are gaining attention in processesalongthe MPLC.Webelieve thatadditionalguidance on the use of patient preferences in assessments and decision makingisnecessarytoincreasetheiruse.Moreover,useofpatient preferencescouldincreaseifregulatoryauthorities,HTAbodies, and payerswouldinformthe industryabout whetherand how theywould usepatient preferencesintheir processes,or would stateinwhatsituationstheyfindpatientpreferencesvaluableor even require the submission of results from patient preference studies.

Manyfactorsandsituationshavetobetakenintoaccountwhen designingand conducting a patient preferencestudy to obtain

valuable results that can be used in assessments and decision making. The maintrends among the factors that we described herethatwillcontributetothevalueofapatientpreferencestudy are: (i) having a multidisciplinary team; (ii) ensuring patient centerednessinthedesignaswellastheconductand communi-cationofresults;(iii)matchingthesampleandthemethodtothe researchquestion;(iv)safeguardingvalidityinthemethod selec-tionand instrumentdesign; (v)reducingcognitive burden;(vi) providing adequate patient education; (vii) guaranteeing that preferenceheterogeneitycan bemeasuredand interpreted;and (viii)tailoringcommunicationofresultstotheaudience.Further research should focus on validating these results through the explorationofstakeholderperspectivesandbyconductingpatient preferencestudies.

Competing

interests

The Patient Preferencesin Benefit-Risk Assessments during the DrugLifeCycle(PREFER)project hasreceivedfundingfromthe InnovativeMedicinesInitiative2JointUndertakingundergrant agreement No115966. This Joint Undertakingreceives support fromtheEuropeanUnion’sHorizon2020researchandinnovation programme and EFPIA. This text and its contents reflects the PREFER project’s view and not the view of IMI, the European Union orEFPIA.J.J. declaresthe followingcompetinginterests: employeeofSanofi,aglobalbiopharmaceuticalcompanyfocused onhumanhealth;andownershipofsharesinSanofi.B.L.declares thefollowingcompetinginterests:employeeofJanssenResearch and Development,LLC;andstockholderin Johnson&Johnson andinaportfoliothatattimesincludesotherpharmaceuticaland healthcare-relatedcompanies.J.K.declaresthefollowing compet-inginterests:representingCSLBehringonIMIPREFER;scientific consultant workingforthepharmaceuticalindustry; and stock-holderinaportfoliothatincludespharmaceuticalandhealth care-relatedcompanies.

Acknowledgments

TheauthorswouldliketothankallmembersofthePREFERproject fortheirinputandsupportduringtheconductofthisliterature review.AspecialthankstoJudithGulpersfromErasmusUniversity Rotterdamwhohelpedrefiningandrunningthesearchqueries. Furthermore,theauthorsareindebtedtotheanonymous reviewersfortheirinsightsandsuggestions.

Appendix

A.

Supplementary

data

Supplementarydataassociatedwiththisarticlecanbefound,in the online version, at https://doi.org/10.1016/j.drudis.2018.09. 015.

References

1EMA(2013)ThePatient’sVoiceintheEvaluationofMedicines.EMA

2Abelson,J.etal.(2016)Publicandpatientinvolvementinhealthtechnology assessment:aframeworkforaction.Int.J.Technol.Assess.HealthCare32,256–264

3MDIC(2015)PatientCenteredBenefit–RiskProjectReport:AFrameworkforIncorporating InformationonPatientPreferencesregardingBenefitandRiskintoRegulatoryAssessments ofNewMedicalTechnology.MDIC

4Anon(2016)PatientPreferenceInformation–VoluntarySubmission,ReviewinPremarket ApprovalApplications,HumanitarianDeviceExemptionApplications,andDeNovo Requests,andInclusioninDecisionSummariesandDeviceLabeling:GuidanceforIndustry,

FoodandDrugAdministrationStaff,andOtherStakeholders.USDepartmentofHealth andHumanServices,FDA,CenterforDevicesandRadiologicalHealthandCenterfor BiologicsEvaluationandResearch

5Meredithm,Y.S.etal.(2016)Patientengagementatatippingpoint—theneedfor culturalchangeacrosspatient,sponsor,andregulatorstakeholders:insightsfromthe DIAconference,‘PatientEngagementinBenefitRiskAssessmentThroughouttheLife CycleofMedicalProducts’.Ther.Innov.Regul.Sci.50,546–553

