ImpactofadaptivelicencingandadaptiveaccessonIntellectualpropertyandregulatoryexclusivityright

periods

October2017

Thework 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 fromworkinggroupD3.06andonlyreflectstheviewsoftheauthors.This project has received funding from the Innovative Medicines Initiative 2 JointUndertaking under grant agreement No 115890. This Joint Undertaking receives supportfromtheEuropeanUnion’sHorizon2020researchandinnovationprogrammeandEFPIA.

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Contents

1. Abbreviations........................................................................................................32. Executivesummary...............................................................................................43. Introduction..........................................................................................................53.1. ScopeofMAPPs.............................................................................................53.2 RoleofExclusivityRights................................................................................6

4. CurrentLandscapeofIPandRegulatoryExclusivityRightsintheEU...................74.1. Patents.......................................................................................................74.2. SupplementaryProtectionCertificates(SPCs)...........................................74.3. RegulatoryDataProtection(RDP)..............................................................74.4. OrphanMarketExclusivity(OME)..............................................................84.5. APaediatricReward.................................................................................104.6. RelevanceoftheExclusivityRights..........................................................10

5. RoleoftheMarketingAuthorisationfortheseExclusivityRights.......................116. Methodology.......................................................................................................116.1. Selectionofmethodology............................................................................116.2. Semi-structuredinterviews..........................................................................116.3. Scenarios......................................................................................................12

7. Results.................................................................................................................127.1. VariousKindsofMarketAuthorisations......................................................127.2. Roleofthe“GlobalMarketingAuthorisation”.............................................157.3. AssessmentoftheidentifiedscenariosandtheimpactofMAPPs..............167.4. Underminingofexclusivityrightsbyoff-labelorcross-labeluse................19a) Off-labeluse.............................................................................................19b) Cross-labeluse.............................................................................................20c) Impactofoff-labelandcross-labeluseonMAPPs.......................................21

8. PerceptualIssuesandConsiderationsoftheimpactofMAPPs..........................219. Discussion............................................................................................................2510. Recommendations...........................................................................................26

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1. Abbreviations

ADAPT-SMART Accelerated Development of Appropriate PatientsTherapies,aSustainable,Multi-stakeholderApproachfromResearchtoTreatment-outcomes

AP AdaptivePathway

CMA ConditionalMarketingauthorisation

CUP CompassionateUseProgram

EPAR Europeanpublicassessmentreports

GMA GlobalMarketingAuthorisation

IP IntellectualProperty

MA MarketingAuthorisation

MAH MarketAuthorisationHolder

MAPPs MedicinesAdaptivePathwaytoPatients

MP MarketProtection

NPS Namedpatientsupply

OrphanRegulation Regulation(EC)No141/2000

OME Orphanmarketexclusivity

PIP Paediatricinvestigationplan

PaediatricRegulation Regulation(EC)No1901/2006

RDP RegulatoryDataProtection

RER RegulatoryExclusivityRights

SmPC SummaryofMedicinalProductCharacteristics

SPC SupplementaryProtectionCertificate

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2. Executivesummary

TheconceptualframeworkofMedicinesAdaptivePathwaystoPatients(MAPPs)hasits basis in fostering access to novel beneficial treatments for the right patientgroups at the earliest appropriate time in the product life-span in a sustainablefashion.EmbeddedintheMAPPsconceptarekeyfacetsofproductsgettingtothemarket earlier and in initially small defined (sub) population, with an emergingevidence base supporting a positive benefit: risk and indication expansion. Thiscreates uncertainty formedicine developers as to how this adaptive developmentand access impacts on intellectual property (“IP”) and regulatory exclusivity right(“RER”)periods.Activitiesof theD3.06workinggrouphavebeen tomapboth thekeylegalimpactsandadditionalkeyperceptualimpactsthatadaptivepathwaysandadaptiveaccesshason IPandRERperiods. The termRERencompasses regulatorydataprotection(“RDP”)andorphanmarketexclusivity(“OME”).

AbroadreviewoftherulesgoverningIPandRERastheyaretoday,andwithrespecttoMAPPs,wasundertakeninthecontextofthefollowing4scenariosdeemedlikelyto occurwithMAPPs: (i) Stand-aloneMA (i.e. single indication only); (ii)MAwithsubsequent indications with the same compound, i.e. indication 1, subsequentlyfollowed by indication 2; (iii) MA under exceptional circumstances or conditionalapprovalthatsubsequentlygetsapprovedfor‘full’MA;and(iv)MA(full,conditional,or exceptional MA) that subsequently is revoked / suspended from a regulatoryperspective. Any direct legal impact of MAPPs were assessed along with anexplorationofseveralperceptualissuespertainingtotheincentivesofadoptingandusingMAPPsfromanIPandRDPperspective.

No legal blocks were found for the 4 above scenarios. Within the current EUframework, current incentives are generally supportive ofMAPPs, yet uncertaintyremains as to how to best protect exclusivity periods fromerosion (particularly insubsequent indications) and how a definitive economic case for MAPPs could berealized and accepted. For example, earlier tomarket (<5 years after the patentfiling) will mean that there can be no supplementary protection certificate (SPC),thus the benefit of earlier to market might be offset by the loss of incentive indevelopmentofother indications.Withregardtoorphanmarketexclusivity (OME)protection, the OME is an indication specific exclusivity right, and a medicinalproductcanobtainmultipleorphandesignations,providedthat thesedesignationsconcern different orphan conditions. Thus the incentives for OME (and otherincentives)willrequireevermorenuancedconsiderationunderMAPPs.

ThecurrentreviewofEUincentives/exclusivityrightsandthepracticaleconomicsofso-calledcrosslabeluse(i.e.genericproductsbeingapprovedwithareducedlabelcompared to their referenceproductdue to specific patentprotection (orRER)ofcertainindicationswhereasthesegenericproductsneverthelessareprescribedandreimbursedforthisprotectedindication)couldnegativelyimpactMAPPs.CrosslabeluseacrossMemberStatescouldalsobeexacerbatedunderMAPPs.

Therewasa strongdesire tomaintain the current EU legal frameworks for IP andRER–MAPPscouldoperateeffectivelywithininit.However,ifinthefuture,theEU

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legislativeframeworkisre-openedforamendmentsitisvitalthatMAPPsconceptisconsidered adequately alongside other existing instruments (e.g. conditionalmarketingauthorisation).

3. Introduction

3.1. ScopeofMAPPs

MedicinesAdaptivePathwaystoPatients(MAPPs)activitiesseektofosteraccesstobeneficialtreatmentsfortherightpatientgroupsattheearliestappropriatetimeinthe product life-span in a sustainable fashion in order to improve the position ofboth the patients in need of novel treatments and the research-basedpharmaceutical industry. The scope of MAPPs covers regulatory approval, healthtechnology assessment (HTA), pricing, reimbursement, and health care delivery.MAPPsaimstobeapplicablewithinthecurrentEUregulatoryandlegalframework1.Itdoesnot foreseeanewdesignationbutanoptimaluseof theexistingtoolsandprocedures(suchasconditionalmarketingauthorisation)toachieveearlierapprovaland reimbursementdecisionsofproducts thatdemonstrateapositivebenefit: riskbalancethussupportinganearlier launchofthemedicinalproductbasedon initialevidence. Additional data generated post-launch aims to support progressivereduction of uncertainty about benefits and risks andmay lead to adjustments inutilisationandpriceinresponse.

