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Implementingadaptivepathways-decisionpointsandresourceimplications

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OriginalTitleforreference:

Decisionpointsincurrentvs.futureprocessesbystakeholdergroups,andresourceimplicationsforaroadmapforimplementation

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ReportofD3.02

Sept2017

IMI’sADAPTSMARTisaCoordinationandSupportAction(CSA)intendedtodeliveraseries of options/recommendations to ensure thatMedicine Adaptive Pathways toPatients(MAPPs)becomesactionable.Accordingly,thisdocumentisaworkingdraftof the collective input fromworking group D3.02. It should not be considered asconfirmationofpolicyorendorsementofthepresentedconceptsbytheparticipatingindividualsororganisations.

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ContentsContents.......................................................................................................................21.ListofAbbreviations................................................................................................32.Executivesummary..................................................................................................43.Introduction.............................................................................................................54.WorkingMethod.....................................................................................................74.1Background.........................................................................................................8

5. Results................................................................................................................105.1. Questionsraisedbyallcategoriesofstakeholders.......................................105.1.1. Definitionandprioritizationofunmetneed............................................105.1.2. Datasourcesforevidencegeneration.....................................................115.1.3. Agreementongoalsandexpectations.....................................................115.1.4. Time,humanresourceandorganisationalgovernance...........................135.1.5. Specificexpertiseandexperience............................................................135.1.6. Numberofavailableexpertsandaccountability.....................................145.1.7. Stakeholderrepresentation.....................................................................14

5.2. Questionsraisedbyaspecificcategoryofstakeholder................................155.2.1. PatientandPatientorganisations............................................................155.2.2. Healthcareprofessionals..........................................................................155.2.3. Medicinedevelopers................................................................................165.2.4. Pricingandreimbursementauthorities...................................................175.2.5. Regulators................................................................................................17

6.Recommendationsandoptionsforfutureworkandnextsteps.........................177.Conclusion..............................................................................................................19APPENDIXA...............................................................................................................21APPENDIXB...............................................................................................................23APPENDIXC................................................................................................................23

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1.ListofAbbreviationsAA–AcceleratedAssessment

ADAPTSMART-AcceleratedDevelopmentofAppropriatePatientTherapies:aSustainable,Multi-stakeholderApproachfromResearchtoTreatment-outcomesCMA–ConditionalMarketingAuthorisationEMA–EuropeanMedicinesAgencyHTA–HealthtechnologyassessorMA-MarketingauthorisationMAA–MarketingauthorisationapplicationMAPPs–MedicinesAdaptivePathwaystoPatientsMEAs–ManagedentryagreementsPRIME–PRIorityMEdicinePRO–PatientreportedoutcomePSA–ParallelScientificAdviceRCT–RandomisedcontrolledtrialRWD-RealworlddataRWE–RealworldevidenceSA–ScientificadviceEUneHTA–EuropeanNetworkofHTAsEAMS–EarlyaccesstoMedicineSchemeMoCA-MechanismofcoordinatedAccessonPharmaceuticalsinitiativeSAG-ScientificAdvisoryGroup(EMA)MCDA-Multi-criteriadecisionanalysisEPF–EuropeanPatient’sForumEURORDIS-EuropeanOrganisationforRareDiseases

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2.Executivesummary

The introductionofanewconcept introducesnewdynamicstowhichthe involvedstakeholders need to adapt.When considering the feasibility and practicalities ofbeing involved in an adaptive pathway to medicines - which includes multi-stakeholder interactions, iterativecyclesofdevelopmentandassessment,and longterm real-world data (RWD) collection - each stakeholder must have a clearunderstandingoftheirremit(currentornew),thetypeofinputrequestedfromthem(adviceordecisions),andtheappropriateresourcesneeded.Atpresentitisunlikelythateachstakeholderwillhavetherequiredcapacitiessuchastime, finance and remit, or capabilities such as specific expertise, to be an activeparticipantinMAPPs.Therefore,theviewsofeachstakeholderontheresourcestheywouldneedtoengageinMAPPsweregatheredthroughajointeffortbetweenD2.05(Seamless pathway) and D3.02 (Decision points) through consensus building andworkshops. Being part of a multi-stakeholder initiative in adaptive pathways requires somespecific knowledge of basic research, clinical development and regulatoryrequirementssuchas;• Science:Diseaseandproduct-specificknowledge.• Processes: Understanding of theMAPPs concept, regulatory tools (such asparallel scientific advice and conditional marketing authorisations), pricing andreimbursement mechanisms, cost effectiveness assessment, managed entryagreements,andprescriptioncontroltoolsandmeasures.• Methodologies: Clinical trial design, data analysis, real world evidencegeneration,andsmallpopulationstudies.The recommendations presented in this document should always be read incombinationwiththeseamlesspathwayreport(D2.05)asitbuildsonthekeydecisionpointsidentifiedinthatdocument.Theremitsofeachstakeholderremain,butnewrolesareemergingand themost impactedstakeholders, in termsofnewresourceneedsandcapacitytomobilizethemeffectively,wereconsideredtobepricingandreimbursementauthorities(includingHTA),patients,andhealthcareproviders(HCP).

The multiple Member State-specific remits and structure for pricing andreimbursementauthoritiesareverychallengingtomapindetail.Theyarenormallynot involved inearlydiscussions,and thecentralizedandbroadconceptofMAPPsmaynotbeapplicableacrossallMemberStates.NewinitiativeslikethejointEMAandEuropeanNetworkofHTAs(EuNeHTA)platformmaybeveryimportantinestablishingcoordinatedadviceondevelopmentplansforearlyscientificadviceandpost-launchevidencegeneration.

Patient involvement is often voluntary. A mechanism to further support,educate,andexpandtheirinvolvementneedstobeconsidered,includinghowbesttoprovidefunding.Streamliningandprioritisinginvolvementviaacentralizedbrokerlikethe European Patients’ Forum (EPF) or European Organisation for Rare Diseases(EURORDIS)orumbrellaorganisationscouldhelp.

