EthicalandLegalAspectsofAdaptiveDecisionMaking

October2017

The work leading to these results was conducted as part of the ADAPT SMART consortium(Accelerated Development of Appropriate Patient Therapies: a Sustainable, Multi-stakeholderApproach from Research to Treatment-outcomes). For further information please refer towww.adaptsmart.eu.Thispaper is theresultof thecollective input fromworkinggroupD3.08andonlyreflectstheviewsoftheauthors.

ThisprojecthasreceivedfundingfromtheInnovativeMedicinesInitiative2JointUndertakingundergrant agreement No 115890. This Joint Undertaking receives support from the European Union’sHorizon2020researchandinnovationprogrammeandEFPIA.

Contents

1.ExecutiveSummary................................................................................................................................................................4

2.Introduction................................................................................................................................................................................5

2.1.Ethicalandlegaluncertaintiesoverlapandaffectdifferentstakeholdersdifferently.........................6

2.2Background............................................................................................................................................................................6

3.Methodology...............................................................................................................................................................................7

3.1Approach.................................................................................................................................................................................7

3.2Semi-structuredinterviewsandAnalysis.................................................................................................................8

4.1Overallresultsandrecommendations.......................................................................................................................9

4.1.1LegalChallenges..........................................................................................................................................................9

4.1.2Ethicalchallenges.....................................................................................................................................................10

5.Recommendationsandconclusions...........................................................................................................................13

Appendix1.....................................................................................................................................................................................15

Appendix2.....................................................................................................................................................................................16

Table1:MajorLegalThemes..............................................................................................................................................16

Table2:MinorLegalThemes..............................................................................................................................................17

Table3:MajorEthicalThemes...........................................................................................................................................18

Table4:MinorEthicalThemes..........................................................................................................................................19

Appendix3.....................................................................................................................................................................................21

Bibliography..................................................................................................................................................................................23

Abbreviations

MAPPs MedicinesAdaptivePathwaytoPatientsADAPT-SMART

AcceleratedDevelopmentofAppropriatePatientTherapies:aSustainable,Multi-stakeholderApproachfromResearchtoTreatment-outcomes

HCP HealthCareProfessionalIMI InnovativeMedicinesInitiativeMA MarketingAuthorizationMS MemberStatesCMA ConditionalMarketingAuthorisationHTA HealthTechnologyAssessmentDHPCs DirectHealthcareProfessionalCommunicationsERN EuropeanReferenceNetworksMS MemberStatesRCT RandomisedcontrolledtrialRWE RealWorldEvidenceSA ScientificAdviceEuNetHTA EuropeanNetworkofHTAsIP IntellectualPropertyP&R PricingandReimbursementGMC GeneralmedicalcouncilGMP GoodmedicalpracticeGMPPD GoodmedicalpracticeprofessionaldevelopmentEPAR EuropeanPublicassessmentreportEUPATI TheEuropeanPatients’Academy

1.ExecutiveSummaryMedicinesAdaptivePathwaystoPatients(MAPPs)canbeviewedasanengagementframeworkwithwhichstakeholderscollectively-throughcoordinatedandrepeateddialogue-prospectivelyplanandusevariousexistingtoolsandproceduresformedicinesdevelopment,marketingauthorization(MA),reimbursement,on-marketuse,andpostmarketingmonitoring,inalifecycleapproach1.ThusMAPPsseekstofosteraccesstobeneficialtreatmentsaddressinganunmetmedicalneedattheearliestappropriatetimeintheproductlife-spaninasustainablefashion.MAPPsisnotanewdesignation,butwilloperatewithintheexistinglegalandregulatoryframework,makingbetteruseofexistingtools,processesandauthorisationroutes.MAPPsproductswillhaveaMAwithaminimaldatapackagethatallowsauthorisation,insmallpopulationsandwiththeneedforlongtermdatacollection,similartothesituationtoday,forexample,withconditionalmarketingauthorization(CMA)ororphanproducts.WithintheADAPTSMARTconsortium,theremitofwork-streamD3.08hasbeentoexploregeneralethicalandlegalissuesthatmayarisethroughtheintroductionoftheMAPPsconcept,theimplicationsforeachstakeholder–inparticular,patientsandhealthcareprofessionals(HCP),andwhatrecommendationscouldbemadetomitigateagainstidentifiedissues.SpecificlegalissuesrelatingtointellectualpropertylawarethesubjectofanotherADAPTSMARTwork-streamandarenotdiscussedhere.

This work stream did not identify any general legal blocks to the MAPPS process,fundamentally because such products are deemed to have reached the required regulatorystandard formarketauthorisation(MA)(albeitwithinasmall clinical indication).Thus it isconsideredthatthereisgreaterchancethatthebenefit:riskassessmentatMAapprovalwillchangewithtime,asmoreinformationontheproductaccumulates.Concernsfrommedicinedevelopers and HCPwere raised that liability claims or legal challenge from patientsmayincrease as a result, although it was acknowledged that liability claims could occur underthesescenarioscurrently.

We found little evidence that prescribers knew the legal status of medicines they wereprescribing–whetherconditionalorfull(standard)MA.Aneducationalopportunityexiststoinformprescribers,sothattheyinturncanexplaintopatientsthenovelnatureofaMAPPsproduct, thedegreeof (un)certainty, andhow itwillbemanaged. Prescribersalsoneed tomaintain an up-to-date knowledge to avoid the accusation by a patient that they have notbeeninformedofapotentialriskorchangeinriskwhichhad,nonetheless,beenidentifiedtoprescribersinapprovedregulatorymaterials.

Likewisenonewethical issueshavebeenidentifiedpersethatarespecifictoMAPPs,butanumber of existing ethical challenges that are present today - with small or restrictivepopulations based on disease or geography, and an emerging post-authorisation evidencebase(e.g.CMAs,orphanproducts,etc)-wereconsideredpotentiallymorelikelytooccur,orhaveagreater impact tooneormorestakeholders.Examples include: theneed forongoingdata collection and the patient and HCP burden this entails, the degree and format ofinformationavailable topatients inorder tomakean informeddecision, implicitorexplicit

patient consent to treatment, the societal need for ongoing data collection to reduceuncertainty set against the patients right to opt out of data collectionwithout jeopardizingaccess, and issues around enacting and maintaining equity of access across healthcaresystemsindifferentMemberStates(MS).

Noneof these legalorethicaluncertaintiesareconsidered tobeablockperseonprogresstowardsabetteruseofadaptivedesignandadaptivelicensing.However,theseuncertaintiesrequiremorecarefulandprospectiveconsideration,takingintoaccountthedivergencesthatmay occur on matters which are national MS competencies rather than those that aregoverned at centralised EU level, and the ethical and legal frameworks that govern thosedifferences-forwhichfurtherresearchisneeded.