The MAPPs conceptual proposal for the core multi-stakeholder engagement andassessmentmomentsenablinganadaptivepathwayissetoutinthebelowdiagram.There,eachproductlife-cyclephaseissymbolisedbyabluecog.Theseparatecogsarecomparativelysizedtorepresentthecharacteristicdurationofthephaseduringthelifespanofatypicalmedicine.Thetophalfofthefigureincludestheassessmentordecisionmomentsbythestakeholderrepresented.Althoughthesemomentsmaybe informed by multi-stakeholder inputs, in the end, the designated stakeholdermakesanassessmentandultimatedecisionbasedontheirrespectiveremits.Withinthebottomportionofthediagram,momentsofmulti-stakeholderengagementareillustrated2.

1 FormoreinformationabouttheInnovativeMedicinesInitiative(IMI)ADAPTSMARTprojectand

MAPPspleaseseehttp://adaptsmart.eu/2 http://adaptsmart.eu/wp-content/uploads/2017/06/ADAPT-SMART-seamless-

pathway_final_website.pdf

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ActivitiesoftheD3.06workinggrouphavebeentomapboththekey legal impactsand the key perceptual impacts that adaptive pathways may have on intellectualproperty(IP)andregulatoryexclusivityright(RER)periods.Whilewedidnotsetouttoundertakeadetailedanalysisofthelegallandscape.Wepresentareviewoftherules governing IP and RER as they are today, in the context of MAPPs, and anyimpacts that affect predominantlymedicine developers and regulators have beenexplored in a series of group workings and extended interviews. This work iscomplementary to other work streams in assessing any current or future legalobstaclesorblockstotheacceptanceandimplementationofMAPPs.

3.2 RoleofExclusivityRights

Theresearchanddevelopmentofnewmedicinesisalong,costlyandriskyprocessas out of thousands of compounds being tested only very few will finally obtainapprovalandbeplacedonthemarket.Adequateprotectionofthesecompoundsbyexclusivityrightsforadefinedperiodoftimeisthereforecriticalinordertoallowforadequate returnon the investmentand tocounterbalance the riskpharmaceuticalcompanies take. Exclusivity rights are considered to be the key incentive for theinnovator industry as they allow the industry to continue to invest in thedevelopment of new medicines, while generic or biosimilar products are madeavailable for the “old” medicines after expiry of the exclusivity rights. Of keyrelevanceare:

§ ‘Intellectual property rights’ which are generally defined and understood as"protections granted to the creators of IP, and include trademarks, copyright,

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patents, industrialdesignrights,andinsomejurisdictionstradesecrets”.3InthecontextofMAPPs,onlypatentsandSupplementaryProtectionCertificates(SPCs)wereconsideredtobeofrelevance.

§ ‘Regulatory exclusivity rights’ (RER) which are understood as those exclusivityrights that are granted to a marketing authorisation holder (MAH) for theireffortsofdevelopingacompoundandconductingthenecessarystudiesinordertoobtainamarketingauthorisation(MA).IntheEU,thoserightsareregulatorydataprotection(RDP)andorphanmarketexclusivity(OME).

4. CurrentLandscapeofIPandRegulatoryExclusivityRightsintheEU

ThecurrentlandscapeofIPandRERintheEUisasfollows(seeFigure1):

4.1.Patents

Patentsareexclusive,nationallyrestrictedrightsinexchangefordetailedpublicdisclosureofan invention.Onthebasisofagrantedpatent, theownerof thepatent is allowed to prevent others frommaking, using, selling, importing, ordistributing a patented inventionwithout permission of the patent holder forthe duration of 20 years after filing of the patent application. The protectionmay in particular refer to the compound itself, its pharmaceutical forms, themanufacturingprocessaswellasitsuses(so-called"medicalusepatents").

4.2.SupplementaryProtectionCertificates(SPCs)

SPCsarepatent-likerightsthatprolongthedurationofabasicpatentprotectionbyamaximumof5years,whereasthetotalcombineddurationofexclusivityofsuchabasicpatentandSPCcannotexceed15yearsstartingwithinitialapprovalofthemedicinalproduct.TheobjectiveoftheSPCrightistocompensateforlossof effectivepatent protectiondue to longperiodof testing and trials and theregulatoryapprovalprocedure.

4.3.RegulatoryDataProtection(RDP)

RDPprovidesprotectionofnon-clinicalandclinicaldatabeingpartofthedossiersupporting the application formarketing authorisation of amedicinal product(thereferencemedicinalproduct)insituationswhereasecondapplicantwishesto refer to thesedata for thepurposeofobtaininga respectivegenericorbiosimilarMA. In the EU, RDP protection is independent from any IP protection("nopatentlinkage").

ThecurrentRDPrulesintheEU4provideforthefollowingprotection:

3 World Trade Organization, What are intellectual property rights? World Trade Organization.

Retrieved2016-05-23.4 Article 14(11) of Regulation 726/2004 formedicinal products being approved centrally by the

European Commission andArticle 10(1) of Directive 2001/83/EC formedicinal products beingapprovednationally.

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• An8yearperiodofdataexclusivity(DE)startingwithinitialMAgrantduringwhich a medicinal product may not be used as a reference medicinalproductforthepurposesofanabridgedapplicationprocedure,and

• An additional 2 year of market protection (MP) period during whichmedicinalproductsauthorisedundertheseabridgedproceduremaynotbeplacedonthemarket.

This 10 year RDP period can be prolonged by one additional year of marketprotection to a total period of 11 years (so-called "8+2+1 rule") under thecondition that during the first 8 year period after initial MA grant a newtherapeutic indication isauthorisedfor thismedicinalproductwhich isheldtobringasignificantclinicalbenefitincomparisonwithexistingtherapies.

It is importanttonotethatthe8yearsofdataexclusivityandtheadditional2yearsofmarketprotectionstartupontheinitialapprovalandaregrantedbylaw“automatically”. The additional “+1” year of market protection requires (1)additionalconditionstobefulfilled(i.e.,approvalofanadditional indicationofsignificant clinicalbenefitwithin the first8yearsafter initialapproval)and (2)pursuanttotheCommission’sNoticetoApplicantsarequesttoEMAtoconfirmthesignificantclinicalbenefitofthisadditional indication.5Irrespectiveofthat,thegrantingofthe+1yearofmarketprotection isgenerallyrare, inparticularwithregardtoconditionalmarketingauthorisations(CMAs).

4.4.OrphanMarketExclusivity(OME)

OME was introduced in 2000 to stimulate research, development andauthorisationofmedicinalproductsforthetreatmentofpatientssufferingfromrareconditionsviaRegulation(EC)No141/2000("OrphanRegulation").Whereamedicinal product fulfils the criteria laid down in Article 3 of the OrphanRegulation for being designated as an orphan medicinal product, Article 8(1)provides that upon obtaining authorisation the designated orphan product isentitledtoatenyearperiodofOMEduringwhichcompetentauthoritiesshallnotacceptaMAapplicationorgrantaMA fora similarmedicinalproduct forthesametherapeuticindication.AsitisthecaseforRDP,OMEisindependentofanyIPprotectionandrunsconcurrently.

5 European Commission, Notice to Applicants, Volume 2A, Procedures for marketing

authorisation,Chapter1MarketingAuthorisation(Revision6),December2016,Section6.2.

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Withregardtothescope,theOMEisthereforeanindicationspecificexclusivityright, and a medicinal product can obtain multiple orphan designations,provided that these designations concern different orphan conditions. If amedicinal product is authorised in different indications corresponding todifferent orphan designations, it is entitled to an independentOME right andperiodforeachindication.6However,accordingtotheCommissionNoticeof18November 2016 (2016/C 424/03) under D.1, the addition of new indicationswithin the same orphan condition does not give entitlement to additionalperiods of OME rights. If the same sponsor subsequently applies for theauthorizationofanadditionalindicationbeingasubsetoftheconditioninwhichthe product got initially authorised, this indication will not benefit from anyadditionalperiodofOME(i.e.thesecondindicationwillbecoveredbytheOMEgrantedtotheinitialauthorization).