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Healthcare professionals would need knowledge on the MAPPs concept,instructions on how to optimise realworld data collection in clinical practice, andspecificinformationontheproductinquestion.Thiscouldbeimplementedviariskmanagement plans or other tools, and co-ordinated through European Referencenetworksorothercompetentbodies.

For the adaptive pathway to become an operational multi-stakeholder tool formedicinedevelopment,werecommendtofurtherexplore3keycomponents:i)Thepoliticalmandateforstakeholdersinmemberstatestoengageinsomeadvisingrole,toenablepatient-centredmedicinedevelopment;ii)Leveragingexistingoverarchingplatformstostreamlineresources,expertiseandknowledgethatwilladvanceMAPPscapacitybuildingforallstakeholders;and iii)Brokertrustbetweenstakeholdersbyexploringopportunitiesandmethodstoensurestakeholdersexecute,overtime,ontheircommitmentswithoutbeingboundbyrequeststhatturnouttobeunreasonableorunfeasible.

3.Introduction

ADAPTSMARTisamulti-stakeholderconsortiumthatwassetupasaCoordinationand Support Action under the EU Innovative Medicines Initiative 2 (IMI2). Theobjective of ADAPT SMART is to establish an enabling platform and engage in adialogue with relevant stakeholders for the coordination of Medicines AdaptivePathway for Patients (MAPPs) related activities. The ADAPT SMART consortiumcomprises all relevant stakeholders in the healthcare ecosystem: patients,academics/providers,medicinedevelopersmainlyrepresentedbytheresearchbasedindustry,regulators,andhealthtechnologyassessmentbodies.SomeEUpayersandpayerorganisationsarewillingtoengageinconstructivedialoguewiththeconsortium(althoughnotasformalpartners)1.

TheconceptofMAPPscentreson3keyfacets;i)aprospectivelyplannedapproachtomedicine development through early multi-stakeholder dialogue; ii) interactivedevelopmentviaapproval instages,confirmingpositivebenefit:risk,andcyclesofevidencegenerationandassessment;andiii)theuseofrealworldevidence(RWE)tosupplementdatafromrandomisedcontroltrials(RCT).Anadaptivepathwaycanbeconsideredasascientificandengagementconceptualframeworkthroughwhichthestakeholders collectively provide input on the best path forward for medicinedevelopment and post-authorisation access, for a particular medicine throughcoordinateddialogue.

1http://adaptsmart.eu/

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To this end, the adaptive pathway represents an evolution away from the typicalprocess of sequential separate stakeholder interactions and decisions. The fivestakeholder categories described herein are the same as those described in theSeamless pathway. The five categories of stakeholders identified in the SeamlessPathway are: Patients; Health care professionals; Price and Reimbursementauthorities; Regulators and Medicine developers. The use of categories helpeddescribe a general MAPPs process but has some limitations. In particular, not allMemberStates (MS)haveseparateHTAcapabilitiesorassessors to informpayers’decisions and throughout this report, HTA bodies and payers will be collectivelyreferredtoas“pricingandreimbursementauthorities”.“Patients”willcustomarilynotbe individual patients per se. In most instances, it is anticipated that a patientorganization will represent patients’ collective views. However, where no formalpatient organization exists, patients and/or their caregiversmay offer key insightsthroughanadaptivepathwayengagementprocess.Healthcareprofessionals (HCP)primarilyrefertotherapeuticexpertsinvolvedinclinicaltrialsortreatingphysicians;yetothertypesofexpertisewereregroupedinthiscategorysuchasethicists,healtheconomists,epidemiologists,andstatisticians.Therefore,astakeholderasidentifiedinthisworkdoesnotnecessarilyrepresentasingleinstitution,butgenericinsights,expertiseandskillsusedbyexpertswhenmakingacertaintypeofrecommendationordecision.

Under the current medicine development and commercialisation pathway,stakeholder remits and resources have been gradually adjusted in order to fit therequirementsandpermittheirinvolvementinthekeydecisionsduringthelifecycleofmedicines.However,asresourcesaredeployedindependentlybyeachstakeholder,thereisnocollectiveunderstandingoftheresourcesultimatelyrequiredforpatientstogetaccessto innovativetreatment.Underadaptivepathways,multi-stakeholderengagementwillrequirespecificresourcecapacityandcapabilitythatmightnotbeavailable today, and a better collective appreciation of the resources deployed bystakeholders.

For each stakeholder to fully immerse into a dialogue, the process must besustainable,andofferclearbenefits,andtheendproductmustresultinsubstantialaddedpatientbenefit. Therefore, it is an important componentof developing andimplementingaconceptualadaptivepathwaythatthedifferentstakeholderresourcerequirements, and the ability to mobilize them at key decision points, areacknowledged,understood,andaccountedfor.

