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PREPARING FOR LAUNCH: MARKET ACCESS PLANNING

FOR A TETRAVELENT DENGUE VACCINE CANDIDATE

SANA RAFIA MOSTAGHIM

A DELTA Doctoral Thesis Submitted to the Faculty of

The Harvard T.H. Chan School of Public Health

in Partial Fulfillment of the Requirements

for the Degree of Doctor of Public Health

Harvard University

Boston, Massachusetts.

May, 2018

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Thesis Advisor: Dr. Peter Berman Sana Rafia Mostaghim

Preparing for Launch: Market Access Planning for a Tetravalent Dengue Vaccine Candidate

Abstract

Over half of the world’s population lives in dengue-endemic regions, and

hundreds of millions of people are infected by the virus each year. A handful of

organizations are working to develop a safe and effective vaccine against this global

public health threat. This dissertation conveys the experience of an 8-month field

assignment to help develop the global market access strategy for Takeda

Pharmaceuticals’ dengue vaccine candidate.

The field work followed a 3-step methodology, based on the following essential

pillars of vaccine market access: evidence generation, pricing approach, supplementary

health initiatives, supply chain, and the policy approach. The first step was to

specifically describe these pillars for the dengue vaccine candidate. The second step was

to categorize potential launch countries based on shared market characteristics. The

culminating step was to craft a strategic direction for combinations of the market access

pillars and country categories generated in the first two steps.

This process resulted in a document presenting Takeda’s market access approach

for the dengue vaccine. During implementation of the first step, a new market access

pillar was added to highlight the people and communities that would potentially use the

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vaccine. The second step produced four country categories: endemic countries with high

readiness for vaccine adoption, endemic with gaps in readiness, travel markets, and

markets that rely on supranational funding. The third step created a set of global

strategic directions for the dengue vaccine. Country teams will then rely on this

guidance to develop national market access plans.

The field work generated insights that are applicable to the broader domains of

public health and pharmaceutical products. Above all, the experience delineated the

concepts of ‘market access’ and ‘access to medicines’; current literature and practice

sometimes conflate these terms, and market access is often defined as a process. The

work underscored the importance of going beyond a process-only definition of market

access in order to assess its aims, assumptions and outcomes. Further insights relate to

the significance of language used by public health and corporate stakeholders, the

importance of leadership and organizational values in shaping market access, and the

crucial role of country teams for implementation.

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ABSTRACT..............................................................................................................................................................IILISTOFFIGURES.................................................................................................................................................VIACKNOWLEDGEMENTS...................................................................................................................................VII1.INTRODUCTION...............................................................................................................................................11.1BACKGROUND.....................................................................................................................................................................11.1.1Dengue............................................................................................................................................................................11.1.2Vaccinesandpublichealth....................................................................................................................................2

1.2THENEEDFORADENGUEVACCINE................................................................................................................................31.3TAKEDA’SDENGUECANDIDATE.......................................................................................................................................41.3.1TakedaProfile.............................................................................................................................................................41.3.2TAK-003.........................................................................................................................................................................5

1.4DELTAPROJECTOVERVIEW............................................................................................................................................6

2.ANALYTICALPLATFORM..............................................................................................................................72.1ATAXONOMYOFACCESS...................................................................................................................................................72.2LITERATUREREVIEW.....................................................................................................................................................112.2.1Dengue..........................................................................................................................................................................112.2.2VaccineforDengue.................................................................................................................................................142.2.3PharmaceuticalAccess..........................................................................................................................................23

2.3VBU’SMETHODOLOGICALAPPROACHTOMARKETACCESS..................................................................................252.3.1GlobalMarketAccessstrategy...........................................................................................................................252.3.2LocalMarketAccessPlan.....................................................................................................................................29

2.4METHODOLOGICALREFLECTIONS................................................................................................................................302.4.1CharacterizingVBU’sapproach........................................................................................................................302.4.2Evaluationframework..........................................................................................................................................32

2.5CASESTUDIESOFVACCINEACCESS.............................................................................................................................342.5.1RotaTeq®..................................................................................................................................................................342.5.2MenAfriVac®............................................................................................................................................................36

3.RESULTSSTATEMENT.................................................................................................................................383.1SUMMARYOFPROGRESSTOWARDSACCESSAIMS....................................................................................................383.1.1ExperiencewiththeglobalMarketAccessmethodology.......................................................................393.1.2Experiencedevelopingacountrymarketaccessplan.............................................................................58

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3.1.3Organizationalandstakeholdercontext.......................................................................................................643.2EVALUATIONOFRESULTS..............................................................................................................................................683.2.1AssessmentusingSmithFramework...............................................................................................................693.2.2CritiqueofSmithFramework.............................................................................................................................72

3.3KEYINSIGHTS...................................................................................................................................................................733.3.1TherelativedefinitionsofMarketAccessandAccesstoMedicines...................................................733.3.2IsMarketAccessjustaprocess?........................................................................................................................743.3.3Theroleofleadershipandorganizationalvalues.....................................................................................783.3.4Thesignificanceoflanguage..............................................................................................................................803.3.5Theimportanceofcountryteams....................................................................................................................813.3.6Interactionsbetweenadvancedmarketplanningandclinicaldevelopment...............................83

4.CONCLUSION...................................................................................................................................................844.1SUMMARY.........................................................................................................................................................................844.2PROPOSEDTOPICSANDQUESTIONSFORFURTHERINQUIRY..................................................................................84

6.APPENDIX........................................................................................................................................................86APPENDIX1:ORGANIZATIONCHART.................................................................................................................................86APPENDIX2:DETAILEDMETRICSFORREVISEDARCHETYPEEXERCISE......................................................................87APPENDIX3:LISTOFACRONYMS.......................................................................................................................................88

BIBLIOGRAPHY...................................................................................................................................................89

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ListofFigures

Figure1.DengueVaccineDevelopmentPipeline

Figure2.Differentiatingcharacteristicsofamarketaccessstrategy

Figure3.Revisedlogicflowforcountryarchetypeexercise

Figure4.Illustrativeoutputofrevisedarchetypeanalysis

Figure5.Illustrativeexampleofsummarymatrix

Figure6.Structureoflocalmarketaccesstemplate

Figure7.Evaluationofmarketaccessmethodology

Figure8.AcomparisonofthelanguageusedinPharmaceuticalAccesswork

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Acknowledgements

IthankJalehforherunfailingsupport,Faiziforhisdailyinspiration,mycommitteeforits

steadyguidanceandtheTakedateamforitscomraderyandprovidingthisopportunityto

workonanimportantglobalhealthissue.

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1.Introduction

ThisdissertationisaboutaDoctoralEngagementinLeadershipandTranslationforAction

(DELTA)projectfocusedonmarketaccessplanningforpharmaceuticalproducts.Itis

basedonan8-monthfieldassignmenttoprepareaglobalmarketaccessstrategyforan

organizationthatisconductinglate-stagetrialsforanewdenguevaccine.Assuch,itoffers

uniqueinsightsaboutanefforttoplanforaproductthathashighpotentialforpublic

healthimpactwhileitisstillundergoingclinicaldevelopment.Thisintroductorysection

setsthestageforthefieldworkbyoutliningthepublichealthchallengethattheDELTA

DoctoralProjectaimedtoaddress.ItisfollowedbytheAnalyticalPlatform,whichpresents

aliteraturereviewanddescribesthemethodologicalapproachthatguidedtheproject’s

activities.TheResultssectionthensharesthemainoutcomesoftheworkalongwithsome

reflectionsonhowtheAnalyticalPlatformevolvedduringprojectimplementation.The

documentconcludesbyofferinginsightsandimplicationsforthebroaderfieldof

pharmaceuticalmarketaccessplanning.

1.1Background

1.1.1Dengue

Dengueisaviralinfectionwithflu-likesymptoms.Itcanprogresstoapotentiallylethal

versionknownasseveredengueordenguehemorrhagicfever.Thevirusiscausedbyone

offourrelatedserotypes.TheyaremainlytransmittedbythefemaleAedesaegypti

mosquito,whichisalsotheprimaryvectorforyellowfever,chikungunyaandzikainfection

(1).

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Thereisarangeofprevalence,incidence,mortalityandmorbidityfiguresfordenguevirus

(2).Regardless,theriskandburdenofdiseaseissubstantial:upto3.9billionpeopleare

thoughttobeatriskofinfection(3)andonewidely-citedstudyestimates390million

infectionsperyear(4).Theannualglobaleconomiccostofdenguewasrecentlyestimated

at8.9billionUSD(5).

1.1.2Vaccinesandpublichealth

Vaccineshavemadearemarkablecontributiontoimprovingpublichealth.Accordingto

theWorldHealthOrganization(WHO),2-3milliondeathsareavertedeveryyearbecause

ofimmunization(6).Vaccinesledtotheglobaleradicationofsmallpox(7),andtheyhave

enableddramaticreductionsinmorbidityandmortalityforvaccine-preventablediseases

suchasDiphtheria,Measles,Mumps,Pertussis,Influenza,RubellaandPolio(8).Vaccines

arealsoregardedasahighlycost-effectivehealthinvestment–a2016studyof94lowand

middle-incomecountries(LMICs)concludedthateveryonedollarspentonvaccines

returnedsixteendollarsofeconomicbenefits(9).Despitethesebenefits,thereare

‘hesitant’individualsthatrefuseordelayvaccinationbecauseofalackofconfidence,issues

withconvenience,orcomplacency(10).Levelsofvaccinehesitancyareheterogeneous

acrosspopulationsandtheyvarywithtime(11),buttheydonotdisplacetheroleof

vaccinesas“oneofthesafestandmostcost-effectivemedicalinterventionsinhistory”(12).

Indeed,governmentleaderscontinuetoprioritizevaccinesbecauseoftheirpublichealth

value;in2012,nearly200countriessignedontotheGlobalVaccineActionPlan(GVAP)to

progresstowardstheaimforallpeopleeverywheretobeprotectedfromvaccine-

preventablediseases(13).

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1.2Theneedforadenguevaccine

Thereiscurrentlynotreatmentfordengue(14).Thepublichealthresponseisfocusedon

earlydetection,careforsymptomaticrelief,andprevention(e.g.vectorcontrol).

Notwithstandingtheseefforts,incidenceestimatesarecharacterizedbyanupwardtrend

overthelast5decades(15).AccordingtoWHO:“thegrowingglobalepidemicofdengueis

ofmountingconcern,andasafeandeffectivevaccineisurgentlyneeded”(16).

Torespondtothisneed,thescientificcommunityhasspentdecadessearchingforan

effectivedenguevaccine.Publicandprivateplayersarecurrentlypursuingasetof

candidatesatvariousstagesofdevelopment.Asummaryofthepipeline,includingeach

candidate’sdevelopmentsponsorandtechnologyplatform,ispresentedinFigure1.Note

“PhaseI”,“PhaseII”and“PhaseIII”indicatetheprogressivestagesofclinicaltrialsinthe

vaccinedevelopmentprocess.Eachphasetypicallyinvolvesdozens,hundreds,and

thousandsofparticipants,respectively.Thesetrialsproducethedosage,safetyandefficacy

datathatnationalregulatoryauthoritiesreviewwhendeterminingwhetherornotto

approveavaccineforuse.

Figure1.DengueVaccineDevelopmentPipeline,asofMarch20161(17)

1DiagramadaptedfromDengueVaccineInitiativeinfographic

REGULATORYAPPROVALPHASEIIIPHASEIIPHASEI

• Glaxo,WalterReadArmyInstitute&Fiocruz[Inactivated]

• WalterReadArmyInstitute[Heteroprimeboost]

• NationalInstituteofAllergyandInfectiousDisease[LiveAttenuated]

• Takeda[LiveAttenuated]

• Instituto Butantan[LiveAttenuated]

• SanofiPasteur[LiveAttenuated]

• NavalMedicalResearchCentre[DNA]

• PanaceaBiotec [LiveAttenuated]

• Merck[Subunit]

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SanofiPasteurisnotableforattainingregulatoryapprovalofitsdenguevaccine,knownas

Dengvaxia®in2015.Itistheworld’sfirstregistereddenguevaccine.Thismilestonewasa

significantstepforwardinthebattleagainstdengue.However,thevaccinehassafety

concerns,focusedprimarilyaroundanincreasedrateofhospitalizationobservedamong

youngseronegativechildrenthatreceivedthevaccine(18).Thesesafetyconcerns,along

withasub-optimalthreedosescheduleandconcernsaboutthepriceofDengvaxia®,have

ledtoanarrowtherapeuticindicationandrelativelylimiteduptakeinahandfulof

countriesforSanofi’svaccine(19).

1.3Takeda’sdenguecandidate

1.3.1TakedaProfile

Takedaisaglobal,integratedpharmaceuticalcompanyfromJapan.In2016,thecompany

markedits235-yearanniversarywithover30,000employeesgeneratingover15billion

USDinrevenueacross70countries(20).

