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SeamlessProcessandDecisionPointsofanAdaptivePathway
June2017Thework leadingtotheseresultswasconductedaspartoftheADAPTSMARTconsortium(Accelerated Development of Appropriate Patient Therapies: a Sustainable, Multi-stakeholder Approach from Research to Treatment-outcomes). For further informationplease refer to www.adaptsmart.eu. This paper is the result of the collective input fromworkinggroupD2.05andD3.02andonlyreflectstheviewsoftheauthors.This project has received funding from the Innovative Medicines Initiative 2 JointUndertaking under grant agreement No 115890. This Joint Undertaking receives supportfromtheEuropeanUnion’sHorizon2020researchandinnovationprogrammeandEFPIA.
Contents
ListofAbbreviations 2
WorkingMethod 3
Introduction 4
IllustrativeSymbols 7
ProposalfortheCoreAdaptivePathwayMoments 8
Conclusion 18
Appendix1:ProposalforAdditionalAdaptivePathwayMoments 19
Appendix2:TraditionalDevelopmentandPost-AuthorisationAccess 26
IMIADAPTSMART|D2.05andD3.02 2
ListofAbbreviations• AA–AcceleratedAssessment
• ADAPTSMART-AcceleratedDevelopmentofAppropriatePatientTherapies:aSustainable,
Multi-stakeholderApproachfromResearchtoTreatment-outcomes• ATMPs–advancedtherapymedicinalproducts
• CMA–ConditionalMarketingAuthorisation
• CMC–chemistry,manufacturingandcontrol• CSA-CoordinationandSupportAction• CT–clinicaltrial• EMA–EuropeanMedicinesAgency• HTA–healthtechnologyassessor• MA-marketingauthorisation
• MAA–marketingauthorisationapplication• MAPPs–MedicinesAdaptivePathwaystoPatients• MEAs–managedentryagreements• PRIME–PRIorityMEdicine• PRO–patientreportedoutcome• RCT–randomisedcontrolledtrial• RWE–realworldevidence
• SA–scientificadvice
IMIADAPTSMART|D2.05andD3.02 3
WorkingMethod
Duringadvancementof theseparate IMIADAPTSMARTdeliverablesof theD2.05and
D3.02workinggroups, important intersectionswererecognised. Intheworkplan,D2.05was
charged with “map(ping) out, within the current EU development/access pathways, thedifferent transition/engagement moments1 with stakeholders, and…(to) explore if thesemoments should be different for aMAPPs pathway”. In turn, theD3.02working groupwasresponsible for “contrast(ing) decision points in current vs. future processes by stakeholdergroupsand(identifying)implicationsforaroadmapforimplementation”.Therefore,overtheprecedingyear,D2.05andD3.02havecollaboratedona jointobjectivetodelineateadaptive
pathwayprocessstepsduringdevelopment,authorisationandpost-authorisationaccessalong
with the critical decision points for the involved stakeholders. There are many additional
ADAPTSMARTworkinggroupswithdistinctobjectivesanddeliverableswithrelevancetothese
D2.05/D3.02 objectives and vice versa where relevant reference is made to reports already
completed.Hence,thisdocumentismerelyprocessfocusedandshouldbereadinconjunction
withotherADAPTSMARTdeliverables;forexample, itdoesnotdescribetheprinciplesofthe
MAPPs concept, engagement criteria forMAPPsproducts,workable ‘strategies’ for payers in
case the product under-performs, or methodologies or data sources for generation of real
worldevidence(RWE).
Moreover,thedocumentshallnotbeunderstoodorquotedasbeingmadeonbehalfof,
orreflectingthepositionofanyparticipatingorganizationorstakeholder,publicorprivate.Itis
not intended to replace or complement official guidelines that may be in place or in
development.ThepaperismerelyintendedtoinformanddrivefuturediscussionsonMAPPs,
both within the ADAPT SMART consortium and in the wider scientific and healthcare
communities.
On6 July2016, theconceptualadaptivepathwaymodelwaspresentedand feedback
receivedduringamulti-stakeholderworkshopinLondon,UK.FromAugustthroughDecember
2016,participantsofD2.05andD3.02–includingrepresentationacrossstakeholderdisciplines
–providedreviewandinputontheconceptualadaptivepathwaypresentedinthisreport.
1Withinthisreport,‘moments’areconsideredassignificantmilestonesduringmedicinedevelopmentandpost-authorisationpatientaccessinwhichanassessment(ordecision)istakenormulti-stakeholderengagementoccurs.
IMIADAPTSMART|D2.05andD3.02 4
Introduction
Thedevelopmentofamedicinalproduct fromsubstance toa finishedproduct,which
canthenbeprescribedtopatients,isacomplexprocessinvolvingmanystakeholders.Withthe
rapidevolutionofscience,societyandtechnology,newmedicinedevelopmentmustadaptto
meet the growing scientific understanding of disease mechanisms but also meet the
expectationsof increasinglyempoweredpatients.Theemergenceofgenomicsallowsamore
tailoreddevelopmentforeachproductbasedonadeeperunderstandingfromthemechanism
ofaction.Technologyisalsodeeplymodifyingresearcherscapabilitiestocollectdataandshare
information.Thereisagrowingsenseofurgencyinthiscontextfrompatientsandphysiciansto
accesspromisingtherapiesasearlyasapositivebenefit-riskbalanceissufficientlyestablished,
thoughatatimewherestakeholderswillstillhaveimportantquestionstoanswertoestablish
thefulltherapeuticvalueofthemedicine.Anadaptivepathwaycanthenbeconceptualisedasa development strategy that proactively considers a life-cycle approach with a focus on
enablingearlyaccessforalimitedpatientpopulationwithahighunmetneed.Thiscustomised
development would benefit from the coordinated and repeated dialogue of the principal
stakeholders. This development approachwould alsooptimally usenewdata sourceswhich
arebecomingincreasinglyavailable.Inasimilarway,EMAhasdefined‘adaptivepathway’asa
“prospectively planned, adaptive approach to bringing medicines to market. The adaptive
developmentplanwillinitiallytargetthedevelopmenttoawell-definedgroupofpatientsthat
is likely tobenefitmost from the treatment. This is followedby iterativephasesof evidence
gatheringandprogressivelicensingadaptations,concerningboththeauthorisedindicationand
the potential further therapeutic uses of themedicine, to expand its use to awider patient
populationasmoredatabecomeavailable.”2
Therefore, we reflect that an adaptive pathway be viewed as a scientific andengagement conceptual framework (fully described in the following section along withAppendix1)throughwhichthestakeholders–collectivelythroughcoordinateddialoguewhenappropriate–provideinputonthebestpathforwardtoamedicinedeveloperfordevelopment
and post-authorisation access, specifically for the particular medicine. In this way, this