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4.WorkingMethod

AstheADAPTSMARTdeliverablesoftheD3.02(Decisionpoints)andD2.05(SeamlessPathway)workinggroupsevolved,keysynergieswererecognised.TheremitofD2.05was to map, within the current EU development/access pathways, the differenttransition/engagementmomentswithstakeholders,andtodelineatethekeyprocess(decision)stepsacrosstheseamlesspathway.Inparallel,theD3.02workinggroupwastasked with “contrast(ing) decision points in current vs. future processes bystakeholdergroupsand(identifying)implicationsforaroadmapforimplementation.”Therefore, in the initialphaseofwork, theD3.02workinggroupcollaboratedwithD2.05todelineatethekeyprocessstepsanddecisionpointsintheseamlesspathway.Once a preliminary framework had been agreed upon, initial discussions andconsensus building under D3.02 highlighted a number of practical (capacity andcapability)enablersandbarriers toengagement in theconceptualMAPPspathwaythatcouldaffectoneormorestakeholders.On6thJuly2016,theconceptualpathwaywaspresentedduringamulti-stakeholderworkshopinLondon,UK.Concurrently,theidentified enablers and barriers were explored further during 3 parallel breakoutsessionsattheworkshopforeachofthepre-definedMAPPsmoments.Briefly,theseconsistedof:i Assessment moments that are stakeholder-specific (remits are maintained as oftoday):Developmentassessment,Authorisation,AppraisalandPricingconsiderations,Regulatory post authorisation decisions, and Pricing and reimbursementreassessments,ii)Multi-stakeholder engagementmoments thatmay differ from today ; Agree onAdaptivePathways as approach, Planning iterativedevelopment (coveringpre andpost authorisation phases), and Patient use (see Appendix A for full diagram anddescriptionofMAPPsmoments).D3.02wastaskedwithmappingtheshiftinresourcesneededbyeachstakeholdertoeffectively engage in MAPPs. Based on the conceptual nature of the seamlesspathway, it is premature to effectively quantify in detail the different resourcesneededateachdecisionpointatthispointintime.Instead,wepresentaconsolidatedsummaryofviewsexpressedbydifferentstakeholdersonresourcestheywouldlikelyneedtoengageeffectivelyintheseamlesspathway.Fromthesesummarieswederived:1. Somegeneralthemesandquestionsforstakeholderstoconsiderintheirreflection

onanadaptivepathwayconceptandtheirabilitytoengagewithit.2. Most stakeholders expressed their views in terms of practical enablers and

barrierstoengageintheseamlesspathway.Weidentifiedwhichwerecommonto

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allandwhichwerestakeholder-specific,andsubsequentlywhatresourceswouldberequiredinordertosustainaneffectiveengagementinMAPPs.

3. Wealso explored if similar resources already existed and could be adapted toMAPPs,orifanewresourceorprocesswouldbeneededtosupportengagementwithMAPPs.

4. Finally, thiswork led to a series of recommendations for futurework towardsimplementingMAPPs.

Consensusbuildingwascomplementedwithanon-systematicreviewofthepublishedand grey literature that included current multi-stakeholder initiatives, multi-stakeholder resource requirements and adaptive pathways/licensing-relatedliterature.

Forstakeholdersthathaveawell-definedremitinthe“traditional”process(i.e.asitis today)asassessorsandgatekeepers,anadaptivepathwaydoesnot impacttheirprimary responsibilities as decision makers. However, the multi-stakeholderengagementmoments around the iterativedevelopmentplan introduce, for somestakeholders,newrolesasdevelopmentadvisors.Thisisespeciallythecaseforpatientorganisationsandpricingandreimbursementauthorities-evenifmostarealreadyfamiliar with these roles through pilots (e.g. joint or parallel EMA - HTA scientificadvice), those roles are still new tomost organisations. (See also the Report onSeamless Process and Decision Points of an Adaptive Pathway). The resourcesidentifiedherearebasedonaMAPPsconceptthat,atpresent,isgeneralizedacrossMemberStates.Asaresult,thisreportidentifiesgeneralstakeholderresources,baseduponthesamegeneralizedconcept.Thesedeliberationswillneedtocontinuewithallstakeholdersasadaptivepathwaysevolvefurther.TherearealsoseveraladditionalADAPTSMARTworkinggroupswithdistinctobjectivesanddeliverableswithrelevancetoD3.02objectivesandviceversa.

4.1BackgroundCurrent multi-stakeholder engagement initiatives between regulator, medicinedevelopersandP&Rauthorities

Some of the tools and initiatives that currently encourage multi-stakeholderdialogue(s)include:i)ScientificAdviceandProtocolAssistanceattheEMA,ii)ParallelScientificAdvicebetweenEMAandpricingandreimbursementauthorities-todiscuss,pre-plan andmaximise efficient, goodquality and appropriate data collection thatmeetstheneedsofallstakeholdersacrossthemedicineslifecycle.

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Theseinitiativescentreonwell-structureddialoguesbetweenstakeholdersthathavemadegreateffortstoberesourcedinregardto:pointsofcontact,pre-meetingwiththe medicine developer, common format for dossier submission by medicinedevelopers,aface-to-facemeeting,andpost-meetingminutes.

One of the learnings and recommendations that came fromEMAand EUnetHTA’sparallelscientificadvicepilotswastomaximizeefficientresourceutilisation,toavoidduplication of effort between stakeholders. In response, timetables and dossiersubmissionshavesincebeenaligned.Theprocesshasbeenoptimised furtherwithpricingandreimbursementauthorities,providinga listof issues(tothesubmissiondossier)andwrittenanswers2.

Other currentmulti-stakeholder initiatives include: theMechanismof CoordinatedAccess on Pharmaceuticals initiative (MoCA) (published in 2013)3which allowed afacilitatory voluntary mechanism for “early dialogue” between companies andcompetent authorities, with pricing and reimbursement authorities, patients, andotherscientificexperts.Confidentialityagreementswereused-adviceandcontinuedinvolvement were non-binding. The lessons learned from the MoCA experiencehighlightedtheneedfortheinvolvedstakeholderstohaveanindepthknowledgeofthe regulatory and drug development process, and the ability to be flexible,constructiveandopenmindedinengagement.

Additionally,EMAsAdaptivePathwayspilots(completedin2016)4highlightedsomeof the resource considerations of such multi-stakeholder interactions and earlydialoguesundersafeharbourdiscussions.Whilethesafeharbourdiscussionswereakey draw for committed and open stakeholder discussions (as preferred to legallybinding),findingappropriatepatientrepresentativeexperienceinshorttimeframeswas challenging. Pricing and reimbursement authorities’ involvement was alsodeemed to be resource-intensive, due to the volumeof simultaneous applicationsreceived,parallelparticipationofregulatory-pricingandreimbursementauthoritiesinscientificadvice,andtheflexibleanditerativenatureofthediscussions.