2.Introduction

ADAPTSMART is a multi-stakeholder consortium that was set up as a Coordination andSupport Action under the EU Innovative Medicines Initiative 2(1). In bringing togethercompanies, universities, small and medium-sized enterprises, patient groups, payers andregulators in collaborativeandpre-competitiveprojects, it aims to tackleEurope’s growinghealth challenges, and secure the future international competitiveness of Europe’spharmaceuticalindustry.TheADAPTSMARTconsortiumcomprisesallrelevantstakeholdersin the healthcare ecosystem: patients, academics, healthcare-providers, the research-basedpharmaceutical industry, regulators, andhealth technologyassessment (HTA)bodies. SomeEU payers and payer organisations arewilling to engage in constructive dialoguewith theconsortium.

MedicinesAdaptivePathwaystoPatients(MAPPs)isawidely-discussedconceptthat“seekstofosteraccessto[novel]beneficialtreatmentsfortherightpatientgroupsattheearliestappropriatetimeintheproductlife-span,inasustainablefashion.”(1)MAPPsisnotanewdesignation.Itdoesnotcreatenewregulatoryorlegalframeworks.Instead,MAPPsdescribestheprospectiveandplanneduseofvariousexistingtoolsandproceduresformedicinesdevelopment,marketingauthorization(e.g.CMA),reimbursement,on-marketuse,andpostmarketingmonitoring-throughcoordinatedandrepeateddialogueoftheprincipalstakeholders.Thus, “[MAPPs] foresee an initial marketing authorisation (MA) and reimbursement of amedicinal product in a well-defined patient subgroup and subsequent widening of theindication to a larger patient population based on additional evidence gathered and/or aconditional marketing authorisation and conditional reimbursement where initial data areconfirmed [inter alia] through the collection of post-authorisation data on the medicinalproduct’suse.”(2)ItshouldberememberedthattheauthorisationofnewmedicinesisgenerallyundertakenatanEUlevelusingthecentralisedprocedure,orbymutualrecognitionusingthedecentralised

procedure. National licensing is unusual for new medicines. However, matters relating toprescribingrightsandrestrictions,deliveryofhealthcare,and(importantly)EUmemberstatereimbursementremainanationalcompetence.

2.1.Ethicalandlegaluncertaintiesoverlapandaffectdifferentstakeholdersdifferently

New concepts such as those proposed under MAPPs – i.e. the use of multi-stakeholderdialogues, prospective, iterative development processes, and early appropriate access to amedicine - brings potential challenges and raises uncertainties in both legal and ethicalaspects,whichmayaffectoneormorestakeholders.Work-streamD3.08hasbeenexploringthese general issues through semi-structured interviews and consensus building withstakeholderssuchashealthcareprofessionals, industry,regulators,HTAbodiesandpatients(includingpatientorganisations).

Legaluncertaintieshavebeenconsideredfromanumberofstakeholders’perspectives–thepharmaceutical company, the regulator, the prescriber, the healthcare institution, and thepatient - generally asking the question, “If something went wrong, where would liabilityrest?” and then asking, “How might this differ from today, under MAPPs?” The primeconsiderationhasbeenaroundsafetyandefficacy(andanysubsequentchangestothis)butwehavealsoconsideredmatterssuchasaccesstothemedicineafterMA,andrequirementsofpatientleveldatacollectionandparticipationinregistries.Whilstacknowledgingitsexistencein this context, we have not considered legal matters such as intellectual property andregulatorydataprotection,whichmaybeimpactedbyearlierMAandpatientaccess.

Ethicaluncertaintieshavegenerallyparalleledthelegaldiscussions,butlookinglessat,“Isitlegal?”andmoreat,“Isitrightorfair?”Issuesconsideredhaveincludedconsenttotreatment,whethertreatmentisconsideredtobeclosertostandardofcareortoaclinicaltrial,equityissues-shouldaproductbeavailableinoneregionorMSbutnotanother-andwhatissuesariseifaproductwithdrawaloccurs,orifthebenefit:riskbalancechanges.

2.2BackgroundThere is a broad spectrum of published work on the ethical perspectives of early patientaccesstomedicinesthatcoverissuesincluding:addressinguncertainty,benefit:riskbalance,personaldataprotectionandconsiderationsofpatientinvolvementinmedicalresearch(3-7).Likewise,thereissomeliteraturecovering:legalframeworksofpersonaldatacollectionanditsuse,informedconsenttobothtreatmentandclinicaltrials,andoff-labeluseandliabilities(8-11).However,todate,thereisalackofliteraturerelatingtoethicalandlegalimplicationsin thecontextofadaptivepathwaysorMAPPs.Thisreflects thereality thatMAPPs isstillarelatively new concept which is rapidly evolving. An understanding of the range ofperspectivesregardingtheethicalandlegalissuesisyettobefullyachieved.

In2016,CASMIproducedareportonpatients’ethicalperspectivesofMAPPsacross3diseasestates (oncology, neurodegenerative and rare disease)(12). From in-depth interviews and

workshops, a number of issues became apparent that warranted further study. Theseincludedi)equalavailabilityofamedicinetoallpatientsonceevidenceofsafetyandefficacywas available ii) the implications for consent and the potential blurring of the boundarybetweenclinicaltrials(whereuncertaintyishigher)andclinicalpractice(whereuncertaintyis lower), and iii) protectionofpatientdata and its usewithin the legal frameworkofdataprivacylaws.

Theoutputofthisoriginalworkformedthebasistobuilduponunderthisprogramofworkand explore ethical and legal challenges relating toMAPPs, and how those challengesmayaffecteachstakeholderdifferently.Tothisend,theremitofworkinggroupD3.08focusedon“ethical and legal aspects of adaptive decisionmaking and recommendations onhow thesecanbeaddressed”.TheD3.08workstreaminitiallyexploredtheseissuesviaanumberofin-depth informal interviews from various stakeholders. On January 17th 2017, these resultswere presented and a consensus was reached during a multi-stakeholder workshop inLondon,UK-theoutputofwhichformsthebasisofthispaper.

The results and recommendations presented here are intended to illustrate key multi-stakeholder concerns of general ethical and legal uncertainties relating to MAPPs, andhighlightanumberofconcernsthat,althoughmaybepresenttoday,areconsideredlikelytooccurmore frequentlyorhavegreater impactononeormorestakeholders,underadaptivepathways.Itwasnotourremittoperformanin-depthanalysisoftheexistingethicalandlegalframeworks within each MS. Such work may form part of the basis for future researchquestionsrelatingtotransferabilityofconceptsandrecommendations.