Withthissubstantialhistoryandresourcesasabackdrop,thecompanyestablishedthe

globalVaccineBusinessUnit(VBU)in2012.AlthoughTakedahasproducedvaccinesin

Japanforover6decades,VBUwasestablishedtodevelop,produceanddelivernew

vaccinestargetedatmajorunmetglobalhealthchallenges.VBU’smissionisto,“develop

anddeliverinnovativevaccinesthattacklethetoughestproblemsinpublichealthand

improvethelivesofpeoplearoundtheworld”(21).Thepipelinecurrentlyincludesvaccine

candidatestargetinginfectiousdiseases:dengue,zika,norovirusandpolio,amongothers

(22).Ifdevelopmentproceedsfavorably,denguewillbethefirstvaccinethatVBUlaunches

intheglobalmarket.

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Dr.RajeevVenkayyaisVBUpresident.PriortoTakeda,Dr.VenkayyawastheDirectorof

VaccineDeliveryattheBill&MelindaGatesFoundation,SpecialAssistanttothePresident

forBiodefenseattheWhiteHouse,andAssistantProfessorofMedicineattheUniversityof

CaliforniaSanFrancisco(23).Thus,hehasservedasaleaderatamajorglobalhealth

donor,thepublicsector,academia,andnowtheprivatesector.Thesediverseroles

constituteararecombinationofexperiencesthataddcredibilitytoTakeda’sglobalhealth

ambitionsforvaccines.

1.3.2TAK-003

Takedaiscurrentlyinlate-stagetestingforitsdenguevaccinecandidate,knownasTAK-

003.“TIDES”(TetravalentImmunizationagainstDengueEfficacyStudy)isevaluatingthe

efficacyofTAK-003topreventdengueofanyseverityandcausedbyanyofthefourvirus

serotypesinchildrenandadolescentsin8countriesacrossAsiaandLatinAmerica(24).

Thecompanycompletedenrolmentof20,100participantsinApril2017,andinitialresults

areexpectedbytheendof2018(22).

TAK-003’sevidence-to-dateispromising.DatafromthephaseIandIIstudiesindicatea

protectiveeffectagainstall4serotypesinindividualsofdifferentageswithnosafety

concerns(25,26).Thescientificcommunityisthus“eagerlyawaiting”(27)thelatesttrial

data.Meanwhile,Takedaispreparingmarket-launchactivitiestoenablerapidregistration

anduptakeintheeventofpositiveTIDESdata.

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1.4DELTAprojectoverview

TheDELTAprojectfocusedonmarketaccessplanningforTakeda’sdenguevaccine.Similar

toanylargeresearchanddevelopmentpharmaceuticalorganization,VBUisstructuredin

functionalgroups.AmongthesearetheDiscovery,Development,MedicalAffairs,

Operations,andCommercialteams.TheassignmentwaswiththeCommercialteam.A

diagramthatsituatestheDELTArolewithinTakeda’sglobalorganizationalchartis

includedasAppendix1.

TheworkoccurredatVBU’sglobalheadquartersinCambridge,Massachusetts.Theproject

wasstructuredasan8-monthassignmentfromJune2017–February2018.Theprimary

objectivewastocontributetotheglobalmarketaccessstrategyforTakeda’sforthcoming

denguevaccine.Thisworkwascomplementedby2peripheralworkstreams,totaling3

altogether:

1. CreatingtheglobalmarketaccessstrategyforTakeda’sdenguevaccine

2. Supportingthedevelopmentofalocalmarketaccessplanforonecountry,based

ontheguidancefoundintheglobalstrategy

3. Developingago-to-marketmethodologytodetermineVBU’soperationalplansto

implementthemarketaccessplans

Takedaadoptedasystematicmethodologyforitsmarketaccessplanning.TheAnalytical

Platformwillsetthisapproachinthecontextofaliteraturereviewandthendescribethe

details,assumptionsandimplicationsassociatedwiththisapproach.Itpresentsthe

baselineapproachandprevailingknowledgeattheoutsetoftheproject.TheResults

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sectionreflectstheprogressthattheDELTAprojectworkmadetowardsimprovingaccess

forTakeda’sdenguevaccineandextrapolateskeyinsightsandquestionsfromthe

experience.Itincludeshowthemethodologyevolvedandkeydevelopmentsintheexternal

andinternalenvironmentthatshapedthecourseofthework.

2.AnalyticalPlatform

TheIntroductiondescribedthepublichealthchallengeofdengueandtheneedfora

vaccine.ItprovidedabackdroptotheobjectivesofthisDELTAprojectworkthatfocused

onmarketaccessplanningforTakeda’sdenguevaccinecandidate.ThisAnalyticalPlatform

providesadeeperassessmentoftheprevailingstateofknowledgeandTakeda’sapproach

attheproject’soutset.Inshort,ithighlightstherelevantinformationandplansthatwere

necessaryforaction.Itisstructuredinfourmainsections.Thefirst,“ataxonomyofaccess”

reflectsontheoccasionallyconflictingusageofthe‘access’phraseandestablishesa

workingdefinitionforthepurposesofthisdissertation.Thisisfollowedbyareviewofthe

scientific,academicandprofessionalliteraturethatisrelevanttotheworkofmarketaccess

planningforanewdenguevaccine.Next,VBU’sspecificapproachtomarketaccess

planningisdescribedandtherearesometheoreticalreflectionsonthismethodology.The

AnalyticalPlatformconcludesbydrawingrelevantinsightsfromtwocasestudiesof

vaccineaccess.

2.1Ataxonomyofaccess

“Access”isacommonlyusedwordinthepharmaceuticalandglobalhealthfields.When

oneconsidershowthephraseisemployedinparticularcontextsandbydifferent

stakeholders,importantdistinctionsandnuancesarise.Abookbythesametitledefinesthe

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termas“people’sabilitytoobtainandappropriatelyusegoodqualityhealthtechnologies

whentheyareneeded"(28).Althoughitishelpful,thisdefinitionleadstomanyimportant

questions.Whoarethepeopleinconsideration?Howisthetechnologyidentified?Howis

quality,appropriateuse,andneeddefined?Towhatend?ThenatureoftheDELTA

assignmentwarrantscloseexaminationandaclear,consistentuseofthisterm.

“Access”isashort-handphrasethatisusuallyintendedtoabbreviateatleastoneoftwo

fieldsofactivity:“marketaccess”and“accesstomedicines”.Thetwotermsarerelatedbut

theydonotnecessarilyrefertothesamething.

Asystematicliteraturereviewoffersthefollowingworkingdefinitionof“marketaccess”:

“theprocessthatensuresthedevelopmentandcommercialavailabilityofpharmaceutical

productswithappropriatevaluepropositions,leadingtotheirprescribingandto

successfuluptakedecisionsbypayersandpatientswiththeultimategoalofachieving

profitabilityandbestpatientoutcomes”(29).Thisdefinitionisliterallyconcernedwith

whatmustbedonebyacompanysoitcangetitsproducttoamarket.Itisprocess-oriented

andthescopeisnotdefinedbyaspecificsubsetofpeopleorcountries.

Thereinliesanimportantdistinctionwith“accesstomedicines”.Thisnotionhasitsorigins

intheUnitedNations’MillenniumDevelopmentGoal(MDG)target8-E,whichaimedto

improve“accesstoaffordableessentialdrugsindevelopingcountries”(30).Indeed,the

AccesstoMedicinesFoundation,whichproducesanauthoritativebi-annualreportonthe

topic,measuresactivitiestomake“medicines,vaccinesanddiagnosticsmoreaccessiblein

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low-andmiddle-incomecountries”(31). Thus, the term “accesstomedicines”isconcerned

withanoutcomeanditcanbecharacterizedbyitsfocusonpeopleinlowandmiddle-

incomecountries.

“Marketaccess”and“accesstomedicines”carryotherimportantdistinctions.Theformeris

acommercialactivityandthelatterismorephilanthropicinnature.Saidanotherway,

“marketaccess”isfocusedonrealizingtheeconomicandhealthvaluepropositionofa

particularhealthassetand“accesstomedicines”ismoreconcernedwithhowpeoplein

resourcelimitedsettingscanbenefitfromahealthproductorservice.Theformerisan

opportunityforcompanies,andthelatterseesitselfasarightforpeople.Marketaccess

placesanimplicitemphasisonwhoiscarryingouttheactions(e.g.thecompany),whereas

accesstomedicinesfocusesonwhoistoreceivethehealthtechnology.

Thedistinctionsarenotonlyconceptual,theyarereflectedinorganizationalstructuresand

activities.AtTakedaforexample,theglobalpharmaceuticalorganizationhastwoseparate

MarketAccessandAccesstoMedicinesteamswithmandatesthatgenerallyalignwith

thesecommercialandcharitablenotionsoutlinedabove(32,33).

Thereisapotentialforconfusionbecausebothofthesephrasesaresometimesabbreviated

tojust‘access’.Forexample,FrostandReich(28)“conceiveofaccessasameansto

addresstheillhealthofpoorpeopleinpoorcountries”.Here,theshorthand“access”is

used,but“accesstomedicines”iseffectivelyimpliedbytheirdefinitions’prominenceof

poorpeopleinpoorcountries.Itisnotdifficulttoimaginemiscommunicationinadialogue

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about‘access’betweencorporateandglobalhealthstakeholders,ifeachpartyapproaches

itwiththerespectivedefinitionsof“marketaccess”and“accesstomedicines”inmind.The

Resultssectionofthisdocumentwillreflectonwhetherthistypeofdisconnectoccurredin

thecaseofmarketaccessplanningforthedenguevaccinecandidate,andifso,howthat

dialoguewasmediated.

Interestingly,itispossiblethattheinconsistentuseofthephrase“access”willgradually

becomelessofapotentialproblem.Thisisbecausethedefinitionsarebeginningtobluras

theirpracticalscopeconverges.Thetraditional“marketaccess”perspectiveincreasingly

prioritizestheroleofemergingmarketsaspharmaceuticalcompanieslooktothemasa

growingrevenuecontributor(34).Conversely,the“accesstomedicines”fieldisgrowing

beyondphilanthropy;aninitialfocusondonationprogramsisexpandingtoinclude

initiativessuchasnovelpricingstrategies,licensingagreementsandsupplychain

strengtheninginitiatives(35).Theoverlapgrowsfurtherasglobalhealthstakeholders

increasinglypursue“market-shaping”approaches(36)toachievepublichealthaims.This

convergingtrendisapplicableforVBUandespeciallyadenguevaccine,becausedengue’s

highburdenpopulationsareprimarilyinresource-limitedsettings.Inthissense,“market

access”and“accesstomedicines”couldeffectivelyentailoverlappingactivitiesand

objectives.

Nonetheless,preciseterminologyisrequiredfortheclarityofthisdocument.“Accessto

medicines”and“marketaccess”willbeusedaccordingtothetraditionaldefinitions

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initiallydescribedabove.Toavoidconfusion,“access”willbeusedasacommonverband

notasashorthandforeitherofthesedefinitions.

2.2Literaturereview

Marketaccessplanningforanewdenguevaccinehasthebenefitofdrawingonseveral

relevantfieldsofliterature.Thisreviewofthatliteratureisstructuredaccordingto3

componentcategoriesthatconstitutedtheessentialscopeoftheDELTAproject:i.dengue,

ii.vaccinesfordengue,andiii.pharmaceuticalaccess(both“marketaccess”and“accessto

medicines”perspectives).Adescriptionofrelevantthemes,anidentificationofareasthat

wouldbenefitfromfurtherinvestigation,andtheimplicationsfortheDELTAprojectwork

ispresentedforeachcategory.

2.2.1Dengue

TheearliestrecordofhumanillnessfromdengueisfromaChineseencyclopediain992

A.D.(37).Overthenextmorethanonethousandyears,humanityhasadvanceditsscientific

understandingofthevirus.Dengueisamemberoftheflavivirusfamily,whichincludes

importantvirusessuchasyellowfever,WestNile,andJapaneseencephalitis(38).Asa

memberofthisfamily,relativelydetailedinformationaboutitsbiologyisknown;dengue’s

pathogenesishasbeencloselystudied(39),andallfourserotypesofthevirusgenomehave

beensequenced(40).

Murray(41)providesasweepingreviewofdengue’sepidemiologichistorythatreferences

itscurrentroleas,accordingtoWHO,“themostimportantmosquito-borneviraldiseasein

theworld”(15).Perhapsforthisreason,theunderlyingtransmissiondynamicshavebeen

12

studiedinsomedegreeofdetail–evenwiththebenefitoflocalfine-scalespatiotemporal

studiesthatprovideinsightsintohowthevirusspreadsinspecificsettings(42).Public

healthauthoritiessuchastheWorldHealthOrganization(WHO)andAmerica’sCentersfor

DiseaseControl(CDC)publishdetailedmaterialsandguidelinesaboutsymptomsand

clinicalmanagement(43,44).

Whilemuchmaybeknownaboutthescienceandtreatment,itcanbearguedthatrelatively

lessisunderstoodaboutthediseaseburden.Thisincludesthepublichealth,socialand

economicimpactofthedisease,andhowtheseeffectsmightvarybetweenandwithin

specificpopulations.Dengueisinherentlydifficulttomeasurebecausethemajorityof

casesareasymptomatic,thepotentialformisdiagnosisgivencommonpresentationwith

otherdiseases,anditscyclicalnature(45).Thesechallengesareamplifiedwhenone

considersthelackofsurveillanceandreportinginfrastructureinresourcelimitedsettings

wheredengueisendemic.Itisacceptedthatalldenguecasesarenotcapturedbyroutine

systems(46),andresearcherstypicallyapplyadjustmentfactors,ofupto10-foldor

greater,toofficialrecordstoaccountforunderreporting(47).Datapointsaboutthe

burdencanvarysignificantlybetweensources,andsometimesevenwithinthesame

source(2).CastroandBloom(45)madeanimportantcontributiontothisgapby

characterizingthechallengestoestimatingthediseaseburdenofdengue,andproposeda

frameworkforestimatingitseconomiccosts.