6Soekhai,V.etal.(2017)Compendiumofmethodsformeasuringpatientpreferences inmedicaltreatment.ValueHealth20,A684–A685

www.drugdiscoverytoday.com 9

Reviews

FOUNDA

TION

7MDCI(2015)MedicalDeviceInnovationConsortium(MDIC)PatientCenteredBenefit– RiskProject(PCBR):AppendixA:CatalogofMethodsforAssessingPatientPreferencesfor BenefitsandHarmsofMedicalTechnologies.MDIC

8EPF(2013)PatientInvolvementinHealthTechnologyAssessmentinEurope:Resultsofthe EPFSurvey.EPF

9deBekker-Grob,E.W.etal.(2017)GivingPatients’preferencesavoiceinmedical treatmentlifecycle:thePREFERPublic–PrivateProject.Patient10,263–266

10Facey,K.etal.(2010)Patients’perspectivesinhealthtechnologyassessment:arouteto robustevidenceandfairdeliberation.Int.J.Technol.Assess.HealthCare26,334–340

11Breckenridge,A.(2011)Patientopinionsandpreferencesindrugdevelopmentand regulatorydecisionmaking.DrugDiscov.TodayTechnol.8,e11–e14

12vanTil,J.A.andIjzerman,M.J.(2014)Whyshouldregulatorsconsiderusingpatient preferencesinbenefit-riskassessment?Pharmacoeconomics32,1–4

13Menon,D.etal.(2014)Involvingpatientsinreducingdecisionuncertaintiesaround orphanandultra-orphandrugs:arareopportunity?Patient8,29–39

14Hockley,K.etal.(2014)StudyProtocol:ElicitingPatientPreferencesontheBenefitsand RisksofTreatmentsforRelapsingRemittingMultipleSclerosis.IMI

15Mol,P.G.etal.(2015)Understandingdrugpreferences,differentperspectives.Br.J. Clin.Pharmacol.79,978–987

16Postmus,D.etal.(2016)Incorporatingpatientpreferencesintodrugdevelopment andregulatorydecisionmaking:Resultsfromaquantitativepilotstudywithcancer patients,carers,andregulators.Clin.Pharmacol.Ther.99,548–554

17Mt-Isa,S.etal.(2014)Balancingbenefitandriskofmedicines:asystematicreview andclassificationofavailablemethodologies.Pharmacoepidemiol.DrugSaf.23,667– 678

18Egbrink,M.O.andIJzerman,M.(2014)Thevalueofquantitativepatientpreferences inregulatorybenefit–riskassessment.J.Mark.Access.HealthPolicy2,1http://dx.doi. org/10.3402/jmahp.v2.22761

19Menon,D.andStafinski,T.(2011)Roleofpatientandpublicparticipationinhealth technologyassessmentandcoveragedecisions.ExpertRev.Pharmacoecon.Outcomes Res.11,75–89

20Kievit,W.etal.(2017)Takingpatientheterogeneityandpreferencesintoaccountin healthtechnologyassessments.Int.J.Technol.Assess.HealthCare33,562–569

21Gaudiano,B.A.etal.(2013)Patients’treatmentexpectanciesinclinicaltrialsof antidepressantsversuspsychotherapyfordepression:astudyusinghypothetical vignettes.Compr.Psychiatry54,28–33

22Bloom,D.etal.(2018)Therulesofengagement:CTTIrecommendationsfor successfulcollaborationsbetweensponsorsandpatientgroupsaroundclinical trials.Ther.Innov.Regul.Sci.52,206–213

23Lim,S.S.etal.(2017)Simulatingclinicaltrialvisitsyieldspatientinsightsintostudy designandrecruitment.PatientPrefer.Adherence11,1295–1307

24Franco,M.R.etal.(2013)Methodologicallimitationspreventdefinitiveconclusions ontheeffectsofpatients’preferencesinrandomizedclinicaltrialsevaluating musculoskeletalconditions.J.Clin.Epidemiol.66,586–598

25Marcus,S.M.etal.(2012)Estimatingthecausaleffectofrandomizationversus treatmentpreferenceinadoublyrandomizedpreferencetrial.Psychol.Methods17, 244–254