4.5.APaediatricReward

A paediatric reward is offered by the Paediatric Regulation in the form of aprolongation of an existing non-expired exclusivity right for the fulfilment ofobligationsbeing subjectof apaediatric investigationplan (“PIP”) agreedwiththeEMA,dependingonthenatureoftheproduct:

• Foranon-orphanproduct,arewardintheformofasixmonthextensionofanexisting,notyetexpiredSPCisprovided;and

• Foranorphandesignatedmedicinalproduct,arewardintheformofatwo-yearextensionoftheOMEperiodisprovided.

4.6.RelevanceoftheExclusivityRights

TheIPRightsandtheRERsarecompletelydifferentinnatureandindependentexclusivity rights, designed to protect different things and to incentivisebiopharmaceutical research anddevelopment in differentways. Eachof theseexclusivityrightshasitsownscopeofprotection:

§ Patents protect inventions regardless of whether they are evercommercialised.

§ RDPprotectstheextensivebodyofregulatorydatageneratedbyoriginatorsfrom being relied upon or referred to unfairly by others during a specificperiodoftime.

§ OME provides protection with regard to a rare indication against similarmedicinalproducts.

Becausetheserightsprotectdifferentthingsandoperateandrunindependentlyof one another, they work together in a complementary, non-duplicative

6 See in this respect the EMA guidance note for sponsors: “Post-orphan medicinal product

designation procedure”, version of 1 December 2015 which states in paragraph 2.3: “Eachorphan designation carries the potential for one ten-year market exclusivity for a particularindication. A medicine that has received several separate orphan designations for differentindicationscanobtainmorethanonemarketexclusivities if theserefer toseparatedesignatedconditions.”

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manner to encourage the development of new medicines. As a result, itdependsontheconcretesituationoftheproductinscopehowrelevanteachoftheserights(ifapplicable)isforitsprotection.

5. Role of the Marketing Authorisation for these ExclusivityRights

TheMAisofutmostimportanceformostoftheabove-mentionedexclusivityrightsas the time of the (first)MA being granted in the European economic area (EEA)definesthestartofthedurationoftherespectiveexclusivityright,andbythisisthetriggerpointforthe“exclusivityclock”.

• WithrespecttotheIPrights,thepointintimeofinitialMAgrantisdecisiveforthedurationofaSPCprotection,andbythisalsoforapotential6monthsSPCextensionasapaediatricrewardfornon-orphanproducts.

• The same concept also applieswith regard to the RER in the EU. The point intimeofinitialMAgrantintheEUdefinesthestartofthe10yearRDPperiod,andwithregardtoorphanmedicinalproductsitalsodefinesthestartofthe10yearOMEprotectionfortheinitiallyapprovedorphanindication(s).

6. Methodology6.1.Selectionofmethodology

The deliverable D3.06 was led by consortium members of CASMI and Novartis.ConsortiummembersthatwereinvolvedwithinD3.06includedrepresentativesfromNovartis,MerckGroup,Pfizer,EFPIA,SanofiGenzyme,andMSD. Inaddition, inputfrom all stakeholders was obtained during several workshops, in particular in theframework of a dedicated 1 day multi-stakeholder workshop includingrepresentatives from the Commission, payers, patient organisations, industry andexternalcounsels.

With respect to MAPPs and adaptive pathways, questions arose how productsauthorisedunderMAPPsareprotected,whethertheearlyauthorisationofanarrowinitialindicationdoesleadtoaprematurelossofexclusivity-ifnotcounterbalancedbyother incentives – andwhether this becomesproblematic for sponsors and foroverallsectorcompetitiveness.

6.2.Semi-structuredinterviews

Group members were requested to reach out to colleagues, partners, andcollaborators within their organisations with relevant experience in legal, IP,Regulatory Affairs and other research & development functions. They were alsorequested to conduct semi-structured informal interviews, as one-to-one or as agroup of 2-3 (max) to explore legal and perceptual issues of IP and RER aroundMAPPs. Outputs from the interviews were anonymised and recorded in thestructuredtablesprovided.

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Apresentationwassharedwithintervieweespriortointerview.Thisincludedabriefbackground about ADAPT-SMART/ IMI, an introduction to the concept ofMAPPs,and an illustration of how that would differ from the current traditional drugdevelopmentpathway.

6.3.Scenarios

Thefollowing4scenarioswereidentifiedunderwhichaMAwouldlikelyoccurunderMAPPsinordertobeexploredfurtherandbasedonthattobeabletofullyassessanypotentialimpactofMAPPsonIPandRERperiods:

i. Stand-aloneMA(i.e.singleindicationonly);

ii. AMAwith subsequent indicationswith the same compound, i.e. indication1,subsequentlyfollowedbyindication2;

iii. MAunderexceptionalcircumstancesorconditionalapprovalthatsubsequentlygetsapprovedfor‘full’MA;

iv. MA (full, conditional, or exceptional MA) that subsequently is revoked/suspendedfromaregulatoryperspective.

Therespondentswereaskedtocommentonthesescenariosforcorrectnessandtoexplore if there were likely legal issues within the current EU framework arisingunderMAPPs. The same scenarios were explored under the question of whethertherewere any perceptual issues arising fromMAPPs relating to IP and RER (i.e.,there was no direct legal issue, however perceptions exist that MAPPs would beunappealingorcouldcauseuncertaintyforavarietyofreasons).

Interview data were consolidated and the results are elaborated below. Theseoutcomeswere used a as a basis for further consensus building in aworkshop inApril2017.

7. Results7.1.Variouskindsofmarketauthorisations

In order to achieve timely access for patients to potentially beneficial treatments,theMAPPsconceptforeseesutilizingexistingregulatoryapprovalpathwaysinstageswithout changing the current regulatory standards forevaluation. Thismeans thatthe requirements to demonstrate a positive benefit: risk balance, as defined inArticle1(28a)ofDirective2001/83,arenotdifferentforproductsbeingauthorisedunderMAPPs than for products being authorised via the 'standard' authorisationprocess. The applicant will have to provide a full dossier containing all requiredquality,non-clinical and clinicaldata inorder toprovide the requiredevidence forthequality,safetyandefficacyoftheproduct.

Due tonatureof theproductsbeing considered in the scopeofMAPPs (i.e. noveltreatmentsintheareaofunmetmedicalneedforthepatientsintheEU),theearliergrantofa centralisedMAgrantedby theEuropeanCommissionwith the scientific

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supportof theEMA is theultimategoal, so that thecentralisedapprovalpathwayanditsinnovativeassessmentpossibilitiescanbeleveraged.

A centralised authorisation of a product under MAPPs could be achieved in thefollowingways7:

a) Standard'full'MA

Forastandard'full'MA,allrequiredquality,non-clinicalandclinicaldatahavebeenprovided8,andtheassessmentofthesedatahasledtotheconclusion,thatthebenefit: risk profile of this product is positive9, and that its quality, safetyandefficacyareestablished.

Sucha fullMA isgranted“unconditionally” (i.e., itsvalidity followsthenormalrulesaccordingtowhichtheMAisvalidforfiveyearsandmayberenewedafter5 years for an indefinite periodof timeon thebasis of a re-evaluationof therisk-benefitbalancebytheCommissionasresponsibleauthority10).Irrespectiveof that, theMA for themedicinal productmay be granted subject to specificconditions (e.g. toconductpost-authorisationsafetyand/orefficacystudiesortheexistenceofanadequatepharmacovigilancesystem11).

b) MAunderexceptionalcircumstances

The legal basis for theMAunder exceptional circumstances is Article 14(8) ofRegulation726/2004.12Suchanauthorisationunderexceptional circumstancesis valid forone year, ona renewablebasis, andmaybeused forproducts forwhichtheapplicant inhisapplication isunabletoprovidecomprehensivedataon theefficacy and safetyundernormal conditionsof use. The reasonsmightbe:

§ Theindicationsforwhichthespecificproductisintendedareencounteredsorarely that the applicant cannot reasonably be expected to providecomprehensiveevidence;

§ In the present state of scientific knowledge, comprehensive informationcannotbeprovided;or

§ It would be contrary to generally accepted principles of medical ethics tocollectsuchinformation.