3.Methodology

3.1ApproachTheworkinggroupofD3.08was ledbyconsortiummembersCASMIandMSD.Consortiummembers that supported these deliverables included a total of nine people fromLysogene,EFPIA, Sanofi,UCB,Bayer, Servier, and theMerckGroup. EMAprovided feedbackon initialinternaldiscussions,howeverwasnotinvolvedinthebelowdescribedinterviewsandisnotanauthorofthisdocument.InitialinternaldiscussionsamongstthisgroupledtoaconsensusofanumberofpotentialethicalandlegalthemesthatcouldaffectoneormorestakeholdersthatmayariseunderMAPPs.Brieflytheyareasfollows:

Legal: i) Patient data privacy, access and use, ii) informed consent, iii) changes in bothliabilityandburdentotheprescriber,medicinedeveloper,regulator,pharmacist,andhealthinsurers,iv)promotionandmarketingoftheproduct(byeithertheHCP,medicinedeveloperorpatientorganisations),v)intellectualpropertyandregulatorydataprotection.

[Although legal concerns of Intellectual Property and Regulatory Data Exclusivity wereidentified here, these topicswere outside the remit ofD3.08andhave been explored in detailunderanotherworkinggroup,D3.06]

Ethical:i)Informedconsent,ii)patientdataprivacy,accessanduse,iii)patientengagementandcyclesofcommunication,iv)patientandpublicperceptionsofindustry,healthproviders,and government, v) patient burden for ongoing data collection, vi) patient eligibility, vii)uncertaintyofsafety,orsafetynotasexpected,viii)clinicalandtreatmentequity,ix)publicvsprivatefundingfordrugusebypatientsand,x)promotionandmarketingofproductsbymedicinedeveloper,HCP,orpatientorganisations.

Sincetherewasinitiallyalargenumberofdiverseissuesandthemesidentified,weconductedsemi-structuredinterviewswithamuchwideraudience,inordertoidentifywhichissuesorthemeswerethemostcommonlyreportedasbeingofgreatestimportanceorgreatestimpact,andwhichstakeholdergroupwouldbeaffected.Therefinedgroupofthemeswereexploredandvalidatedatalargemulti-stakeholderworkshop.

3.2Semi-structuredinterviewsandAnalysisGroup members conducted semi-structured informal interviews either one-to-one or as agroupof2-3(max)fromapoolofcolleagues,partnersandcollaborators.Thequestionswerecheckedbyanindependentresearcherforbiasandlanguage*(seeappendices).Theinterviewslide deck was sent to the interviewee 2-3 days prior to interview. At the start of theinterview,theconceptoftheMAPPspathwayandhowitmaydifferfromthecurrentpathwaywasexplained.

Theinterviewerusedtheslidesandsupportingdocumentstofurtherprompttheintervieweefor their opinions on specific ethical or legal topics. Responses were anonymised andresponderswereonlyidentifiedbystakeholdergroup.Atotalofsixquestionswereaskedfortheethicalimplicationsandagainseparatelyforlegalimplications,andarelistedinAppendix1.

Expert opinions were transcribed from written notes, and analysed (by an independentresearcher*) using a thematic analysis frameworkmethod,which identified the themes foreach factor at their respective structural organisation levels (13). Severalmajor, distinctivethemes(i.e.thosethatwerereportedmostfrequently)emergedfromethicalandlegalsectorswithsomecommonandoverlappingissues.Anothersetofdistinctivebutminorthemes(i.e.reported less frequently) also emerged from experts across ethical and legal sectors, withmoredistinctdivergencebetweenthemes.

Resultswerepresented(Appendix2)duringajointmulti-stakeholderworkshoponJan17th2017 with patients, HCP, ethicists, industry, regulators, HTA, payers, pharmacists andacademics.Threehypothetical case studieswereused (Appendix 3) to assist in consensusbuilding around the key themes. A set of recommendations to manage these issues weredevelopedduringtheworkshop.

4.1Overallresultsandrecommendations

4.1.1LegalChallengesNogenerallegalbarriershavebeenidentifiedregardingproductsthatwouldbegrantedamarketingauthorisation(conditionalorfull)wherethedevelopmenthasfollowedanadaptivedesign.Since“MAPPs”simplydescribesaniterativeandinteractiveroutetoamarketingauthorisation,ratherthanbeinganauthorisationcategoryperse,productswillhavemettheregulatorystandardsofquality,safetyandefficacy(i.e.positivebenefit:riskdemonstrated)asisthecasetoday,andthuslegalriskperseshouldnotchange

Nonetheless,intermsoflegaluncertainty,byvirtueofthenarrowpopulation,thesmallabsolutenumbersstudiedorthedurationoffollow-up,itwasconsideredthattheremaybeanincreasedlikelihoodofachangeinpostMAbenefit:risk,orefficacyandsafetyassessmentswhichcouldresultinadditionalcautions,warnings,restrictionorlossofaccess,orproductwithdrawalforeconomicreasons.Itisnotedthatthiscouldbethesamewithotherproductsapprovedonsmallnumbersorshortdurationoffollow-up,regardlessofwhethertheroutetoauthorisationwasadaptive.

Weheardconcernfromsomecompanyandgeneralmedicallawyersthatthiscouldbereflectedinanincreaseinthelikelihoodoflitigation(e.g.fromapatienttoapharmaceuticalcompany,orregulator).Liabilityfordefectiveproducts(Directive85/374/EEC)maintainsitsstatusquowiththemanufacturerorMAHmostlikelytobeatriskofbeingsuedbypatients-thegenerallyacceptedprinciplesofstandardlegaldefencewouldapply,asisthesituationtoday.

Asthechannelbetweeninformationprovidedbythepharmaceuticalcompanyandapprovedby the regulators (e.g. Summary of Medicinal Product Characteristics, package insert), theHCPplaysacrucialroleinconveyingandexplainingtherelevantinformationrelatingtotheproduct and treatment regime, so that consent to treatment is based on a patients’understanding of the known benefits, risks and uncertainties. But consent (implicit orexplicit) also allows the physician to demonstrate that he/she has done his/her duty toprovide the most correct and up-to-date information. We found little evidence thatprescribersknewthelegalstatusofthemedicinestheywereusing–whetherconditionalorfull marketing authorisations. There is clearly an educational opportunity to informprescribers,sothattheyinturncanexplaintopatientsthenovelnatureoftheproduct,andthedegreeofcertaintyorotherwisethatexists. Witharapidlyevolvingevidencebaseforagivenproduct,itisimportantthatprescribersmaintainanup-to-dateknowledgetoavoidtheaccusationbyapatientthattheyhavenotbeeninformedofapotentialriskorchangeinriskwhichhad,nonetheless,beenidentifiedtoprescribersinapprovedregulatorymaterials.ForexampleproductswhichhaveaconditionalMA,alsowouldhavea‘blacktriangle’symbolontheSmPC–indicatingthatthisproductisunderspecificextrasurveillanceduetothenatureofthedataavailableatthetimeofauthorization.

4.1.2Ethicalchallenges

Consenttotreatment

ProductsapprovedthroughanadaptivepathwaywillhaveanMA(likelyeitheraConditionalMA or full MA in an initially restricted population), with a reduction in uncertainty andconfirmation of a positive benefit: risk as post MA data evolves. Provision of adequateinformationtoenableapatienttomakeaninformeddecisionisseenbypatientgroupsasacritical element to successful implementation and mitigation of both legal and ethicaluncertaintieswithinthecontextofMAPPs.