conceptualadaptivepathwayrepresentsanevolutionfromthetypicalprocessofmoreorless
isolatedstakeholder interactions,particularly forpost-authorisationdatacollection (Appendix
2). It can be further conceptualised as a navigable pathway inwhich the developer engages
stakeholdersthroughcoordinateddialoguetoconsidertheirdistincttoolkits3ofapproachesto
2http://www.ema.europa.eu/docs/en_GB/document_library/Report/2016/08/WC500211526.pdf[accessedJan.2017]3Theanalogyofthetoolkitisintendedtoconveythat,withinanadaptivepathway,thestakeholderswillspecificallydiscusstailoreddevelopmentandpost-authorisationmeasures-maybeprocesses,infrastructure,prerequisitesorrequirements-foreachindividualproduct.Assuch,someofthesemeasuresortools(e.g.,realworldevidence,registriestomonitorappropriate
IMIADAPTSMART|D2.05andD3.02 5
optimallysupportdevelopment,authorisationandpost-authorisationaccessprocesses.Inthis
way, themedicine developer can institute an adaptive pathway to optimally coordinate and
align the existing processes and involved stakeholders in a more integrated manner. For
example, during development, regulators may offer the developer advice on the use of a
number of regulatory tools such as (but not limited to); orphan designation, the PRIority
MEdicine (PRIME) scheme, joint or parallel regulator/HTA scientific advice (SA) – currently,
being used with more frequency – as well as accelerated assessment (AA) or conditional
marketingauthorisation(CMA).Theobjectiveistoidentifytheoptimalstrategythatwillallow
patients with high unmet needs to access a beneficial therapy at the earliest possible time
point.Anadditionalobjectiveisprospectiveagreementontheevidencepackageandfollow-up
measures to answer the remainingquestions relevant for the varied stakeholder to evaluate
thelong-termvalueofthemedicine.Certainly,anadaptivepathwayapproachisnotsuitable
for all medicines. More precisely, multi-stakeholder dialogue under an adaptive pathway
approachisenvisagedforthosepotentialmedicinesthatareconsistentwiththeADAPTSMART
engagementcriteria(e.g.,addresshighunmetneedwithreasonableexpectationofsubstantial
added benefit for patients, and use of different data sources). These criteria are question
based4:
1. Canwedefineatargetpopulationwithahighunmetmedicalneed?Doesthe
productholdsufficientpromisetoaddresstheunmetneed?
2. Canaprospectiveiterativepost-(initial)marketingauthorizationdevelopmentplan
beproposed,developed,implementedandagreed?
3. Arethereworkabletoolstoensureappropriateproductutilization?
4. Arethere‘workable’strategiesforpayersincasetheproductunder-performs?
5. Istheresufficientcommitmentandresourcesfromrelevantstakeholderstoensure
successfulinteraction?
6. Whichcriticalaspectsforpharmaceuticaldevelopmentwouldneedtobe
considered?
The tools of this conceptual framework are currently available. The intent of an
adaptive pathway approach is to enable the developer to prospectively and collectively
implement them by involving stakeholders to best navigate the course of the medicine’s
lifespan.Assuch,theoverallobjectiveofanadaptivepathwayistoagreetheoptimalstrategy
for theregulatoryandHTA/payerevidencerequirements tobemet in themostefficientand
effectivewaypossibletofacilitatedevelopmentofandaccessstonewmedicinesinhighunmet
need.Inthisway,anadaptivepathwayasconceptualisedinthisreportisnotactuallynovelnorpatientusage)willlikelybeconsideredonaroutinebasis,whileothers(e.g.,inclusionintothePRIMEscheme,adaptivetrialdesign)willlikelybeimplementedonacase-by-casebasisbasedontheparticularcircumstances.4ADAPTSMARTDiscussionpaperonEngagementCriteriaforMAPPsfromDecember2016:http://adaptsmart.eu[accessed24January2017]
IMIADAPTSMART|D2.05andD3.02 6
anofficialdesignation–ratheradeliberatemethodforfacilitatingandfocusingcollectivemulti-
stakeholderengagementeffortsacrossthedevelopmentlife-cycle.
Also,withinthisreport,thereisapictographicrepresentationoftheproposedmedicine
development and access process steps or core ‘adaptive pathway moments’. This diagram
visualisestheconceptualengagementinstancesofsignificanceinwhichinvolvedanddecision-
makingstakeholderssharetheirrespectiveviewsortakeadecision,basedontheirremits,to
continueprogressionofapotentialmedicinealongaconceptualadaptivepathwaytopatients.
ThesestepsaredescribedbasedontheexistingEUregulatoryandgeneralisablecountryaccess
processes.Asaresult,thisreportidentifiesapproachesandengagementmomentsenablingan
adaptive pathwaywithin these existing frameworks – i.e., ensuring that all existing tools are
used in themost optimalway. Finally, this report does not aim to prescribe solutions or to
assignrolesandresponsabilities.Thesedeliberationswillneedtoevolvewithstakeholdersina
nextphaseofADAPTSMART.Therefore,thereportlistsanumberofremainingquestionsinthe
concludingremarks.
Appendix 1 describes, in detail, the generated data, key events and involved
stakeholders separated into each consequent phase of this adaptive pathway conceptual
model.Undereachgraphicinthisreport,atablereferencesthespecificadjustmentsthatwill
enabletheadaptivepathwayconceptwithintheprocessestypicallyinuseforthedevelopment
andpost-authorisationaccessofmedicinesintheEU.Finally,thereisanarrativedescriptionof
theessentialchangestobeconsideredwithineachstage.Deliberately,asimplisticmodelhas
beendepictedto illustrate thepotentialdecisionandtransitionmoments in the lifespanofa
medicine.Itisacknowledgedupfrontthatimplementationinpracticewillrequirefurtherwork.
Considered in this way, the report provides a basis for continuing development of the
framework allowing a dialogue amongst stakeholders about what the conceptual modelactuallyshouldinclude,andcorrespondinglybydefault,whatitshouldnot.
IMIADAPTSMART|D2.05andD3.02 7
IllustrativeSymbols
There are countless distinctions possible for the diverse range of stakeholder groups
represented within this depiction, which are not possible to fully explore in this conceptual
overview. For instance, countries are differently organised to decide on pricing and
reimbursement.Not all havedistinctHTA capabilitiesor assessors to informpayers’ decision
making. Different authorities in national healthcare systems will be in charge of evidence
standards, healthcare priorities, price negotiations, budgetmanagement and reimbursement
decisions.