26Utens,C.M.A.etal.(2014)Theuseofresearchevidenceonpatientpreferencesin pharmaceuticalcoveragedecisionsandclinicalpracticeguidelinedevelopment: exploratorystudyintocurrentstateofplayandpotentialbarriers.BMCHealthServ. Res.14,540

27Levitan,B.etal.(2017)Theballisinyourcourt:agendaforresearchtoadvancethe scienceofpatientpreferencesintheregulatoryreviewofmedicaldevicesinthe UnitedStates.Patient10,531–536

28Wolka,A.M.etal.(2017)Effectivepartneringinconductingbenefit-riskpatient preferencestudies:perspectivesfromapatientadvocacyorganization,a pharmaceuticalcompany,andacademicstated-preferenceresearchers.Ther.Innov. Regul.Sci.52(4),507–513

29Marsh,K.(2016)IncorporatingPatientPreferencesintoProductDevelopmentandValue Communication:Why,WhenandHow?TheEvidenceForum

30Selig,W.K.D.(2016)KeyConsiderationsforDeveloping&IntegratingPatientPerspectives inDrugDevelopment:ExaminationoftheDuchenneCaseStudy.Biotechnology InnovationOrganization

31Lowe,M.M.etal.(2016)Increasingpatientinvolvementindrugdevelopment. ValueHealth19,869–878

32Cross,J.etal.(2016)CaregiverpreferencesforthetreatmentofmaleswithfragileX syndrome.J.Dev.Behav.Pediatr.37,71–79

33Morel,T.etal.(2016)Quantifyingbenefit–riskpreferencesfornewmedicinesinrare diseasepatientsandcaregivers.Orphanet.J.RareDis.11,70

34Stewart,K.D.etal.(2016)Preferenceforpharmaceuticalformulationandtreatment processattributes.PatientPrefer.Adherence10,1385–1399

35Ervin,C.M.etal.(2014)Assessmentoftreatmentresponseinchronicconstipation clinicaltrials.Clin.Exp.Gastroenterol.7,191–198

36Minion,L.E.etal.(2016)Endpointsinclinicaltrials:whatdopatientsconsider important?AsurveyoftheOvarianCancerNationalAlliance.Gynecol.Oncol.140, 193–198

37Stamuli,E.etal.(2017)Identifyingtheprimaryoutcomeforarandomised controlledtrialinrheumatoidarthritis:theroleofadiscretechoiceexperiment.J. FootAnkleRes.10,57

38Walter,S.D.etal.(2017)Estimationoftreatmentpreferenceeffectsinclinicaltrials whensomeparticipantsareindifferenttotreatmentchoice.BMCMed.Res. Methodol.17,29

39Gryczynski,J.etal.(2013)Patientperspectivesonchoosingbuprenorphineover methadoneinanurban,equal-accesssystem.Am.J.Addict.22,285–291

40Olschewski,M.etal.(1992)Analysisofrandomizedandnonrandomizedpatientsin clinicaltrialsusingthecomprehensivecohortfollow-upstudydesign.ControlClin. Trials1,226–239

41King,M.etal.(2005)Conceptualframeworkandsystematicreviewoftheeffectsof participants’andprofessionals’preferencesinrandomisedcontrolledtrials.Health Technol.Assess.9,1–186

42PreferenceCollaborativeReviewGroup(2008)Patients’preferenceswithin randomisedtrials:systematicreviewandpatientlevelmeta-analysis.BMJ337, a1864

43Johnson,R.E.etal.(2007)Activeexercise,education,andcognitivebehavioral therapyforpersistentdisablinglowbackpain:arandomizedcontrolledtrial.Spine 32,1578–1585

44George,S.Z.andRobinson,M.E.(2010)Preference,expectation,andsatisfactionin aclinicaltrialofbehavioralinterventionsforacuteandsub-acutelowbackpain.J. Pain11,1074–1082

45Chaudhuri,S.E.etal.(2018)Patient-centeredclinicaltrials.DrugDiscov.Today23, 395–401

46Montazerhodjat,V.etal.(2017)UseofBayesiandecisionanalysistominimizeharm inpatient-centeredrandomizedclinicaltrialsinoncology.JAMAOncol.3(9), e170123http://dx.doi.org/10.1001/jamaoncol.2017.0123

47Anon(2016)PatientPerspectiveValueFramework(PPVF):DraftMethodology.Avalere andMilkenInstitute