Anysuchimprovementsindengue’sburdenestimateswouldassistthemarketaccess

planningforanewvaccineintwokeyways.First,ithasbeendocumentedthatuncertainty

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inestimatesimpedepolicymakers’abilitytoprioritizeandallocatefinancialresourcesfor

interventions(45).Clarityarounddengue’shealthandeconomicimpactcanaddressthis

andhelpencouragecoherentactionfromanetworkofstakeholders,includingthe

pharmaceuticalcompanies.Similarly,reliablefigureswillhelpbuildacompany’sinternal

businesscasebecausetherewillbegreaterconfidenceintheprojections,potential

economicvalueandstrategicbenefitthattheassetstandstooffer.Thereishopefornew

approachestodiseasesurveillance,suchasusingdataoninternetsearchqueriestotrack

andpredictdengueoutbreaks(48).

Thelevelofglobalstakeholdercoordinationandresourcemobilizationfordengueis

relativelylowbutitseemstobeimprovinginrecentyears.Forexample,despiteWHO’s

identificationofdengueastheworld’s“mostimportantmosquito-borneviraldisease”(49),

WHOdoesnotcurrentlypublishanannualglobaldenguereport.Suchisthecasefor

malaria(50)andothermajordiseaseslikeTuberculosis(51).Thereis,atleast,theglobal

strategyfordenguepreventionandcontrolwhichcoversfrom2012to2020(15).Arecent

specialreportinLancetInfectiousDiseasesdescribesthecurrentstateandprioritiesfor

dengue(52).Althoughitalludestounprecedentedlevelsofresourcesandcommitments

fromstakeholders,aspecificanalysisofthepartners,andtheiractivitiesislacking(52).

Someconsolidateddiscussionofthevariousstakeholders,theirrolesandresourceswould

strengthencoordinationandhelpprioritizemarketaccessplanningbyallowingaclear

identificationofoverlapsandunmetneeds.

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Encouragingly,in2016fourleadingdengueinstitutionsconsolidatedtoformtheGlobal

DengueandAedes-transmittedDiseaseConsortium(GDAC)(53).Theseimprovements

coincidewithapotential“neweraofdenguecontrol”(54)usheredinwithSanofi’s

licensureofthefirstdenguevaccine.Inthislight,Takeda’ssuccessfuldevelopmentand

launchofTAK-003isanopportunitytofurthercatalyzemomentum.

2.2.2VaccineforDengue

Vaccineprofile

Inordertoaidindevelopment,WHOhasissuedguidanceaboutthedesiredquality,safety

andefficacyofadenguevaccine(55,56,57).Thespecificcharacteristicsofadesirable

denguevaccinearealsodescribedinthebroaderscientificliterature.Forexampleina

comprehensive2015Lancetseminaraboutthestateofdenguediagnosis,treatment,and

prevention,GuzmanandHarris(58)presenttheprofileofanidealdenguevaccine.Mostof

thefeaturescanberegardedasstandardrequirementsthatanyusefulvaccineshould

ideallypossess–e.g.easeofstorageandtransportation,long-lastingprotection,andcost

effectiveness(58).

Somefeaturesarespecifictodengue.Mostnotablyistheneedtoprotectagainstallfour

virusserotypes.Apersonthatisinfectedbyoneserotypegainslife-longimmunitytothat

serotype,butthatpersononlybenefitsfromtemporaryprotectionagainsttheothervirus

strains.Thus,theneedtocoverallfourserotypesconstitutesaspecialchallengefora

denguevaccine.Thisisunlikeyellowfeverandothersingle-strainmembersofthe

flavivirusfamilyforwhichvaccinedevelopmenthassucceeded(59).

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Thisneedforatetravalentvaccineformulationhasproventechnicallychallengingto

achieve(26,60).Thismaybeexplainedbythepotentialforadenguevaccinetoactlikea

primarynaturalinfectionandrenderapersonmorevulnerabletoaseveredenguewitha

secondaryinfection.Someattributethispossibilitytoaphenomenonknownasantibody

dependentenhancement(ADE).ADEisthoughttooccurwhenantibodiesendupbeing

beneficialforthevirusordiseasethattheyaremeanttoprotectagainst(61).The

mechanismsofADEarenotcompletelyunderstoodandtheevidenceofitsroleindengue

pathogenesisdoesnotalwayssupportthisexplanation(62).Attributingtheincreased

hospitalizationsamongchildrenthatwereseronegativeatbaselineinSanofi’sdengue

vaccinetrialstoADEhasbeencontentious–mostexpertsattributetheresultstothe

vaccine-inducedADE(63,64),althoughthiswasrecentlyrefutedinapaperwrittenbyfour

authorswithvariousfundingtiestoSanofi(65)andthedebateremainedopenatthetime

theDELTAprojectbegan.Interestingly,inNovember2017alandmarkstudypublishedin

SciencedemonstratedADEbyanalyzingbloodsamplesfromacohortofover6,000children

(66).Thestudyhasthepotentialto“silenceADEskeptics”(67)sinceitpresentsthefirst

timetheeffecthasbeendocumentedinhumans.Note,thestudy’sresultsdemonstratethe

rangeofantibodylevelsthatcontributetoseverediseasebuttheydonotdirectlymake

claimsaboutthepotentialroleofvaccinationorSanofi’sresultsinparticular.

16

Regardlessofthecontentionaroundthecauses,Sanofi’strialresultsledWHOtoinitially

recommendthevaccineforuseinendemicpopulationswithhighbaselineseropositivity,

andnotamongchildrenunder9yearsofage(68).Thus,whentheDELTAprojectbeganin

June2017Sanofi’svaccinehadonlyreceivedahandfulofrelativelynarrow

recommendationsforuseinendemicareasinaccordancewithWHO’sposition.

ReturningtotheimplicationsforTakeda’smarketaccessplanning,Sanofi’sexperiencecan

leadonetoexpectthepossibilityofanenhancingeffectontheseverityofsecondary

infectionstobecloselyscrutinizedintheTIDESresults.Itfollowsthattheextenttowhich

Takeda’svaccineprofilefacessimilarconcernswillhaveasignificantimpactonthe

breadthofnormativeguidelinesthatshouldbeexpected,whichwilldefinethescopeand

natureofmarketaccessplanningactivities.

Costeffectivenessofdenguevaccination

Thereisagrowingbodyofresearchexploringthepotentialcosteffectivenessofdengue

vaccination.PublishedstudiesfocusonendemiccountriesinLatinAmericaandSoutheast

Asia:Brazil(69,70),Mexico(71),Thailand(72),Malaysia(73),Philippines(74),and

Singapore(75).NotablymissingarecosteffectivenessstudiesofvaccinationforIndia,the

highestburdendenguecountry(4)andanycountriesfromAfrica.Allcosteffectiveness

studiesarebasedonmathematicalmodelsandnotevidence,asitispresumablytooearly

forfieldresultsfromearlyexperiencewithSanofi’svaccine.Thepublishedstudiesall

similarlyconcludethatadenguevaccinecouldreducetheburdenandhasthepotentialto

becosteffective.Ofcourse,theirconclusionsrelyheavilyontheassumptionsthatare

17

used.Intuitively,researchsuggeststhatbroadeningthescopeofbenefitsconsidered,

especiallyfromthesocietalperspective,furtherimprovesthecosteffectiveness

propositionofvaccination.Thishasbeendemonstratedforearlychildhoodvaccinationin

LMICsingeneral(76),andinthecaseofadenguevaccineinparticular(77).

Returningtotheroleofassumptionsinthedenguevaccinecosteffectivenessstudies:the

conclusionsaboutcosteffectivenessvaryfollowingdifferentassumptionsfor3critical

inputs–theburdenlevelandunderlyingtransmissiondynamicsinasetting,thevaccine

profile(efficacyandsafety),andvaccineimplementationcosts.

Thefirstdimensionpointstotheneedforreliable,localburdendata.Thisisusuallynot

availableinallsettingswheredengueisendemic.Availablestudiesarefocusedon

countrieswithrelativelygoodreportingandsurveillancethatisapplicablefordengue–

forefrontamongtheseareBrazilandThailand.Thequalityofavailabledatacanbe

improvedwithdedicatedinvestmentsandanalysis.Intermsofthevaccineprofile,cost

effectivenessstudiesrelyonassumptionsandrangesofestimatesuntilaproducthasbeen

approved.AllexceptoneofthepublishedstudiesuseSanofi’sDengvaxia®productasa

baseline.

Thepriceofthevaccineisanimportantfactorinthetotalcostofvaccineimplementation

(78).Unliketheburdenandproductprofile,thevaccinesponsorisabletodirectly

influencethepriceofthevaccine.Indeed,oneofthekeyrolesofMarketAccessplanningis

todeterminethepricethatwillbechargedforavaccinetoagivenpopulation.Thus,

18

althoughtheavailablestudiessuggestavaccinecanbecosteffectivefollowingarangeof

pricingassumptions,itwouldbecircularforamarketaccessplanningactivitytoaccept

thisatfacevaluewithoutconductingindependentanalysistodetermineappropriateand

effectivepricing.

Regulatorystrategiesforadenguevaccine

Animportantdecisioninmarketaccessplanningforadenguevaccineisaboutthe

regulatorystrategyandcountrylaunchsequencing.Historically,vaccineslaunchinhigh-

incomecountriesandthenlowerincomemarkets.Forexample,ittooktwodecadesafter

launchinginhighincomecountriesforHepatitisBandHaemophilusinfluenzaetypeb

(Hib)vaccinestobemadeavailableinLMICs(79).Denguehasthepotentialtobedifferent,

becausetheburdenofendemicdengueisnotinhigh-incomemarkets(i.e.notNorth

AmericaandWesternEurope).

Arecentarticleoutlinedtheharmonizedregulatoryreviewapproachthatwasfollowedfor

thefirstdenguevaccineregistrations(80),whereinregulatorybodiesfromseveralhigh

burdencountrieswerehostedbyWHOtoreviewdatatogetherandthenstillmake

separatedeterminationsaccordingtotheirnationallawsandprocedures.This

streamliningreviewisinnovative;itwouldbereasonabletohopethatothervaccinescan

followasimilarapproach.

19

Vaccinesaspartofanintegrateddengueresponse

Anydenguevaccinewillbeoneofseveralmeasuresavailabletoministriesofhealthand

partnerswhenrespondingtothethreatofdengue.Thebroadlyaccepted‘integrated

denguemanagement’approach(52,81,82)espousestheroleofvectorcontrolalongside

theuseofavaccineafteritbecomesavailable.Thus,researchthatfocusessolelyonthe

impactofadenguevaccinehaslimitedpracticalvaluefordecision-makers.Themorethe

potentialinteractions,synergies,andinterferenceofvaccinesandvectorcontrolare

explored,themorepracticalthatresearchwillbeforinformingpolicydecisionsand

Takeda’smarketaccessplanning.Thefollowingparagraphsprofilethecurrentstateofthe

literaturerelatingtovectorcontrolandvaccinationfordengue.

Vectorcontroliscurrentlytheprimaryapproachtopreventdenguetransmission(83).

WHOvectormanagementandcontrolguidelinesfocusonthemainvector,theAe.Aegypti

mosquito(43).Recommendedeffortstargetbothadultandlarvae,andcanbroadlybe

categorizedastargetingthevectordirectly(e.g.chemicalcontrol,biologicalcontrol)or

throughenvironmentalcontrols(54).Somehistoricalperspectiveisrelevanthere:vector

controlcampaignsinthemidtwentiethcenturyledtotheeliminationofAe.Aegyptiinthe

Americas(84).However,reintroductionhassinceoccurred.Moreover,arecentsystematic

reviewandmeta-analysisof41studiespublishedbetween1980and2015demonstrated

“theremarkablepaucityofreliableevidencefortheeffectivenessofanydenguevector

controlmethod”(83).

20

Itisthereforenotsurprisingtofindadearthofinformationexploringthepotentialimpact

ofavaccineandvectorcontrolincombination.Therelationshipisthoughttobecomplex–

vaccinationisexpectedtohaveacomplimentaryeffectonvectorcontrolandreducethe

necessarythresholdsofvectorcontrollevelsinanon-linearfashion(85).Thereisonlyone

studyonthetopicofdenguecontrolandvaccinationtogether;itdescribesamarked

improvementindenguetransmissionandburdenwhenvectorcontrolandvaccinationare

modeledtogetherinsteadofinisolation(86).Moremodelsand,ultimately,evidenceare

required.Thisiscriticalformarketaccessplanningofadenguevaccinebecausedecisions

aboutadoptionandroll-outofavaccinewillbemadeinthecontextofallexisting

alternatives.Withoutdatademonstratingpotentialsynergies,insomecountriesavaccine

andvectorcontrolcouldbeconsideredascompetinginvestmentsanddetractresources

fromoneanother.Inothersettings,itispossiblethatdifferentstakeholderswillcontrol

separatebudgetsandplans.Asanillustrativeexample,theMinisterofHealthmaybe

responsibleforvaccinationandtheMinisterofEnvironmentcouldhandlevectorcontrol.In

theseinstances,evidenceconnectingthetwointerventionscouldspurfurther

coordination,collaborationandintegratedefforts.