• Pricingandreimbursementauthorities:Throughoutthisreport,HTAandpayerswillbecollectivelyreferencedas“pricingandreimbursementauthorities”.
• Health-care professionals: Along with health-care professionals such as therapeuticexperts and physicians, other experts such as ethicists, health economists,
epidemiologists,andstatisticiansmayalsobeconsulted, thoughtheseexpertsarenot
directlyrepresentedhere.
• Patient representatives: The stakeholder of “patient representatives” will not
customarily be individual patients per se. In most instances, it is anticipated that a
patientorganisation(s)willrepresentpatients’views.Although,forsomerarediseases
whenaformalpatientorganisation isnotestablished,patientsand/ortheircaregivers
mayofferkeyinsightsthroughanadaptivepathwayengagementprocess.
• ProcessReflections: Inthisreport,“processreflections”arerepresentkeytimepoints
orperiodswithintheadaptivepathwaymodel.
IMIADAPTSMART|D2.05andD3.02 8
Proposalforthecoremultistakeholderengagementandassessmentmomentsenablinganadaptivepathway
Withinthebelowdiagram,eachproductlife-cylephaseissymbolisedbyabluecog.The
separate cogs are comparatively sized to represent the characteristic duration of the phase
duringthelifespanofatypicalmedicine.Thetophalfofthefigureincludestheassessmentor
decisionmomentsbythestakeholderrepresented.Althoughthesemomentsmaybeinformed
bymulti-stakeholderinputs,intheend,thedesignatedstakeholdermakesanassessmentand
ultimatedecisionbasedontheirrespectiveremits.Withinthebottomportionofthediagram,
momentsofmulti-stakeholderengagementareillustrated.
AdaptivePathwayMoments DescriptionoftheProcessStepsandDecisionPoints
Developmentassessment Priortothemedicinedevelopermakingadecisionforaproducttoenterdevelopment,the
developerassessestheopportunityofapotentialmedicine,forexample,consideringgeneralinputand/orguidancefromvariousstakeholders.
Agreeonadaptivepathway(AP)asoptimalapproach
Basedontheengagementcriteria,stakeholdersofferacollective,documenteddecisionunder“safe-harbour”discussionsregardingtheiragreementtoprogresswithanadaptivepathwayengagementapproachforaparticularpotentialmedicine.
Iterativedevelopmentplan Aniterativedevelopmentplanisanevolvingproductdevelopmentstrategyproposedbythe
developerandadaptedthroughmulti-stakeholderengagement.Theevidencegenerationplanisdiscussedamongthestakeholdersandtakesintoconsiderationthecriticalquestionstobeaddressedpreliminarilyinordertoalsosupportsubsequentpricingandreimbursementdecisionsatthenationallevel.Theiterativedevelopmentplanisuniqueandextendsovera
IMIADAPTSMART|D2.05andD3.02 9
significantperiodoftime(andlikelyiterations)supportinganadaptivepathwayfromthebeginningtotheend.Evidencegenerationmayinvolvemultipleclinicaltrials,single-armstudiesorasinglePhase2trialorRWEdependingonthespecificproduct.Forexample,• Agivenplanconsiderstheevidencegenerationcommitmentsandfollow-upmeasuresfor
aconditionalmarketingauthorisation(CMA),forpharmacovigilanceand/ornewstudiestoexpandthepatientuse.
• Itshouldalsoconsiderthepostauthorisationevidencegenerationmeasuresnecessarytomeetthepricingandreimbursementrequirementsandanagreementonthetimelinesforreviewandreassessment.
Regulatoryauthorisation Regulatorydecisiontoauthoriseamedicineforpatientuseinagiventherapeuticindication(s).
Appraisalandpricingconsiderations
AttheEUlevel,considerationsforthepre-aswellaspost-authorisationdatacollectionplantakeplacepriortoauthorisationasacomponentoftheiterativedevelopmentplan.Atthenationallevel,discussionsonpricingandreimbursementfollowregulatoryauthorisationandreflecttheiterativedevelopmentplan.
Patientuse Thefoundationforanadaptivepathwayconceptistoprovidepatientswhoexperienceahighunmetmedicalneedwithaninitialorimprovedtreatmentoptionthroughtoolstoenableon-labelprescribing.Inparalleltoanadaptivepathway,patientusemayalsocomprisefurtherclinicaltrialsprogramsasappropriate.
Regulatorypost-authorisationdecisions
Regulatorydecisionsarealsotakenduringthepost-authorisationphase.Forexample,regulatorydecisionsmayleadto:• wideningorcontractionofthemarketingauthorisation,e.g,.intermsofeligibletreatment
population,or• reinforcementofsafetymeasures,or• grantingofafullmarketingauthorisationfromaninitialCMA,or• authorisationofanewindicationwithorwithoutfollowupmeasures.
Pricingandreimbursementreassessments
Predefinedmomentswhendecisionsonpricingandreimbursementbynationalauthoritiesarereviewed.Theconclusionofthereassessmentsmaytriggerpotentialadjustmentsofreimbursementorpriceconditionsatthenationallevel.Asanexample,anegativereassessmentcouldleadtotheendofreimbursementfortheindicationinscope.
The above model illustrates the core moments of an adaptive pathway and each is
described in detailwithin this report. While these adaptive pathwaymoments are depicted
two-dimensionally,ofnote,someoftheengagementmomentswilllikelyoccurinparalleland
iterativelyastheprocessprogresses.Theconceptualadaptivepathwayapproachisproposed
within thecurrentEuropeanandnational legal frameworks. It isnot the intention tosuggest
changesintheselegalframeworks.
It is anticipated that the full implementation of the conceptual adaptive pathway
approachmayhavesignificantadvantagesforeachstakeholder.Foremost,therefore:
• Patientswillexperiencebenefitsthroughtheopportunitytoprovideorganisedinputtonew
optionsfortheirmedicalneedsandearlieraccesstothesenewmedicines.
• Regulators have alreadymechanisms in place to facilitate adaptive pathway interactions,
through multi-stakeholder scientific advice, and could make use of different regulatory
instrumentssuchasconditionalmarketingauthorisation(CMA)andriskmanagementplans.
• Health-care professionals or therapeutic experts will be able to contribute expectations
about themedicine’s use and positioningwithin the currentmanagement of the disease
andassistinframingpotentialclinicalvalue.
