ContentslistsavailableatScienceDirect
Health
Policy
jo u rn al h om ep a g e :w w w . e l s e v i e r . c o m / l o c a t e / h e a l t h p o l
An
overview
of
critical
decision-points
in
the
medical
product
lifecycle:
Where
to
include
patient
preference
information
in
the
decision-making
process?
Chiara
Whichello
a,∗,1,
Karin
Schölin
Bywall
b,1,
Jonathan
Mauer
c,
Stephen
Watt
d,
Irina
Cleemput
e,
Cathy
Anne
Pinto
f,
Eline
van
Overbeeke
g,
Isabelle
Huys
g,
Esther
W.
de
Bekker-Grob
a,
Richard
Hermann
h,
Jorien
Veldwijk
aaErasmusSchoolofHealthPolicy&ManagementandErasmusChoiceModellingCentre,ErasmusUniversityRotterdam,P.O.Box1738,3000DRRotterdam, TheNetherlands
bCentreforResearchEthics&Bioethics,UppsalaUniversity,Uppsala,Sweden,Husargatan3,Box564,75237Uppsala,Sweden cPfizer,Inc.,500ArcolaRoad,19426Collegeville,PA,USA
dPfizerInc.,235East42ndStreet,10017NewYork,NY,USA
eBelgianHealthCareKnowledgeCentre(KCE),Doorbuilding(10thfloor),Kruidtuinlaan55,1000Brussels,Belgium fMerck&Co.,Inc.,Kenilworth,NJ,USA
gClincialPharmacologyandPharmacotherapy,UniversityofLeuven,Herestraat49-Box521,3000Leuven,Belgium hAstraZenecaPharmaceuticalsL.P,OneMedImmuneWay,20878Gaithersburg,MD,USA
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received12September2019 Receivedinrevisedform9June2020 Accepted20July2020
Keywords: Patientpreferences
Patientpreferenceinformation Decision-Making
HTAdecision-making Regulatorydecision-making Industrydecision-making
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r
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Background:Patientpreference(PP)informationisnoteffectivelyintegratedindecision-making through-outthemedicalproductlifecycle(MPLC),despitehavingthepotentialtoimprovepatients’healthcare options.Afirststeprequiresanunderstandingofexistingprocessesanddecision-pointstoknowhowto incorporatePPinformationinordertoimprovepatient-centricdecision-making.
Objectives:Theaimswereto:1)identifythedecision-makingprocessesanddecision-pointsthroughout theMPLCforindustry,regulatoryauthorities,andreimbursement/HTA,and2)determinewhich decision-pointscanpotentiallyincludePPinformation.
Methods:Ascopingliteraturereviewwasconductedusingfivescientificdatabases.Semi-structured inter-viewswereconductedwithrepresentativesfromsevenEuropeancountriesandtheUS,includingindustry (n=24),regulatoryauthorities(n=23),reimbursement/HTA(n=23).Finally,validationmeetingswith keystakeholders(n=11)wereconducted.
Results:Sixcritical decision-pointswereidentifiedforindustrydecision-making,three forregulatory decision-making,andsixforreimbursement/HTAdecision-making.StakeholdergroupsagreedthatPP infor-mationisnotsystematicallyintegrated,eitherasobligatoryinformationorpre-setcriteria,butwould benefitallthelisteddecision-pointsinthefuture.
Conclusion:Currently,PPinformationisnotconsideredasobligatoryinformationtosubmitforanyof theMPLCdecision-points.However,PPinformationisconsideredanimportantcomponentbymost stakeholderstoinformfuturedecision-makingacrosstheMPLC.TheintegrationofPPinformationinto 15identifieddecision-pointsneedscontinueddiscussionandcollaborationbetweenstakeholders.
©2020TheAuthor(s).PublishedbyElsevierB.V.ThisisanopenaccessarticleundertheCCBYlicense (http://creativecommons.org/licenses/by/4.0/).
∗ Correspondingauthor.
E-mailaddresses:whichello@eshpm.eur.nl(C.Whichello),Karin.bywall@crb.uu.se(K.S.Bywall),jonathan.mauer@pfizer.com(J.Mauer),
stephen.watt@pfizer.com(W.Stephen),Irina.cleemput@kce.fgov.be(I.Cleemput),cathy.pinto@merck.com(C.A.Pinto),eline.vanoverbeeke@kuleuven.be(E.vanOverbeeke), Isabelle.huys@kuleuven.be(I.Huys),Debekker-grob@eshpm.eur.nl(E.W.deBekker-Grob),Richard.hermann@astrazeneca.com(R.Hermann),veldwijk@eshpm.eur.nl (J.Veldwijk).