7 As laidoutabove,MAPPswilltakeplaceunderthecentralisedpathwaysothat inthisandthe

following sections will only discuss the centralised approval pathways and authorisationpossibilities.

8 SeeArticles6(1)ofRegulation726/2004inconjunctionwith8(3)ofDirective2001/83.9 The risk-benefit balance is positive if the therapeutic effects of the medicinal product do

outweighitspotentialrisks.10 SeeArticle14(1)and(2)ofRegulation726/2004.11 The MAH may be obliged to conduct a post-authorisation efficacy study (PAES), imposed in

accordance with Regulation (EC) No 357/2014, or a post-authorisation safety study (PASS) inaccordancewithArticle1(15)ofDirective2001/83.

12 TherelevantdocumentationforapplicationsinexceptionalcircumstancesarelaiddowninPartIIofAnnexIofDirective2001/83/EC,asamended.

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Consequently, the authorisation under exceptional circumstances is grantedsubject toa requirement for theapplicant to introducespecificprocedures, inparticular concerning the safety of the medicinal product, notification to thecompetent authorities of any incident relating to its use, and action to betaken13.

c) ConditionalMA

Thelegalbasisforaso-calledconditionalMA(CMA)isArticle14(7)ofRegulation726/2004.CMAswillbevalidforoneyear,onarenewablebasis,andtheMAHwillberequiredtocompleteongoingstudiesortoconductnewstudies(specificobligations)withaviewtoconfirmingthatthebenefit:riskbalanceispositive.Inaddition, specific obligations may be imposed in relation to the collection ofpharmacovigilancedata14.

ThereasonforthepossibilityofaCMAisthatforcertaincategoriesofmedicinalproducts,inordertomeetunmetmedicalneedsofpatientsandintheinterestofpublichealth, itmaybenecessary initially tograntMAsonthebasisof lesscomplete data than is normally required. In such cases, it is possible for theCHMP 15 to recommend the granting of a MA subject to certain specificobligations tobe reviewedannually. Thismayapply tomedicinal products forhuman use that are eligible for centralised approval by the Commission andwhich:

§ Aim at the treatment, the prevention or themedical diagnosis of seriouslydebilitatingdiseasesorlife-threateningdiseases;or

§ Are to be used in emergency situations, in response to public threats dulyrecognised either by theWHO or by the Community in the framework ofDecisionNo.1082/2013/EU;or

§ AredesignatedasorphanmedicinalproductsinaccordancewiththeOrphanRegulation.

ACMAmaybegrantedwheretheCHMPcomestotheconclusionthat,althoughcomprehensiveclinicaldatareferringtothesafetyandefficacyofthemedicinalproducthavenotbeensupplied,allofthefollowingrequirementsaremet:

§ Thebenefit:riskbalanceofthemedicinalproduct,asdefinedinArticle1(28a)ofDirective2001/83,ispositive;

§ It is likely that the applicant will be in a position to provide thecomprehensiveclinicaldata;

§ Unmetmedicalneedswillbefulfilled;and

13 See EMA pre-authorisation procedural advice for users of the centralised procedure of 30

August2017(EMA/821278/2015)under1.10.14 The provisions for the granting of such an authorisation are laid down in Regulation (EC) No

507/2006.15 CommitteeforHumanMedicinalProducts(CHMP),oneofEMA'scommittees.

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§ Thebenefit topublichealthof the immediateavailabilityon themarketofthemedicinalproductconcernedoutweighstheriskinherentinthefactthatadditionaldataarestillrequired16.

d) MAsandotherauthorisationsforaccesstomedicinalproducts

Theterm“MA” includesmore than just the fullapproval,butallkindsofMAs(i.e., also the CMA and the MA under exceptional circumstances). As aconsequence,CMAsandMAsunderexceptionalcircumstancesalsobenefitfromRDPandpossiblyOME. In this regard, theCommission recently stressed in itsNotice on the application of Articles 3, 5 and 7 of the Orphan Regulation141/2000thatinordertomaintainorphandesignationatthepointofMAgrantthesubmitteddatapackagehastoprovideevidencewithregardtotherequiredsignificantbenefitoverexistingtreatments,andthatthisappliesirrespectiveofwhetheritisafullMAoraconditionalMA17.

However, necessary regulatory approvals for making available a medicinalproductinthecontextofacompassionateuseprogram(CUP)ornamedpatientsupply(NPS)isnotequaltoand/orcannotbeconsideredaMA.Theruleisthatamedicine can bemarketed in the EuropeanUnion (EU) only after it has beenauthorised.However, it issometimes inthe interestofpatientstohaveaccesstomedicinespriortoMAgrant.Inordertodoso,theEUlegislatorprovidedthepossibility for Member States to set up special programmes to make thesemedicines available to patients under defined conditions. This is commonlyknown as ‘compassionate use’. Even if an approval by a national competentauthority (NCA) isneeded for the suchmakinganactivity, suchanapproval isdifferentandnotequaltoafullMA,sothattheydonottriggertheclockforanyoftheabovementionedexclusivityrights18.

7.2.Roleofthe“GlobalMarketingAuthorisation”

ThecalculationofRDPandSPCperiodsbeginsatthepointoftheinitialMAgrantforthatproduct.Thisisregardlessofwhethertheauthorisationisbasedona‘standard’MA, a conditionalMA or aMA under exceptional circumstances, as these are allauthorisationsinaccordancewithArticle6(1)ofDirective2001/83andArticle14(1)of Regulation 726/2004. Thus, any process that facilitates obtaining earlierregulatory approval than currently experienced – even if it is only in a restrictedpatientpopulation,orona conditionalor stepwisebasis – starts the clockofRDPandtheSPCprotectionperiod,whichasaconsequencecouldleadtoanerosionofprotectionperiodsinsubsequentindications.

16 See EMA pre-authorisation procedural advice for users of the centralised procedure of 30

August2017(EMA/821278/2015)under1.9.17 CommissionnoticeontheapplicationofArticles3,5and7ofRegulation(EC)No141/2000on

orphanmedicinalproducts,OJC424of18.11.2016,p.3.18 The EFTA Court recently confirmed this with regard to similar permissions for veterinary

medicinalproductsinitsjudgmentdated9April2015inthecaseE-16/14(PharmaqASvIntervetInternationalBV).

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As laid out above, due to the so-called “Global Marketing Authorisation” (GMA)principle19,onceamedicinalproducthasreceivedaninitialMA,anyfurtherproductdevelopments such as new indications, strengths, pharmaceutical forms anddifferent presentations of existingmedicinal products are considered to belong totheGMAoftheinitialproductandwillnotleadtoneworseparateRDPperiods.TheconsequenceoftheGMAisthatalltheseproductdevelopmentswillhavethesameRDPperiodasthatoftheoriginalinitialproduct(i.e.maximumof10+1yearsfromthedateoftheinitialMA).

As the OME right is linked to a specific therapeutic indication and not to thecompoundthenatureandscopearedifferent fromRDPas itdoesnotprotect theactive substance overall but provides for an indication specific protection. As aconsequence,theGMAconceptdoesnotapplytoOMEperiods.Inaddition,astheOMEislinkedwiththeapprovaloftheproductintherespectiveorphanindication,itrunsconcurrentlywiththeRDPperiodsasfarasitconcernsitsinitialapproval.