IMIADAPTSMART|D2.05andD3.02 10
• Pricing and reimbursement authoritieswill have enhanced opportunities to provide early
inputonthedatanecessarytosupporttheirdecisions,andgainaclearerunderstandingof
theevidencepackagethatwillbeavailableattimeofinitialregulatoryapproval.Pricingand
reimbursement authorities will also be able to shape the post-authorisation evidence
generationplan,anticipate indicationsandusageof themedicine thatwillbeauthorised,
and gain earlier insights into horizon scanning and budgetary planning activities. The
framework foresees an initial negotiation moment for payers as well as reassessment
moments where the collected evidence is reviewed and pricing and reimbursement
decisionspotentiallyrevisitedbasedonthedata.
• Medicine developers will obtain early, and continuous tailored, iterative input on the
development plan to enhance the way in which development and post-authorisation
evidence generation will transpire. Early interactions could expedite local pricing and
reimbursement decisions and assist in determining suitable managed entry agreements
(MEAs).
While thesepotential benefits arenoteworthy, therearepotential challenges suchas
stakeholder capability and resource implications that must likewise be considered, and are
further mentioned within this report. The multi-stakeholder consultation will also provide
greater visibility to the trade-off choices that stakeholders must consider. In sum, adaptive
pathways will facilitate the utility of the generated data – both pre- and post-marketing
authorisation (MA) – allowing stakeholders to make earlier, well-informed decisions with a
mechanismtoreevalutethesedecisionsasmoreinformationbecomesavailable.
Developmentassessment
As an initial activity (i.e., represented by in the figure), the medicine developer5
shouldassesstheopportunity(e.g.,severityofdisease,characteristicsofapotentialmedicine,
regulatory therapeutic guidance and tools, pricing and reimbursement authorities’ data
interests) of each potentialmedicine, for example, seeking input from various stakeholders.
This canalreadyoccur inpractice,but for completeness this step is added in the conceptual
framework since adaptive pathways places a special emphasis on high unmet need. It is not
anticipatedthatthiswouldbeaninteractionwitheachstakeholderatthisdevelopmentstage
giventhenumberofproductsthatareevaluatedduringdiscoveryandpre-clinical.Rather,the
medicinedevelopermaywishto informallyseek input(e.g., frompatientrepresentativesand
health-careprofessionals)and/orassesstheevolvingcontextualenvironmentinwhichtheyare
5Medicinedeveloperismodeledforillustrativepurposesasacompany;however,itcouldbeamedicinedeveloperfrommanyothersettingssuchasacademia,advocacyorganisation,etc.Assuch,someprocessesmaybeslightlymodifieddependingonthenatureordisciplineofthedeveloper.
IMIADAPTSMART|D2.05andD3.02 11
operating(e.g.,fromtheperspectivesofregulators,pricingandreimbursementauthorities)to
betterunderstandatherapeuticareaorcondition.
Forexample, themedicinedeveloperwill listpatientorganisations,evaluate registries
or assess the most recent therapeutic area guidelines written by regulators, health care
organisationsandpricingandreimbursementauthoritiesaroundtheglobe. Inordertomake
aninformeddetermination,thedeveloper’sdecisionshouldreflectearlyupontheunmetneeds
ofpatients and thebroaderhealthcareecosystem, aswell thepotential valuepropositionof
the medicine. The medicine developer would typically consider a range of development
approaches for each of its products, and portfolio tradeoff options across products even
amongst those being developed for the same indication. At this early stage, the inputs
primarily involve definingwhat the actual unmet patient need is to stimulate discovery and
development.Alongwiththeadaptivepathwayengagementcriteria,theseassessmentsinform
andinfluenceearlyconsiderationofthepotentialvalueofusinganadaptivepathwayapproach.
Agreeonadaptivepathway(AP)asoptimalapproach
Anadaptivepathwayapproach isonly feasible if involvedstakeholdersagree that the
medicine shows sufficient promise and – as a starting point for additional considerations -
fulfills an unmet need. Considerations also include an assessment that the risks are likely
proportionate,acceptable, andcanbemanagedby theproposed strategy. For thispurpose,
ADAPTSMARTproposedengagementcriteriaforanadaptivepathway(seeIntroduction).Theessential element for this decision is the willingness of each stakeholder in contributing
resourcestoprovidemeaningfuladvicetobeconsideredintheevidencegenerationplan( ).
Theprocessofreachingagreementonadaptivepathwayengagementisnotdetailedasofyet.
However,thisadaptivepathwaymomentisexpectedtooccurduringeitherthepre-clinicalor
earlyclinicaldevelopmentstages.Itisalsoclearthatitwillinvolveadditionalresourcesofeach
stakeholderandrequirethefacilitationofaprojectmanager.Therolesandresponsibilitiesof
such a project manager as well as their affiliation need to clarified further (see Concludingremarksandoptionsforfuturework).
Iterativedevelopmentplan
An“iterativedevelopmentplan”isadevelopmentplaninitiatedbythedeveloper,which
integratesthefeedbackfromthestakeholdersandoutlinesthedevelopmentofthemedicine
during its lifespan, including the phase after initial authorisation.Within this report iterativedevelopment is applied as a broad term also accounting for the generation of additional
evidenceand/oruncoveringofnewfactsastimeprogresses. The iterativedevelopmentplan
extendsoverasignificantperiodoftime(andinteractions)andsupportsanadaptivepathway
approachfrombeginningtoend. It isthevehicleformulti-stakeholderengagementatcritical
IMIADAPTSMART|D2.05andD3.02 12
developmentmoments.Basedonthedataandinputcollected,thedevelopmentplanwill be
regularlyadjusted( ).
It is envisaged that development planning discussions likely begin as informal, safeharbour interactions, andprogress tomore formal interactions such as joint or parallel EMA
andHTAscientificadvice(SA).ThePRIMEschemeofferedbytheEMAmaybeagoodstartto
theprocess.Scientificadviceandstakeholderdiscussionsshouldoccurinanearlyanditerative
mannerinordertoinformthedecisionpointsalongtheproductlifespan.Multi-stakeholderSA
offertheplatformforstakeholderstoalignontheevidencepackagerequiredtodemonstratea
positivebenefit-riskprofileandsupport regulatoryauthorisation. These interactionswillalso
be used to consider the critical questions to be addressed, which warrant the discussion of
plansfordatacollectionpre-andpost-authorisation.Scientificadviceconsidersmanyaspects
ofproductdevelopmentandevidencegenerationsuchasbiomarkers,surrogateandcomposite
endpoints, subpopulations, chemistry,manufacturing and control (CMC) issues, adaptive trial
design, patient reported outcomes (PROs) and key milestones to review post-authorisation
evidencerequirements.