2Reportofthepilotonparallelregulatory-healthtechnologyassessmentscientificadvice:http://www.ema.europa.eu/docs/en_GB/document_library/Report/2016/03/WC500203945.pdf3FinalreportonMoCa:http://download.eurordis.org.s3.amazonaws.com/moca/history/WG%20MoCA-OMP%20Final%20Report.pdf4Finalreportonadaptivepilot:http://www.ema.europa.eu/docs/en_GB/document_library/Report/2016/08/WC500211526.pdf

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5. Results

SeveralpracticalenablersandbarrierstoMAPPsengagementhavebeenhighlightedbelow.Bothcapacityandcapabilityfactorswereidentified,withtheformerbeingthemainresourceneedsthatwefocusonhere.Theseenablersandbarriersshouldbeunderstoodasgapsthatneedtobeaddressedandwould likelystimulateresourcemobilisationforoneormorestakeholders.Inthissection,wealsodistinguishbetweenneedsthatwereraisedbyallcategoriesofstakeholdersandbetweenspecificneedsraised by one category of stakeholder.In Figure 1 the different MAPPs assessment moments and multi-stakeholderengagementmomentsaredepictedaspertheSeamlessPathwaywhichissetagainsttheidentifiedcommonandstakeholderspecificresourceneeds.Furthermomentsinthe medicine lifecycle where a decision on resources might be needed are alsohighlightedinthepicture.Forexample,onceallstakeholdershaveagreedonanAPapproach, additional resourceswouldneed tobeplannedovermultiple years (i.e.estimated lifecycle of theproduct). The focusof our discussion is however on themajorthemesandstakeholderspecificresourcesasdescribedabove.

5.1. Questionsraisedbyallcategoriesofstakeholders

5.1.1. DefinitionandprioritizationofunmetneedAt the time of notification that a MAPPs approach is the optimal solution for acandidateproduct,stakeholdersshouldagreeontheunmetneedthattheproductaimstosatisfy,assetoutbytheMAPPsEngagementCriteria(seeAppendixBforfullcriteria).

Unmetneedisthuscontextuallydefinedasfollows5:“TheMAPPs focus should be on disease transformativemedicines, targetingwell-definedpatientpopulationswithahighunmetmedicalneed,i.e.lifethreateningorseverelydebilitatingconditionsforwhichnotreatmentornosatisfactorytreatmentexist.”

Differentstakeholdersmightstillinterpretdifferentlywhatconstitutesan‘unmetneed’.

PilotsinaverydifferentcontextliketheoneconductedbytheBelgianHealthcareKnowledgeCenter(KCE)todefineunmetmedicalneedscouldprovideusefullearningonmethodstoreachaconsensus6.

5fromcurrentGlossaryofterms,andEngagementCriteriadocuments6https://kce.fgov.be/publication/report/multi-criteria-decision-analysis-for-the-appraisal-of-medical-needs-a-pilot-study#.Wa_JnG996M8

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ItwasfeltthatamethoddocumentinghowaconsensuswasreachedwhenconsideringtheMAPPsengagementcriteriainthecontextofaspecificdevelopmentprogramwouldbeuseful.Theobjectiveisforallstakeholdertoharmonizetheirinterpretationofthecriteriainaspecificcontextnotunlikewhatisdonewithratingscalesusedinclinicaltrials.

5.1.2. DatasourcesforevidencegenerationFor each product utilizing a MAPPs approach, there will be a need for earlyidentificationoftheinfrastructuresalreadyavailableforfurtherdatacollectionofrealworldevidencethatcanbeusedoradaptedtothedevelopmentrequirements.Theseinfrastructuresandthedatacollectedshouldideallybeaccessibletoallstakeholdersinvolved in earlymulti-stakeholder dialogues.Having at least greater transparencybetweenallstakeholdersastothedatacollected,methodsusedandinterpretationofthefindings,comparedtotoday,wouldbeofgreatbenefit.

Multipleinitiativesexisttooptimizeregistryrepositoriesandtostrengthenthevalueofrealworlddata.ThelearningsderivedfrominitiativeslikeIMIGetReal7,ENCePP8andotherprojects9shouldbeusedinMAPPstosupportanadequateuseofRWE.

5.1.3. AgreementongoalsandexpectationsTheneedtoestablishtrustamongstallstakeholders,andintheMAPPsprocessitself,wastheadvicemostoftenreceived.Ifeachstakeholder’sgoalsandexpectationsareclarifiedprospectively,theMAPPsprocesswillmorelikelybeviewedasfitforpurposeandactuallydelivertheexpectedbenefits.Trustbuildswhen,“membersofanetworkacknowledgethelegitimacyofeachother’sgoalseveniftheydifferfromone’sown.”10 Stakeholders also need confidence that, upon entry into MAPPs, they cancollectivelyagreeon ‘commonground’.Theneedtoacknowledgeasharedmutualgoal in the form of patient centricity is key, and will enhance trust amongststakeholders.Withthisenabler,thereisincreasedconfidencethatcommitmentsbyallpartieswillbemetateachdecisionpoint.

7https://www.imi-getreal.eu/8http://www.encepp.eu/9https://rarediseases.org/registries-for-rare-diseases-involve-the-patient/10ManringS2007Creatingandmanaginginter-organisationallearningnetworkstoachievesustainableecosystemmanagement,Organization&Environment,Vol.20No.3,September2007325-346

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Figure1SchematicdepictionofthekeyAssessmentandMulti-stakeholderengagementmomentsoftheSeamlessPathwayagainststakeholderresourcerequirementstoengagewith,andactupon,decisionmaking.Bothcommonresourcesandcommonthemesraisedbyallstakeholdersaredepicted(greyboxesandarrows).KeyAssessmentmoments(orangecircles)andMulti-stakeholderengagementmoments(darkbluecircles)oftheSeamlesspathway,aredepictedinadditiontonumerousothermoments(smalllightbluecircles)wherestakeholderspecificresourcesneedtobeunderstoodandengaged.