7.3.AssessmentoftheidentifiedscenariosandtheimpactofMAPPs

InordertofullyunderstandtheimplicationsofadaptivelicensingandMAPPsonthecurrent existing exclusivity rights, the above mentioned 4 scenarios that arepredictedtooccurunderMAPPshavebeenexploredandassessedbyD3.06workinggroupthroughinterviewsandgroupconsensusbuildingasfollows20:

a) Scenario1:Stand-aloneMA

In this scenario, the active substance is developed and authorised in a singleindicationonly,andinthisinitialscenariotheassumptionisthattheMAwillnotbewithdrawn/revokedatalaterpointoftime(“noexit”).Forthepurposeofthisdiscussion,itiscalledastand-aloneMA.

Inthisscenario,theabove-mentionedexclusivityrightsapplyasfollows:

§ Incaseofpatentprotection, theproduct isprotected for20years startingwiththerespectivepatentfilingasperthescopeofthepatent.Ifitisabasispatent,thisprotectioncanbeprolongedbyaSPC–dependingonthetimeofMAgrant–foranadditionaltimeofmaximum5years.

§ Uponauthorisation, theRDPperiod for the8yearsofdataexclusivityandadditional2yearsofmarketprotectionstarts.

§ In case of an authorisationof the product as orphanmedicinal product, itwillalsobenefitfroma10yearOMEstartingwiththeapprovaldate.

§ Finally, depending on the timely fulfilment of the PIP obligations and thestatus(orphanornon-orphan),theproductmightbenefitfromapaediatric

19 TheGMAconceptislaiddowninArticle6(1)ofDirective2001/83/EC.20 Of note: This analyses is focusing on the legal implications and does not include other

considerations, e.g.whether the respective exclusivity periods are considered to be adequateforthenecessaryreturnoninvestmentincaseofearlierapprovalforlimitedpatientpopulationbasedonlimitedefficacydataandhigherriskofMAsuspensionincaseadditionaldatacannotbeprovided.

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reward in the form of either a 6 months SPC extension (for non-orphanproducts)or2yearsOMEextension(fororphanproducts).

b) Scenario2:MAforproductwithsubsequentapprovalofadditionalindications

In this scenario, the active substance is developed in several indications withsubsequent authorisations (i.e., first indication 1, subsequently indication 2).Therefore,thepharmaceuticalcompanywillobtainaninitialMAforindication1andsubsequentlyanauthorisation for theadditional indication–again,undertheassumptionof“noexit”.

In this scenario, with regard to the initially authorised indication 1, theexplanationsaboveunder(a)apply.

Withregardtothe impactontheexclusivitysituationduetothesubsequentlyauthorised indication 2, it must be distinguished further (1) whether for theinitialindication1wasapprovedunderanorphanMAorasnon-orphan,and(2)whetherthesubsequentindication2isorphanornon-orphan,too:

(1) Indication 1 and 2 are non-orphan: The authorisation of the secondindicationmight lead to a prolongation of RDP period by 1 year of additionalmarket protection if indication 2 provides a significant clinical benefit and isauthorisedwithin the first eight years after initialMAgrant.With this regard,the Court of Justice of the European Union (CJEU) recently confirmed in its“Aclasta” decision that the GMA of a medicinal product includes allauthorisations of an active substance granted to the sameMAH, in particularalso any subsequent authorisation of new indications, irrespective ofwhetherthenewindicationisauthorisedundertheexistingMAasavariationorwhetherit isauthorisedunderaself-standingMA21.Asaconsequence, thenon-orphanindication 2will not benefit froma self-standing RDP, butmay only lead to aprolongationofRDPby1year.

(2) Indication1non-orphan, indication2orphan: In thisscenario, thesecondindication may only be authorised under a self-standing MA as pursuant toArticle7(3)oftheOrphanRegulationorphanandnon-orphanindicationscannotbeauthorisedunderthesameMA22.Ifthereforethe2ndindicationisauthorisedasanorphanproductunderaself-standingMA, itwouldbenefit from itsownandself-standing,indicationspecificOMEprotection.Ifthesecondindicationisauthorisedwithinthefirst8years,itmayalsoleadtoaprolongationofRDPby1year.

(3) Indication 1 orphan, indication 2 orphan: As already laid out above, ifindication 2 concerns a different condition than indication 1, the second

21 CJEU,Novartis Europharm vs Commission, joined cases C-629/15P and C-630/15P (“Aclasta”),

judgmentof28.6.2016.22 PursuanttoArticle7(3)oftheOrphanRegulation,"themarketingauthorisationgrantedforan

orphanmedicinalproductshall coveronly those therapeutic indicationswhich fulfil thecriteriasetout inArticle3".But in its secondsentence,Article7(3)allows forasponsorofanorphanmedicinalproductto"applyforaseparatemarketingauthorisationforotherindicationsoutsidethescopeofthisRegulation".

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indication is entitled toan independentOME rightandperiodofprotection.23However, if thenew indication2 iswithin the sameorphan condition, it doesnot give entitlement to an additional period of OME right for this secondindication. As above, if the second indication is authorised within the first 8years,itmayalsoleadtoaprolongationofRDPby1year.

(4) Indication1orphan, indication2 non-orphan: In thisscenario, thesecondindicationdoesnotbenefitfromanyseparateorself-standingRER:Asindication2 isnotanorphanindication, itdoesnotbenefit fromanOMEright.Althoughindication 2 will need to be authorised under a self-standing MA as inaccordancewithArticle7(3)oftheOrphanRegulationorphanandnon-orphanindicationscannotbeauthorisedunderthesameMA,itwillnotbenefitfromaself-standingRDP,butmayonlyleadtoa1yearextensionoftheoriginalRDPfortheproductofupto11years.

c) Scenario3:ConditionalMAsubsequentlygetsapprovedfor‘full’MA

In this scenario, initially, a conditional MA was granted for the medicinalproduct, and subsequently, this got switched to a fullMA – again, under theassumptionof“noexit”.

As laid out above, a conditional MA is equal to a full MA as both areauthorisationsaccordingtoArticle14(1)ofRegulation726/2004.Therefore,theinitialconditionalapprovalkicksofftheSPCandRDPperiod,irrespectiveofthefact that for theyearly renewaladditionaldatawillneed tobeprovided.Asaconsequence, theexplanations fora stand-aloneMAaboveunder (a)applyasusual.

If under such a conditional MA subsequently an additional indication isapproved - which in accordance with EU Commission guideline will only bepossible if also this additional indication is also approved conditionally -, theexplanationsaboveunder(b)applysimilarly.

d) Scenario 4: Subsequent revocation / suspension of (conditional) MA ("exitscenario")

In this scenario, theMA– irrespectiveofwhether it is a fullMA, aMAunderexceptional circumstances or a CMA - is subsequently revoked or withdrawn(e.g.,becauseincaseofaCMAtheconfirmatorydataundertheconditionsofaconditionalMA orMA under exceptional circumstances were not fulfilled, orbecauseincaseofafullMAseriousadverseeventsoccurredthatdidleadtotheconclusion that a positive benefit: risk balance is no more given). For thepurposeofthisdiscussion,thisscenarioiscalled“exitscenario”

23 See in this respect the EMA guidance note for sponsors: “Post-orphan medicinal product

designation procedure”, version of 1 December 2015 which states in paragraph 2.3: “Eachorphan designation carries the potential for one ten-year market exclusivity for a particularindication. A medicine that has received several separate orphan designations for differentindicationscanobtainmorethanonemarketexclusivities if theserefer toseparatedesignatedconditions.”