For developers, scientific dialogue opportunities could assist in identifying the
expectations of regulators and pricing and reimbursement authorities in terms of evidence
requirements, which the developer can take into account when designing the medicine’s
clinical development plan. The early dialogue may also inform the developer's assumptions
aboutthepotentialimplicationsoftheevidencerequirementsforsubsequentnationalpricing,
reimbursement, and funding conditions. Having all relevant stakeholders together to discuss
tools,methodsandsourcesofdatamay increasethemutualunderstandingofthechallenges
related to the generation of the required evidence, help inform potential tradeoffs, and
ultimatelyincreasetheconfidenceinfuturestudyresults.
In terms of data generation during preliminary evidence generation or clinical
development, at ahigh level, this approachenvisages theavailabilityof iterative results (i.e.,
both ‘early’ and ‘late’ phase study results). Under an adaptive pathway, it is envisaged that
clinical research will follow a more continuous design enabled by integrated stakeholder
dialogue.Asispossibletoday,theearlydialoguemightfacilitatestakeholderagreementonthe
design of initial trials that focuses on high unmet need in more severe populations where
shorterand/orsmallertrialsmayallowforthedetectionoftreatmenteffect. Also,discussed
amongstthestakeholdersisthepotentialintegrationofRWEasanadjuncttorandomisedCTs
(RCTs).RWEandCTsinthepost-authorisationsettingmaybeconsideredtorefineandconfirm
early benefit-risk assessments or the clinical effectiveness of the medicine after the initial
authorisation.Thesame iterativedevelopmentplanwill supportexpansion (orcontraction, if
thenewdata isnotsufficientlysupportive)of thepatientpopulationand/ornew indications.
IMIADAPTSMART|D2.05andD3.02 13
However,theextenttowhichtheuseofRWEmightbeusedinsupportofRCTswillbehighly
dependentonthenatureoftheproduct,endpointsused,methodologies,feasibilitytocollect
qualityevidence,andthecurrentorproposed indication.TheappropriateroleofRWEwithin
thisadaptivepathwayscontextwillneedtobedeterminedonacase-by-casebasisandplans
will need to be tailored to the product in question. Other possible information and data
changesunderanadaptivepathwayinclude:increaseduseofexploratoryhypothesesbuiltinto
adaptivetrials,greateruseofPROs,surrogateandbio-markers (e.g.,co-developmentofdrug
andbiomarker),andconfirmatorystudiescontinuingpost-initialauthorisation(e.g.,pragmatic
trials with inclusion criteria reflecting real-world practice and less-standardised treatment
protocols).
During these iterative development planningmoments, as evidence accumulates it is
expectedthatthedevelopmentstrategywillbediscussed,thentheplanbeadjustedandlater
reassessed, basedon stakeholder dialogue and scientific advice. Notably, there is a need to
identify the requisite competencies and expertise, and then to allocate and mobilise the
required resources of stakeholders throughout the iterative development planning
engagement. Leading up to initial marketing authorisation, the iterative development plan
discussionsmay include a number of topics across disciplines though pertinent to the post-
authorisation phase. In the peri-authorisation period there are stakeholder discussions and
agreements regarding the post-authorisation approach such as risk management planning,
measuresfornextmilestoneengagementmoments(e.g.,afteracertainnumberofpatientsuse
themedicineorafteragiventimepoint).Theevidencegenerationplanisdiscussedamongthe
stakeholders and considers the critical questions to be addressed in order to also support
subsequent pricing and reimbursement decisions at the national level. Further examples of
discussion and agreement topics include, the collection of additional evidence through RWE
(e.g., registries), post-authorisation safety studies (PASS), post-authorisation efficacy studies
(PAES),andprospectivelyplannedfutureindications.Managedentryagreementsarediscussed
with national pricing and reimbursement authorities during pricing negotiations, though it is
expected that theywill draw on the evidence generation plan for their data needs. As the
medicineisappropriatelyusedbypatientsintherealworldsetting,stakeholderswillconfirm
benefit-risk,assessappropriateutilisation,and/ordemonstratevalue.
RegulatoryAuthorisation
Authorisation( )isthedecisionbytheregulatoryauthoritytoapproveamedicinefor
patientuseinagiventherapeuticindication(s)basedontheassessmentofefficacy,safetyand
quality. Under an adaptive pathway approach, it is anticipated that authorisation may be
conditional(i.e.,CMA)orafullMAinawelldefinedpopulation.
IMIADAPTSMART|D2.05andD3.02 14
Appraisalandpricingconsiderations
The Member States have the sole responsibility for decisions with regard to
reimbursement and pricing. The adaptive pathway moment of pricing and reimbursement
authoritiesconsiderations( ) includestheassessementofthemedicine’srelativeefficacyor
effectiveness, the pricing negotiations and potentialmanaged entry schemes/conditions. As
pricingandreimbursementprocessesaredifferentineachMemberState,inthisreport,only
high-level remarks will be offered regarding how an adaptive pathway approach could be
implementednationally.
Thepriceofthemedicineforthegivenindication(s)isdeterminedbythelocalpriceand
reimbursementauthorities.Asanoption,MEAsareformalarrangementsbetweenadeveloper
and a payer or healthcare provider that enables access to (coverage/reimbursement of) a
health technology (such as a medicinal product) subject to specified conditions. These
arrangements can use a variety of mechanisms to address uncertainty about the clinical
benefit, utilisation or budget impact of the technology in clinical practice conditions. Under
adaptive pathways, themedicine developerwould engage in parallel SA involving regulators
and HTA bodies to discuss a prospectively planned and integrated evidence generation plan
addressingtheregulatoryrequirementsandtoconsiderthecriticalquestionsfromdownstream
pricingandreimbursementauthorities.
The parallel SA discussions prior to the initialmarketing authorization could facilitate
betteralignmentofstakeholdersaroundtheevidencepackageexpectedtobecomeavailableat
the time of the initial regulatory authorisation as well as the evidence generation plan and
resultingdataexpectationsatsettimelinespost-authorisation.Inprinciple,theinitialevidence
packagewouldsupportboth the regulatoryauthorisation (i.e.,provideevidenceofapositive
benefit-riskprofile)andenabletheinitialpriceandreimbursementnegotiationsanddesignof
suitable MEAs (or alternative pricing and reimbursement approaches) across the different
national juridictions. Typically, payment models would have to be aligned with national
processes and be tailored to the product in question and or preferences of payers and
developers. Underthisconceptualadaptivepathwaymodel, localHTArecommendationsand
reimbursementdecisionswill hopefully rapidly follow the regulatorydecision sinceHTAsand
somepayers(asrepresentedby“pricingandreimbursementauthorities”inthismodel)would
havebeeninvolvedintheseearlyanditerativeSAmoments.