48Janssen,E.M.etal.(2017)Educationandpatientpreferencesfortreatingtype2 diabetes:astratifieddiscrete-choiceexperiment.PatientPrefer.Adherence11,1729– 1736

49Hollin,I.L.etal.(2017)Patient-centeredbenefit-riskassessmentinDuchenne MuscularDystrophy.MuscleNerve5,626–634

50Ho,M.etal.(2016)Aframeworkforincorporatingpatientpreferencesregarding benefitsandrisksintoregulatoryassessmentofmedicaltechnologies.ValueHealth 19,746–750

51Marsh,K.etal.(2017)Amplifyingeachpatient’svoice:asystematicreviewof multi-criteriadecisionanalysesinvolvingpatients.Appl.HealthEcon.HealthPolicy15,155– 162

52Marsh,K.etal.(2018)Patient-centereddecisionmaking:lessonsfrommulti-criteria decisionanalysisforquantifyingpatientpreferences.Int.J.Technol.Assess.Health Care34,105–110

53Hauber,A.B.etal.(2013)Quantifyingbenefit-riskpreferencesformedical interventions:anoverviewofagrowingempiricalliterature.Appl.HealthEcon. HealthPolicy11,319–329

54Marrone,A.K.etal.(2017)Theregulatoryperspectivesonendoscopicdevicesfor obesity.Gastrointest.Endosc.Clin.N.Am.27(2),327–341http://dx.doi.org/10.1016/ j.giec.2016.12.004

55Mott,D.J.(2018)Incorporatingquantitativepatientpreferencedatainto healthcaredecisionmakingprocesses:isHTAfallingbehind?Patient XX,YYY– ZZZ

56Puhan,M.A.etal.(2012)Aframeworkfororganizingandselectingquantitative approachesforbenefit–harmassessment.BMCMed.Res.Methodol.12,173

57Irony,T.etal.(2016)Incorporatingpatientpreferencesintomedicaldevice benefit-riskassessments.Stat.Biopharm.Res.8,230–236

58Puhan,M.A.etal.(2015)Quantitativebenefit–harmassessmentforsettingresearch priorities:theexampleofroflumilastforpatientswithCOPD.BMCMed.13,157

59Weernink,M.G.M.etal.(2014)Asystematicreviewtoidentifytheuseofpreference elicitationmethodsinhealthcaredecisionmaking.Pharm.Med.28,175–185

60Mott,D.J.andNajafzadeh,M.(2016)Whosepreferencesshouldbeelicitedforusein health-caredecision-making?Acasestudyusinganticoagulanttherapy.ExpertRev. Pharmacoecon.OutcomesRes.16,33–39

61IQWiG(2013)AnalyticHierarchyProcess(AHP)–PilotProjecttoElicitPatientPreferences intheIndication‘Depression’.IQWiG

62IQWiG(2014)Choice-BasedConjointAnalysis–PilotProjecttoIdentify,Weight,and PrioritizeMultipleAttributesintheIndication‘HepatitisC’.IQWiG

10 www.drugdiscoverytoday.com Reviews
FOUNDA TION REVIEW

63Dirksen,C.D.(2014)Theuseofresearchevidenceonpatientpreferencesinhealth caredecision-making:issues,controversiesandmovingforward.ExpertRev. Pharmacoecon.OutcomesRes.14,785–794

64Moes,F.etal.(2017)Contestedevidence:aDutchreimbursementdecisiontakento court.HealthEcon.PolicyLaw12,325–344

65Pisa,G.(2015)AStepTowardsPatient-Centricity:AnalysisofHTARequirementsfor PatientPreferenceDataCollectioninGermany.KantarHealth

66Mu¨hlbacher,A.C.etal.(2016)Patient-focusedbenefit-riskanalysistoinform regulatorydecisions:theEuropeanUnionperspective.ValueHealth19,734–740

67Hailey,D.etal.(2013)Involvementofconsumersinhealthtechnologyassessment activitiesbyInahtaagencies.Int.J.Technol.Assess.HealthCare29,79–83

68BilvickTai,B.W.etal.(2016)Asystematicreviewofhealtheconomicevaluation studiesusingthepatient’sperspective.ValueHealth19,903–908

69Rodriguez,J.M.etal.(2011)Theuseofquality-adjustedlife-yearsintheeconomic evaluationofhealthtechnologiesinSpain:areviewofthe1990–2009literature. ValueHealth14,458–464