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Also in this scenario, existing IPandRERapplyasusual. Even in the case thatafter initial suspension of the MA of a product and its withdrawal from themarket the product later on is reintroduced - which is considered to be anextremely rare case -, the current legal frameworkdoesnot foresee awayof“clockstop”insuchacase.ThesamewouldbetrueifwithregardtoaCMAtheconditionssetoutarenotmetandbythis,theCMAisnotrenewed.

If,therefore,thepharmaceuticalcompanywantedtoobtainanewapprovalforthis active substance (e.g., based on new,more compelling data, or in a newindicationbasedon totally different data), itwill not benefit froma newRDPperiodastheRDPclockwasstartedwiththe initialapproval.Thesameistruewith regard to any SPC protection. With regard to OME, if the product isauthorisedinthesameconditionastheinitialapproval,itwillnotbenefitfromaneworseparateOMEright.Onlyifthenewindicationisinadifferentcondition,itmaybenefitfromaself-standingOMEprotection.

Thus in the 4 scenarios discussed above, with the consideration of MAPPs,existingIPandRERapplyasusual.

7.4.Underminingofexclusivityrightsbyoff-labelorcross-labeluse

Thequestionwasraisedwhetherandunderwhichconditionsexclusivityrightscouldbe undermined by off-label or cross-label use, and whether this might have animpactonMAPPs.

a) Off-labeluse

The EU legal framework for medicinal products for human use regulates theauthorisationofmedicinalproductsby setting standardsof safety,qualityandefficacy.Asarule,anauthorisationisrequiredforallmedicinalproductsbeforeentering the EU market24, and exceptions are only possible in defined casesunder strict conditions 25 . During the MA procedure, the conditions areestablishedunderwhich theproduct canbeusedsafelyandefficaciously.TheSummary of Product Characteristics (SmPC) describes these terms and is thebasis of information for healthcare professionals (HCPs) on how to use themedicinalproduct.However,sometimesproductsareusedoff-label.

Off-labelusecanbedefinedasanyintentionaluseofanauthorisedproductnotcoveredbythetermsofitsMAandtherewithnotinaccordancewithitsSmPC.Off-labelusemayrefertotheuseoftheproductforadifferentindication,inadifferent dosage, with a different dosing frequency or duration of use, adifferentmethodofadministration,orbyadifferentpatientgroup(e.g.childreninsteadofadults).EUlegislationdoesnotregulatetheoff-labeluseofmedicinalproductsinmedicalpractice.

24 Article6(1)ofDirective2001/83.25 Theseexceptionsare(1)thecasesdefinedinArticle3(1)ofDirective2001/83,(2)ifaMember

State makes use of the medical need exception laid out in Article 5(1), for investigationalmedicinalproductsused in clinical trials, and for compassionateuseunder the conditions laidoutinArticle83ofRegulation726/2004.

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The prescribing of an authorisedmedicinal product -whether on-label or off-label-isadecisiontakenbythetreatingHCP,andtheultimateresponsibilityforthedefinitionof healthpolicy and thedeliveryof health services andmedicalcare lies with the Member States (Article 168 (7) TFEU). Off-label use ismeanwhilesubjecttonationallegislation26,andisalsorecognisedasaconceptbyEUpharmaceuticallaw27.TheGeneralCourtoftheEUrecentlystatedintheOrphacol case28that “off-labelprescribing isnotprohibited,oreven regulated,by EU law” and that “There is no provision which prevents doctors fromprescribingamedicinalproductfortherapeutic indicationsotherthanthoseforwhichamarketingauthorisationhasbeengranted.”

However,ifanauthorisedmedicinalproductisusedoutsideitsauthorisedlabelin an indication for which another product is authorised, and if this otherproduct benefits from an exclusivity right, these exclusivity rights may beunderminedandviolated.Suchafindingwasrecentlysubjectofthejudgmentofthe General Court of the EU in the “Orphacol Case” with regard to the OMEright:

§ Subject of this case was the question whether a reference to non-authorised indications contained in the SmPC and European publicassessment report (EPAR)of aproduct (Kolbam) constitutesa violationofthe OME of another product (Orphacol) as this product is not onlyauthorised for these indications, but alsoobtainedanOME right coveringtheseindications.

§ The Court decided that in order to ensure the effectiveness of the OMEprotectionofan indicationofauthorisedproduct, theoff-labelprescribingof another medicinal product for indications covered by this OME rightshouldnotbe facilitated.As the information setout in the SmPCand theEPAR of Kolbam was not limited to its authorised indications, but alsocontainedinformationrelatingtotheclinicalefficacyandsafetyofKolbamwith regard to indications of Orphacol, the Court found that thesedocumentswere liable to facilitate theoff-labelprescribingofKolbam forthe Orphacol therapeutic indications, taking into account that off-label-prescription is the sole responsibility of the prescribing physician. As aresult, the information was found to give rise to circumvention of theOrphacolOME,andasaresulttheMAofKolbamwasannulled.

b) Cross-labeluse

While the term "cross-label use" is not a legally defined term, it is commonlyused to describe the following situation: Certain indications of the originator

26 E.g.,health insuranceand liability legislation(liabilitymayarise ifoff-labelprescribing isnot in

linewith thestandardofcareofHCPs,but inappropriate) tocriminal lawaswellas toethicalandprofessionalstandardsofHCPs.

27 See e.g. Recital 2 of Paediatric Regulation and pharmacovigilance provisions in Directive2010/84/EU.

28 GeneralCourtoftheEU,LaboratoiresCTRSvCommission,T-452/14,judgmentof11June2015,paragraph79).

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productmaybeprotectedbyapatent(so-called"secondmedicalusepatent")asanincentiveforthedevelopmentofthisindicationforaperiodoftimewhichis longer than the protection of the compound. In recognition of the rightsconferred by such a second medical use patent, the health authorities allowapplicantsforgenericproductstoexcludethepatentprotectedindicationsfromthelistofapprovedindicationsforthegenericproduct.This"carve-out"ofthepatent protected indications leads to a so-called "skinny label", which in theSmPCandinthepackageinsert leaflet(PIL)only includesorreferstothenon-patent-protected indications. If irrespective of that, the generic product isprescribedandusedfortheprotectedindication,thissituationiscalled"cross-labeluse".

From an exclusivity perspective, it is necessary that a longer protection ofcertain indications by medical use patents needs to be reflected in the waymedicinal products are procured, prescribed and dispensed. Otherwise, if agenericproductisdispensedforanindicationforwhichtheoriginatorstillholdsapatentandforwhichthegenericproduct isnotauthorisedandlabelled,thisunderminestheeffectivenessofthesecondmedicalusepatent29.

c) Impactofoff-labelandcross-labeluseonMAPPs

Both off-label and cross-label use may impact products approved utilisingMAPPs. If a product is authorised underMAPPs in an area of unmetmedicalneedandisprotectedbyanindication-specificexclusivityright,theuseofotherproducts not authorised for this indication would undermine the exclusivityrightsgranted to theMAHof theproductbeingauthorisedunderMAPPs.Thesamewouldbetrueiftheproductisdevelopedfurtherinadditionalindications,andiftheMAHobtainsindicationspecificexclusivityrightsfortheseadditionalindications (e.g., via respective second medical use patents, or via OMEprotection).

8. Perceptual Issues and Considerations of the impact ofMAPPs

Inaddition toassessing the concrete legal issuesasdefinedabove, concernswereraised based around identified themes pertaining to the perceptual impactsassociated withMAPPs introduction.While some of these scenarios already existtoday, itwasfeltthatMAPPsaccentuatestheseandposespotentialroadblocksforadoptionanduptakeofMAPPsiftheyareneitherconsiderednorresolved.