The evidence accumulated post-authorisation would be re-assessed by the relevant
stakeholdersaccordingtopre-settimelinesandmayinsomeinstancesandgeographiesleadto
a renegotiationof the initial price andor reimbursement conditions. The termsof theMEAs
IMIADAPTSMART|D2.05andD3.02 15
may specify the consequences on price and reimbursement conditions of successful and
unsuccessful confirmation of the value proposition. In this context, an adaptive pathway
approachmayrequireanadaptivepricingapproachwithpriceandconditionsnegotiatedona
percountrybasisandrevisitedatsetmilestonesinlightoftheresultsoftheevidenceavailable
post-authorisation.
Patientuse
Thefoundationforanadaptivepathwayconceptistoprovidepatientswhoexperience
ahighunmetmedicalneedwithaninitialorimprovedtreatmentoptionwithintheindication(s)
of the marketing authorisation as early as a positive benefit-risk is established ( ). The
engagementcriteriaforadaptivepathwaysunderscorestheneedforsufficientassurancethat
the medicine will reach the right patient and only the right patient. (Note that these
considerationsarealso important factors fornon-adaptivepathwaymedicines.) If this isnot
feasible, an adaptive pathway approach might not be the best solution for a particular
medicine.Underanadaptivepathway, the topics forwhich it isnecessary to informpatients
aboutusingamedicineshouldbediscussedincludingbythe‘patient’stakeholdersthroughthe
adaptivepathwayengagementmoments.
Promotionofoff-labelusewillbecontrolledandaccesstoproductusedon-labelcanbe
furtherrestrictedbyreimbursementcriteriaatthenational level. However, inmostMember
States,health-careprovidershavethefreedomtoprescribeforthepatientbenefitamedicine
outside of its approved indication(s). (Note that in some Member States this may require
regulatoryauthorization.)Incaseofauthorisationunderanadaptivepathway,toolsshouldbe
considered tooptimise theappropriateuse. Forexample, in addition to theSmPC, theblack
triangle indicating additional monitoring, the risk management plan and the follow up
measures contained in the iterative development plan (e.g., ongoing CTs), therapeutic
guidelinesorrestrictedaccessthroughacenterofexcellenceshouldbeconsideredwithhealth
practitioners.Themeasureswilldepend,inpart,uponnationallawsandcanbediscussedwith
nationalauthoritiesduringtheaccessnegotiations.Thesuiteofoptionsshouldbeconsidered
under early stakeholder discussions. Finally, consideration of early patient access (e.g.,
compassionate use) may occur on a case-by-case basis accounting for national laws and
systemsandthequalityofthedatapackage.
Considerationtowidentheindication(s)
This proposed adaptive pathway foresees the possibility of an initial MA in a well-
definedpatientsubgroupandsubsequentconfirmationorwideningoftheindicationtoinclude
IMIADAPTSMART|D2.05andD3.02 16
additionalindicationsinalargerpatientpopulationbasedonadditionalevidencegathered(e.g.,
RCTs,RWE)and/oraCMAwhereinitialdataaresupportedorconfirmedthroughthecollection
ofpost-MAdataontheproduct’suseoradditionalCTs.
Regulatorypost-authorisationdecisionsandpricingandreimbursementreassessments
Theserepresentacommitmenttowardsstakeholderstoprovidemoredata,aneedfor
justificationincasethedeveloperneglectstofollowup,andawaytoenactconsequencesifthe
data are not generated or do not confirm the early assumptions. The multi-stakeholder
dialogue during the iterative development plan offers the opportunity to discuss upfront
expectationsandsomeofthedevelopmentandfeasibilitychallengesthatmightemerge.
Thepost-authorisationaccess adaptivepathwaymomentsof regulatorydecisionsand
pricingandreimbursementreassessments(representedas and ,respectively)occurasper
theconditionsagreeduponatinitialassessmentandcompiledintheevidencegenerationplan.
Thesearethemomentsplannedbystakeholderstoreviewthecommitmentsanddataagreed
upon in the iterative development plan. These decisions are taken and reassessments are
conducted separately by the various stakeholders. However, stakeholders, including
developers,shouldinformeachotheraboutdecisionstaken,asthesemayhaveconsequences
fortheotherstakeholders involved. Notethatthenatureoftheseinteractionsneedsfurther
deliberationandclarification.
Importantly,asinthepre-authorisationadaptiveinteractionmoments,duringdecision
and reassessment moments, each stakeholder maintains their well-defined remit and
responsibilities:
• Regulatoryauthoritiesmonitor the fulfillmentofobligationsand reviewrespective
data generation (e.g. as part of a CMA) with the possibility subsequently to take
regulatoryaction(e.g.variationorwithdrawal),andconductregularreviewsofthe
benefit-risk balance based on an assessment of any other collected post-MA
evidence.
• Health-careprofessionalsandpatientrepresentativesmaybe involved inadjusting
therapeuticareapracticeguidelinestoaccommodatenewinformationobtained.
• Pricingandreimbursementauthoritiesmayconductareviewoftheoptimalusageof
amedicine based on assembled RWE. Pricing and reimbursement reassessments
willoccuratpredefinedtimepointsandmaytriggerpotentialadjustmentsofprice
orreimbursementconditionsatthenationallevel.
Itisforeseen,inthisconceptualframework,thatinsomeinstancesthepost-authorisationdata
may not fully support the initial indication or patient population. In these situations,
IMIADAPTSMART|D2.05andD3.02 17
stakeholderswould takeefforts to collaboratequicklywithanappropriate reaction toensure
patients’bestinterests.Asaconsequence,itmaybenecessarytodiscontinueormodifyearly
access (i.e., patient usage, contract) as per the post-authorisation data for this particular
indication.