During thevariousworkshopsand inputsessions,particularlywithpatientrepresentatives,therewasacall foradequate informationtobeprovidedonthebenefitsandrisksofanewmedicinebeforeapatientagreestotreatment.Whetherthisagreementshouldtaketheformsimilartoroutinecare-verbal,implied/informal-orsomethingmoreakintothatofaclinicaltrial - written, explicit/formal - is inconclusive, and indeed it may vary from product toproduct. There is a need to clearly communicate to the patient the distinction betweenconsent for participation of a clinical trial (where uncertainty of efficacy and safety exists)versusthatofconsenttotreatmenttoanoveltherapywhich,whilstauthorised,isnonethelessnewandforwhichthefullefficacyandsafetydatasetarestillmaturing.

We heard repeatedly from patient representatives that provision of information anddocumentation of consent - beyond that of just implied consent – should takeplace. Theseshouldinclude:thecurrentlyknownandanticipatedbenefits,thecurrentlyknownrisks,theuncertainties(e.g.alackoflargescaleorlongtermdataatthetimeofaccess),thepossibilityof product withdrawal, or restricted availability in the event of a negative change in thebenefit: risk balance, or for commercial reasons. While all of the above issues could arisetodaywithproducts thathaveaCMA(orotherwise), inpractice,despite the ‘blacktriangle’symbol for denoting a product undergoing enhanced surveillance, prescribers are rarelyawareoftheMAstatusofaparticularmedicine(forexampleifithasaconditionalMA).Thusit is considered evenmore important than today that the regulatory status of a product isknowntoaprescriber, includingthenatureofongoingdatacollection. Therefore, thisarearequires better and more structured education for prescribers regarding the emergingevidencebaseonaproduct-by-productbasis. ThiscouldbefacilitatedthroughbetteruseofrelevantprescriptionmaterialsandeducationaldocumentationsuchastreatmentguidelinesandDirectHealthcareProfessionalCommunications(DHPCs).ThiscouldinitselfbeenabledbytherespectivecompetentauthoritiesandHCPumbrellaorganisationsintheMS.

Additionally, it is acknowledged that while it is common practice for surgeons to providepatients with the pros and cons of a surgical procedure (in line with some of the abovementioned reasons), followedby documenting the informed consent process, by nature oftheirrole,thissamepracticeislesscommonforphysicians(whereconsentisofteninformalorimplied).TheconsentprocessbetweenpatientandHCPisaverycomplexprocessduetothe variances in its contextual application. Therefore, training and toolsmay be needed tofacilitate amore detailed consent process for products undergoing an adaptive pathway tomitigatesomeoftheseconcerns.

Useofregistriesaspostauthorisationtools

Giventhelikelihoodofaneedforongoingpost-MAandpost-accessdatacollectiontoconfirmefficacyandsafety,and for (relative)effectivenessandcosteffectiveness, theuseofpatientregistriesisanaspirationasanenablingtoolfordatacollectiononproductsapprovedusingaMAPPs approach (acknowledging MS differences in HTA/payer remit and structure). Theproportionateuseofpost-authorisationsafetyandefficacyassessments,whichmay includeregistries, isgenerallyaccepted.Whilst it ishighlydesirable forproducts thathaveusedanadaptivepathway toapproval tobe thesubjectofcarefulsurveillanceand forconfirmatorydatatobecollectedandanalysed,thereisethicaltensionbetweenanindividualpatient’srightto consent to their data being collected andused (or not), and that of the broader societalneed to collect more data (for example, safety and efficacy for regulators and medicinedevelopers, and (relative) effectiveness and cost effectiveness for payers) to support thereduction of uncertainty. Froma legal perspective patients voluntarily enter a register andconsent for processing of their data in registries cannot bemandated as a precondition ofaccess to a medicine. Thus, there remains concern from patients surrounding whichcircumstances,andtowhatextentextrapatientdatawouldbecollectedforMAPPsproducts.For example, the distinction is needed between data collected under conditions of anindividual’s standard of care, (e.g. CT scan every 6 months to assess progression) versusinterventionsthatbenefittedsociety’sneedtodemonstratebroadersafety,efficacyandcosteffectivenessmeasures.Ifdataweretobecollectedonaproduct-specificbasisforthelatter,then it could form thebasis for example, a clinical trial orPostAuthorisation Safety Study,which presents an extra patient burden, obligation and expectation that would requireprospectiveandcontinuedtransparencyandclarity.Thisdilemmacanbepartlymitigatedbyimproved patient education as to the importance of data collection for example, throughdirectHCPinteractionsorviaumbrellapatientorganisationsandpatientdriveneducationalinitiativessuchas,TheEuropeanPatients’Academy(EUPATI).Inaddition,exploringflexibleapproaches to longitudinal data collection, such as disease registries, data extraction fromelectronichealthrecords,ortheprovisionofdatabythepatientthroughanApp,forexample,couldbepermissive.

Patientleveldatasubjectright,andwhetherpharmaceuticalcompanieshaveaccesstoit,isconsideredtobeofalesserconcernperse.Thedevelopmentanduseoflongitudinaldisease-basedregistrieswheretreatmentinaspecifiedfieldispreferabletothatofproduct-basedregistries.MakinguseofexistingEuropeannetworksandregistries(andcross-borderdatasharinginitiatives)tosupportMAPPsshouldbeexploredinthiscontext,ratherthancreatingbespokeregistriesperproduct.

Thusthereremainsatensionbetweenapatient’sdesireforaconsenttotreatmentbeingmorethansomethingthatissimplyimplied-butnottotheformallevelofaclinicaltrial(duetotheregisteredstatusofaMAPPsproduct)–togetherwithsociety’sneedforapatient’sentryintoa registry to facilitate additional data collection (that is akin to, for example, a PostAuthorisationSafetyStudyorclinicaltrial)whichrequiresaformalconsentfordatacollectionanduse,withtherighttooptoutofthatconsentwithoutjeopardizingaccess.Thepreference

from patients is for an opt-in decision-point – “do you agree to your data being collected”ratherthanadefaultof-“youdoagreetoyourdatabeingcollected”.

A similar tension exists in other early access schemes like the UK’s EAMS – and is beingaddressed through creation of decision trees for medicine developers and educationalmaterialastowhattypeofpatientdataisneededandwhenitiscollected.Learningsfromthisandsimilarinitiativescouldbesharedhere.