Lookingattheevolvingpipelineofnovelvectorcontrolmethods:theidealpublichealth

responsewillincludebothnovelvaccinesandnovelvectorcontrolmethods,notoneorthe

other.AccordingtoaforemostdengueexpertDuaneGubler,“ifwecanusenewvaccines

[fordengueandZika]toincreaseherdimmunity,andatthesametime,newtoolslike

Wolbachiaandinsecticidestoreducethemosquitopopulation,weshouldbeableto

controlthesediseases.”(87)

21

Anotherneedforvaccinestobeconsideredaspartofabroaderresponseariseswhenone

considersdiagnosticsfordengue.Thecurrentlyusedserologytestswilllikelybe

invalidatedinthepresenceoflarge-scalevaccinationcampaigns(54,55);asaresult,new

diagnosticswillberequiredtomonitorandtreatdengueasvaccineimplementationgrows.

Marketaccessplanningforadenguevaccinemightstandtobenefitfromsome

considerationofthediagnosticpipelineandpartnerships.

Nationalvaccineadoption

Thereisagrowingfieldofresearchexploringthedecision-makingprocessfornational

adoptionandprocurementofvaccines.Inasystematicreviewofthetopic,Burchettetal.

(88)identified21uniqueframeworksforvaccineadoptiondecisionmaking.Ofthese,4

werefrompractice(i.e.usedbynationalimmunizationtechnicaladvisorygroups,or

‘NITAGs’),andtheremainderwereproposed.Acrossallframeworks,9categoriesemerged

forconsideration.Theyare:i.Theimportanceofthehealthproblem(actualandperceived),

ii.Vaccinecharacteristicsiii.Programmaticconsiderationsiv.Acceptabilityv.Accessibility,

equityandethics,vi.Financial/economicissues,vii.Impactofvaccination,viii.

Considerationofalternativeinterventions,ix.Decision-makingprocess(88).Thisresearch

aboutwhatmatterstodecisionmakersoffersavaluablesignalforwhatshouldbeincluded

andprioritizedinamarketaccessstrategyforadenguevaccine.

Thereisalsospecificresearchexploringtheinterestandlikelihoodofnationaladoptionfor

adenguevaccine.Asurveyofnearly160keyopinionleadersandpolicymakersin8dengue

22

endemiccountriesfoundthattheinterestinadenguevaccinewasgenerallyhigh(89).One

ofthefindingsconveyedthehighpoliticalandpublicpressureondecisionmakersabout

theimportanceofdengue.Thisisavaluableinsightformarketaccessplanningbecauseit

suggeststhatincorporatingpublicadvocacycouldbeaworthwhileactivity.Another

findingrelatedtotheimportanceoflocaldenguesurveillancedata.Thismustbeaddressed

inthecountry-levelmarketplansinordertomeettheevidentiaryrequirementsofspecific

agenciesandwintheconfidenceofkeyopinionleaders.Themostimportantfactorwasthe

potentialsafetyprofileofapossibledenguevaccine.Thisisconsistentwiththehesitations

observedforDengvaxia®surroundingthepotentiallyenhancingeffect,andunderscores

theimportanceofanewvaccine’ssafetyprofileforanylocaluptake.

Marketaccessplanningdoesnotendwhenaproductisadopted.Particularlyrelevantfor

vaccinesistheroleofadverseeventsfollowingimmunization(AEFI)andthepotential

impactthattheymighthaveonimmunizationprograms.WHOdefinesanAEFIasany

“untowardmedicaloccurrencewhichfollowsimmunization”(90).Acrucialcomponentof

thisdefinitionisthattheeventdoesnotnecessarilyhavetobecausedbythevaccine–

programerrorsandevencoincidencesarealsotechnicallyconsideredAEFIs(91).Itisthe

potentialforinadequatelyaddressedAEFIs–regardlessofthecause–toderail

immunizationprogramsthatismostrelevantforadenguevaccine’smarketaccessplanto

consider.Indeed,thepotentialimpactisverifiedbyexamplesofsetbackstoother

immunizationprogramssuchasforpolioinUganda,diphtheria-pertussis-tetanusin

Sweden,andtetanus-diphtheriatoxoidinJordan(91).Inshort,astrongmarketaccessplan

23

foranyvaccine,includingdengue,shouldconsiderthepost-introductionactivitiesand

environmentasitpertainstothepotentialforAEFIsandacountry’scapacitytorespond.

2.2.3PharmaceuticalAccess

Thissectionexploresthestateofaccessliterature–accordingtoboth‘marketaccess’and

‘accesstomedicines’definitions–anditsimplicationstotheworkofthisDELTAproject.

Section2.1abovecharacterized‘marketaccess’asatermthatisprincipallyusedbythe

pharmaceuticalindustryandonethatisnotnecessarilydefinedbyanemphasison

reachingpeopleinLMICs.Thereisstillarangeofdefinitionsforthescopeofmarketaccess

underthisbroadunderstanding.Ontheonehand,someexpertsandpractitionersregard

marketaccessasaverywidesetofcrossfunctionalactivities.Inthemostextremecase,

marketaccessispresentedasthefourthandfinalphaseinaproduct’slife-cycle,following

basicresearch,translationalresearch,andclinicaldevelopment(92).Othersregardthe

scopeofmarketaccessmorenarrowlyandlimititsscopetothefinancialreimbursementa

companygetsforaproduct,focusingonactivitiesassociatedwiththeagreementsbetween

payersandcompanies(93).Aqualitativestudyseekingtodefinepharmaceuticalmarket

accessstrategyidentifiedmanyvaryingdefinitionsacrossthiscontinuum,evenwithinthe

samecompany(94).Thiswidespectrumandvariationofmeaningsimpliestheimportance

ofestablishingacleardefinitionandexpectationsforwhatamarketaccessplanfordengue

shouldentail.

24

Ingeneral,mostavailableliteratureaboutpharmaceuticalmarketaccessemphasizes

reimbursementandfocusesonWesternmarkets.Thisisarguablylessrelevantforthe

purposesofmarketaccessplanningforadenguevaccine,giventhehighestburdenregions

areinLMICs.Amajorityoftheknowledgeandexpertiseformarketaccessplanningis

presumablynotinthepublicdomainandkeptproprietarytocompaniesforcompetitive

reasons.However,thecomponentelementsthatunderpinthebroadfieldofmarketaccess

(e.g.costeffectiveness,healtheconomics,regulatorysciences)arethefocusof

methodologicalandempiricalinquiryintheacademicliterature.Thetoolsandresearch

fromthesefieldscanbeappliedtothemarketaccessplanning.Insum,therelevant

literatureformarketaccessplanningbroadlyislackinginrelevancefordengue,butthe

detailedsub-sectionsdoholdpromise.

Theoppositecharacterizationringstruefortheglobalhealthperspectiveonaccess.There

isrelativelymorearticles,reports,andconferencesdedicatedtoexploringtheoverall

themeof‘accesstomedicines’inthepublicdomain(e.g.31,95,96,97).Butdeep

substantiveresearchonthecomponentaspects(e.g.outcomesofdonationprograms,

detaileddesignofmarketinterventions)isstillevolving.Arecentanalysisfoundthatonly7

outof120accesstomedicinesinitiativeshadpublisheddataabouttheimpactofthe

activities(98).

ThisdynamichasimplicationsforaDELTAprojectthatisdevelopingmarketaccessplans.

Ontheonehand,thereisrelativelylittleguidanceandnoend-to-endframeworksthatare

explicitlytailoredforvaccineMarketAccessplanninginthepublicdomain.However,

25

specifictechnicalcomponentsoftheworkitselfhavethebenefitofdrawingonthe

appropriateacademicknowledge.Asanillustrativeexample,onesecondarydeliverable

fortheDELTAprojecthadtodowithdevelopinga‘gotomarket’strategy.Thisconcerns

theprocesspharmaceuticalcompaniesundergoinassessinghowtoexecutetheirmarket

accessstrategy(e.g.partnership,internalresourcing).Detailedsearchesinacademic

databasesandconsultationwithinformationresearchspecialistsatHarvardBusiness

School’sBakerlibraryledtotheconclusionthatthereisnodirectlyapplicableliterature.

Rather,thisislefttocompanies’internalpracticesandtheworkofexternalconsultantsto

developcontext-specificplans.Ontheotherhand,anessentialcomponentofthedengue

globalmarketaccessstrategy’sdevelopmentwillbetheevidencegenerationfordossiersto

supportnormativeinclusioninnationalimmunizationprograms(NIP).Here,asmentioned

above,thereissignificantliteratureoncosteffectivenessingeneralandsomework

modelingthecaseofadenguevaccineinparticular.

2.3VBU’sMethodologicalapproachtoMarketAccess

2.3.1GlobalMarketAccessstrategy

VBU’sconceptofmarketaccessforvaccinesisalignedwiththebroadinterpretationof

marketaccess.Infact,itmirrorstheworkingdefinitionfromtheacademicliterature

presentedabove.VBUdefinesitas:“theprocessthatensuressustainableavailabilityof

licensedvaccineswithvaluepropositions,leadingtotheirrecommendation,fundingandto

successfuluptakedecisionsbyrelevantexternalstakeholderswiththeultimategoalof

achievingpositiveimpactonpublichealth”(99).Itfollowsthattheglobalmarketaccess

strategydocumentforDengueshoulddescribethehigh-levelapproachtorealizethis

26

processforTAK-003.Reflectionsontheimplicationofthisdefinitionareofferedinsection

2.4.1.

First,concerningtheprocess:VBUadoptedanexplicitframeworkforhowtocreatethis

marketaccessstrategy2.Theframeworkdescribes3genericstepsthat,whenfollowedin

sequence,shouldproduceaglobalmarketaccessstrategyforaspecificvaccine.Theyare:

1. Characterizingthedenguevaccineaccordingto“pillars”ofvaccinemarketaccess

2. Groupingcountriesin“archetypes”accordingtocommoncharacteristics,and

3. Combiningtheresultsofthefirsttwostepstoproducea“globalstrategicdirection”

foreachpossiblecombinationofpillarandarchetypepairing.

Theglobalstrategicdirectionwouldthenactasthestartingpointforacountryteamto

developanational-levelmarketaccessplan.

Stepone:TheEssential‘Pillars’ofMarketAccess

VBU’sapproachdescribesfivepillarsthatareessentialfordevelopingavaccine’sglobal

marketaccessstrategy.Thesepillarsaregenericandmeanttoberelevantforanynew

vaccine.Thefirstphaseinthemethodologyinvolvescharacterizingeachofthesepillars

specificallyforthepurposesofthedenguevaccinecandidate.Thegeneralpillarsare:

1. Evidencegenerationandsynthesis–thispillarprimarilyconcernsthedataneeds

ofpayers,healthtechnologyassessmentagenciesandnationalimmunization

2Thedescriptionsandphrasesregardingspecificaspectsofthisapproachtomarketaccess(e.g.“essential

pillarsofmarketaccess”,“archetypedimension”,“vaccineaccessreadiness”,etc.)arethetermsthatVBU

employed;theywerenotconceivedbytheauthor.

27

programs.Notethisistypicallybroaderthanthesafetyandefficacydatathatisfiled

withregulatoryagenciestogainlicensureinagivencountry.Thispillarisexpected

tooutlinetherequirementsandstudiesnecessarytosupportanevidence-based

approachtoaccessforavaccine.

2. PricingandReimbursement–thissectionismeanttodescribetheglobalapproach

topricingforbothpublic(i.e.governmenttenders)andprivate(i.e.individual

people)useofthevaccine.

3. HealthInitiativesandServices–thispillarisanopportunitytopresentvarious

effortsthatwillstrengthenahealthsystem’sabilitytousethevaccineforpublic

healthimpact.Itincludesbroadeffortsthatarenotspecifictoonevaccineproduct.

Itisintendedtoincludealistofpossibilitiesandprioritizationforactivitiesatthe

national,regionalandlocallevel.Examplesincludecoalitionsforimmunizationand

healthsystemstrengtheninginterventions.

4. Supply&Logistics–thissectionoutlinesthelogisticsmanagementapproachfor

thevaccine.Itshouldincludethegoalsandstrategy;thescopeshouldencompass

everythingfromthemanufacturinguntildelivery.

5. Policyandstakeholderapproach–thispillarisconcernedwiththepoliciesthat

willenablerapidandeffectiveaccesstothevaccine.Itshouldincludethegoals,

valuemessages,stakeholdersandworkplansfortailoredapproachesattheglobal,

national,andsub-nationallevel.

AlthoughtheVBUteamprepareddetaileddescriptionsabouttheoverallmethodology,the

specificformatoftheoutputsforthisfirststepwerenotexplicitlydefinedbeforehand.