70Thebaut,C.(2013)Dealingwithmoraldilemmaraisedbyadaptivepreferencesin healthtechnologyassessment:theexampleofgrowthhormonesandbilateral cochlearimplants.Soc.Sci.Med.99,102109

71Terris-Prestholt,F.etal.(2016)Parameterisinguseruptakeineconomicevaluations: theroleofdiscretechoiceexperiments.HealthEcon.25(Suppl.1),116–123

72Martin-Fernandez,J.etal.(2014)Willingnesstopayforaquality-adjustedlifeyear: anevaluationofattitudestowardsriskandpreferences.BMCHealthServ.Res.14,287

73Tinelli,M.etal.(2016)What,whoandwhen?Incorporatingadiscretechoice experimentintoaneconomicevaluation.HealthEcon.Rev.6,31

74Goto,D.etal.(2017)Regression-basedapproachestopatient-centered cost-effectivenessanalysis.PharmacoEconomics35,685–695

75Muhlbacher,A.C.andSadler,A.(2017)Theprobabilisticefficiencyfrontier:a frameworkforcost-effectivenessanalysisinGermanyputintopracticeforHepatitis Ctreatmentoptions.ValueHealth20,266–272

76Bewtra,M.andJohnson,F.R.(2013)Assessingpatientpreferencesfortreatment optionsandprocessofcareininflammatoryboweldisease:acriticalreviewof quantitativedata.Patient6,241–255

77Finnell,S.M.E.etal.(2012)Applicationofclassicutilitiestopublishedpediatric cost-utilitystudies.Acad.Pediatr.12,219–228

78Mu¨hlbacher,A.C.etal.(2017)Preferencesforantiviraltherapyofchronichepatitis C:adiscretechoiceexperiment.Eur.J.HealthEcon.18,155–165

79Kay,S.andFerreira,A.(2014)Mappingthe25-itemnationaleyeinstitutevisual functioningquestionnaire(NEIVFQ-25)toEQ-5Dutilityscores.Ophthal.Epidemiol. 21,66–78

80Beresniak,A.etal.(2015)Validationoftheunderlyingassumptionsofthe quality-adjustedlife-yearsoutcome:resultsfromtheECHOUTCOMEEuropeanproject. Pharmacoeconomics33,61–69

81Gutknecht,M.etal.(2016)Asystematicreviewonmethodsusedtoevaluatepatient preferencesinpsoriasistreatments.J.Eur.Acad.Dermatol.Venereol.30,1454–1464

82Hughes,D.etal.(2013)RecommendationsfortheMethodologyandVisualisation TechniquestobeUsedintheAssessmentofBenefitandRiskofMedicines.IMI

83Hockley,K.etal.(2013)PatientandPublicInvolvementReport:Recommendationsfor PatientandPublicInvolvementintheAssessmentofBenefitandRiskofMedicines.IMI

84ICH(2016)IntegratedAddendumtoICHE6(R1):GuidelineforGoodClinicalPracticeE6 (R2).InternationalCouncilforHarmonisationofTechnicalRequirementsfor PharmaceuticalsforHumanUse(ICH).ICH

85PublicPolicyCommittee, andInternationalSocietyofPharmacoepidemiology, (2016)Guidelinesforgoodpharmacoepidemiologypractice(GPP).

Pharmacoepidemiol.DrugSaf.25,2–10

86Torgerson,D.J.etal.(1996)Patientpreferencesinrandomisedtrials:threator opportunity?J.HealthServ.Res.Policy1,194–197

87Tervonen,T.etal.(2017)MCDAswingweightinganddiscretechoiceexperiments forelicitationofpatientbenefit-riskpreferences:acriticalassessment.

Pharmacoepidemiol.DrugSaf.26,1483–1491

88Janssen,I.M.etal.(2016)Importanceofhemodialysis-relatedoutcomes: comparisonofratingsbyaself-helpgroup,clinicians,andhealthtechnology assessmentauthorswiththosebyalargereferencegroupofpatients.PatientPrefer. Adherence10,2491–2500

89Tinelli,M.etal.(2012)Whatdeterminespatientpreferencesfortreatinglowrisk basalcellcarcinomawhencomparingsurgeryvsimiquimod?Adiscretechoice experimentsurveyfromtheSINStrial.BMCDermatol.12,19http://dx.doi.org/ 10.1186/1471-5945-12-19