EquityofAccesstoMedicines

Irrespective of the route to authorization, variation in the availability of a medicine fromcountry-to-country is seen as a substantial ethical problem. Access to a specific medicine,funded by the MS health system, is a national competence and may be a decision at thenational level (e.g.Germany)or sub-national level (e.g. EnglandandScotland), or local andhospital level (e.g. Spain). Likewise, whilst current cross-border legislation (EU Directive2011/24/EUontheapplicationofpatients’rightsincross-borderhealthcare)allowspatientstotravelfortreatment,itdoesnotfacilitateaccesstotreatmentsthatarenotavailableinone’shome country. For example, a gene or cellular therapy (as such likely to benefit from anadaptivepathwayapproach)mayonlybeavailableinasinglespecialistcenterinoneMSonly.MemberState-specificaccesstopromisingtreatments,whilstnotanewissue,requirescarefulconsiderationunderMAPPs;inparticular,betweencountrieswhohavehighervslowerGDPexpenditureonhealthcare(forexamplesomeCEEcountries).Theunderlyingfactorsdictatingdifferential access to new (transformative) medicines are multi-factorial and include; P&Rconsiderations (price, affordability and how healthcare ‘value’ is defined in each MS),differentHTAandpayerprocesses ,degreeofinvestmentinhealthcare,ethicalframeworks,availability and use of data collection infrastructures (inc. registries), the extent of (any)cross-border collaborations, availability and impact of prescription tools andmethods, andsocietal preferences. For particularly rare conditions, the clinical expertise may also notresideinallMS,andthuscross-borderopportunities(suchasjointplatforms)becomemoreimportant,andiflackingmaybecomemoreprohibitiveforaccess.

Themost powerful driver of these factorswill be P&R considerations. It is predicated thathighlytransformativeproducts,suchasthoselikelytoreachaconditionalmarketingapprovalby an adaptive processwill have aminimum data set but may have a high price,may beapplicable(atleastinthefirstinstance)inrelativelysmallpopulations,andrequirecontinueddatacollection toconfirmbenefit: risk.This is true too, formanyorphanproducts today. ItmightbeexpectedthatMAPPsproductsmaybemorelikelyinitiallytobefullyreimbursedinMSwhereexpenditureonhealthcareisrelativelyhigh,wheredatainfrastructuresarebetterestablishedandpermissiveforlongtermpostMAdatacollection,andHTA/payerauthorities’processes allow flexibility and resources to be involved in the early and continued multi-stakeholder dialogues of an adaptive approach. Thus some MS with relatively lowerexpenditure on healthcare could be at a distinct disadvantage and unable to facilitateequitableaccesstothesenewmedicines.

Optimizing cross-border initiatives such as cross-border data sharing, utilizing diseaseregistries,andjointplatformssuchasEUnetHTA-whichalreadyincludessomeCEEcountrieswould strengthen the understanding of some of the barriers, and facilitate strategies toimprovethetransferabilityofsuchproductsmorebroadlyacrossMS.

Earlydialoguewithallstakeholders isseenascritical inaddressingtheabove issueswherepossible.DialoguewithHTAbodiesandnationalpayers isseenas important tounderstandhowcosteffectivenesscouldbeassessedforsuchproducts,whereuncertaintyof longtermbenefitsandrisksisseenasachallengetoreimbursementdecisions-flexiblepricingmodelsare seen as one way forward. Likewise, early dialogue with patient organizations is alsocritical for all stakeholders to understand the impact of the new medicine. Patientorganizationsinparticular,urgedflexibilityonthepartofindustry,HTAbodiesandpayers,toensureequitableaccessacrossdiseasestatusandacrossMS.

There isanacknowledgment that therewouldbeoccasionswhereaproductwasno longercommercially viable, or did not demonstrate clinical outcomes that supported its cost-effectiveness,sothatcontinuedaccesswouldcease.Thereisariskthatsuchdecisionsarenotuniform across the EU, further increasing inequitable access. There is also likely to be adifferenceinhowpatientsalreadyreceivingamedicinearetreated,comparedwithpatientsyettobestartedonamedicine,despiteidenticalclinicalprofiles.Toaddressandprepareforsuchsituations,a strategyshould ideallybepreparedat launch toaddressall stakeholders’concerns, particularly those of patients and HCP, regarding continuity of treatment. Forexample,intheUK,insomeinstanceswherepatientaccessisgrantedbutlaterdemonstrationofcost-effectivenessislacking,accessremainsforthosepatientsalreadyonthemedicine,butno new patients have access. In cases of withdrawal due to changes in effectiveness (andhence cost effectiveness), a multi-stakeholder agreement could be envisaged to explorecontinuedaccess for thosepatientsalreadybeing treated.Thenatureofsuchanagreementwouldrequirefurtherexploration.

InformationandPatientEducation

Accesstoreliable information isconsideredkeytomitigateagainstpatientuncertaintiesonethicalandlegalmatters. InformationandcommunicationaboutadaptivepathwaysandthenuancesofMAPPs,amongpatientsandcivil society, representsacommonunderlyingbasisfortheabove-mentionedthemes-itrequiresacontinueddialoguewithotherstakeholderstoensure ongoing and accuratemechanisms to disseminate information effectively. Informedandeducatedpatientswouldbemoreempoweredandabletoparticipateasequalpartnersinshared decision-making regarding the choice of therapy; and it would increase theirwillingnessandabilitytocontributetotheongoingdatacollection.

5.Recommendationsandconclusions

Educationofallstakeholdersabout(MAPPs)productstatus

Thereisarealneedforprescribersandphysiciansinparticulartobeeducatedaboutmatterssuch as conditional MA, how that differs from a full MA, as well as the routes to thoseapprovals (e.g. positive benefit: risk with a comprehensive data set compared to a lesscomprehensivedataset).Thiswouldhelpthemunderstandwhyaproduct isrestrictedtoasmall indication initially and how that may affect the possibility of product restriction(including, in the extreme,withdrawal), and the desirability of ongoing data collection, etc.Provision of patient level information (including the above) prior to consent to treatmentneeds to be done in a language-specific, health literateway. Patient organisations can helpand should be involved in co-creating such materials and through training and educationprogramssuchasIMI’sEUPATIinitiative.Educationalmaterialforprescribers(e.g.outlineofapprovalstatus,thelevelandtypeofongoingdatacollectionneeded,andpointstoincludeindiscussing treatment options with patients) could be developed by the manufacturer andformpartoftheregulatorypackage.Thiscouldbecomplementedby,forexample,proactivedissemination of information available on the medicine developers’ website and companydossiersthatisinlinewithMSprocesses.Educationalmaterialforpatients(e.g.outliningtherisks,benefits,datarequirements,etc.)couldbedevelopedbytheMAapplicantinpartnershipwithpatients inahealth literatemanner,andmadeavailable toallusers.Consideration forbothof theabove shouldalsobegiven tonewmodalitiesofpatient centric communicationsuchas apps, andvideos - not simplywritten information.This is an importantpart of theevolving landscape of patient involvement and may account for hard to reach patientpopulations(i.e.rarediseases,youngorelderly).PartneringwithnewplatformssuchasIMI’sinitiative on enhancing patient engagement across the lifecycle of medicine development(PARADIGM)willbekey.