1 Sharedfirstauthorship
https://doi.org/10.1016/j.healthpol.2020.07.007
1. Introduction
Thepharmaceuticalindustry,regulatoryauthorities,and reim-bursement/HealthTechnologyAssessment(HTA)bodies(including payers)generallyagreethattheuseofpatientpreference infor-mation(PPinformation)couldbebeneficial todecision-making throughoutthemedicalproductlifecycle(MPLC)inEuropeandthe US[1–3].PPinformationisdefinedasinformationresultingfrom “assessmentsoftherelativedesirabilityoracceptabilitytopatients of specified alternatives or choices among outcomes or other attributesthatdifferamongalternativehealthinterventions”[4]. PPinformationcanbedeterminedthroughqualitativeand quan-titativemethods, and includes therelative importance of what mattersmosttopatients,enablingtheexaminationoftrade-offs that patientsarewilling tomake between benefitsand harms. Therefore,PPinformationisdifferenttopatientreportedoutcomes (PROs),butitcanprovidethroughwhichoutcomescanbe priori-tised.Itnotonlycapturespatientneedsandconcerns,butitalso providesasignificantopportunityforpatientstoexpressimportant preferencesandhavethisinformationincorporatedinto decision-making[5]. Patient-centric decision-making not only results in bettertransparencyandaccountabilityofmedicalproduct develop-ment,butmayalsoresultinbetteroutcomesforpatients,improved qualityofresearchandstudyoutcomesmorerelevanttopatients, moreproductsdevelopedinlinewithpatients’needs,and increas-ingoverallwell-being[5–7].
Before PP information can be formally integrated within decision-making,aclearoverviewofthecurrentdecision-making processes,includingcriticaldecision-points,alongtheMPLCmust beformulated.We definea criticaldecision-point asan identi-fiedfixedmomentwhereadecisioninfluencesthecourseofthe medicinedevelopment,authorisationorreimbursementprocess. Theseareessentially“go-or-no-go”decisions.Therefore,thisstudy willbefocusingonstakeholdersthatdirectlyaffectthe progres-sionofmedicalproductsalongtheMPLC(i.e.industry,regulatory authorities,andreimbursement/HTA).Inaddition,itneedstobe determinedwhichdecisionscanpotentiallybenefitfromthe inclu-sionofPPinformation.Todate,thereisnoconsolidated,published overviewconcerningthecriticaldecision-pointsalongtheMPLC forthedifferentstakeholdersinvolved,aswellashow,andbased onwhatinformationandcriteria,thesestakeholdersmaketheir decisions.
The current study aims to: 1) identifythe decision-making processes and critical decision-pointsthroughout the MPLC for industry,regulatoryauthorities,andreimbursement/HTA,and2) determinewhichofthesecriticaldecision-pointshavethepotential toincludePPinformation.
2. Materialsandmethods
Afour-stepapproachwasusedinthisstudy,includingascoping literaturereview(step1),semi-structuredinterviews(step3),and validationmeetings(steps2&4)(seeAppendixVII).
2.1. Scopingliteraturereview
Instep1,aliteraturesearchwasperformedtoidentifyrelevant whiteandgreyliterature[8].Whiteliteratureincludedrelevant, peer-reviewedarticlespublishedinscientific/academicjournals. Theliteraturewasretrievedviafivescientific databases: Guide-linesInternationalNetwork,Embase,PubMed(includingCochrane CentralandMedline),PsycINFOandEconLit.Searchqueries con-sistedof MeSHterms and freetextwords inorder tooptimise thebreadthofresults(e.g.decisionmaking,patient preference, decision-point,anddruglifecycle).Thedatabasesweresearched
forrelevanttitlesandabstractspublishedbetweenJanuary2011 andApril2017.Greyliteraturewascollectedinordertoincorporate themostcurrentinformationandknowledgewrittenbyindustry, regulatoryauthorities,andreimbursement/HTA.
Threeresearchers(CW,KSB,JV)independentlyreviewedthe abstracts of the literature and applied inclusion and exclusion criteria. Inclusion criteria were: conceptual or applied descrip-tionsof(i)decisionsmadebyindustryorregulatoryauthorities orreimbursement/HTArelatedtomedicalproducts;(ii)theuseof patientpreferencesindecision-makingbyindustryorregulatory authorities or reimbursement/HTA regarding medical products. Thefollowingexclusioncriteriawereapplied:(i)notwrittenin English, (ii) no full text article available, (iii) published before 2011,(iv)countryoutsideof US/EUbecauseof thefocus onEU decision-processesanddifferencescomparedtotheUS,(v) confer-enceabstracts,conferencenotes,bookreviews,andpresentations. Dataextractionwasconductedbyfourresearchers(CW,KSB,JV, SW),byassessingthefulltextsofwhiteandgreyliteraturebasedon thesameinclusionandexclusioncriteriaastheabstractscreening. Throughthisprocess,keydecision-pointsanddecisionprocesses wereidentifiedforeachstakeholdergroup,makingapreliminary listtobeconfirmedinthenextstepsofthemethodology.