90Gries,K.S.etal.(2016)Preferencesforprostatecanceroutcomes:acomparisonof thepatientperspective,thegeneralpopulationperspective,andapopulationatrisk forprostatecancer.ValueHealth19,218–225

91Katz,E.G.etal.(2016)Physicianandpatientbenefit-riskpreferencesfromtwo randomizedlong-actinginjectableantipsychotictrials.PatientPrefer.Adherence10, 2127–2139

92Svedsater,H.etal.(2013)Qualitativeassessmentofattributesandeaseofuseofthe ELLIPTATM

drypowderinhalerfordeliveryofmaintenancetherapyforasthmaand COPD.BMCPulmon.Med.13,72http://dx.doi.org/10.1186/1471-2466-13-72

93Peay,H.L.etal.(2014)Acommunity-engagedapproachtoquantifyingcaregiver preferencesforthebenefitsandrisksofemergingtherapiesforDuchennemuscular dystrophy.Clin.Ther.36,624–637

94Roy,A.N.etal.(2015)Adiscretechoiceexperimenttoelicitpatientwillingnessto payforattributesoftreatment-inducedsymptomreliefincomorbidinsomnia. Manag.Care24,42–48

95Silverman,S.etal.(2013)Patientweightingofosteoporosismedicationattributes acrossracialandethnicgroups:astudyofosteoporosismedicationpreferences usingconjointanalysis.OsteoporosisInt.24,2067–2077

96Ho,M.P.etal.(2015)Incorporatingpatient-preferenceevidenceintoregulatory decisionmaking.Surg.Endosc.29,2984–2993

97Nafees,B.etal.(2016)Managingneurogenicboweldysfunction:whatdopatients prefer?Adiscretechoiceexperimentofpatientpreferencesfortransanalirrigation andstandardbowelmanagement.PatientPrefer.Adherence10,195–204

98Smith,M.Y.etal.(2016)Patientengagementatatippingpoint—theneedfor culturalchangeacrosspatient,sponsor,andregulatorstakeholders:insightsfrom theDIAconference,‘PatientEngagementinBenefitRiskAssessmentThroughout theLifeCycleofMedicalProducts’.Ther.Innov.Regul.Sci.50,546–553

99Faggioli,G.etal.(2011)Preferencesofpatients,theirfamilycaregiversandvascular surgeonsinthechoiceofabdominalaorticaneurysmstreatmentoptions:the PREFERstudy.Eur.J.Vasc.Endovasc.Surg.42,26–34

100Gonzalez,J.M.etal.(2017)Patientandphysicianpreferencesforanticancerdrugs forthetreatmentofmetastaticcolorectalcancer:adiscrete-choiceexperiment. CancerManag.Res.9,149–158

101Gold,D.T.etal.(2011)Development,reliability,andvalidityofanewpreference andsatisfactionquestionnaire.ValueHealth14,1109–1116

102Stewart,M.J.etal.(2008)Patientandcliniciantreatmentpreferencesdonot moderatetheeffectofexercisetreatmentinchronicwhiplash-associateddisorders. Eur.J.Pain12,879–885

103Johnson,F.R.andZhou,M.(2016)Patientpreferencesinregulatorybenefit-risk assessments:aUSperspective.ValueHealth19,741–745

104Sa´nchezMartı´nez,F.I.,PintoPrades,J.L.,Abella´nPerpin˜ a´n,J.M.,Martı´nezPe´rez,J. E.Theroleofnon-transparentmatchingmethodsinavoidingpreferencereversalsinthe evaluationofhealthoutcomes,Publishedonline.[cited15May2017].Available from:http://www.revecap.com/encuentros/trabajos/s/pdf/193.pdf.