Assessmentmoments

Multistakeholderengagementmoments

Suggesteddecisionpointstoengageresources

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It is expected that stakeholders might disagree in good faith and disengage fromMAPPs.However,thisisnotwithoutconsequencesfortheotherstakeholders-thereshouldbeaclearrationalewithadequatemethodsinplaceforconflictresolution,andamechanismtodisengagefromMAPPs.

5.1.4. Time,humanresourceandorganisationalgovernanceItiscriticalforeachorganizationtoconsiderhowtheirroleinMAPPsfitswithintheircurrentmissionandprocesses.UltimatelywhethertheorganisationhasthemandateanddesiretobeinvolvedwithcertainaspectsofMAPPswilldictatetheallocationofresourcesforthistypeofactivity.

Greater clarification on the likely number and frequency of interactions betweenstakeholdersoveramedicinelifecyclewasrequested,asthiswasseenastheprimarydriverofresourcesneeded-thiswillhoweverlikelyvaryfromproducttoproduct,aswell as the number of medicines going into an adaptive pathways route. Theconceptual design of the seamless pathway does not, at this stage, allowquantification of the time commitment expected from each stakeholder enteringMAPPs.

As the MAPPs process becomes more firmly established, a project manager at aEuropeanlevelshouldbeappointedtoorchestratethedifferentflowsofinformationandinteractions,andtoactasapointofcontactforallstakeholders.Thededicatedpersonnelwouldhaveaclearremitforbrokeringdiscussionsbetweenstakeholders.The exact nature, remit(s) and decision making powers of the project managerproposedhereneedsfurtherdeliberation.

5.1.5. SpecificexpertiseandexperienceStakeholders recognized that taking an active part in any multi-stakeholderengagement moment requires specific expertise that they might not possessinternally-especiallywhentheorganisationissmall(e.g.somepatientorganisations,SMEs,andcompetentauthoritiesinsmallermemberstates),orarenewtothistypeofengagement.ItislikelythataMAPPsengagementmomentwillbeaplacewhereinnovativesolutionswillbebroughtupfordiscussionandexpertsmightbeinvitedtogiveforward-lookingadviceacrossanumberofexpertiseareas.Therewillalsobeaneed to generate practical experience to make MAPPs a learning process.Threebroadcategoriesofcriticalexpertisewerehighlighted;

• Science:Diseaseandproduct-specificknowledge• Processes:UnderstandingofMAPPsconcept,regulatorytools(suchasparallel

scientific advice and conditional marketing authorisations), pricing and

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reimbursement mechanisms, cost effective assessment, managed entryagreements,andprescriptioncontroltoolsandmeasures

• Methodologies: Clinical trial design, data analysis, real world evidencegeneration,smallpopulationstudies

Acquiringthiscriticalexpertisein-housewouldpartlyhavetobeestablishedthroughspecificeducationandknowledgeexchange.

5.1.6. NumberofavailableexpertsandaccountabilityMultiplerequestsaddressedtoalimitedpoolofavailableexpertswillfurthercreatedilemmasfororganizationsthatwilleitherneedtofindawaytoexpandtheirpoolofexperts ormight have to limit their participation at some chosenmoments in theprocess.It is envisaged that initial development planning discussionswould likely begin asinformal,safeharbourinteractions,andprogressintoMAPPswouldcorrespondwithmore formal interactionsandstructuredagreements,suchas throughanEMAandHTAscientificadvice(SA).Eachstakeholder’saccountability,whengiving inputandrecommendations during the various engagement moments, requires carefulconsideration; to be open enough to promote trust and commitment, yet robustenoughthataccountabilityfordecisionsmadeandresourcesmobilizedatanygivenpointcanbeupheld.

5.1.7. StakeholderrepresentationThe seamless pathway describes five categories of stakeholders that will need tointeractthroughoutthedrugdevelopmentprocess,tosupportaneffectiveiterativedevelopment plan that will span the entire drug life cycle (Patient and PatientOrganizations, Healthcare Professionals, Medicine Developers, Pricing andReimbursementauthoritiesandRegulators).

Therearecountlessdistinctionsandnuancespossiblebetweenstakeholdersthathavebeen grouped together in one single category. Stakeholders will be differentlystructured organizationally; they may be individuals or institutions and will havedifferentremitsandmissionsbothwithin,andbetween,memberstatesandacrosstherapeuticareas.

The challenge is for an individual stakeholder to present a collective view that isspecificenoughtoinformdecisionsatanearlystage,yetremainsrepresentativeoftheir broader, generic stakeholder group. Patient organisations have developedengagementwiththeEMAthroughthe“patientandconsumerworkingparty”,orwithPricing and Reimbursement authorities (for example in Scotland with the PACEprocess) - they are the stakeholdermost familiar with this challenge and how tomanageit.

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5.2. Questionsraisedbyaspecificcategoryofstakeholder

5.2.1. PatientandPatientorganisationsPatient literacy across the entire value chain and in the MAPPs process itself isrequired for full, consistent, and valuable engagement and involvement in thedecisionmaking process. In some cases, a barrier to engagement is language andterminology-evenmoresothanspecificexpertise.Patientrepresentativesrequireaccess to specific knowledge, particularly in clinical development and regulatoryprocesses, and a clear understanding of technical and scientific language.Disease-specific expertise can come froma greater consolidation of best practicesacrosscurrentinitiativesandumbrellaorganisations,incombinationwithdevelopingandimplementingaframeworkforobtainingneworgreaterpatientengagementinthemedicinelifecycledevelopment.

Patientorganisations(sofar)arevoluntarilyinvolvedandnotboundbycommitments.ItwillbechallengingforpatientsinvolvedinMAPPstomanageaccountabilitytowardstheir peers, and if the views they representwithin theMAPPs process lead to anoutcomethatisseenasbeingatoddswithpatients’bestinterests(forexamplewhenother stakeholders disagree and withdraw), direction from similar initiatives’ bestpracticesshouldbetakenintoaccount.