28

Therewasageneralexpectationthattheprocessofcharacterizingthepillarsfordengue

wouldinvolveanalysis,brainstormingandconsensusworkshopswithinternalteamsand

thesupportofexternalexperts.

Steptwo:Countryarchetypes

Accordingtothemethodology,thegoalofthisstepistoorganizethelistofpotentiallaunch

countriesaccordingtocommonmarketcharacteristics.Thisstepwillhelpcraftstrategies

thatareappropriateforcountrieswithcommonfeatures.Doingsoshouldofferprocess

efficienciesandresultincountryplansthatarepartofacoherentoverarchingstrategy.

Accordingtothemarketaccessmethodology,fourkindsofvariablesshouldbeconsidered

todefinethecountryarchetypes:

1. Vaccineaccessreadiness–thisdimensionisfocusedonthevariousagencies

andprocessesthatareinvolvedinvaccineprocurement.Itseekstoassessthings

liketherelativelevelofdevelopmentofacountry’sNationalImmunization

TechnicalAdvisoryGroup(NITAG)andbaselinepopulationcoverageforother

vaccines.

2. Diseaseburdenandenvironmentmaturity–thissectionseekstodefinethe

dengueburdenandtheextenttowhichitisunderstoodinagivencountry.Ithas

towiththeepidemiology,surveillanceprogramsandavailablestatisticsrelating

tothehealthandeconomicburden.

3. Payersophistication–thisdimensionfocusesonacountry’strack-recordand

potentialforinnovativefinancingandpartnership.

29

4. Descriptivevariables–thisfinaldimensionisavailabletocapturegeneral

characteristicsnotspecifictoacountry’simmunizationlandscape(e.g.GDP)and

factorsthatarerelevanttohighlightforaspecificcountry,butdonotfitthe

otherthreedimensions.Examplesofthelatterarethepoliticallandscapeand

country-specificrequirementsformarketinganddistributingpharmaceutical

products.

Stepthree:GlobalStrategicDirections

Afterthepillarshavebeencharacterizedandthecountrieshavebeenclusteredinto

commonarchetypes,thenextstepinVBU’sframeworkistocombinetheresultsofthese

firsttwoexercises.Thepurposeistocreateaglobal“strategicdirection”forcombinations

ofapillarandaparticulararchetype.Forexample,iftherewerea‘highburden,low

sophistication’archetype,thisthirdandfinalstepwouldinvolvedevelopingthestrategic

directionforeachofthe5pillarsthatshouldbefollowedbythecountriesthatbelongto

thisarchetypewhenitcomestimetodevelopcountrymarketaccessplans.

Accordingtothismethodology,theglobalmarketaccessstrategyforavaccineisessentially

envisionedasacollectionofglobalstrategicdirectionsforeachpillar-archetype

permutation.Theseglobalstrategieswouldthenguidethedevelopmentoflocalmarket

accessplansatthecountrylevel.

2.3.2LocalMarketAccessPlan

Thelocalplanisthedocumentthatdescribestheanalysisandtacticsthatwillbe

implementedbyaTakedacountryteaminordertorealizethemarketaccessaimsfora

particularvaccine.Itconsistsof3sections:

30

1. Set-up:ThissectiondescribestheoverarchingstrategicobjectivesthatTakedahas

establishedforthevaccine.

2. Localmarketoverview:Thissectionfocusesontheexternalenvironmentinwhich

thevaccinewillbeintroduced.Itincludescomponentssuchas:anassessmentofthe

publichealthcontext,stakeholdermapping,anddefiningthecompetitivelandscape

inthecountry.

3. Localmarketaccessapproach:TheactivitiesandrationaleforTakeda’sapproachin

aparticularcountryaredescribedhere.Thissectionincludesalocalversionofthe

‘5pillars’ofmarketaccessthatwouldhavebeenpresentedintheglobalstrategy

exercise,andculminatesinthedefinitionofafinallocalvaluepropositionforthe

vaccineinthecountry.

Theexpectationsforthislocalplanwerethoroughlydefined;theframeworkdelineates

specificsub-componentsforeachofthesesections,eachwithcorrespondingactivitiesthat

shouldbeconsideredbythelocalteamduringimplementation.Itisworthnotingthatthe

globalteamprovidedresourcesandtoolstosupportthedevelopmentofacountryplan.

Mostnotablyamongtheseisthe‘roadmap’,whichisaseriesoftemplatesandmaterials

thataidacountryteamtogothroughthemethodologyandproducealocalplan.

2.4Methodologicalreflections

2.4.1CharacterizingVBU’sapproach

ThissectionofferssomeinitialreflectionsonthemethodologyadoptedbyVBUtoproduce

marketaccessplansfordengue.Thisinitialassessmentstartsbycharacterizingthe

approach’sfeaturesandthendiscussessomeoftheirimplications.Itfocusesonmattersof

31

design–e.g.whatisincluded,excluded,prioritizedandde-emphasizedbytheapproachto

marketaccess.Assuch,itisaninitialandconceptualassessmentofthemethodology.The

experiencewithactuallyimplementingthemethodology–e.g.outcomesandlessons–will

beexploredintheResultssectionofthisdocument.

VBU’sframeworkcanbecharacterizedashighlymethodical;ithasaprescribedsetof

explicitstepsthataretobefollowedinordertoproducetheenvisionedmarketaccess

strategy.Theapproachisalsofundamentallyinductiveinitsorientation;itadoptsa

‘bottom-up’approachthatreliesontheexpectationthatthestrategywillemergefrom

rigorouswork,analysisanddecisionsrelatingtodetailedanddistinctcomponentsof

marketaccess.Thisisincontrasttoapotentially‘top-down’approachwhichwouldstart

withanoverarchingmarketaccessvisionforavaccineandthenusethattodevelopits

componentdimensions.

Anapproachwiththesecharacteristicshasbenefitsandpotentialshort-comings.

Regardingtheadvantages:itishighlysystematic.Thishelpsensurethestrategyisrational,

objectiveandgroundedinreason.Theprocessalsoplacestheultimateresponsibilityof

developingplansatthecountrylevel.Indeed,reflectingontheprocessasdescribedabove

revealsanexpectationthatthetacticaldecisionsanddetailedplanningwilloccurinthe

countryplans.The‘globalstrategy’isessentiallyacollectionofcuesthatwillthenbetaken

upbycountry-levelteamstodevisetacticalplansandimplement.Thisissuitablein

conditionswheremarketsarethoughttobehighlyvariableandrequiretailored

approaches.Thisseemssuitablegivendengue’svariableepidemiologyandcomplex

32

stakeholderenvironment.Thecountry-heavyemphasisshouldalsohelpdevelopsupport

fromlocalinternalstakeholders.Thirdly,theorientationbypillarisadvantageousforthe

allocationofresponsibilityandexecutionoftasks,insofarastheorganizational

responsibilitiesofteamsaligntothedomainofthepillars.Thisisparticularlyvaluablein

matrixedandmultifunctionalorganizations,suchasTakeda.

Theapproachalsohaspotentialdraw-backs.First,itisrathercomplex.Thiscomplexity,

arguablynecessaryforanuancedandmeaningfulplan,maydetractbuy-inandmaskor

displacepotentialdisagreementstolaterintimeorotherpartsoftheprocess.Itcouldalso

bearguedthatthereisaninherenttrade-offwhenadoptingahighlyinductiveapproach;it

ispotentiallyamissedopportunityforoverarchingglobalstrategicvision,sincethehighest

unitofscopeisatthelevelofonemarketaccesspillar.Third,themethodologyitselfdoes

notemphasizeoutcomesorspecificaccessgoals.Thisobservationiselaboratedoninthe

Resultssection.Finally,notablymissingfromthe‘pillars’ofmarketaccessisadedicated

pillarforpatients.Thislimitationwasaddressedintheprojectwork(seeSection3.1.1)

2.4.2Evaluationframework

Smith(94)outlinesninedifferentiatingcharacteristicsofapharmaceuticalmarketaccess

strategy.Thiscanbeausefulguidetoassessthemarketaccessplanmethodologythatwas

implementedforVBU’sdenguevaccine.Conveniently,Smithoutlinescriteriabywhichto

judgeeachofthedimensionsasbeingpartofeither“strong”,“mediocre”,or“weak”market

accessstrategies.Thedimensionsarepresentedverbatiminfigure2.Anassessmentand

modificationsareproposedintheResultssection3.2.1,drawingonlessonsfromthe

33

experienceofimplementingthemarketaccessmethodologytodevelopaglobalstrategy

forVBU’sdenguevaccine.

Figure2.Differentiatingcharacteristicsofamarketaccessstrategy(94)

1. Theextenttowhichthemarketaccessstrategyrecognizesheterogeneitywithinthemarketenvironment

2. Theextenttowhichthemarketaccessstrategymakeswell-definedresourceallocationchoicesbetweenalternatives

3. Theextenttowhichthemarketaccessstrategyofferspayer-perceivedeconomicvaluetoeachtargetedsegmentwithinthemarket

4. Theextenttowhichthemarketaccessstrategyanticipateschangeinthemarket

5. Theextenttowhichthemarketaccessstrategyalignstothestrengthsandweaknessesoftheproductandorganizationrelativetoappropriatecomparators

6. Theextenttowhichtheactivitiesthatflowfromthemarketaccessstrategyarecomplete,consistentwiththestrategyandareinternallycoherent

7. Theextenttowhichtheactivitiesthatflowfromthemarketaccessstrategymatchthetargets’decisionmakingprocesses

8. Theextenttowhichthemarketaccessstrategyanticipatesandsupportsmanagementoftheproductlifecycle

9. Theextenttowhichthemarketaccessstrategyisconsistentwiththeorganization’sfinancialgoals

34

2.5CaseStudiesofVaccineAccess

2.5.1RotaTeq®

Merck&Co.receivedUSlicensureforapentavalentrotavirusvaccinecalledRotaTeq®in

2006.Duringthatsameyear,thevaccinewasregisteredinNicaragua–alowincome

countrywithahighburdenofinfantdiarrhealdiseasecausedbyrotavirus.Theconcurrent

registrationwaspartofapublic-privatepartnershipbetweenMerck,theNicaraguan

MinistryofHealth,andotherpartners.Thepartnershiphad3objectives,to:“i.be

introducedrapidlyinadevelopingcountry,ii.besuccessfullyintegratedintotheexisting

vaccinedeliveryinfrastructure,andiii.haveasignificantandmeasurablepublichealth

impactattheendofthe3-yearprogram”(100).ItincludedaprovisionforMercktodonate

overonemilliondosesofRotaTeq®toimmunizeNicaragua’sentirebirthcohortduringthe

3years.Thisprogramisgenerallyregardedasasuccess(101).

Theinitiativeincludedaphilanthropicproductdonationanditfocusedonadeveloping

country.Thisleanstheprojecttowardscategorizationasan‘accesstomedicines’initiative.

Butitwasmorethanjustanexerciseincorporatesocialresponsibility(CSR)becauseit

waspartofabroaderstrategytomakeRotaTeq®widelyavailableacrosstheworld(102).

So,althoughitshouldbecharacterizedasapredominantly‘accesstomedicines’initiative,

itnonethelesswarrantsexaminationinordertounderstandwhat,ifany,lessonscouldbe

applicabletomarketaccessplanningforadenguevaccine.

35

First,somekeydistinctionsbetweentheRotaTeq®caseandanynewdenguevaccinesuch

asTAK-003shouldbeconsidered.Rotavirusanddenguehavedistinctepidemiologic

profilesandtheyspreadviadifferentmeans.Thereforestakeholder’sattitudesandthe

overallneedforvaccinationaredifferent.Thevaccinesinquestionarealsofundamentally

different;forexampleRotaTeq®isorallyadministeredandTakeda’svaccinewouldbe

availableasaninjectionifitisapprovedforuse.Anotherimportantdistinctionisthat

NicaraguahadahighdiseaseburdenanditwasalsoaGAVI-supportedcountry.Manyof

thehighburdendenguecountriesarenotGAVI-eligible.Thishasimportantimplicationsfor

thefinancialsustainabilityofthecasestudy.PresumablytheGAVIsupportwasakey

considerationthatmadeaproductdonationtenable;otherwisetherewouldbekey

questionsoffinancialsustainabilityafterMerck’sdonationconcluded.

Withthesedifferencesinmind,doesanythingremainasrelevantforthisDELTAproject?

Toanswerthis,oneshouldconsidertherolethattheNicaraguanprojectplayedin

acceleratingbroadermarketaccesstotherotavirusvaccine.Aboveall,itprovided

implementationexperienceandgeneratedreal-worldevidenceforRotaTeq®.Accordingto

theDirectorGeneralofthePanAmericanHealthOrganization(PAHO)whentheinitiative

launchedin2006,“Themoreweknowaboutsuccessfullyimplementingarotavirus

vaccinationprogram,thebetterchancewehaveofhelpingtoprotectchildrenfromthis

disease”(102).Similarlyregardingdatageneration:whenvaccinesarefirstapprovedfor

usebyregulatoryauthoritiestheyonlyhave,bydefinition,datafromclinicaltrials

demonstratingthatthevaccineissafeandefficacious.Whilecrucial,thisisnotthesameas

evidencethatshowsitseffectivenessunderreal-worldconditions,orverifiableresults

36

showingitsimpactondiseaseepidemiologyatapopulationlevel.Itisreasonableto

assumethatfavorableevidenceofthisnaturebeyondclinicaltrialswouldonlystandto

advancethepaceandscaleofadoptioninnationalimmunizationprograms.Indeed,the

datafromtheRotaTeq®project,combinedwiththeoriginalclinicaltrialdata,supported

theWHO’sdecisiontoexpanditsguidanceaboutrotavirusvaccinesfromcertainregionsto

aglobalrecommendation,whichinturnledtoGAVIincreasingitsrotavirussupportin

AfricaandAsia(101).