105MacLean,S.etal.(2012)Patientvaluesandpreferencesindecisionmakingfor antithrombotictherapy:asystematicreview:AntithromboticTherapyand PreventionofThrombosis,9thed:AmericanCollegeofChestPhysicians Evidence-BasedClinicalPracticeGuidelines.Chest141(2Suppl),e1S–e23S

106Gagnon,M.P.etal.(2011)Introducingpatients’andthepublic’sperspectivesto healthtechnologyassessment:asystematicreviewofinternationalexperiences. Int.J.Technol.Assess.HealthCare27,31–42

107Kleme,J.etal.(2014)Patientperspectiveinhealthtechnologyassessmentof pharmaceuticalsinFinland.Int.J.Technol.Assess.HealthCare30,306–311

108Ijzerman,M.J.etal.(2012)Acomparisonofanalytichierarchyprocessand conjointanalysismethodsinassessingtreatmentalternativesforstroke rehabilitation.Patient5,45–56

109Janssen,E.M.etal.(2017)Improvingthequalityofdiscrete-choiceexperimentsin health:howcanweassessvalidityandreliability?ExpertRev.Pharmacoecon. OutcomesRes.17,531–542

110Swinburn,P.etal.(2011)Preferencesforantimuscarinictherapyforoveractive bladder.BJUInt.108,868–873

111Eliasson,L.etal.(2017)Evaluationofpsoriasispatients’attitudestoward benefit-riskandtherapeutictrade-offsintheirchoiceoftreatments.PatientPrefer. Adherence11,353–362

112Postmus,D.etal.(2018)Individualtrade-offsbetweenpossiblebenefitsandrisksof cancertreatments:resultsfromastatedpreferencestudywithpatientswith multiplemyeloma.Oncologist23,44–51

113Fraenkel,L.etal.(2017)Subjectivenumeracyandtheinfluenceoforderandamount ofaudibleinformationonperceivedmedicationvalue.Med.Decis.Mak.37,230–238

114vonArx,L.B.etal.(2017)Becarefulwhatyouaskfor:effectsofbenefitdescriptions ondiabetespatients’benefit-risktradeoffpreferences.ValueHealth20,670–678

115Louviere,J.J.(2006)Whatyoudon’tknowmighthurtyou:someunresolvedissuesin thedesign andanalysisof discrete choiceexperiments.Environ.Res.Econ.34, 173–188

116Fischhoff,B.etal.(2011)CommunicatingRisksandBenefits:AnEvidence-BasedUser’s Guide.FDA

117EUPATI(2018)WhatisEUPATI?EUPATI

www.drugdiscoverytoday.com 11

Reviews

FOUNDA

TION

118Anon(2005)CriteriaforJudgingtheQualityofPatientDecisionAids.International PatientDecisionAidStandards

119Bowling,A.andEbrahim,S.(2001)Measuringpatients’preferencesfortreatment andperceptionsofrisk.Qual.HealthCare10(Suppl.1),i2–i8

120Howard,K.andSalkeld,G.(2009)Doesattributeframingindiscretechoice experimentsinfluencewillingnesstopay?Resultsfromadiscretechoice experimentinscreeningforcolorectalcancer.ValueHealth12,354–363

121Mu¨hlbacher,A.andBethge,S.(2016)Whatmattersintype2diabetesmellitusoral treatment?Adiscretechoiceexperimenttoevaluatepatientpreferences.Eur.J. HealthEcon.17,1125–2240

122EMA(2014)RegulatoryandMethodologicalStandardstoImproveBenefit–Risk EvaluationofMedicines.EMA

123HernandezAlava,M.etal.(2012)Tailsfromthepeakdistrict:adjustedlimited dependentvariablemixturemodelsofEQ-5Dquestionnairehealthstateutility values.ValueHealth15,550–561

124Brennan,D.F.(1995)Patientpreferences.Ann.Emerg.Med.26,240–241

125Brooker,A.S.etal.(2013)Quantitativepatientpreferenceevidenceforhealth technologyassessment:acasestudy.Int.J.Technol.Assess.HealthCare29,290–300

126Ryan,M.etal.(2017)UsingDiscreteChoiceExperimentsinHealthEconomics: TheoreticalandPracticalIssues.UniversityofAberdeen

127ICH(2016)ICHHarmonisedGuideline:RevisionofM4EGuidelineonEnhancingthe FormatandStructureofBenefit-RiskInformationinICH.ICH

128Brazier,J.E.etal.(2012)Developingandtestingmethodsforderiving preference-basedmeasuresofhealthfromcondition-specificmeasures(andother patient-basedmeasuresofoutcome).HealthTechnol.Assess.16,1–114

129Danner,M.etal.(2011)Integratingpatients’viewsintohealthtechnology assessment:analytichierarchyprocess(AHP)asamethodtoelicitpatient preferences.Int.J.Technol.Assess.HealthCare27,369–375

12 www.drugdiscoverytoday.com Reviews
FOUNDA TION REVIEW