2.2. Semi-structuredinterviews
In step 3, interviewees representing one of the stakeholder groups(industry,regulatoryauthoritiesandreimbursement/HTA) wererecruitedviapurposivesamplingandsnowballing(i.e. ask-ingconfirmedintervieweestosuggestothers).Theinterviewswere conductedbetweenApril2017andAugust2017inSweden,theUK, Italy,theNetherlands,France,GermanyandRomaniawhich pro-videdrepresentationfromalldifferentcardinalregionsinEurope. InterviewswerealsoconductedintheUStoexamineperspectives outsidetheEU.Potentialintervieweesreceivedinformationonthe studyandprovidedinformedconsent.Thisstudywasapprovedby theEthicsCommitteesineachofthecountrieswhereinterviews wereconducted.
Aninterviewguide wasdevelopedbased ontopicsthat had emergedfromtheliteraturereviewdetailedinstep1.Interviews wereconductedbyfiveresearchersandtookapproximatelyone hour and were conducted via telephone or face-to-face. Inter-viewswereconductedinEnglish,audiorecorded,andtranscribed verbatim.Transcriptswereanalysedthroughframeworkanalysis [9]usingNVivosoftware[10],where thedatawereinterpreted forconsensusesandobservationsacrossthestakeholdergroups, which createdthematic ‘codes’. Aftera ‘familiarisation process’ [9]inwhichthecoders(CW,KSB,RH)examinedtranscriptsfrom eachstakeholdergroup,open-codingwasappliedtothree tran-scripts,along withdeductive codes reflecting key stages ofthe MPLCidentifiedfromthescopingreview.Thesuccessofthesecodes encapsulatingthethemeswithineachtranscriptwerecompared, andthenservedasthebasisofthecodesthatwerethenapplied totheentire70transcriptsample.Thesectionsoftranscriptthat correspondedtoacodewereindexedintoachartthatidentified thecoded materialforeachparticipant’sstakeholdergroupand country.Thesechartswereanalysedbyfourresearchers(CW,KSB, JM,SW)forcommonattitudesandopinionsoftherespondents, comparingsimilaritiesbetweenstakeholdergroupsandcountries. 2.3. Validationmeetings
In steps 2 and 4, meetings with representatives from each ofthestakeholdergroups(industry,regulatoryauthorities, reim-bursement/HTA)werescheduledtovalidatetheresultsfromboth theliteraturereviewand thesemi-structuredinterviews.These stakeholderrepresentatives,fromboththeEUandUS,werenot
participantsin thesemi-structured interviews.During thisstep, informationwasretrievedondifferencesindecision-making pro-cessesbetweenEUandUS.Thefirstroundofmeetingswitheach stakeholdergroup(onemeetingwithtwoindustryrepresentatives, fourmeetingswithfourregulatoryrepresentatives,onemeeting withonereimbursement/HTArepresentative)wasconductedafter thescopingliteraturereviewtoconfirmtheidentified decision-makingprocesses.Thesecond roundof separatemeetingswith eachstakeholdergroup(twomeetingswithtwoindustry repre-sentatives,twomeetingswithtworegulatoryrepresentatives,one meetingwithtworeimbursement/HTArepresentatives)tookplace afterthesemi-structuredinterviewstodiscusstheresultsofthe interviews.
3. Results
Duringstep1,723recordswerescreenedontitle,abstract,or tableofcontents(seeAppendixVII).Fromthese,223recordswere selectedforfull-textscreening(ofwhich32related toindustry, 89toregulatoryauthorities,and102toreimbursement/HTA)and 57recordswereselectedfromthefulltextscreening(ofwhich 10 related to industry, 14 to regulatory authorities and 33 to reimbursement/HTA).Generaldecision processes,chronologyof decision-making,andtype ofinformationrequiredduringthese processes,wasextracted.Notallworksaredirectlycitedinthe results,becausemostarticlesnamedthedecision-pointsbutdid notdescribethecontentof thedecision-points, ortherequired information,indetail.
Duringstep2,sevenvalidationmeetingswereconducted(n=2 industry,n=4regulatory,n=1reimbursement/HTA).The decision-making processes from step 1 were confirmed,the differences betweenEUandUSdecision-makingprocesseswasexamined.
Duringstep3,70 interviewswereconductedwith represen-tatives from industry (n = 24), regulatory authorities (n = 23) (includingUSregulators,European-levelregulators,andnational EUregulators)andreimbursement/HTA(n=23).Inthisstep,six industrydecision-points,fourregulatorydecision-points,andsix reimbursement/HTAdecisionpointswereidentified.
Duringstep4,sixvalidationmeetingswereconducted(n=2 industry,n=2regulatory,n=2reimbursement/HTA).The decision-pointsidentified in step 3 wereconfirmed, and one regulatory decision-pointwasremoved.Expertsconfirmedthat‘orphan des-ignation’isadesignationprocesswhichcreatesseparateprocesses andtimelines,andnotadecision-point(go-or-no-godecision)that existsforeverymedicalproduct.
Conclusively, six industry decision-points, three regulatory decision-points,andsixreimbursement/HTAdecisionpointswere identified.