Althoughitdoesnotnecessarilyhavetobeachievedthroughidenticalmeans,thestrategic

prioritytogainexperienceandgenerateevidenceisavaluabletake-awayforTAK-003’s

marketaccessplanning.Therotavirusvaccine’sprecedentofconcurrentregistrationisalso

anencouragingexamplethatishighlyrelevantfordenguebecausethedengueburdenis

predominantlynotinhighincomecountries.Overall,theRotaTeq®caseillustratesa

promisingintersectionwherebyapredominatelyA2Minitiativeadvancedbroadermarket

accessobjectives.

2.5.2MenAfriVac®

TheMeningitisvaccineprojectbroughttogetherTheBillandMelindaGatesFoundation,

WHO,PATHandSerumInstitutetodesign,develop,testandintroduceanewvaccinethat

couldbemadeavailabletoAfricaatscaleandatanaffordableprice.Theprogramdelivered

theMenAfriVac®productwithin10yearsatlessthanone-tenththecostofatypical

vaccine(103).By2016over260millionpeoplehavebeenvaccinatedandrollouthasledto

37

thevirtualdisappearanceofgroupAmeningitisinsub-SaharanAfrica(103).Itisnot

surprisingthereforethatithasbeenheraldedasa“remarkablepublichealthsuccess”

(104).

MenAfriVac®istheextraordinaryresultofauniquepublicprivatepartnership(PPP).

Takeda’sdenguevaccineisbeingdevelopedanddeliveredbyanindependentcommercial

entity.What,ifanything,isinstructiveaboutthisexperiencefordenguemarketaccess

planning?

AfewkeyfeaturesoftheMenAfrivacinitiativeareinstructive.Thefirstistheregional

approach.Inthiscase,therewasastrongepidemiologiccaseandvalueinadoptinga

regionalapproachthatfollowedthe‘meningitisbelt’ofcontiguouscountriesonthe

continent.Theremightbesimilaradvantagestoconsideringaregionalapproachtoa

vector-borneillnesssuchasdengue.Therefore,marketaccessplanningdoesnot

necessarilyhavetobelimitedinscopetoonlyglobalornationallevels.

Forexample,PAHOistheregionalpublichealthauthorityinLatinAmerica,aregionwith

manydengueendemiccountries.Thelessonaboutregionalengagementunderscoresthe

importanceofthisorganizationforaregionally-orienteddenguestrategy.

TheMenAfriVac®initiativewascreatedinresponsetoacallfromAfricanministersof

healthfollowingameningitisoutbreakthatkilled25,000peoplein1996(103).

Unfortunately,thisdoesnotbodewellasanexampleifitisinterpretedtomeanthata

large-scaledenguecrisiswouldberequiredtomobilizesubstantialstakeholdermomentum

aroundanewdenguevaccine.

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3.Resultsstatement

ThissectiondescribestheoutcomesoftheDELTAprojectwork.Itisstructuredinthree

parts.Thefirst,“summaryofprogresstowardsaccessaims”,isprimarilydescriptivein

nature.Itpresentswhattranspired,accordingtoeachstepinVBU’smarketaccessplanning

methodology.Thefocusisonkeydevelopmentsandchangestothemarketaccess

methodology.Italsoincludesadescriptionoftheinternalandexternaleventsthathada

significantbearingontheprojectwork.Theseresultsarethenevaluatedbyusingthe

frameworkpresentedaboveinsection2.4.2.Thefinalsectionextrapolateskeyinsightsand

includesreflectionsontheexperiencethatarerelevantforthebroaderfieldofpractice.

TheinsightsfromtheliteraturereviewandmethodologydescribedintheAnalytical

PlatformarereferencedthroughoutthisResultsStatement.

3.1SummaryofprogresstowardsAccessaims

Torecap,VBUisfollowingasystematicmethodologytoproduceaglobalandcountry-level

marketaccessplansforitsdenguevaccinecandidate.Theend-to-endsequenceconsistsof

thefollowingsteps:characterizingpillarsofmarketaccessforthespecificvaccine,

organizingmarketsintoarchetypes,articulatingglobal‘strategicdirections’,andthen

producingcountry-levelplansaccordingtothestrategicdirectionsthatapplytoagiven

country’sarchetype.

Allstepswerepursuedduringthe8-monthDELTAassignment.Thisresultedinaglobal

marketaccessstrategydocumentforTakeda’sdenguevaccine,andapartialcountry-level

planforonecountry.Bothdeliverablesare‘livingdocuments’thatwillcontinuetoevolve,

39

particularlyaftersafetyandefficacyresultsfromtheongoingTIDEStrialcandeterminethe

specifictargetproductprofile(TPP)andpotentialrole,ifany,inimmunizationprograms.

Tofollowisadetaileddescriptionoftheprogressanddevelopmentsaccordingtoeachstep

inthemethodology.

3.1.1ExperiencewiththeglobalMarketAccessmethodology

Step1–Characterizingtheessentialpillarsofmarketaccess

Thisstepprovedtoberelativelyuncomplicated;theexperiencewasmore-or-lessas

anticipatedinthebaselinemethodology.Keydevelopmentsinclude:theadditionofanew

marketaccesspillar,adoptingatailoredprocessaccordingtotheneedsofeachpillar,and

accountingforinterdependenciesandtheorganizationaldynamicsassociatedwitheach

pillar.

Addinganewpillar

Themostsignificantdevelopmentwastheadditionofanewmarketaccesspillar,

tentativelylabeledas“vaccineesandtheircommunities”.Thissixthpillarisfocusedonthe

peoplethatTakeda’sdenguevaccineisultimatelymeanttoserve.Itisnowpartofthe

methodologyalongsidetheotherpillarsof‘evidencegenerationandsynthesis’,‘pricingand

funding’,‘healthinitiativesandservices’,‘supplychainandlogistics’and‘policyand

stakeholders’toconstitutethecriticaldimensionsofmarketaccessthatmustbe

characterizedinaplanforanyvaccine.

TherationaleforthisdecisionisindicativeofVBU’sprioritiesandvalues.Ontheonehand,

itcouldhavebeendeterminedthatsucha‘people’dimensionwasinherentlydistributed

acrossthefiveexistingpillars,andthereforeitdidnotrequireastand-alonesection.

40

Accordingtothislogic,thepeoplethatthevaccinewouldprotectaresofundamentalthatit

iseffectivelyubiquitousandcould‘gowithoutsaying’.Indeed,the‘people’dimensionis

necessarilyinvolvedinvaluepropositionthatevidencegenerationaimstosupport(pillar

1),people’spreferencesandabilitiesareanimportantfactorinanypricingapproach(pillar

2),peoplelieatthecenterofmosthealthinitiatives(pillar3),peopleformtheend-pointof

asupplychain(pillar4)andtheaffectedpopulationsaretheultimatestakeholdergroup

foranypolicy(pillar5).Notethissamelogiccouldapplytoahandfulofothercross-cutting

topicsthatarecriticaltomarketaccessbutdidnothaveadedicatedpillar.Forexample,a

similarrationaleappliesforregulatoryactivities,legalconsiderationsandcompliance

needs.

Thedecisionwastakentocreateanewpillarspecificallyfocusedon‘people’inorderto

highlighttheimportanceofthisdimensionandmaximizeitsvisibilityinthemarketaccess

planningprocess.ThisprioritizationwasultimatelyjustifiedbyreferencingTakeda’s

corporatephilosophy,whichendeavorstobuildapatient-centricorganization(105).The

notionof‘people’isadmittedlybroadandgeneric.Thereforeitrequiressomeexplanation

tosetexpectationsforthispillar’sroleinthemarketaccessmethodology.Noteadiscussion

abouttheuseoflanguageandtermthatwasselectedtodescribethepillarwillfollow.

Conceptually,itisincludedtorepresentallthingsconcerningtheend-userofthevaccine,in

amanneranalogoustohowagenericconsumerproductcompanymightplacethe

customeratthecenterofitsstrategy,oranautomotivecompanymightfocusonthedriver.

However,becausevaccinesdirectlyimpacthealth,thisdimensioninvolvesadditional

considerationstotraditionalretailgoodsandservices.Foremostamongthese

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considerationsistheneedtodifferentiatespecificsub-populationswithinthebroad

categoryof‘people’.Itissignificantbecausedefiningspecificgroupsofpeoplewill

presumablycarrydifferentimplicationsfortheiraccesstothevaccine,andthereby

determinetheextenttowhichtheywillbeprotectedornotprotectedfromdengue.Given

itsroleasasignificantandpotentiallylife-threateningillness,thisimplicationisnottrivial.

Howwillthesub-populationsbedefined?WillTakedavalueuptakebyonegroupequallyto

another?BecauseitisanewadditiontothemethodologythataroseduringtheDELTA

implementation,thesecrucialandpragmaticconsiderationsarestillunderdevelopment.At

thisstage,theupdatedmethodologyarticulatestheneedtodefinespecificpopulation

profilesbutdeferstheundertakingtothestrategy’srefinementandultimatelytothe

country-levelplansforexecution.

Returningtoitsroleintheoverallapproachtomarketaccessplanning:withoutthisnew

pillarinthemethodology,theresultingstrategymighttendtofocusontheneedsof

Takeda’simmediatecustomer(e.g.thegovernmentpurchasingthevaccine,ordistributor

forprivateclinicians,etc.).Thiswouldhavebeensuboptimalbecausedoingsowould

essentiallydefertheresponsibilitytoincorporatethepatient’sneedstothesepurchasers

(byassumingthatpeople’sneedswillbeaccountedfordown-streambyTakeda’s

immediatecustomerandthedecisionsthattheytaketoservetheircustomers).Bydirectly

articulatingthispillarinVBU’sglobalstrategyfordengueandcascadingittothecountry

plans,Takedaistakingaccountabilityandcreatinganopportunitytodirectlyrespondto

people’sneedsandtherebyincreasethepotentialpublichealthimpactthatrollingoutthe

vaccine’smarketaccessstrategycanhave.Indeedalthoughitmayseemsymbolicor

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theoretical,thisdecisiontoaddanewpillarcarriesimportantimplications.Itssignificance

comesintofocuswhenoneconsidersthepivotalroleofthepillarsinthemarketaccess

methodology.Accordingtothemethodology’sdesign,eachpillaristohaveglobalstrategic

directionscraftedforit,alongwithworkplansandresourcesthatareallocatedfortheir

achievement.Inthecaseofdengue,theadditionofthissixthpillarresultedinprioritizing

potentialinitiativessuchastheneedforestablishingdenguepatientadvisoryboards,

assessingthecaseanddesignofsupportprogramsforvulnerablepopulations,and

communitycrisis-responseplansinthecaseofadengueoutbreak.Moreoverlooking

beyonddengue,thismodificationtothemethodologymeansthatsubsequentvaccineswill

alsocharacterizeasixthpillarfocusedonthepeoplethatthevaccineismeanttoserve.

Asabriefaside,thechoiceoflanguageforthetitleprovedtobeanimportantfactorwhen

addingthisnewpillar.Theintentiontoarticulatetheroleandneedsofpeoplebrought

attentiontoauniqueaspectofthevaccinefield.Typicallyinthepharmaceuticalbusiness-

andatTakedaoutsideofVBU-theword‘patient’isusedtodescribethepersonthatwill

benefitfromthecompany’sproducts.Althoughthisisappropriatefordrugs,thismay

technicallynotbesuitableforimmunizationbecausevaccinesareadministeredtohealthy

peopleandtheword‘patient’hasconnotationsofasickpersonreceivingtherapy.Hence,

theteamconsideredtheuseoftheword“vaccinees”forthisnewpillar.Althoughaccurate,

thisinvolvedacceptingatrade-offsince“vaccinees”isalesscommonlyusedwordand

riskssoundingoverlytechnicalorimpersonal.Inpracticethepillarwassometimesstill

referredtoas‘thepatientspillar’becausethatresonatedmorewiththereferencepoint

thattheteamhasfromothermarketaccessplanningandTakeda’sbroaderpatient-centric

43

mantra.Abroaderdiscussionofthesignificanceoflanguageasitrelatestothefieldof

marketaccessworkisincludedintheKeyLearningsofsection3.3.4.

Adoptingatailoreddevelopmentprocess

Theprocessforhowtocharacterizethefive(nowsix)pillarswasnotexplicitlydescribed

attheoutset.Astheworkgotunderwayitquicklybecameclearthateachpillarwould

requireadifferentapproachbasedonthetiming,work-to-date,andtheteam’sgeneral

understandingofwhatthepillarshouldinclude.Althoughthecontentsofeachpillaris

specifictoTakedaanditsdengueprogram,someaspectsoftheexperiencearebroadly

applicableandvaluabletohighlight.