Managingdatacollection

Each product approved through an adaptive pathway should prospectively outline its datacollectionstrategytodocumentpostMAsafetyandefficacy.Thereisjustificationtoconsiderrestricting access (at least initially) to centres of excellence where disease-specific clinicalexpertise and data collection infrastructure is generally optimal and permissive forconfirmingthebenefit: riskprofileand forexample,demonstratingcosteffectiveness in theinitial indication. However, from a patient-centric point of view, expertise and data shouldtravel,andnotthepatient.Participationinregistries,etc.shouldnotbemandatedormadeacondition of access, thus a mechanism for initial or continued access outside of theseregistriesisneeded.Patientdriven(i.e.viaEUPATI)andHCPdriven(i.e.viaDHCP)materialcaneducateastotherationalfordatacollectiongenerallyandthatwhichisproductspecific.Data collection therefore, should be streamlined, flexible, internet-based (where possible),andinteractivewithotherdatasourcessuchascarefullydesigneddiseasespecificregistriesand data extraction from electronic health records. A survey of HCPs (Work package 3)suggests that they seem ready to generate post approval data collection for productsdevelopedunderMAPPs.Aspartofthedatastrategyandcontrolleddistribution,MAholdersshould consider using centres of excellence, including the European references network

(ERN)sites.Datacollectionthatrequiresnon-clinically-indicated investigationsare likely torepresent interventional clinical trials, unless the additional patient and HCPinconvenience/riskisminimal(orfacilitatorystructuresandprocessesareinplace).Furtherstrategies for optimizing real world data (RWD) collection and streamlining cross-borderinitiatives are detailed in other IMI initiatives – BD4BO and GETREAL, for which futureresearcheffortshereshouldaligncloselywith.

Maintainingequityofaccess

Theabilitytomaintainequitableaccesscanbepartlyaugmentedthroughearlyandcontinueddialogueswithpatientorganizations,inorderforallstakeholderstounderstandtheimpactofthe new medicine and any subsequent changes to that access. Clearly, if the benefit: riskbalance should become less favourable in time, regulators retain the right to furtherrestrictionsonavailability,andcompaniesretaintherighttochangedecisionsofavailabilitybasedoneconomicassessments.Theimpactofthesedecisionsonbothexistingpatientsandonpotentialrecipientswillneedtobeaddressedonthebasisofthenewdata,andshouldbeuniform across member states. Early dialogues with all stakeholders will help clarify theproductspecificissuesandembedmitigationstrategiestoaddressthis.Additionallyutilizingexpertise and critical mass from platforms such as EUnetHTA (that include some CEEcountries) would facilitate broader strategies to improve the transferability (andaccessibility)ofhighlytransformativeproducts(inc.thoseunderMAPPs)acrossMS.

For all of the above recommendations discussed, there remains a clear case for furtherdetailed researchof case studies of existing ‘MAPPs-like’ products that are available acrossselectedMS, thathaveeitherhighor lowGDPexpenditureonhealthcare, inordertoassessthepracticesandethicalandlegalframeworksthatarecurrentlyinplaceandhowtheaboveissueswere(orwerenot)dealtwith.Fromthis,morediscretesolutionstotheacceptanceandtransferabilityofMAPPscanbedevised.

Appendix1

Interviewees were broken down into the following groups: Legal- Company lawyers (3)Regulatory affairs (1), Medical lawyers/litigation (2), Patient reps/advocates (2), Ethical-regulatory affairs (1) HCP (2) Company or academic ethics/bioethics (2), patientreps/advocate(1).

Belowarelistedthesemi-structuredinterviewquestionsusedtoidentifyethicalandlegalconcerns.

1) Pleasesummariseyourareaofwork.2) Doyouhaveexamplesofwhereyou/yourorganisationshavebeeninvolvedindrug

developmentandpatientaccesswherethecurrentsystem/frameworkcausedethicalconcerns?

3) Doyouhaveexamplesofwhereyou/yourorganisationshavebeeninvolvedinrecentexplorationsoftheethicalconceptsofadaptivepathwaysorearlyaccesstomedicines?

4) IfadrugreceivedaninitialMarketingAuthorisationviaaMAPPspathwaywhatethicalimplicationsdoyouforeseeandforwhichstakeholdergroupsdotheissuesapply?

5) DotheethicaldilemmasposedbyMAPPSdifferfromthoseassociatedwithcurrentdrugdevelopmentprocesses?

6) AretheretypesoftherapyorcircumstancesinwhichMAPPSwouldnotbeappropriateonethicalgrounds?

Appendix2

Tablesofintervieweeresponsestolegalandethicalconcerns

Thefollowingtablesrepresentthemajorandminorlegalandethicalthemesidentifiedfrom14interviews(8legaland6ethical–seeappendix1).Thethemespresentedhereconsistof issues thatwere raisedby the interviewees thatwereeither specific toMAPPs,ormorecommonly,issuesthatexisttodaybutwereconsideredtobeofgreaterlikelihoodofoccurring/havegreaterimpactthanwouldbethecasetoday

*SuzanneIi,CASMIundertooktheindependentverificationandanalysis.

Major=mostfrequentlyreportedtheme

Minor=lessfrequentlyreportedtheme

Table1:MajorLegalThemes

*Thedegree towhichpatient consent to treatment is informed, obtainedanddocumentedvaries inroutinehealthcare(comparedwiththeformalwritteninformedconsentofaclinicaltrial).HowdoesthisapplytoaMAPPsapprovedproductwhereuncertaintymaystillexist?The form of consent to treatment (implied or formal) was debated by the interviewees and theworkinggroup(seediscussion).Table2:MinorLegalThemes

LegalConcern Stakeholderitimpacts

Reason

Increasedlikelihoodofliabilityactionagainstprescribers(HCP)

HCP,InsurersPatients

IfpostMAdatadoesnotconfirmthepositivebenefit:riskofinitialMA,orifharmisdone,cliniciansmaybeheldresponsible.Wouldcurrentindemnitycoverthis?

Changingliabilityresponsibilitiesofeachstakeholderduringlifecycleofproduct

HCP,Manufacturer

Sponsorsareresponsiblefordrugsinclinicaltrials,buttheinherentuncertaintyisstatedandconsentedtobytheparticipant.No-faultindemnitymaybeinplace.Thisisgenerallylessso,postMA,ifusedinaccordancewithlabel.

Formalapproachtoinformedconsent

HCP,Patients Cliniciansneedtoformallyreviewanddiscussinformationwithpatientstoprotectthemselves.Patientsneedtobemadeawareofalltherisksandconfirm(sign/initial)thattheyunderstandthem*.