NoteonTraditionalSequentialModelofInteraction
The possibility exists for a product which was once progressing under an adaptive
pathway to no longer meet the engagement criteria, and therefore, lose the benefits (seeexamplesofanticipated‘benefits’introducedunderthe“Proposalforthecoremultistakeholder
engagementandassessmentmoments”sectionabove)ofthisapproach.Thiswillapplywhen
anadaptivepathwayapproachceasestoaddvalueandstakeholdersdecidetostopusingthis
route to support the pre- or post-authorisation development of a specific medicine. An
adaptive pathway approach has been conceptualised here as a scientific framework using
existing tools and standards and assisting in their holistic implementation through the
prospectiveengagementof stakeholders. Exiting this coordinatedengagementapproachwill
primarilyaffectanyadditionalsupportofferedthroughmulti-stakeholderconsultationsandthe
emphasisonearlyaccess,thoughthetoolsandstandardswillstillbeavailable,asapplicable,to
themedicinedeveloper,outsideofanadaptivepathwayapproach.Themechanismofceasing
anadaptivepathwaysapproachrequiresfurthercarefuldeliberationstotakeintoaccountthe
variousconstituentstakeholders’considerations.
IMIADAPTSMART|D2.05andD3.02 18
Concludingremarksandoptionsforfuturework
This report proposes a framework with pictographic representation of an adaptive
pathwaycontainingkeymoments,eventsandinvolvedstakeholders,ineachphase.Thismodel
ispurposefullypresentedrathersimplistically in this firstevolution,acknowledgingthatthere
remainseveralquestionstobeanswered–bothuniquetoeachindividualpotentialmedicine
aswellastofullimplementationofanintegratedadaptivepathwayapproach.
Somekeyquestions(amongstothers)arisingfromthisworkareasfollows:
i) HowcanMemberStatesthatdonothavepricingandreimbursementauthority
resourceseffectivelycontributetoearlyinputwithinthisframework?
ii) Howwillstakeholderresourcingbeplanned,managed,measuredandassessed(in
termsofimpact)?
iii) Towhatextent,andhow,areformalinteractionsbetweenstakeholdersgoverned
underanadaptivepathway?
iv) Howbestshouldtheprocessensurethenecessarypatientinputs?
v) Howcanasingleiterativeevidencedevelopmentplanbemaintainedwhilesupporting
MemberState-specificpost-authorisationprocessesregulatedbynationallaws?
vi) Whatisthenature,remit,andstakeholderaffiliationofaprojectmanagerforan
adaptivepathwayfromstarttofinish?Wheredoespotentialprojectmanagement
expertiseandresourcescurrentlyreside?
The success of adaptive pathways, at least initially,mayhingeondemonstrating true
value via ‘live assets’ going through thepathwayand integrating those key learningsmoving
forward. Greater shared experiences of pricing and reimbursement authority evidence
requirementsacrossMemberStates,coupledwiththeirearlyconsiderationwithinanadaptive
pathway(onaproductspecificbasis)wouldbeavitalenablerforthedevelopment,pricingand
reimbursement processes, and reassessment decisions, of a successful adaptive pathway
productdevelopment.
The nature of the early informal, and later formalmulti-stakeholder interactions,will
require a delicate balance between maintaining appropriate levels of transparency versus
confidentiality, being respectful to the political mandate of each stakeholder’s involvement,
andensuringmutual trust thateachstakeholder is,and remainscommitted to, thedecisions
andprocessestheyhaveagreed.Thedevelopmentand implementationofsuchamechanism
requirescarefulconsideration.
IMIADAPTSMART|D2.05andD3.02 19
Appendix1:MoreDetailedDescriptionofeachAdaptivePathwayPhase
InAppendix1,thedistinctphasesordisciplinesofmedicinedevelopment,authorisation
and post-authorisation access are reviewed in greater detail. This section of the report is
intended to highlight additional technical aspects of an adaptive pathway as supportive
information to the core adaptive pathwaymoments previously outlined. Over time, further
processanddecisionstepdetailscouldbeamplifiedbyADAPtSMARTusingAppendix1asthe
conceptualframework.Keycomponentsoftheadaptivepathwayconceptualmodelinvolve:
(i) an evolution from the traditional sequential approach with limited concerted
multi-stakeholderinteractions,involvingadaptiveandoverlappingprocesses;
(ii) useofthesametoolsbutinadifferentorderinmanycases;and
(iii) an emphasis on early multi-stakeholder interactions, – with predominantly
prospectiveplanningandstrategising.
Severalyearsago, theconceptwasgiven the titleofMedicinesAdaptivePathways toPatients,abbreviatedasMAPPs.Fittingly,asdescribedinthisconceptforaseamlesspathway
throughadaptiveinteractionsofstakeholders,anindividualproductwouldtakeadiscretepath
through the integrated phases of an adaptive pathway approach. Consequently, one can
furthercorrelate“MAPPs”toa ‘map’bywhichthecourseofanactualmedicine’s life-cycle is
chartedthroughtheinvolvementofengagedstakeholders.Withinthesubsequentdiagrams,a
‘compass’ (represented below) offers an orientation to the full complement of proposed
adaptivepathwaymoments, significanteventsandgenerateddatanecessary tonavigate the
passageforanewmedicine.Thesefiguresillustratetheadditionaladaptivepathwaymoments
beyondtheessentialmilestonesdescribedearlierinthisreport.Someofthemoments,events
anddatamayoccuroverarangeoftimepointsoracrossanumberofphasesandmaynotbea
singularactivity. Forreferenceandcontrast,thetraditionaldevelopmentapproach, including
thekeyprocessesandtools,isincludedinAppendix2.
IMIADAPTSMART|D2.05andD3.02 20
Pre-clinicalAdaptivePathwayMoments
AdaptivePathwayMoments DescriptionoftheProcessStepsandDecisionPoints
Developmentassessment Aspreviouslydescribedincoreadaptivepathwaymoments.
CMCdevelopment SomemodificationstothetraditionalCMCdevelopmentparadigmareforeseenandshould
beconsideredearlyforaproductthatmayfittheadaptivepathwayengagementcriteria.
Considerationofspecialdevelopmenttools
Themedicinedevelopershouldgiveinitialconsiderationofthespecialdevelopmentand/orregulatorydesignationsandtools(e.g.,PRIME)todetermineifanyareapplicableforaparticularpotentialmedicine.
CMCDevelopment
During the pre-clinical phase,much of the activities are commenced by themedicine
developer. Chemistry, manufacturing and control (CMC) development considerations may
needtobeinitiatedearlierforpotentialproductsinordertoenteranadpativepathway.Inthe
diagram, the CMC development ( ) adaptive pathway moment reflects that some
modifications to the traditional paradigm are foreseen and should be considered early for a
product thatmay fit theadaptivepathwaycriteria. By itself,CMCdevelopment isacomplex
seriesofactivitiesratherthanasinglemoment.CMCmaytakeaprominent–andrate-limiting
role–especiallyforadvancedtherapymedicinalproducts(ATMPs)whichmayrequirethestart
ofstakeholderengagementevenearlierthanforconventionalproducts.