The ability to mobilize resources also requires dedicated funding to ensure“professionalization” of the patient representatives. Adequately covering financialsupport for recurrent activities could come from publicmonies or from a fee-for-service.

5.2.2. HealthcareprofessionalsHealthcareprofessionals(HCP)areexpectedtocontributeintheMAPPsengagementmoments and in themedicinedevelopment in a similarwayas the SAG (ScientificAdvisory Group) currently does. Scientific societies could encourage a ‘MAPPsinvestigatorhubacrossscientificsocieties’–anetworkofHCPwhowouldbepioneersintheMAPPsprocess–andaddrelevantexpertiseandopportunitiesforcooperationbetweenexperts.ItisanticipatedthatMAPPswillalsosolicitresourcesatthepointofcarebeyondcurrentgeneralcapacity.Asisthecasetoday,atthepointofcare,HCPare responsible for post-Marketing Authorisation data collection to fulfil therequirementsof, forexample, theConditionalMarketingAuthorisation. Medicines

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authorised underMAPPswould be expected to be on the list ofmedicines underenhancedmonitoringidentifiedbyablacktrianglesymbolontheSmPC.11

This enhancedmonitoringwill require additional time and personnel resources toensurecontinuousandup-to-dateinformationisconveyedtopatients,andadditionalmonitoring and adverse event reporting. Managed entry agreements, includingtargetedprescriptionmechanismsandrealworlddatacollection,willfurtheraddtotheadministrativeburdenofthetreatingphysician.MechanismstofurtherincentiviseHCPandpatientsastotheimportanceofcontinued,structuredRWdatacollectionisvitalinthecontextofMAPPs.EuropeanReferenceNetworksmightplayanimportantroleincross-bordercollaborationondatacollectionsandtechnologywherepossible(i.e. electronic health records, wearable technology) throughmaximising availableresourcesandreducingindividualburdenfortheHCP.

5.2.3. MedicinedevelopersAsaninitialactivity,themedicinedeveloperassessesthedegreeofunmetmedicalneed, what would constitute value for the different stakeholders, and the valueproposition of each potential medicine. To prepare for MAPPs involvement,developers should gather input from various sources and stakeholders on, forexample:severityofdisease,unmetmedicalneed,diseaseandtreatmentpathways,regulatory and evidence requirements, regulatory therapeutic guidance and tools,andpricingandreimbursementauthorities’datainterests.Theseinitialactivitiesareatthediscretionofthedeveloperastheystarttoelaborateadevelopmentplan.Eachmedicinedeveloperwillbeorganiseddifferently,buttypically,mostdonotassembleamultidisciplinaryteamsoearlyinthedevelopmentprocesswhenalotofproductattrition still occurs. Compared to existing processes, the earlier and continuousiterativenatureofmulti-stakeholderengagementmomentsacrossthelifecycleofaproductwilllikelyrequireanearlierandmoreintensivemobilisationofresourcesandexpertsforthepreparationofdocumentationtosupporttheiterativedialogue.

Withagreaterinputfrompricingandreimbursementauthorities,patientsandHCPinparticular,dossierswouldneedtobeinbothtechnicalandlaytermsandmightneedtoincludeEUlanguagesotherthanEnglish.

In this case, resources formedicinesdeveloperswill expand to includeearlier andadditionalclinicalandRWDgenerationskillsinthedevelopmentteams,aswellasdataanalysisandmanpowerforrecurrentdossiersubmissions.

11http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/document_listing/document_listing_000365.jsp&mid=WC0b01ac058067bfff

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5.2.4. PricingandreimbursementauthoritiesInmostcountries,pricingandreimbursementauthoritiesarenottypicallyinvolvedinthemedicine lifecycle development until post-Marketing Authorisation discussions(althoughanumberofHTAbodieshavebeeninvolvedinearlyadviceinitiatives).Morefrequent and systematic involvement of pricing and reimbursement authorities inearlydialoguesanditerativecyclesofdevelopmentmayrequireagenuinelynewsetof capabilities, skills and processes, and significant increase in dedicated resourcecompared to the standard process seen today. New scientific and disease-specificknowledge resourceswould need to be acquired andmobilized across competentbodies.Currently,pricingandreimbursementauthoritiesinsmallsizedcountrieshaveverylimitedcapacitytobeinvolvedinactivitiesattheEuropeanlevelbeyondtheircurrentmandate.

5.2.5. RegulatorsWhile scientific advice and conditional marketing authorisation are tools used byregulators, it was clear from the EMA’s adaptive pathway pilots that the iterativenature of multi-stakeholder dialogues was resource-intensive and required adedicated coordinator to manage the multi-stakeholder dialogues andsubmission/evaluationprocesses.Likeotherstakeholders,regulatorsmustcarefullyconsider the amount of information required for MAPPs regulatory assessments.

6.Recommendationsandoptionsforfutureworkandnextsteps

Theproposedconceptualadaptivepathwaysframework12presentsaseriesofcriticaldecision-making points along the development pathway, where multi-stakeholderinteractionswill requirededicated resources. Experiencesof stakeholders involvedwith similar initiatives, existing expertise within each involvedinstitution/organisation,and resourcegovernance,playa role indeterminingwhatadditionalresourceswouldberequiredinordertoengageeffectivelyinMAPPs.Whatwepresenthereareaseriesofrecommendationsaimedatsupportingstakeholdersintheirreflectiononhowtoaccessresourcestoeffectivelyparticipateinthemulti-stakeholderinteractions13.

The recommendations presented in this document should always be read incombinationwiththeseamlesspathwayreport (D2.05)-as itbuildsontheMAPPs

12http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2017/07/WC500230414.pdf13Asdescribedintheseamlesspathwayandengagementcriteriadocuments

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moments identified in that document. However, the exact nature of the resourceneedsis,asyet,anunknown,andisnotpossibletoquantifyatthisearlystageoftheMAPPsconceptualdevelopment.