ConcernNo1:AnearlierapprovalinalimitedpatientpopulationhasahigherchanceofbeingaCMAandbythismightbelinkedwithahigherriskofMAsuspensionorrevocation

29 SeeEFPIAPositionPaper"NewIndications&Cross-LabelDispensing"of11.11.2015.

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UnderMAPPs, it is predicted thatwith the earlier granting of anMA itwillmorelikelyoccurintheformofaCMA–thatforMAPPsproductsaCMAcouldbecomeasomewhat‘default’routetomarket(ratherthananexception).Whilethiscouldbeseenasanadvantageoffirsttomarket,witharelativeincreaseintheuseofCMAscomes the parallel theoretical likelihood in a greater number of MAs beingrevoked/suspendedduetonon-confirmatorydata.

Since their inception in 2006, the use of and experience with CMAs has steadilyincreased. In the10years to2016,30CMAshavebeengranted,ofwhich11havebeenconverted into“standard”MAs,17authorisationsremainconditional,2havebeenwithdrawn for commercial reasons, and importantly, nonehavehad theMArevoked or suspended for regulatory and/or scientific reasons.30 Therefore, oncurrentevidence,the likelihoodthattheCMAwouldbesuspended/revokedseemslow.

Thus under the current framework an earlier initial approval dis-incentivises thefurther"adaptive"approvalofadditionalindicationsasforallsubsequentindicationsthe time until loss of exclusivity becomes shorter and the remaining exclusivitycovers lower market use (sales versus time until exclusivity expiration).Consequently, attractiveness of adaptive approach will be influenced by theadequacyoftheremainingIPprotection.

It is a generally held opinion that the situation underMAPPswill not be differentthanforanyotherCMAproductastoday.EarliermarketaccesscouldevenprovideabenefitthroughextendingtherelativeperiodofIPprotectionforthefirstindication.Withearliermarketaccess, thetimebetweenpatentprotectionbeginningandthefirstMAgrantcouldbereduced(i.e.,firstMAoccurringafterphaseIIvsafterphaseIII/IV),hencetheremainingIPprotectionperiodforacompoundcould,intheory,belonger. To address these concerns, as part of the key early multi stakeholderdialogue,andprospectivedevelopmentplan,medicinedevelopersmaywanttoseekandobtainmuchgreaterinputfromregulators,HTAandpatientorganisationsastothelikelypopulationsizeforagivenindication,possibleindication(s)expansionandwhenthatmightoccur,andearly inputfrompayersastoestimatesofreturn.Thiswould in turn provide important direction to medicine developers as to earlyestimates of total (or remaining) IP and RER periods per product and/or perindicationaspartofanassessmentof theeconomicvalueofpursuinganadaptivepathway. Otherwise, a variety of other standard instruments for productdevelopment (e.g. standard marketing authorisation proceeding or acceleratedassessment)arestillavailabletothem.

Concern No 2: Earlier market access and public availability of European PublicAssessmentReports(EPAR)andclinicalstudyreports(CSRs)leadstoacircumventionofIPandRERrights

30 See www.ema.europa.eu/docs/en_GB/document_library/Report/2017/01/WC500219991.pdf

andwww.ema.europa.eu/docs/en_GB/document_library/Report/2017/01/WC500219991.pdf.

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With more products coming to market earlier and thus more publically availabledataontheseproductsalsobecomingavailableearlierduetothedatatransparencyinitiatives of EMA, concerns were expressed that European public assessmentreports(EPAR)andclinicalstudyreports(CSRs)mightbeusedbygenericcompaniesor other thirdparties to circumvent existing exclusivity rights, and that thiswouldpresentadistinctincentivebiasagainstamedicinedeveloperusingtheroutestoaMA(e.g.,CMA)envisagedunderMAPPs.

This concern that was raised would also be the same for products underMAPPscomparedtoanyothermedicinalproductstoday.Accessandpublicavailabilityarelimited to documents and information redacted of commercial confidentialinformation(CCI)31.Irrespectiveofthat,evenifsuchinformationispubliclyavailable,itmaynotbeusedbygenericcompaniesorcompetingoriginatorsduring theRDPperiod.Inaddition,anydatadisclosureisnotofrelevancewithregardtoOMErightsas these exist as administrative rights irrespective ofwhether underlying data areusedornot.

ConcernNo3: Itwillbemoredifficult forproductsunderMAPPstoobtainorphandesignationandOME,andeveniftheproductbenefitsfromOME,itwillnotprovideeffectiveprotection.

OrphandesignationandrelatedOMEareintendedtoprovidecommercialincentivesthat otherwisewould not exist under normalmarket conditionswhen developingmedicines intended for small numbers of patients. The criteria for orphandesignation include in particular that the product must be intended for thetreatmentofa lifethreateningorchronicallydebilitatingdiseasewithaprevalenceof no more than 5 in 10,000 people in the EU, and it must provide a significantbenefittothosebeingaffected.TheengagementcriteriasetoutunderMAPPsisthatthepotentialtreatmentmeetsahighunmetmedicalneed.Bydefinitionthetypesofproduct under MAPPs may to meet the criteria for orphan designation and as aconsequencebenefitfromOME.

WithregardtotheeffectivenessoftheOMEprotection,thesituationforaproductapprovedunderMAPPsisnotdifferentthantoa"normal"medicinalproduct.Aslaidout above, in order to provide an effective exclusivity right, indication-specificprotections granted by OME have to be respected by the players in the marketirrespectiveofwhethertheinitialapprovalwasgrantedearlierthanusual.

The basis for an adaptive pathway concept is to provide access of an initial orimprovedtreatmentoptionwithintheindication(s)oftheMA,asearlyasapositivebenefit:riskbalanceisestablished,tothosepatientswhoexperienceahighunmetmedicalneed.Whilepromotionofoff-labeluseisstrictlyprohibitedbylaw,on-labelprescribing isprimarilyguidedbycentrally regulatedtoolssuchas thesummaryofmedicinal product characteristics (SmPC). Additional tools and guidelines at the

31SeeArticle4(2)ofRegulation1049/2000.TherearecurrentlyseveralcasespendingattheEuropean

Courts about when and under which conditions documents being subject of a MAA can beconsideredtobe"commercialconfidentialinformation".TheoutcomeoftheselitigationswillbeequallyrelevantforproductsunderMAPPsandallothermedicinalproducts.

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nationallevelincludeHCPtreatmentguidelines,specialistcertifications,orrestrictedreimbursementcriteria.AsHCPshavethefreedomtoprescribeamedicinalproductoutsidetheapprovedindication(s),itwillbeimportantthattheexclusivityrightsofproducts being authorised under MAPPs are not undermined by off-label use ofother authorised medicinal products, and that in particular prescribing treatmentguidelinesaccuratelyreflecttheauthorisedMAPPsproduct.

Concern No 4. An early MA may adversely affect SPC resulting in loss ofattractivenessofpursuinganearlytomarketoption.

Concernswere raised thatanearlyMA (<5yearsafter thepatent filing)willmeanthat therecanbenocompoundSPC– inotherwords, thebasiccompoundpatentprotectionwilllastonly20yearsfrompatentfilingandcouldnotbeextendedbyanSPC,andthismaymakeitlessattractivetoinvestinnecessaryclinicaltrialsforthelaterdevelopmentofotherindications.