3.1. Decision-pointswithinindustrydecision-making
Weidentifiedsixcriticaldecision-pointsintheindustry pro-cesses (Fig. 1). These decision-points start immediately after pre-discovery, and run through the MPLC, with the final decision-point concluding in post-approval. In general,product developmentanddecisionswhethertoproceedareinthecontext ofregulatoryrequirements,whichmaydifferbetweenproductsor regulatorydesignations(e.g.orphanstatus).Themostcommonly followeddecision-pointsaredescribedbelow.
Select&prioritisetargetsandleads:thisdecision-pointis gen-erallybasedonbiologydatasuchastheextenttowhichhumanand animaldiseasepathologyoverlap.Thecandidateselectiondecision isbasedonanimalefficacyandtoxicity,pharmacology, pharma-cokinetics,anddrugmetabolismcharacterisedusinginvitroassays andefficacyusinganimal modelsofdiseaseorinvitrotests on
humancellsortissue[11,12].Thesemi-structuredinterviewswith industryrepresentativesintheEUandUSrevealedapositive per-spectivetowardspatientpreferenceinformation(PPinformation) inearlystages oftheMPLC.AnEUinterviewee suggestedearly integrationofPPinformationwillhelp“[identify]fieldsinwhich newtherapies,whetheritbemedicaldevicesormedicines,shouldbe developed”(Netherlands).
Prioritise studies (Early clinical development): data and conclusionsonwhethertoenterclinicaldevelopmentare peer-reviewedbytechnicalandoperationalmanagementcommittees thatverifysafety,quality,regulatorydocumentationandresource availability. Thedecisiontoenter clinicaldevelopmentisbased onpre-clinicalevidencesupportingconfidenceinthebiologic tar-get,literaturedata,manufacturingdata,operationalfeasibilityand verificationthatthemedicinecandidatecouldmeettheneedsof thetarget productprofile.Representatives fromtheUS andEU suggestedthatcompanieswhichroutinelyengagepatientsbetter informandcommunicatetheirdecisions.Onerepresentativefrom EUsaid“patientpreferenceon,forexample,targetproductprofiles [...]informgo/no-go[development]decisions”(UK).
Prioritiseassets(Earlyclinicaldevelopment):dataand con-clusionsonwhethertoenterPhase2ofclinicaldevelopmentare peerreviewedbytechnicalandoperatingmanagement commit-teestoensuresafety,qualityandfavourablemedicalbenefit-risk tosupportcontinueddevelopmentinalargerclinicaltrial[14].The decisiontoenterPhase2developmentisbasedonevidencethat themedicineishavingapharmacologiceffectonthetargetorgan ofnormalhealthvolunteers(orinpatientsforoncologyproducts) operationalfeasibility, and confidencethemedicine candidate’s performancecouldhitthetargetproductprofile[13,14].Duringthe interviews,anumberofindustryrepresentativessaidthatPP infor-mationinformstrialsby“look[ing]attheendpointsofyourstudy, definingthem”(Netherlands),byassessing“clinicaltrialfeasibility” (US),andbytranslatingPPinformation“intoanoutcomemeasure” (UK).
Optimise & Prioritise assets (Late clinical development):
data andconclusions onwhetherand how toenter Phase3 of clinicaldevelopmentarepeerreviewedbytechnicaland operat-ingcommitteestoensuresafety,qualityandfavourablemedical benefit-risktosupportcontinueddevelopmentinasubstantially larger Phase 3 patientstudy. The benefit-riskprofile is further developedandmayincluderiskmanagementplanningtomitigate safetyrisksandincreasetheprobabilitythatthebenefit-riskprofile remainspositive[15].Technicalperformanceincludesdatafrom Phase2withsufficientdose-responseevidencetosupportPhase 3dose-selection,safety,qualityandfavourablemedical benefit-risk in the appropriate patient population [13,14]. Widespread PP information integrationbyindustry willimprove healthcare by increasing resource allocation efficiency and by developing productswithstrongervaluepropositions,orasoneEUindustry representativeexplained “betterdecisionswillbetakenand[...] patientvaluewillincrease”(Sweden).
Regulatory Submission & Launch: committeesreview effi-cacy and safety data to ensureevidence supports a favourable medical benefit-riskprofileand plannedlabelclaims.Technical performanceincludesPhase3datafrompivotalregistrationstudies demonstratingefficacyandsafety.Thedecisiontoapplyfor regula-torymarketingauthorisationtypicallyrequires:Phase3technical performancethatsupportsthetargetproductprofile;desiredlabel claims; and commercial opportunityor considerations [13]. An industryrepresentativestatedthatincludingPPinformationin“the dossiersthatyouputtogetherforregulatoryauthoritiesorHTAs[...] providescontexttoeitherthecompanynarrativeorcompany conclu-sionsaroundthedatasets”(UK).