Increasedlikelihoodofpatientlitigation:

ineffectivetreatment,negligence,inaccessibilitytodrug

Patients,HCP,Insurers

Patientsmayfileanegligenceclaim,maysueorfileaconsumerprotectionclaimforineffectivetreatment,negligenceorinaccessibilitytodrug

Restrictionsorguidelinesforappropriateprescribing

HCP Therearecurrentguidelinesthatprescriberscanandshouldfollowregardinglevelsofspecialistexpertiserequired,facilitiesavailablewhenprescribingcertainmedicines(e.g.GMC,GMP,GMPPD).Fewarebindingandfewerstillarefail-safe.

Table3:MajorEthicalThemes

EthicalChallenge Stakeholderitimpacts

Reason

Informedconsent:-Formalprocessfortransparency-Mandatoryfordatacollectionandaccess-RCTvsstandardofcare

Patients,HCP Patientsneedtobemadeawareoftheimplicationsassociatedwiththeuncertaintyattimeofconsente.g.unknownsideeffectsand/ornoefficacy,potentialofwithdrawalofthetreatmentandthepossibilityofdatacollectionbeingaconditionofdrugaccessWhattypeofconsentisneeded–thesameasRCTconsentorthatofstandardofcare

Patientcommunication:-Clarityofinformationavailabletopatients

Patients,HCP Comprehensive,clearinformationforpatientsaboutthedrugdevelopment,treatmentoptionsandaccess.IdentifiedthatHCPs(andsubsequentlypatients)arenotwellversedinconditionalauthorizationsetc.Currentcommunicationplatformsdonotallowforup-to-datecommunicationtobesharedwithpatientsinreal-time

[Ethically]Acceptablelevel(s)ofriskwithearlypatientaccess

AllStakeholders

RiskanduncertaintiesneedtobedocumentedandbasedonethicalprinciplesortheethicalreviewguidanceReinforcementofscientificrigourisneeded

Longtermpatientsurveillanceandreassessment:-Continuedpatient

Patients Practicalconcernsexistaboutlong-termfollow-upand/oranexitstrategy.Theseissuesneedtobespecifiedandaframeworkputintoplace.Viabilityandvalidityofregistries–who/what

LegalConcern Stakeholderitimpacts

Reason

Additionalfinancialburdenofliabilityinsurance

Manufacturer Pharmaceuticalcompaniesmayneedmoreexpensiveliabilityinsurancethantheclinicaltrialinsurancethatisused.

Patientdataprivacy,accessanduse

Patients Patientsmaybeconcernedwiththedatabeingcollected,howitiscollected,storedandused.Canparticipationinadatacollectionactivity(e.g.registry)bemandatedinordertoaccessaparticularmedicine?

Appropriatepharmacovigilancesystem

AllStakeholders

ArecurrentpostmarketingpharmacovigilanceactivitiesappropriateforaMAPPs-approvedmedicinewheremoreactivesurveillancemaybemoreappropriate?

surveillanceofbenefit:risk-Surveillanceuponpatient‘exit’(choiceorimposed)

maintains?

TransparencyofBenefit:Risk

AllStakeholders

Conciseinformationneedstobeputinplaceaboutrecruitmentandthebenefit:riskoftheprogramorproduct.Needtohaveatransparentframeworkinplace**.

**ForauthorisedmedicinalproductsaEuropeanPublicassessmentreport(EPAR)ispublishedreflectingoutcomeofscientificassessment

Table4:MinorEthicalThemes

EthicalChallenges Stakeholderitimpacts

Reason

Equityoftreatment Patients InitialMA(inrestrictedpopulation)wouldhavetoconsideronacase-by-case,medicine-by-medicinebasis.Therecouldbestaggeringtoincludedifferentpatientswithvaryinglevelsofdiseaseseverityandagetogiveallanopportunitytohaveaccess.

Equityofbenefit(individualvscollectivebenefit)

Patients Ifthereisanegativeclinicaltrialoutcomeforadrug(itcannotbeexcludedthatitcanbenefitotherpatients),thedrugcouldpotentiallybenefitotherpatients-‘Trueaffect’intheminorityofpeopleanda‘trulynegativeaffect’inthemajorityofpeople.

Equityofaccess Patients Patientsfallingoutsideoftheeligibilitycriteriaarevulnerabletomajorethicalconsiderations,particularlywhenthereisnootheralternativeandtheotheroptionisanearlydeath

Inconsistentperspectivesofethicscommittees

Researchers/Academics

DifferentethicscommitteeswithinandacrossMShavedifferingperspectivesregardingethicalconcerns,hencethereisariskofreceivingclashesofopinionsbetweendifferentethicscommitteesregardingthesameethicalquestion.

Transparencyofprocess(healthsystemvsindustry)

AllStakeholders Thecostingofthemedicineshouldreflectthemultifacetednatureofcosts-medicinedevelopercostsandanypublichealthsystemcontributiontoitsdevelopmentandaccess.Withpublichealthsystems,costsshouldbeatransparentandafairprocess.

Treatment-standardofcarevsRCT

HCP,researchers

WhatcountsasstandardofcarepracticeandRCT(research)?Thelinesmaybeblurredbecausethedutiesaredifferentbetweendoctorsandresearchers

Appropriatepharmacovigilancesystem(under

Patients PatientsmaybemorevulnerableinMSwherepharmacovigilancereportingislesscommon–mayneedtobeenhancedpharmacovigilance

* 2010 PV amendments to Directive 2001/83 addressed this issue via the inverted black diamond on allmedicinal products for at least the first five years after marketing approval - and included AE reportinginformationinthepackageleafletforpatients.

**"TheMAPPsfocusshouldbeondiseasetransformativemedicines,targetingwell-definedpatientpopulationswith a highunmet medical need, i.e. life threatening or severely debilitating conditions for which notreatment or no satisfactory treatment exist.” –Definition fromADAPTSMARTGlossary of terms and alsofrom Regulation 507/2006 on the CMA:http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-1/reg_2006_507/reg_2006_507_en.pdf(seearticle4.2)

greateruncertainty) reporting.Needtoreportalladverseevents.*Offlabelandcompassionateuse–howisthisaccountedforwithpharmacovigilancereporting?Couldthisbeutilizedasalearningopportunity

SeverediseaseconditionsApplicabilitytonon-pharmaceuticaltreatments?

Patients NeedstobeaMAPPsstructureforthemostdebilitatingdiseasesthatrequirenewtypesoftherapy:gene,cell,etc.

Ethicsanditsdefinition

Regulators Therearedifferentusesofethicsandapplicationtovariousissues.

Timepoints(moments)ofEthicalevaluation

Patients,HCPandregulators

Moral/ethicalevaluationtimepointsarerequiredtocomplementscientificevaluationtimepoints-e.g.Evaluatingtheethicalneedsofpatientsforalternativetreatments).