Thefirstsetofinsightsrelatetothenuancesassociatedwiththefocusofeachpillar.The

processofdefiningthevaccine’sevidencegenerationandsynthesisneeds(pillar1)

highlightedtheimportanceofusingnon-technicallanguagetodescribethecontent.The

domainisusuallytheconcernofhealthexpertswell-versedinthefieldofhealthtechnology

assessment(HTA)suchashealtheconomists,epidemiologistsandclinicians.Thechallenge

foraglobalstrategy,therefore,wastodrawonthisexpertisebutdescribeitinawaythat

wouldbeaccessibletothebroaderteam.Forexample,thekindsofevidencethatshouldbe

generatedforaproductshouldbeinformedbythecost-effectiveness(CE)analysisthatis

envisionedasnecessarytodemonstratethepotentialvalueofavaccineforacountry.CEis

distinctfromcostbenefitanalysis(CBA),andthisshouldbeclearforallaudiencesofthe

plan.Moreover,CEinvolvesspecificbest-practicesofcalculatingthecostsandimpactfrom

adirecthealthcareperspective,aswellasfromasocietalperspective(106).Bothwere

relevantfortheeffortofmarketaccessplanningforadenguevaccine;thepurposein

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highlightingthemhereistoemphasizetheimportanceofusingpreciseandclearlanguage.

Conveyingthedesiredscopeaccuratelyisimportant,particularlyinthecaseofavaccine

likedengue,whichhassubstantialeconomicimpactwhenoneconsidersmorbidityand

drainoneconomicproductivity(5).

Theexperiencewithpricing(pillar2)alsoofferedimportantlessons.Thispillar,perhaps

morethananyother,putintoperspectivethecurrenttimingofthemarketaccessplanning

effortinrelationtothevaccine’sclinicaldevelopmentandcommercialization.More

directly:ithighlightedimportantdependenciesontheresultsoftheTIDEStrial.Itwould

notbeappropriate,orpossible,tofinalizeanyspecificdecisionaboutpricingwithout

confirmingthepotentialuse,or‘label’ofthevaccinecandidate(i.e.whatage-groupit

wouldbeavailablefor,thedosingschedule,etc.).Thelabelisultimatelydeterminedby

nationalauthorities,andthesedecisionswillrelyonthesafetyandefficacyresultsofthe

ongoingTIDEStrial.Therefore,anyexpectationsforthispillartodeterminethespecific

priceofthevaccinewerenotrealistic.Instead,theworkfocusedonahigh-levelpricing

philosophyforthedenguevaccine.Thisisin-linewithTakedaPharmaceutical’sglobal

positiononpricing,whichfocusesonthevalueofthemedicinesforindividualsandsociety,

accesstopatients,andfindingnewapproachestopartnership(107).Theworkofthispillar

alsoplannedtheprocessandanalysisthatwillberequiredtodetermineandimplementa

pricingstrategy.

Animportantevolutionintheapproachwastobroadenthescopebeyondjustafixationon

thepricetagperadoseofdenguevaccine.Althoughthepillarinitiallywasdescribedas

45

“pricingandreimbursement”,thiswasbroadenedfurtherto“pricing,reimbursementand

funding”.Thisdecisiontoadd‘funding’wasanacknowledgmentthatconceivingan

approachtopricingwouldbeoflittlevalueifitwasdonewithoutdueconsiderationforthe

feasibilityandfundingneededbycountriestopurchaseandusethevaccine.Thisis

particularlyrelevantinthecaseofadenguevaccine,whichstandstobenefitfromnovel

approachesandsourcesoffundinginlightofthefactthatitslarge-scaleadoptionwouldbe

anewexpenditure,andthereforerequireexpansionordisplacementofexistingbudgets.

Insummaryregardingthepricingstrategy,twothingsareclear:thefinaldecisionwillbe

important,anditishighlycomplex.ItisimportantbecausethepricethatTakedaofferswill

influencethefinalcostofimplementationthatcountriesandprivateindividualswill

considerwhenassessingthevaccine’svalue.Thisdecisionwilldefinethepotentialextent

ofpublichealthimpact.Moreover,uniquefeaturesofthevaccinemarketintroduce

significantcomplexityintothisprocess.Althoughstakeholdersmayfocusonthelink

betweenacompany’scostsandthepricethatisset,theconnectionisusuallynotso

straightforwardinthecaseofvaccines.Acompany’scostsmaybeoffsetbygovernmentsor

foundationsthroughsubsidies,rebatesortaxexemptions(108).Moreover,mostvaccine

manufacturersdonotpricebasedoncostbutrather,focusonmarketdynamicsandthe

economicvalueassociatedwithavoidingtreatmentcostswhenpricingvaccines(108).

Notethesubsidiesandindustrypracticesarenotmentionedhereasanindicationofwhat

Takedawillorwillnotdo.Theyarehighlightedtoconveythecomplexitiesofthecontext

withinwhichthedecisionwillbemade.ThiscomplexitywillfollowthroughfromTakeda’s

decisiontotheeffectivepricethattheend-consumermustbear.Especiallyinnational

46

immunizationprogramswheregovernmentsorglobalentitiesnegotiateaprice,thecostis

notbornbytheend-userandthusaclassicalsupplyanddemandanalysisattheconsumer

leveldoesnotapply.

Themainlessonfromthehealthinitiativesandservices(pillar#3)isthattheintentofthis

pillarwasnotinitiallywellunderstood.Infact,thesub-teamresponsibleforleadingthe

pillar’sdevelopmentinitiallywonderedaboutitsroleinthemethodology.Thiswas

addressedbyhavingacross-functionalbrainstormingmeeting.Aclarifyinginsight

emergedfromthismeeting,namelythatthehealthinitiativesandservicespillarwould

involveallpossibleinitiativesthatstandtoadvancethecauseoffightingdengueina

country,butwerebroaderthanjusttheTAK-003product.Thishelpedclarifytheboundary

betweenpillar3andthepolicyactivitiesofpillar5,whichwouldbespecificallyrelatedto

thedenguevaccinecandidate.Thedistinctionalsohelpedtopullinpotentialinitiatives

relatedtobroaderenvironmentalconditionssuchashealthsystemstrengthening(HSS),

vectorcontrol,andeducation.Itisalsoimportanttoclarifythattheenvisionedinitiatives

wouldnotnecessarilyhavetobeimplementedbyTakeda.Thisrealizationbroughtinto

focustheimportanceofdefiningthepotentialroleforTakedaineachinitiative–asa

coordinator,funder,partnerorimplementer.Thedecisionofwhatinitiativetoimplement

ishighlydependentonthecountrylandscapeandneeds.Therefore,theroleintheglobal

planistooffera‘menu’ofalternativesandrationalethatcanthenbetakenupinthe

nationalimplementationplanning.

47

Theremainingpillars(supplychainandpolicy)hadthebenefitofdedicatedplansand

resourcesalreadywellunderdevelopmentbytheirrespectivefunctionalteams.Therefore,

theroleofthemarketaccessstrategydevelopmentwastocapturetheseplansandconvey

theminasuccinctwayaspartoftheend-to-endframework.Thispointstoabroadly

applicablelessonconcerningtheintegrationofmarketaccessplanningwithother

functionsinvolvedindevelopingandcommercializingavaccine.Thebroadnatureof

marketaccessnecessarilytouchesactivitiesthatwilllikelybeinflightatthetimeaplanis

beingdeveloped;itsdevelopersshouldstrivetounderstandongoingeffortsand–where

plansalreadydoexist-synthesizetheminaproductivewaysoastoreducethepotential

forredundancyorconflictingguidance.Themotivationtoaddthesixthpillar,‘vaccinees

andtheircommunities’hasalreadybeendescribedabove.

Asecondinsightfromtheefforttocharacterizethepillarsrelatestotheirinterdependence.

Theuseofdiscretepillarsofmarketaccesshasorganizationaladvantages;itlendsitself

welltosub-teamsandleadershipfromcontentexpertswithintheorganization.However,

thisadvantagebringswithittheneedtoaccountforstrategiesandinitiativesthatspan

acrosspillars,ofwhichtherearemany.Forexample,itissuperficialtoconsiderpricing

(pillar2)withoutduethoughttotheevidence(pillar1)neededtosupportthatprice,and

thepolicyneededtoembraceit(pillar5).Similarly,supplychain(pillar4)isinherently

involvedinrespondingtotheneedsandrequirementsthatcouldbedefinedinthesixth

pillarfocusingonvaccineesandtheircommunities.

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Arecognitionofthisinterdependenceimpliestheneedtoaddresstwoconsiderations:how

toaccountforlinkagesthatconnectmultiplepillars,andhowdifferentaspectsofastrategy

thatarecommontomultiplepillarswillbevaluedandprioritizedifnecessary.Thelinkages

wereaddresseddirectly,butthearguablymoreimportantneedtoassignweightsin

anticipationoftrade-offswasnotexplicitlyincorporatedintothemethodology.The

followingparagraphelaboratesontheapproachtolinkages.Theextenttowhichthe

methodologyhasvaluesinitsassumptionsanditssuitabilitytofacilitatetrade-offsisa

mainthemeoftheoverallobservationsattheendofthisResultssection.

Thelinkagesbetweenthepillarswasaddressedintwokeyways.First,itwasexplicitly

cross-referencedinthedocumentfortheprominentareaswhereitwasapplicable.The

secondwasthroughthestrategy’sdevelopmentandreviewprocess.Whilecontentwas

developedwithinternalexpertsandspecificfunctionleadsforagivenpillar(e.g.supply

chainteamforpillar4,medicalaffairsandpolicyteamforpillar5,etc.),theconsolidated

documentwasthensenttoallinvolvedcolleagueswithanexplicitrequestthattheyreview

theentirestrategyandnotjusttheirrespectiveareasoffocus.Theintentionwastoensure

overallcohesionanddrawoutadditionaldependencies.

Step2–Classifycountriesintoarchetypesbasedoncommonfeatures

Theexperienceofclassifyinglaunchcountriesintocommonarchetypesinvolvedthemost

significantadjustmentstoVBU’smarketaccessmethodology.Thebaselineexpectationwas

toassessalllaunchcountriesaccordingtofourdimensions:Vaccineaccessreadiness,

Diseaseburdenandenvironmentmaturity,Payersophistication,andDescriptivevariables

49

(seesection2.3abovefordetails).VBU’svisionforthisprocesswasverydetailed.

Accordingtothemethodology,anassessmentofover30metricswastobeconductedfor

eachcountry.Thisanalysiswouldproducecomplexoutputs–includingthree-dimensional

graphsanddetaileddocumentationoftheresultsforeachmetric.Sixpreliminary

archetypecategoriesweredefined,basedondifferentpermutationsofhowcountries

mightbeassessedinthefirstthreedimensionsofanalysis.Theexpectationwasthatall

launchcountrieswouldbeassessedandthenclassifiedintooneofthesesixarchetypes.

Theseproposedcategories,accordingtothebaselinemethodology,were:

• Archetype1–Highreadiness,burdenandsophistication

• Archetype2–Highburden,lowsophistication

• Archetype3–Mediumburden,lowsophistication

• Archetype4–Highreadiness,lowburdenandhighsophistication.Archetype4was

separatedintothreesub-variantsaccordingtothedescriptivevariables.

Challengesandlimitationsofthisapproachquicklybecameevidentwhentheeffortgot

underway.Theseissueswereaddressedbymakingadjustmentstothearchetype

developmentprocess.

Intermsofthechallenges:aboveall,theexperiencesuggestedthattheenvisioned

frameworkwashighlycomplexandthisundermineditspracticalvalue.Moreover,reliable

andconsistentdatawasnotreadilyavailableforalloftheenvisionedvariablesand

countries.Evenifoneweretoembracethecomplexityandovercomethedatagaps–they

wouldbefacedwithseveralfundamentaltheoreticalquestionsaboutthedetailsofthe

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approach.Forexample,are‘readiness’and‘sophistication’reallytwodistinctcategories?

Thetwoarearguablynotmutuallyexclusive,asacountrywithafavorablereadinessscore

willpresumablyalsohaveahighsophisticationscore.Evenifoneacceptsallthree

categoriesasmutuallyexclusive,theyarenotcollectivelyexhaustive.Arotecalculationof

thepossiblevaluesindicates12possiblearchetypes,notincludingthefourthdimensionof

descriptivevariables.Althoughitmightbejustified,itleavesonetowonderwhythereare

onlythe4maincategoriesandwhatistobeimpliedbytheomissionoftheothers.For

example,thereisnoarchetypeforcountriesthatare“lowburden,lowsophistication”.

Thetheoreticalchallengescontinue.Onemightalsoask:isitnotproblematictohave

‘diseaseburden’and‘environmentmaturity’togetherinonedimension?Presumablysome

countriesmayhavepolarizinglevelsof‘burden’and‘environmentmaturity’,makingit

irreconcilablewithasingle‘high’or‘low’overallvalue.Similarly:howsubstantialisthe

differencebetween‘medium’and‘high’or‘low’burden?Moreover,thedescriptivetitlesof

Archetype2andArchetype3donotmentionthelevelof‘readiness’–whatistobeinferred

abouttheirrankoftheseconddimension‘Vaccineaccessreadiness’?