ManageMPLC&Prioritiseopportunities:includesdecisions thataremadeaftercommercialisation.Productsmaybeenhanced
Fig.1.Thecoreindustrydecision-makingprocess,includingthecriticaldecision-points(inblackarrows),alongthemedicalproductlifecycle.
tofurthersatisfymedicalneeds.Ideasmayarisefrommany poten-tialsourcesincludingobservationalstudies(e.g.,tocomplywith regulatorycommitments), investigator-initiatedstudies, patient advisory boards, focus groups, surveys, and structured patient interviews[16].Anumberofrepresentativesidentifiedthevalue ofPPinformationtoinformdecisionsinthepost-approvalsetting, includingreimbursement,comparativeeffectiveness,addressing new safety signals and informing shared-decisions between a patientandtheirhealthcareprovider.AnEUindustry represen-tativesuggestedthat“ifpatientpreferencesaretakenintoaccount, thecosteffectivenessofatherapymightbebetterandreimbursement mightbeeasiertodecideon”(Netherlands).
3.2. Decision-pointswithinregulatorydecision-making
Threecriticaldecision-pointswereidentifiedwithinregulatory decision-making,definedasafixedmomentwhereadecisionis takenthatinfluencesthecourseoftheauthorisationprocess(Fig.2). Theidentifiedcriticaldecision-pointsaresubmissionand valida-tion,scientificopinion,andcommissiondecision.Otherregulatory processes,definedasactivitiesthatdonotneedago-or-no-go deci-sion,butareconductedinordertoinformfuturedecision-points, werealsoidentified(inwhiteinFig.2).Dependingonthe prod-uct,aswellaswhetherthemedicalproductwillgothroughthe centralisedprocedureoftheEMAortheFDA‘sregulatory decision-making,some decision-pointsmayvary. For example, separate processesandtimelinesexistforproductsthataredesignatedto beorphanproductsforrarediseasesorpaediatricproducts.A com-parisonofthedecision-pointsoftheFDAandEMAcanbefoundin Fig.3.
Submission&validationhappenswhencompaniessubmita MarketingAuthorisationApplicationdossierfortheapproval of amedicine.Specifics dependontheapplication: fornew appli-cations,a full dossier(electronic Common Technical Document (eCTD))needstobecompleted,foravariation,newchangesneedto besubmittedonly.Ifapplicable,arenewalconfirmsthatall infor-mationisuptodateandaPeriodicSafetyUpdateReportaddsnew informationtotheoriginaldossier.Formedicinestogothrough toscientificevaluation,submittedmaterialsareassessedfor com-pleteness(eCTD)andtheyhavetomeetallthelegalrequirements [18].RegulatoryrepresentativesintheEUandUSsaidthatthey occasionallygetPPinformationwhenpharmaceuticalcompanies applyforMarketingAuthorisationandthattheiragencysupports thisinformation:“Wegetthemoccasionally,lessfrequentlythanI wouldlike[...].Soifwegetthem,wehavetotakethemintoaccount” (Germany).
Scientificopinionis apositive ornegativerecommendation given by the Committee for Medical Products for Human Use (CHMP), onwhethertoauthorisea medicine basedonthe sci-entific evaluation [17,18]. All information gathered during the
pre-submission is needed to make a scientific opinion, includ-ingacomplete submissiondossier(eCTD).Apositive opinionis issuedwhenapositivebenefit-riskbalance,includingefficacy,is sufficientlydemonstrated and when thedossiermeets alllegal requirements[5].A’summaryofopinion’isimmediatelypublished aftertheopinionissubmittedtotheEuropeanCommission[18]. Duringtheinterviews,regulatoryrepresentativesrecognisedthe valueofincludingpatientsasexpertsindiscussionsthatleadto thescientificopinion.However,representativesinboththeEUand USweresurethattherearenoformalorsystematicallyintegrated protocolsforincludingPPinformationintheregulatoryprocessat thismoment:“Therearenotformalprotocolsforthat,Ithinkmuch yet.ButIthinkthatthatwillbeimportanttoprovide”(US).
Acommission decision,iswhen theEuropeanCommission, grants,refuses, changes,suspends orrevokes marketing autho-risation.Thecommission decision is basedonthe‘summary of opinion’andlegalrequirements[18].Thesummaryisreplacedby afullEuropeanPublicAssessmentReport(EPAR)oncethe Euro-peanCommissionhasdecidedtoapprovemarketingauthorisation ornot [18].Thesafety monitoringandtheongoing benefit-risk assessmentsmightfeedbacktosubmissionandvalidationifthere is;avariation,arenewal,needforaperiodicsafetyupdatereport (PSUR), a referral or switch toOver theCounter (OTC)for the medicine[18].SomeoftherepresentativesinboththeEUandUS expressedalimitedacceptanceforPPinformationandthatthere isaneedforastructuredwaytoincludePPinformationin com-missiondecisions.Onerespondentstated,“Allthesethingsarevery importantbutyouhavetocreateawayofmeasuringtheimpactof takingintoaccountpatientpreference”(Italy).