To fulfil some of the resource needs expressed by stakeholders (see section 5) toengageinmulti-stakeholderMAPPsmoments,werecommendto:

1. Identifyandpilotmethods(see5.1.1)-inclusiveofallstakeholders’pointofview - to support the MAPPs engagement and test the feasibility of theengagementcriteria.TheuseofMCDA(multiplecriteriadecisionanalysis)inthiscasecouldbeveryfitting.Thepilotwillalsohelpclarifywhetherfurtherwork is needed to harmonize stakeholder’s interpretation of the criteria(includingunmetneed)inaspecificdevelopmentcontext.

2. Make available an inventory of registries that are accepted data sources(5.1.2,5.2.2)insupportofMAPPs.

3. A concordat or non-binding agreement between all involved stakeholders,setting out stakeholders’ common ground and specific expectations (see5.1.3),commitmentstoproducedata,documents,time,expertiseandeffort,wouldgoalongwaytosolidifyingthetrustbetweenstakeholdersandensurethesuccessofMAPPs.Thiswouldincludemechanismsforinitialengagement(safe harbour), templates for conflict resolution, and mechanisms ofdisengagementinthedecisionmakingprocess.

4. Asupportanddevelopmentplatform forstakeholders involved inMAPPs -involvingexperiencedindividualsthatactascoach,mentorandmediator-thatcouldsustainaccurateandcontinualtransferofknowledgeandexperiencetootherstakeholders(hubandspokemodeloflearning).(see5.1.5,5.1.7,5.2.1,5.2.4and5.2.5) Suchmodels arewidelyused inhealthcareand could spangeographical boundaries, and facilitate wider involved learning andacceptancetoEasternEuropeanMemberStates.Onepossiblesolutionmightbeanexplicitagreementbetweenpricingandreimbursementauthoritiestouseapoolofadvisors,whereeachspecializesinaparticulardiseaseareaormethodology.

5. Resourceplanning(see5.1.4)canbederivedinpartfromestimationsfortimeand personnel, from initiatives where multi-stakeholder interactions havebeen piloted, andwhere structured dialogues occur over several iterations(meetings,feedback,resubmissions),andoveranumberofmonths–suchasAdaptivePathwayspilots,MoCaandjointEMA-EUnetHTAinitiatives.

6. DefineaprocesstoprioritizepotentialMAPPscandidates,tolimitthenumberofproductsperyear(initiallyatleast)–stakeholdersneedareasonablenoticeperiodinordertoplanaheadfordedicatedresourcesandtimelyinputovermultipleyears.(see5.1.4)TheMAPPsengagementcriteria(D2.03)willassist

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developersinself-selectingonlythemostrelevantcandidatestotakethroughanadaptivepathway.

7. Seekpoliticalsupport forMAPPsconcept (see5.2.1and5.2.4) inorder formemberstatestoallocatetherequisiteresourcestohireanddevelopexperts.Asnotedintheintroduction,whiletheremitsofeachstakeholderremain,thestakeholders that might most need new resources were considered to bepricing and reimbursement authorities, patients, and healthcare providers(HCP). This is also critical tobeable to implement recommendation4.Oneenabler forgainingbroaderpoliticalsupportmightbe fundstoundertakeafewMAPPspilots.

8. Provideaplatformand framework toenhancepatientengagement acrossthe medicine development chain - that accounts for diverse patientpopulations and marginal sub populations. Increasing patient literacy andknowledgeinkeyareasofmedicineR&D(see5.2.1),refiningthevalueoftheshared mutual patient centricity goal (see 5.1.1 and 5.1.3), and managingconflicts,willcontributetomorestructuredandrelevantpatientinput(see5.2.1). Existingefforts through, forexample, theEUPATI initiative, couldbeleveraged to include MAPPs-specific training and knowledge brokering,alongside greater use of existing resources from the PCWP networks tosupportimplementation.

9. Severalinitiatives,forexampleEMAsParallelScientificAdvice,MOCAandtheUK’s EAMS, have strived tomake an efficient resource utilisation to avoidduplication between stakeholders, by aligning timetables and agreeing onusing single dossier submissions (see 5.2.3 and 5.2.4) where possible. Thepractical lessons derived from these initiatives should be integrated whenformalizingdetailedprocesses forMAPPs.Atthesametime,theneedforadedicated MAPPs project manager to orchestrate the different flows ofinformation and act as a point of contact for all stakeholders should beconsidered.(see5.1.4,5.1.5and5.1.7)

7.Conclusion

Inconclusion,foranadaptivepathwaytobecomeanoperationalmulti-stakeholderroute for medicine development, we recommend to further explore 3 keycomponents:

1.The“political”mandateforstakeholdersinmemberstatestoengageinsomesortof advisory role to enable patient-centred medicine development is needed. Theconditionalmarketing authorisation tool, additional (data)monitoring procedures,

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andtheprogressmadeinscientificadvicewiththeearlydialogueworkingpartiesatthe EMA, aremechanisms that are supportive ofMAPPs implementation. MAPPsspecific processes and procedures can be further expanded from this currentfoundation, if all stakeholders arewilling to and able to engage around the samepatient-centricgoal.

2. The need to have access to new core expertise is central to all stakeholderengagement in MAPPs. Leveraging existing overarching platforms to streamlineresourcesandexpertiseseemsthemostpracticableandreliablewaytoadvancewithMAPPscapacity-buildingforallstakeholders.ExamplesofplatformstoeithermodelfromorcontributetoaMAPPshubareEUPATI,thepatientandconsumerworkingparty at EMA (PCWG), the scientific advisory groups (SAGs), the scientific adviceworking party (SAWG), EunetHTA and also potentially the MEDEV, EuropeanReferenceNetworkandscientificsocieties.