IMIADAPTSMART|D2.05andD3.02 21
Considerationofspecialdevelopmenttools
The symbol represents the general periodof timeduring development inwhich a
developer should initiate discussions about the potential applicability of the special EU
designations,developmentandregulatorytools–i.e.,reflectiononusingthevarioustools.For
example, amongother tools, conditionalmarketingauthorisation (CMA),orphandesignation,
PRIMEscheme,multi-stakeholderscientificadvice (regulatoryandHTAs). Earlyconsideration
oftheuseofsomeofthesetoolsincludingnoveldevelopmenttoolscouldhelpinformclinical
trial protocols. An initial, informed strategy will also help the medicine developer in
preparationsforthemulti-stakeholderadaptivepathwayengagementmomentsthatfollow.
IMIADAPTSMART|D2.05andD3.02 22
PreliminaryEvidenceAdaptivePathwayMoments
AdaptivePathwayMoments DescriptionoftheProcessStepsandDecisionPoints
Assignmentofprojectmanager Aprojectmanagementresourcecoordinatesthemulti-stakeholderdecisiononcommitment
toanadaptivepathwayandtheiterativedevelopmentplanning.
AgreementonMAPPsengagement
Aspreviouslydescribedinadaptivepathwaymoments.
Adaptivedevelopmentplan Aspreviouslydescribedinadaptivepathwaymoments.
Assignmentofprojectmanager
Thepreliminaryevidencephaseoftheproposedadaptivepathwayintroducesanumber
of instrumental process modifications compared to typical development approaches – all
intendedtoenhancethestakeholderinteractionsinordertogaininsightsontherelevanceof
data generation and facilitate timely patient access. Through an appreciation of the
complexities of logistical coordination, nuanced remits and responsibilities, and differing
processesofthestakeholders,aprojectmanager(referencedasPMinthepaperand inthe
diagram) is necessary to coordinate the logistics and manage the enhanced, iterative
engagement moments. The PM should serve as a consistent point of contact for all
stakeholderswhowillprovideinputintotheiterativedevelopmentplan.Thedetailedrolesand
responsibilitiesofthePMneedtobefurtherexplored(seeConcludingremarksandoptionsfor
futurework).
IMIADAPTSMART|D2.05andD3.02 23
RegulatoryReviewAdaptivePathwayMoments
AdaptivePathwayMoments DescriptionoftheProcessStepsandDecisionPoints
Regulatorconsiderationofspecialtools
Itshouldbepossibletoidentifyapplicable,earlycandidatesforCMAandAA.
Regulatoryauthorisation Aspreviouslydescribedinadaptivepathwaymoments.
Regulatorconsiderationofspecialtools
Wellbeforethemarketingauthorisationapplication(MAA)issubmitted,andfollowing
theprospectiveproposalbythemedicinedeveloper,finalconsiderationsshouldbegiventothe
applicabilityofspecialregulatoryauthorisationtoolssuchasCMAandacceleratedassessment
or AA ( ). These actions will continue the considerations during iterative development
planningtoearlyprepareforpost-authorisationdatacollectionactivities.
IMIADAPTSMART|D2.05andD3.02 24
Post-AuthorisationAccessAdaptivePathwayMoments
AdaptivePathwayMoments DescriptionoftheProcessStepsandDecisionPoints
Appraisalandpricingconsiderations
Aspreviouslydescribedinadaptivepathwaymoments.
Measurestoenableon-labelprescribing
Considerationsandtoolstoenabletheprescriptioninthedesiredpopulationtobeacceptablyconsistentwiththeauthorisedtherapeuticindication(s).
Patientuse Aspreviouslydescribedinadaptivepathwaymoments.
Iterativedevelopmentplan Aniterativedevelopmentplaninthepost-authorisationsettingreferstoanevolving
productdevelopmentstrategy,followinganinitialMAdecision.
Considerationtowidentheindication(s)
CasesofaninitialMAandreimbursementofamedicinalproductwithinawell-definedpatientsubgroupandasubsequentwideningoftheindicationtoalargerpatientpopulation
Regualtorypost-authorisationdecisions
Aspreviouslydescribedinadaptivepathwaymoments.
Pricingandreimbursementreassessments
Aspreviouslydescribedinadaptivepathwaymoments.
Measurestoenableon-labelprescribing
Particularlyapplicabletotheearlypost-authorisationtimeframe,thisadaptivepathway
moment represents the multi-stakeholder discussions and agreement on tools to enable
prescription in the desired population with usage to be acceptably consistent with the
authorisedtherapeuticindication(s).Therearemeasuresavailabletomultiplestakeholdersto
IMIADAPTSMART|D2.05andD3.02 25
help facilitate thisactivity. Forexample,dependingon the jurisdiction,approachesofpayers
andguidelinedeveloperscouldbeharnessed(seesectiononPatientUse)( ).
Iterativedevelopmentplan(post-authorisation)
An iterative development plan after marketing authorisation reflects the evolving
productdevelopmentstrategy,which isagile inaccommodatingtheviewsofthestakeholders
( ) gained through multi-stakeholder interactions. Planning for post-MA development is
alwaysinitiatedinthepre-authorisationphaseandwill includeconsiderationsonthemeritof
real world evidence (RWE) collection and analysis, and adaptive trial designs to answer the
relevantquestions,but continuespost-MAandcanbeviewedasa cohesive, singularplanas
previously mentioned. As the medicine is used by patients in the real world setting,
stakeholderscontinuedialogueonadditionalevidentiaryneedstoconfirmbenefit-risk,assess
appropriate utilization, and/or demonstrate value. Likewise, the post-MA development plan
iterationmomentsshouldcontinuetobeorganisedbyaprojectmanager. Theseaspectsare
purposelypresentedanddiscussedatageneral,conceptuallevelwithinthispaper.
IMIADAPTSMART|D2.05andD3.02 26
Appendix2:TraditionalSequentialDevelopmentandPost-AuthorisationAccess
This diagramdepictes a collated and high level summary of the key R&D and patientaccessphases,andkeyeventsandinteractionswithkeystakeholders,astheytypicallytranspiretoday. This provides a useful comparative reference to the proposed conceptual adaptivepathwayapproach.
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