3.3. Decision-pointswithinreimbursement/HTAdecision-making There are six critical decision-points during the reimburse-ment/HTA decision-making processes (Fig. 4). These include filtration,prioritisation,andappraisal,andalsowhenthesethree decision-pointsare repeated for reassessment. Other HTA pro-cesses,definedasactivitiesthatdonotneedago-or-no-godecision, butareconductedinordertoinformfuturedecision-points,were alsoidentified(inwhiteinFig.4).Theprocess bywhich differ-entcountriesconductthesedecision-pointsisgenerallysimilarin practice,althoughalsodependsonthecountry’sunique health-caresystem[26].EUcountriesoperateunderproceduralrulesand timelinessetbytheEuropeanCommission,although methodolog-icalandproceduraldifferencesexistbetweennationstates[27,28]. IntheUS,healthpayersandorganisations,includingboth commer-cialhealthpayersandgovernmentpayersmaketheirowndecisions regardingreimbursement[29].
The filtration of potential assessment topics is often con-ductedinordertonarrowdownprospectiveassessmenttopicsto amanageablenumber,althoughnotalwaysrelevantto
reimburse-Fig.2. Thecoreregulatorydecision-makingprocess,includingthecriticaldecision-points(inblackarrows),alongthemedicalproductlifecycle.
Fig.3. ComparisonofEMAandFDAdecision-points,includingthecriticaldecision-points(inblackarrows),alongthemedicalproductlifecycle.
Fig.4. ThecoreHTAdecision-makingprocess,includingthecriticaldecision-points(inblackarrows),alongthemedicalproductlifecycle.
ment/HTAbodiesthataddressallmedicines[1,30–32].Medicines thatareexpectedtohavealimitedimpactonthehealthcaresystem orpatientsareconsideredtobealowerpriority.Filtrationselects productsbyapplyingpre-establishedcriteria,whichdonotvary widelyacrosstheEUandNorthAmerica [33].Thecriteriaoften addresswhetherthetechnologyisnewandinnovative,isa modifi-cationofanexistingproduct,orisanexistingproductbeingusedfor anewindication.Furthercriteriaareoftenrelatedtotheassociated diseaseburden;whetherthereareexistingtreatmentsforthe con-dition;theanticipatedclinical,economic,orsocietalimpacts;the appropriatenessforrelevantstakeholdersorhealthcaresystem;or
thetimeframethatitwouldtaketheproducttobecommercialised andincorporatedintopractice[34].
Theprioritisationofpotentialassessmenttopics,ifapplicable totheparticularreimbursement/HTAbody,aimsatdetermining thesignificanceofthefilteredtechnologiesforthehealthcare sys-tem,and deciding which technologies willbe investedin with limitedassessmentresources[35].Filtrationandprioritisationare oftenconductedthroughhorizonscanningorearlyawarenessand alertactivities.IntheUS,thisisoftentheAHRQ(Agencyfor Health-careResearchandQuality),orprivatesectorcompanies[29].The majorityofexplicitcriteriautilisedbyreimbursement/HTA
con-cernpatientgroupsizesandtheburdenofdisease;thepotential clinicalbenefitonmorbidity,mortalityorqualityoflife;thecost oreconomicimpact,bothtothepatientandtostakeholders;social impactincludingethicalorlegalconcerns;theanticipatedspeedof adoption;andtheavailabilityofevidenceoradditionalinputfrom patientgroups[36].However,oneEUrepresentativestatedthat frequently“onepatientissittinginonebigHTAbig[sic] decision-makingbodyandtheydon’tbelieve thembecause –‘oh yeahone singlepatient’”(Germany), indicatingthatone patientmightnot carrymuchweightfordecision-makers.
Afterevidenceisobtainedduringtheassessmentstep,the crit-icaldecision-pointof theappraisal occurs,where theevidence is reviewed and a decision is made regarding reimbursement. Generally,assessmentscollectscientificclinicalandeconomic evi-dence:safetyandefficacyinformation(oftenrelativetoavailable alternatives),clinicaleffectiveness(oftenrelativetoavailable alter-natives), time required for diffusion, costs, or financial impact [30,36,37].Thiscanbeincludedinformofliteraturereviews, clini-calevidencefromcliniciansormanufacturers,cost-effectiveness analysis, estimated QALYs, observational studies, or combined sources.Additionalevidencefrompatientsandpatient organisa-tionscanalsobesubmitted.Theappraisalcommitteecanconsider socialorethicalimpacts,equityissues,theproduct’sdegreeof inno-vation,theburdenofdiseaseandprojectedepidemiologicaltrends, and other patient issues [38]. All stakeholder representatives mentionedthat PPinformation is notrequiredor implemented systematically,withcost-effectiveness and efficacy given prior-ity instead.AnEU representative said,“By the time itcomes to HTAbodiesit’sabittoolatetostartthinkingaboutpatient prefer-ences”(UK).ThereislimitedguidanceforPPinformationinclusion, asanEUrepresentativeindicated,“We don’thaveanything,any explicit criteria [...] that specifies “this is the weight of patient preferenceweshouldtakeinthedecision”(France).Althoughall rep-resentativesaccuratelyunderstoodtheconceptofPPinformation, manyhadamisconceptionthatpatientpreferencesaresufficiently accommodatedthroughQALYs,despitetheircalculationfrequently incorporatingpublicpreferences,andnotpatientpreferences.An EUparticipantdescribed QALYsas“implicit”patientpreferences andstated,“wesupposethatpatientpreferencesareincludedinthis tool”(France).