Inaddition,concernswereraisedastotheeffectivenessofpatentprotectionand/orRER protection in second or subsequent indications in the same product, inparticular with regard to their enforcement. Specifically, obtaining an initial MAearlierthannormalinsomecasescouldmeanthat:

i)aSPCwasnotapplicable(i.e.<4.5yearsafterpatentfilingtoMAgrantwouldnotpermitanSPC32)andbythisapaediatricrewardwouldnotbepossible.

ii)ifanSPCispossible,itwouldlapseiftheCMAiswithdrawn(evenifundercurrentcircumstancesitmightbeconsideredtobeextremelyrarethataproductlateronisreintroducedintothemarket,insuchascenario,therewouldbeconsiderablelegaluncertaintyastowhetheranewSPCcouldbegrantedthereafterbaseduponlaterapprovalinadifferentindication),or

iii) loss of secondary patent protection due to earlier disclosure of data in theframeworkofEMA’sclinicaltrialdatatransparencyregime.

With regard to the discussed scenarios, it may be perceived as insufficient thatadditionalindicationsareonlyprotectediftheseareorphanindicationsinadifferentcondition,orifprotectedbymedicalusepatents.Inparticularifabroadnon-orphanindication without any second medical use patent protection is obtained - whichmight be the most common scenario, the only currently available incentive is aprolongationofRDPby1 year. Thus, thebusiness case for utilizingMAPPs shouldcome from the engagement criteria and the early multi-stakeholder dialogues.Therefore, theoverallbusinesscase forearlyaccessviaMAPPswillbedeterminedbyseveralfactorsand,othercommercialadvantagesthatwillincludetheexclusivitysituationdeterminedbyIPandRER.

32Seebothi)CJEU,MerckSharp&DohmevDeutschesPatent-undMarkenamt,C125/10,judgmentof 8 December 2010 and ii) EFTA Court,Merck Sharp & Dohme v Icelandic Patent Office, E15/17,judgmentof21December2017,ontheso-called“negativetermSPC”.

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9. DiscussionThe current legal and regulatory framework applies to products approved underMAPPsinthesamewayasanyothermedicinalproducts.Thisisnotonlytruewithregard to theauthorisationpossibilitiesandprocedures,but inparticularalsowithregardtotheIPandRERs.Nodirectlegalroadblockswereidentified.Thecurrentlyavailable incentives are generally supportive of MAPPs, yet some uncertaintiesremain, inparticularwithregardtotheriskofoff-labeluseofcheaperproductsortheeffectiveprotectionofadditional,subsequentlyapprovedindicationsduetotheriskofcross-labeluse.

WithregardtoRDP,theauthorizationofanadditionalindicationmayonlyleadtoaprolongationofRDPby1yearifcertainconditionsaremet(seeabove),evenifthisadditional indication is in a different therapeutic area and authorized under aseparate,self-standingMA.

In addition, it was discussed on the one hand whether additional protection offurtherdevelopmentsmightbeneeded,whileon theotherhandwhetherexistingexclusivity rights might not always provide effective protection, especially at theMemberStatelevel,andmightbeundermined.

The current European Commission analysis of EU incentives/exclusivity rights andthepracticaleconomicsofso-calledcross-labelusecouldnegativelyimpactMAPPs.Cross-labeluseacrossMemberStatescouldbeexacerbatedunderMAPPs.

However, there was strong support for HTA/payer input and perspectives to betaken intoconsiderationearly inprospectiveplanning,and that thiswasseenasagreatereconomicdriverfor industryandreturnoninvestmentcomparedtoIPandRER.

There was support to further map and understand the scope of necessary legalcommitmentsofallstakeholdersinMAPPsatthebeginningoftheprocessandhowthat might be implemented as well as the value which might be generated withtheseupfrontcommitments.

Therewasalsoa strongdesire tomaintain thecurrentEU legal frameworks for IPandRER–MAPPscouldoperateeffectivelywithininit.However,ifinthefuture,theEU legislative framework is re-opened for amendment it is vital that the MAPPsconcept is considered equally alongside other existing instruments to ensure thatany changes to exclusivity periods can be optimized prospectively in support ofMAPPs. This is particularly important in view of the current incentives analysisreferredtoabove.33

33 The European Commission announced in January 2017 to conduct an analysis of the current

legal framework of incentives and rewards, their nature, safeguards, possibilities to combinethem fora singleproductandananalysisof theiractualusebypharmaceutical innovators, inparticularlookingatthecombineduseoftheseincentivesandrewards.

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10.RecommendationsThecurrentlegalframeworkforIPandRERrightsprovidesclearanswerswithregardtoall4 identifiedscenarios.Atthesametime, itdoesnotprovideanyflexibilityorfor special solutions with regard to products approved under MAPPs. Thusrecommendationsforfutureworkareasfollows:

1. BuildingabusinesscaseforexclusivityperiodsunderMAPPsthatisbothpermissiveandappealingtomedicinedevelopers

A practical solution to incentivise the use ofMAPPs would be to develop a clearbusiness case – this could be co-developed with medicine developers usingalgorithms similar to those utilized by MIT/NEWDIGS for scenario building ofstratifiedmedicines.34Furtherlearningneedtobeabsorbedanddisseminatedfromcase studies of ‘MAPPs-like’ products and how IP and RER considerations wereaccounted.Furtherextrapolation fromproductscontinuingthroughEMA’sadaptivepathwayspilots arewarranted tounderstandhowearlydialoguesguidedbothpreandpostMAdecisionsonIPandRDE.

2. Takeintoconsiderationoutputsfromthisgroup

FutureworkinparticularoftheEuropeanCommissionwhenconductingtheanalysisof the current legal framework of incentives and rewards, should take intoconsiderationtheoutputsfromthisgroupwithregardtotheinterplayofMAPPsandtheexistingIPandRERs.ReciprocaldialoguesandlearningcouldproveinvaluableasMAPPsevolvedfurther.

3. Early, prospective dialogue and considerations of all regulatoryinstrumentsavailable

Akeydrivertosuccessfullynavigatingadaptivepathwaysforamedicinedeveloperandtomaximizemarketvaluewouldbetoengageintheearliestpossibledialoguewith other stakeholders in order to get a clearer picture of the enabling toolsavailable. This refers for example to the possibility of a CMA, the framework oforphandesignationandOME,thePRIMEschemeandthepossibilityofacceleratedassessment,and themulti-stakeholder scientificadvice (regulatoryandHTAs).Thiswould allow early discussions to identifywell defined patient subpopulations, thepracticalitiesandfeasibilityof indicationexpansion,adetailedevidencegenerationplanandsteerfromregulatorsastothelikelypostmarketingcommitmentsandtimeframesforconfirmatorydatacollection:“Adevelopmentprogrammenotadherentto

34 TrusheimMR1,Burgess B,Hu SX,Long T,Averbuch SD,Flynn AA,Lieftucht A,Mazumder

A,MilloyJ,ShawPM,SwankD,WangJ,BerndtER,GoodsaidF,PalmerMC.,Quantifyingfactorsfor the success of stratified medicine, Nat Rev Drug Discov. 2011 Oct 31;10(11):817-33. doi:10.1038/nrd3557.

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receivescientificadvicewasmorelikelytofailtoreceiveaCMA,whileanadherentdevelopmentmorelikelytoresultinaCMAbeinggranted”35.

4. Mechanismtomapoutandmanagecommitmentofallstakeholders

Thereisaneedforamechanismtomapthescopeofnecessarylegalcommitmentsofallstakeholders inMAPPsatthebeginningoftheprocess,andtomanagethosecommitments throughout aMAPPs product lifecycle. The exact level of sharing ofinformation early in product development, and level of informal or formalcommitments would need careful consideration in order to meet the minimumneedsandexpectationsofmedicinedevelopers,whilebeingsufficientlypermissiveforotherstakeholderstoengagefullyintheprocess.

***

35 European Medicines Agency, Conditional marketing authorization, Report on ten years of

experienceattheEuropeanMedicinesAgency(EMA/471951/2016),2017,slide37.