Learninghealthsystems

Patientgroups,HCP

Patientsareenthusiasticatengaginginlearninghealthcaresystems.Theyshouldhoweverstillhavebestcare/practiceavailabletothemeveniftheydonotengageinlearninghealthsystems(e.g.takingpartinresearch)

Unpredictableresults

Regulators,HCP,patients

Needtohavearobustdatacapturesysteminplacethatcanbechangedasethicalissueschangeovertime

Appropriatenessofdisease

Patients MAPPsisappropriateforlifethreateningdiseases(andthoseclassifiedashighunmetneed**)andconfirmingthebenefit:riskoftheproduct

Understandingincreaseduncertainty

Patients,HCP Howwouldtheincreaseduncertainty[relatedtoanemergingevidencebase]beexplainedduringconsentbetweenpatientsandclinicians?

Technologyrestriction

Patients,HCP,regulators

MAPPsconceptswouldbedifficulttoapplytoinnovativetechnologies

Appendix3Belowarelisted3hypotheticalcasestudiesthatwereusedtoJan17thworkshoptostimulatediscussionoftheethicalandlegalissuesathand.AnadditionalsetofscenarioswaslaterusedtostimulatediscussiononpossiblerecommendationsHypotheticalcasestudy1:OncologyCondition:

• Sub population of a haematological malignancy with a distinct biomarker mostcommoningeriatricpatients,slowlyprogressivebutnocure.

• Current treatmentusually “watch ‘nwait” followedby standard chemotherapy,withmodestefficacy.

• Treatedincentresofexcellencebylimitednumberofspecialisthaematologists.Technology:

• New technology shows promise in studies lasting 2 years based on biomarkerresponsebasedonn=60

• Oraltreatment,takendaily• Dataimmature–MAgrantedinsingleindicationonbasisofasinglearmstudy,withno

randomised controls but historical data from the natural history of the diseasesuggeststhetreatmentslowsprogression

• Medianoverallsurvivalandmedianprogressionfreesurvivalnotyetreached• The patients are continuing to be followed with ongoing clinical trials and via a

registry.Hypotheticalcasestudy2:NeurodegenerativediseaseCondition:

• Rare inherited genetic degenerative disease, progressive – fatal genotype by earlyadolescence

• NocurrenttreatmentoptionsTechnology:

• New technology shows promise in small clinical study lasting 2 years based onsurrogateendpointsn=12

• I.V.infusion,weekly• Data immature – MA granted on basis of a single arm study, with no randomised

controlsandnostudiesverifyingcontraindications,orotherpossibleindications(sex,age,etc)

• AsaconditionoftheMAafurther2yearrandomisedcontrolstudymustbeperformedtoverifytheclinicalbenefit.

• Medicinedevelopersetsahighpricefordrugtocoverextraliablerisks

Hypotheticalcasestudy3:VeryrareinheritedpaediatricdiseaseCondition:

• Diseasehas4differentsubtypeswiththefirstsubtypebeingveryrapidlyprogressivetothe4thtypebeingmoreslowlyprogressive.Patientsdonotsurvivebeyondthe2nd-3rddecade.

• Potential therapies should be initiated as early as possible, even at birth pre-symptomatically (before knowing the subtype) to prevent irreversibleneurodegeneration.Thereisnodiseasemodifyingtreatment

Technology:• Genetherapytechnologydevelopedtoaddressallsubtypesofthedisease. Onetime

administration• Single arm study performed in a subpopulation of children at a particular

developmentalage.Datacomparedtothenaturalhistory.• MA/accessrestrictedtothepivotalstudypopulationi.e.excludesveryyoungchildren

andolderchildren.• Additionalstudiesareextremelycomplexbecauseofthesmallnumberofpatientsand

phenotypicvariability• Limitedlong-termsafety

Part2–Additionalscenariostobeexploredundereachcasestudy

• TheMAhasbeengrantedonasmallcohort,withapositivebenefit:risk- Shouldpatientsbeabletoreceivethismedicineonlyiftheyagreetosafetyandefficacy

databeingcollected(PV)?-Shouldconsentfortreatmentbeobtainedormandatory?-Whathappenstopatientswhodeclinetohaveextradatacollected,oragreethenchange

theirmind?• ReimbursementhasbeenagreedinFrancebutnotintheUK.

- Shouldpatientsbeallowed to travel toget treatmentandhowdoes that impactdatacollection?

• After2years,itbecomesclearthatthereisa3%incidenceofacardiomyopathywithheart failure. Many patients who are on treatment are happy and doing well. Thepharmacompanywantstoconsiderwithdrawingfromthemarket.

- Canacompanybelegallyforcedtomaintainsupply?- Shouldpatientsbeallowedtocontinuetreatment?Whosedecisionisit?- CanapatientwhodevelopsthisAdverseEventseekcompensation,andifso,fromwho?

Bibliography

1. ADAPTSMART.Projectoverview2017[Availablefrom:http://adaptsmart.eu/.2. ADAPTSMART.Glossaryofterms.2017.3. FadenR,KassN,WhicherD,StewartW,TunisS.Ethicsandinformedconsentforcomparativeeffectivenessresearchwithprospectiveelectronicclinicaldata.MedCare.2013;51(8Suppl3):S53-7.4. KassNE,FadenRR,GoodmanSN,PronovostP,TunisS,BeauchampTL.Theresearch-treatmentdistinction: a problematic approach for determining which activities should have ethical oversight.HastingsCentRep.2013;SpecNo:S4-S15.5. Longman S. Patient centric benefit-risk assesment-supporting regulatory and patient accessdecisionmaking.20152015.6. MorelT,AymeS,CassimanD,SimoensS,MorganM,VandebroekM.Quantifyingbenefit-riskpreferences for new medicines in rare disease patients and caregivers. Orphanet J Rare Dis.2016;11(1):70.7. Smalley JB, Merritt MW, Al-Khatib SM, McCall D, Staman KL, Stepnowsky C. Ethicalresponsibilities toward indirect and collateral participants in pragmatic clinical trials. Clin Trials.2015;12(5):476-84.8. LamasE, BarhA,BrownD, JaulentMC. Ethical, Legal and Social Issues related to thehealthdata-warehouses:re-usinghealthdataintheresearchandpublichealthresearch.StudHealthTechnolInform.2015;210:719-23.9. Lenk C, Duttge G. Ethical and legal framework and regulation for off-label use: Europeanperspective.TherClinRiskManag.2014;10:537-46.10. Mithani Z. Informed consent for off-label use of prescription medications. Virtual Mentor.2012;14(7):576-81.11. OyeK,BairdLG,ChiaA,HockingS,HuttPB,LeeD,etal.Legalfoundationsofadaptivelicensing.ClinPharmacolTher.2013;94(3):309-11.12. CASMI. medicines adaptive pathways for patients2016 2016. Available from:https://www.gov.uk/government/publications/medicines-adaptive-pathways-for-patients.13. RitchieJ,J.Lewis,C.M.NichollsandR.OrmstonQualitativeresearchpractice:Aguideforsocialsciencestudentsandresearchers.2nded:SAGEPublicationsLtd;2014.