4. Discussion
Thispaperrepresentsasignificantfirstattempttoidentify15 criticaldecision-pointsfromkeystakeholderswiththeobjective toincorporatepatientpreferenceinformation(PPinformation)in theMPLC.Anoverviewofallidentifiedcriticaldecision-pointsis giveninAppendixVIII.Eachofthecriticaldecision-pointsrequires differentinformation,basedonpre-determineddecisioncriteria, tobesubmittedtothedecision-makers.Adescriptionofthe infor-mationneedsanddecisioncriteriaforeachdecision-pointcanbe foundinAppendixI-III.Somedecisioncriteriaalreadyallowfor PPinformationtobeincorporatedmorereadilythanothers,but PPinformation iscurrentlynot routinelyconsideredone ofthe requirementsfordecision-making.However,withinallstakeholder groupsthishasbeenrecognisedasavaluablecomponenttoinform decisionmakingacrosstheMPLCinthenearfuture.
In general, industry representatives spoke positively about increasingtheintegrationofPPinformation toinform decision-makingthroughouttheMPLC, especiallyin thedevelopmentof a new medicines since it provides context which informs and helps communicate their decisions. Regulatory representatives expressed that there is limited acceptance for PP information withintheirdecision-making processes since there is currently norecognisednorstructuredwaytoinclude and/orvaluesuch
information.However,someregulatorsstatedthatPPinformation couldbemoreimportantinspecificsituations,likeforrare dis-eases.The EMAand FDAvaluetheperspectivesofpatientsand arecommittedtoencouragingpatientinputthroughoutmedicine developmentandproductreviews[4,39,40].BothEMAandFDA playanimportantroleinprovidingguidancetoindustryand reim-bursement/HTA on how to best incorporate PP information in futureassessments[4,39].Allreimbursement/HTArepresentatives agreedthatPPinformationissometimesincludedinassessment dossiers, but not required. According to representatives from EUPATI(EuropeanPatientsAcademyonTherapeuticInnovation) andHTAi(HealthTechnologyAssessmentinternational), mecha-nismsexisttocollectpreferencesfrompatientsthathelpidentify and select potential reimbursement/HTA topics that are most importantorpressing.
Greaterdiscussionandcollaborationisrequiredbetweenkey stakeholders, especially regulators and reimbursement/HTA, in ordertoconsolidateeffortstointegratePPinformation.Despite PPinformationhavingthepotentialtobeintegratedatnumerous stagesoftheMPLC,therestillarevariousbarrierspreventingits inclusion.TheintegrationofPPinformationintoindustry decision-makingappearsreadilyfeasible,whereasreimbursement/HTAand regulatoryauthoritiesfirstneedtodecidehowmuchweightshould begiventoPPinformationcomparedtootherrequired informa-tion.Althoughnottheobjectiveofthispaper,timelines,budgets, andotherissuesoffeasibility(e.g.,methodselection)needtobe appraisedandresolvedbythesestakeholdersbeforePP informa-tioncanbeintegrated.Recommendationsareneededtoinformall decision-makersabouthowbesttocapturepatientpreferences, whichmethodstouse,whoshouldbestconductpatientpreference studiesinordertoavoidpotentialbias,howtointerprettheresults, andsatisfyparticulardecisioncriteriaforeachdecision-point.It wasalsonot theobjective ofthisstudytodeterminewherePP informationshouldbeintegrated,orassessatwhichdecision-points itwouldbemorevaluable.However,identifyingdecision-points wherePPinformationcanbeintegratedservesasanimportantfirst step.
Ourresultsfocusedonmedicinesinsteadofmedicaldevices, althoughthelatteraddsotherimportantdimensionsandnuances tothisdiscussion.Withinindustry,medicaldevicedevelopment ishighlyvariablewithdifferentcompanyprocedures,depending onregulatoryauthorities’assignedrisklevelandtheintendeduse ofthedevice.However,decisionsaregovernedbythesame prin-ciplesas medicinedevelopment.High risk-levelmedicaldevice developmentcanbeanalogoustomedicinedecision-makingfrom PhaseIIIonwards[17].Forreimbursement/HTAintheEU,most internationalguidelines for economicevaluation are writtento be applicable to both medicines and medical devices. Some EU countriesappraisemedical devices through specialist reim-bursementagencies,separatefrommedicines. TheUSappraises medicaldevicessimilartomedicines,buthasseparateprocesses: privateandgovernmentpayersdecideuponreimbursement deci-sionsofmedicaldevicesbyconductingatechnologyassessment whichislargelydependentonclinicalimpactorutilityand cost-effectiveness[29].Thestarkestdifferencebetweenmedicinesand medical devices occurs during regulatory decision-making. All devicesareclassifiedbasedontherisklevel.Aclinicalinvestigation canbeassignedandapprovedbytheapplicableauthoritybefore submission.ForalldevicesinEU,aEuropeanCEMarking Certifi-cateisissuedforthedeviceaftersuccessfulcompletionofaNotified Bodyaudit[18].IntheUS,theprobablebenefitsshouldoutweigh theriskswithoversightfromanInstitutionalReviewBoardoran appropriatelocalcommittee[22].CurrentliteraturesuggestsPP informationshouldbeseenasadditionaldatainthedevelopment andsubmissionofmedicaldevices[23–25].