3.Buildingtrustbetweenstakeholdersrequiresacommongoalbalancedagainsteachstakeholder’sinterests.Furtherresearchshouldexploreopportunitiesandmethodsonhowtoensure stakeholdersexecute,over time,on their commitmentswithoutbeingboundbyrequeststhatturnouttobeunreasonableorunfeasible.Safeharbourdiscussionshavedemonstratedacertainlevelofimpliedtrustbetweenstakeholderswhichcouldbefurtherformalizedthroughatypeofresearchconcordat.Thedegree(s)towhichadvice/commitmentsisbindingornon-bindingundersuchaconcordatneedstobeexploredcarefullytoreflecteachstakeholder’saccountability.

Therecommendationsinthispaperfocusonenablingthemulti-stakeholderengagementanddecisionmomentsinMAPPs,andhighlightthefactthatnexttothein-depthexpertiseneededbyeachstakeholder,thereisanopportunitytodeveloptrustandbuildsoftskillstoallowstakeholderstodevelopanadvisoryroleandincreasetheirimpact.

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APPENDIXA

SchematicandexplanatorytableoftheSeamlessPathway(FromD2.05)

Eachproductlife-cylephaseissymbolisedbyabluecog,inthebelowdiagram.Eachcogissizedcomparativelytorepresentthecharacteristicdurationofthephaseduringthe lifespanofatypicalmedicine. Thetophalfof thediagramincludesthe‘assessment’ or ‘decision’ moments by the stakeholder represented. Within thebottom half of the diagram, moments of ‘multi-stakeholder engagement’ arerepresented.

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AdaptivePathwayMoments

DescriptionoftheProcessStepsandDecisionPoints

Developmentassessment Priortothemedicinedevelopermakingadecisionforaproducttoenter

development,thedeveloperassessestheopportunityofapotentialmedicine,forexample,consideringgeneralinputand/orguidancefromvariousstakeholders.

Agreeonadaptivepathway(AP)asoptimalapproach

Basedontheengagementcriteria,stakeholdersofferacollective,documenteddecisionunder“safe-harbour”discussionsregardingtheiragreementtoprogresswithanadaptivepathwayengagementapproachforaparticularpotentialmedicine.

Iterativedevelopmentplan Aniterativedevelopmentplanisanevolvingproductdevelopmentstrategy

proposedbythedeveloperandadaptedthroughmulti-stakeholderengagement.Theevidencegenerationplanisdiscussedamongthestakeholdersandtakesintoconsiderationthecriticalquestionstobeaddressedpreliminarilyinordertoalsosupportsubsequentpricingandreimbursementdecisionsatthenationallevel.Theiterativedevelopmentplanisuniqueandextendsoverasignificantperiodoftime(andlikelyiterations)supportinganadaptivepathwayfromthebeginningtotheend.Evidencegenerationmayinvolvemultipleclinicaltrials,single-armstudiesorasinglePhase2trialorRWEdependingonthespecificproduct.

Forexample,

• Agivenplanconsiderstheevidencegenerationcommitmentsandfollow-upmeasuresforaconditionalmarketingauthorisation(CMA),forpharmacovigilanceand/ornewstudiestoexpandthepatientuse.

• Itshouldalsoconsiderthepostauthorisationevidencegenerationmeasuresnecessarytomeetthepricingandreimbursementrequirementsandanagreementonthetimelinesforreviewandreassessment.

Regulatoryauthorisation Regulatorydecisiontoauthoriseamedicineforpatientuseinagiventherapeuticindication(s).

Appraisalandpricingconsiderations

AttheEUlevel,considerationsforthepre-aswellaspost-authorisationdatacollectionplantakeplacepriortoauthorisationasacomponentoftheiterativedevelopmentplan.Atthenationallevel,discussionsonpricingandreimbursementfollowregulatoryauthorisationandreflecttheiterativedevelopmentplan.

Patientuse Thefoundationforanadaptivepathwayconceptistoprovidepatientswho

experienceahighunmetmedicalneedwithaninitialorimprovedtreatmentoptionthroughtoolstoenableon-labelprescribing.Inparalleltoanadaptivepathway,patientusemayalsocomprisefurtherclinicaltrialsprogramsasappropriate.

Regulatorypost-authorisationdecisions

Regulatorydecisionsarealsotakenduringthepost-authorisationphase.Forexample,regulatorydecisionsmayleadto:

• wideningorcontractionofthemarketingauthorisation,e.g,.intermsofeligibletreatmentpopulation,or

• reinforcementofsafetymeasures,or• grantingofafullmarketingauthorisationfromaninitialCMA,or• authorisationofanewindicationwithorwithoutfollowupmeasures.

Pricingandreimbursementreassessments

Predefinedmomentswhendecisionsonpricingandreimbursementbynationalauthoritiesarereviewed.Theconclusionofthereassessmentsmaytriggerpotentialadjustmentsofreimbursementorpriceconditionsatthenationallevel.Asanexample,anegativereassessmentcouldleadtotheendofreimbursementfortheindicationinscope.

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APPENDIXBEngagementCriteria(fromD2.03)FrameworkofquestionstobeaddressedbystakeholderswhenconsideringtheMAPPspathwayforagivenmedicinalproduct:1.Canwedefineatargetpopulationwithahighunmetneed?Doestheproductholdsufficientpromisetoaddresstheunmetneed?2.Canaprospectiveiterativepost-(initial)marketingauthorisationdevelopmentplanbeproposed,developed,implementedandagreed?3.Arethereworkabletoolstoensureappropriateproductutilisation?4.Arethereworkable‘strategies’forpayersincasetheproductunder-performs?5.Istheresufficientcommitmentandresourcesfromrelevantstakeholderstoensuresuccessfulinteractions?6. Whichcriticalaspectsforpharmaceuticaldevelopmentwouldneedtobeconsidered?

APPENDIXCTableofpartnerswhocontributedtothisworkUniversityofOxford(CASMI)

SanofiGenzyme

Amgen

BMS

Lysogen

Merck/MSD

Novartis

Roche

EFPIA

EURORDIS

EMA