4.1. Strengthsandweaknesses
Thisstudyincludedacomprehensivefour-stepapproachwhere internationalrepresentatives(n=70)fromallthethreestakeholder groupsin theMPLCwereincluded,creatinga novelandhighly representativeoverview thathasnot beenoutlinedin previous literature.Thescopingliteraturereviewincludedgreyliterature whichenrichedthecollectedinformationwithcurrentknowledge andpractices.TheliteraturereviewonlyincludedEnglishpapers anddocuments,whichcouldbeapotentiallimitation.However, thevalidationmeetingsconfirmedthefindingsofboththe litera-turereviewandthesemi-structuredinterviews,whileclarifying differences betweenEU and US. Apotential limitationwasthe snowballingrecruitmenttechniqueoftheinterviewees,the major-ityof whomwerefoundthrough connectionswiththePREFER consortium,whichmayinadvertentlyintroduceasamplingbias. Someparticipantsmayhavewantedtoparticipatebecausethey alreadyfoundthetopicinteresting orvaluable.Inaddition,five interviewersconductedtheinterviewsineightdifferentcountries, meaningtherecouldbevariationintheconductoftheinterviews. Weexpectthisvariationtobeminimal,however,becauseall inter-viewersusedthesameinterviewguideandinstructionmanual. ThisstudyexaminedthreestakeholdersdirectlyinvolvedwithPP informationintegrationbecauseitwasfocusingonpolicyandMPLC decision-making. However,theperspectivesofpatients, patient organisations, academics, clinicians,and otherstakeholders are alsovitalinthesuccessfuluseandintegrationofPPinformation.
5. Conclusion
Patientpreference(PP)informationiscurrentlynotroutinely consideredoneoftherequirementsfordecision-making.With sup-portalreadybeinggeneratedbyallthesestakeholders,thisstudy providesanoverviewof15decision-pointswiththepotentialto includePPinformation.Thisroadmap,combinedwithcontinued discussionbetween key stakeholders,is needed to successfully implementPPinformationintodecision-making,andstrengthen acrucialpathforwardintopatient-centrichealthcare.
DeclarationofCompetingInterest
ThePatientPreferencesinBenefit-RiskAssessmentsduringthe DrugLifeCycle(PREFER)projecthasreceivedfundingfromthe InnovativeMedicinesInitiative2 JointUndertakingunder grant agreementNo 115966. ThisJoint Undertaking receivessupport fromtheEuropeanUnion’sHorizon2020researchandinnovation programmeandEFPIA.Thistextanditscontentsreflectthe PRE-FERproject’sviewandnottheviewofIMI,theEuropeanUnionor EFPIA.JMandSWareemployeesofPfizer,Inc.CAPisanemployee ofMerck&Co,Inc.(Kenilworth,NJ,USA),andisastockholderin thiscompany.RHisanemployeeofAstraZeneca.Allotherauthors havenocompetingintereststodeclare.
Acknowledgements
This work received support from the EU/EFPIA Innovative MedicinesInitiative[2]JointUndertakingPREFERgrantn◦115966. Informedconsent wasobtainedfromallindividual participants includedin thestudy.Authorswould liketothankthePREFER consortium.Thank you Rosanne Janssens (KULeuven)for con-tributingtotheinterviewsandtheliteraturesearchand Selena Russo(Institute ofEuropeanOncology,Milano)for contributing totheinterviews.AuthorswouldalsoliketothankMario Men-doza(Pfizer),SuchitraIyer(Agency forHealthcareResearchand Quality), Harald Enzmann(EMA),Francesco Pignatti (EMA) and
Iordanis Gravanis (EMA), Telba Irony (FDA),Laura Lee Johnson (FDA),AninditaSaha(FDA),FrankBreitenbücher(TÜVRheinland LGAProductsGmbH),andTomasByström(SwedishMedical Prod-uctAgency)forparticipatinginvalidationinterviews.Wewould liketothankJudithGulpers(ErasmusUniversityRotterdam)for assistancewiththeliteraturesearch.ThankyoutoFilipMussen (Janssen Research & Development), Mats G Hansson (Uppsala University),UlrikKihlbom(UppsalaUniversity),BennettLevitan (JanssenResearch&Development),and JuhaeriJuhaeri(Sanofi), forthethoroughreviewofthemanuscript.
AppendixA. Supplementarydata
Supplementarymaterialrelatedtothisarticlecanbefound,in theonlineversion,atdoi:https://doi.org/10.1016/j.healthpol.2020. 07.007.
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