Aboveall,themostfundamentalproblemwasthis:itwasnotimmediatelyclearhowthe

differentcategorizationswouldactuallymatterwhenconsideringtheirroleinthemarket

accessmethodology.Returningtotheaforementionedexampleaboutdifferentlevelsof

burden–wouldtherebesomethingfundamentallydifferentinthestrategicdirectionsfor

marketaccessplansinhighandmediumburdencountries?

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Theseissueswereaddressedbymakingadjustmentstothemethodology.Overall,theteam

maintainedtheapproachofassessingeachcountryaccordingtovariablesorganizedby

uniquedimensions.Butamorepragmaticandstreamlinedtacticwasadopted.Figure3

presentsthelogicflow.Thecorrespondingdetailedmetrics–includingthevariable,

definition,scoringparametersanddatasource,areincludedasAppendix2.

Figure3.Revisedlogicflowforcountryarchetypeexercise

First,allcountrieswereseparatedintotwobroadcategoriesaccordingtothenatureof

diseaseburden.Fordengue,thiswaseffectivelydeterminedbythepresenceofdengue-

transmittingvectorsinthecountry.Morespecificdatarelatingtothelevelofburden(e.g.

incidence,DALYs,etc.)wasalsocollectedandwillbeusedindetailedcountryplanning.For

Non-endemic

Readiness:• NITAG sophistication1• Routine Vx coverage• Funding availability2• Dengue Vx experience

Market Archetype:

Disease Burden:• Existence of dengue-transmitting vectors

• [Incidence (cases / 100k)]• [Indirect - Productivity costs]• [Direct – HC cost of disease]• [DALYs]• [Mortality]

4. Donor Markets (GAVI, UNICEF etc.)

Endemic

High Some gaps

• Country K• Country L• Country M

• Country N• Country O• etc.

2. Endemic with high readiness

3. Endemic with gaps in readiness

• Country F• Country G• Country H

• Country I• Country J• etc.

Supra-national funding

1. Travel Markets

Additional differentiation for country-level plans based on: 1. GNI/capita, 2. Market structure (public / private mix) 3. Influence of supra-national procurement entities (e.g. PAHO RF)

• Country A• Country B• Country C

• Country D• Country E • etc.

[1] NITAG sophistication based on the level a countries NITAG, if present, satisfies WHO’s 6 recommended best practices[2] Based on total Vaccine spend, and Vaccine spend per capita for the government and private buyers

• Country P• Country Q• Country R

• Country S• Country T• etc.

52

thepurposesoftheglobalcategorization,thefundamentalobjectivewassimplytoseparate

countriesintothosethathavesomedegreeofendemicdengueandthosethatdonot,

becausethepublichealthroleofavaccineisfundamentallydifferentinthosetwo

scenarios.

Theseconddimensionconsideredacountry’s‘readiness’fortheadoptionanduptakeofa

vaccinesuchasTakeda’sdenguecandidate.Acountry’sscoreinthiscategorywasthe

resultofamulti-factorassessment.Onedimensionfocusedonacountry’sNational

ImmunizationTechnicalAdvisoryGroup(NITAG).NITAGsarethemaindecision-making

bodyforacountry’simmunizationpolicy.ThestrengthofaNITAGwasassessedbythe

extenttowhichitconformedtoWHO’sguidance(109)forawell-functioningNITAGina

givencountry.WHO’sguidanceconsidersproceduralfactorssuchasthefrequencyof

meetingsandwhetherornotagivenNITAGhasformaltermsofreference.Although

perhapsbasic,thiscriteriaisobjective.Thismadeitvaluableforthearchetypeanalysis

becauseitallowedacomparisonoftherelativesophisticationofNITAGsacrosscountries.

Otherfactorsofthereadinessscoreconcernedfundingavailabilityandacountry’s

experienceandtrack-recordrollingoutanalogousvaccines.

Ascoringexercisewasconductedafterthedatawascollectedforallmetrics.Theoutput

wasamatrixplotthatpresentedallcountriesaccordingtothetwodimensionsofburden

andreadiness.Ageneralizedexampleispresentedinfigure4.

53

Figure4.Illustrativeoutputofrevisedarchetypeanalysis

Acountry’sarchetypewasdeterminedbyitslocationontheabovematrix;coordinates

werebasedonthecountry’sreadinessscore(y-axis)andburdenrank(x-axis).Sincethis

positionwastheresultofamechanicalanalysisbasedonthevalueforeachvariableinthe

dimension,stakeholderfeedbackwascriticaltoensuretheresultsweremeaningful.

Encouragingly,theconclusionswerein-linewithexpectations.Thus,theoutputdrewthe

strengthsoftheoriginalmethodologyinthatitwasdata-driven,systematicandrigorous.

Buttherevisedapproachalsofoundastrengthwheretheoriginalmethodologyraninto

trouble;theprocesswasefficientandtheresultsweremeaningfulandintuitiveforthe

teaminvolvedincreatingandimplementingtheplans.Theactivityofseekinginputfroma

broadgroupofinternalexpertsprovedtobeanessentialstepintheprocessmethodology.

First,thisisbecausethefeedbackonwhichvariablestoconsiderwasvaluabletorefinethe

approachasitdeveloped.Also,thebuy-inandconfirmationwascriticaltoensurethe

conclusionswouldbeusedasintendedbydecisionmakerslaterinthemethodology.

3. Endemic with Gaps in Readiness

2. Endemic with High Readiness

Burden rank (est Incidence / 100k pop)

Readiness

(weighted score)

“Non-endemic”(<10 cases / 100K pop)

High Readiness

(score > 8)

Some Gaps(score < 8)

4. Donor Markets1. Travel Markets

“Endemic”(>10 cases / 100K pop)

Country A

Country B

Country C

Country D

Country E

Country FCountry G

Country H

Country I

Country J

Country KCountry L Country M Country N

Country O

Country P

Country Q

Country S

Country R

Country T

54

Theadditionofthefourtharchetypecategory,“DonorMarkets”warrantsexplanation.It

wasaddedtoprovidespacefortheuniquemarketaccessneedsofcountriesthatrelyon

supranationalfunding(e.g.GAVI,UNICEF).Inthesecases,manyofthepillarswouldhave

marketaccessrequirementsthatwouldnotbeadequatelyemphasizedintheotherthree

categories.Forexample,aspectsofpricingandfunding(pillar2)wouldtypicallybe

determinedwiththeglobalpurchasingbodyandnotdirectlyatthecountrylevel.Similarly,

supplyandlogistics(pillar4)wouldinvolvesomeconsiderationsforcentralized

procurement.Itisalsoreasonabletoexpectthatthepolicyapproach(pillar5)would

probablyinvolvearecommendationfromasupranationalnormativebodyevenmoreso

thanothercountries.AlthoughforeaseofcommunicationtheDonorMarketsarchetype

wasdisplayedasacontinuouscategoryregardlessof‘readiness’values,runningthe

assessmentwouldstillprovevaluabletoinformcountry-specificplanning,inparticularas

itrelatestothespecifichealthinitiativesandservices(pillar3)thatmightberelevant

whendevelopingtheplanforaspecificcountry.Notethattheprocessandcategorizations

forthisarchetypesteparespecifictodengue;futureimplementationsofVBU’smarket

accessmethodologyforothervaccineswillneedtomatchtheparticulardiseaseburden

andenvironment.

Althoughhelpful,organizingcountriesintocommonarchetypesinvolvesaninherent

limitation.Acountrylevelassessmentisnot,bydefinition,wellsuitedtoaccountfor

variationwithinacountry.Thisconcernisparticularlyrelevantinthecaseofdengue

becauseburdenpattersarevariablebasedonlocalspatialdifferencesin“rainfall,

55

temperature,relativehumidity,degreeofurbanizationandqualityofvectorcontrol

servicesinurbanareas”(110).Itfollowsthatanygivencountrycouldhaveverydifferent

needsforavaccinedependingontheregionwithinthatcountry.Diseaseburdensmust

thereforebecontextualized.Althoughthisisnotideallyaccomplishedatthestageofa

globalplanningexercise,theshortcomingwasaddressedintwokeyways.First,thereisan

opportunitytocaptureintra-countryvariationsinthemethodologyduringthelocal

countryplanningstage.Second,thepossibilityofanendemiccountrycontaining‘travelers’

whogofromnon-endemicregions(i.e.acitywithhighaltitudesandnodengue

transmission)toanotherregionwithhighdenguetransmissionwashighlightedduringthe

globalplanningprocess.

Theexperiencealsohighlightedanotherrealitythataccompaniestheuseofcountriesas

theunitofanalysis:themethodologydoesnotexplicitlyaccommodateregionalevaluation

duringthissecondstepofarchetypedefinition.Inthecaseofdengue,regional

organizations(e.g.PAHO)andregionalepidemiology(e.g.cross-bordertransmission)are

veryimportant.Toaccountforthis,regionalorganizationsandstrategieswerespecifically

consideredinthepolicyplans(pillar5ofthefirststep).Moreover,VBU’sglobalmarket

accessteamincludesseniorregionaldirectors;assuchitispositionedtohelpincorporate

carefulconsiderationofregionaldynamicsduringthedevelopmentofthecountry-level

marketaccessplans.

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Step3-CraftingStrategicDirections

TheculminatingsteptodevelopaglobalmarketaccessstrategywastodefineStrategic

Directions.AStrategicDirectionistheguidancefromTakedaVBU’sglobalmarketaccess

teamthatismeanttoinformcountry-levelmarketaccessplanningandaction.Close

alignmentbetweenthecountry-levelmarketaccessplansandtheglobalstrategyiscritical

toasmoothandeffectiverolloutofthevaccineforpeople.TheStrategicDirectionsare

meanttofacilitatethatalignmentbyofferingthebroadintentionandtypesofactivitiesthat

canbecustomizedandpursuedinaspecificcountry.

Forexample,aStrategicDirectionforthefirstpillarofmarketaccess,“EvidenceGeneration

&Synthesis”shoulddescribethekindsofstudiesandanalyticalmodelsthatwillenablea

compellingandbalanceddossierforthedenguevaccinetobesubmittedtohealth

authoritiesinagivencountry.Thiswilldependonthevaccine’sprofileandobjectivesfor

itspotentialroleinthatcountry’spublichealth.

TheexperiencewithdevelopingtheStrategicDirectionswasmore-or-lessasenvisioned;it

wasinlinewiththeinitialexpectationsfoundinthemarketaccessmethodology.The

definitionofdiscreteareasprovidedbythepillarswasamenabletohavinginternalleaders

actaschampionsforeachpillar.Theseleadswerespreadacrosstheorganization,andnot

onlylimitedtotheCommercialteam.Eachleadwasbestpositionedtoshareplans-to-date

andconsultaboutpotentialstrategicdirectionsforthepillar.Thiscouldthenbe

synthesized,withthewholedocumentsenttoallleadsforend-to-endinput.Withoutthis

57

definedscopeandsequencing,thewidescopeof‘marketaccessplanning’riskedbeingtoo

broadandchallengingtomakeconcreteprogressbybroadconsensusfromtheoutset.

WhiletheroleoftheStrategicDirectionsinthemethodologywasclear,theformatwasnot

initiallyprescribed.Thisprovedtobeanimportantcomponentofthestrategy

developmentprocess.UltimatelyeachStrategicDirectionwasarticulatedinatemplate

involving3components:i.)StatementoftheStrategicDirection,ii.)Rationale,iii.)Global

resources.ThestatementofStrategicDirectionisself-explanatory.TheRationaleprovided

keyfactstoestablishcontextandjustificationforthestateddirection.Theinformationin

thissectionwasthoroughlyreferencedwithsourcesfromthescientificandacademic

literature.Thisaddedtotheobjectivityoftheplansandwouldhopefullymakethemmore

accessibleforthein-countrycolleaguesthattheplanisintendedtoassist.Thethirdsection

abouttheglobalresourceswasaddedwiththisend-userinmind;itisalistofthevarious

resources(e.g.documents,trainings)thatwillbeavailablefromtheglobalorganization

relatingtotheStrategicDirectionsforagivenpillar.

Onefinalproceduralinsightisaboutthevalueofincludingavisualsummary.VBU’smarket

accessmethodologyquicklybecomescomplexwhenoneconsidersthepossible

combinationofarchetypesandstrategicdirections.Forthisreason,asummarymatrixwas

developedwhichconvenientlyshowedtherelativeapplicabilityofastrategicdirectionfor

agivenarchetype.Pleaserefertofigure5fortheformatofthismatrix.Itoffersvalueasa

succinctsummaryoftheplan’scontents.Perhapsmoreimportantly,italsoactsasaguide

forin-countrycolleaguestoquicklylookandidentifywhichsectionsarerelevantforthe

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countrythattheyareworkingin.Again,thedesignofthissummarywastheresultof

rememberingthecountry-baseduseroftheglobalplan.Note:theroleofthismatrixshould

notbeover-promised–itisaguideforwhereaparticularreadershouldfocustheir

attentioninthedocument,anddoesnotcontainadditionalinsightorsynthesisofhowa

particularstrategyoughttobeimplemented.

Figure5.Illustrativeexampleofsummarymatrix

3.1.2Experiencedevelopingacountrymarketaccessplan

AttheoutsetoftheDELTAproject,theintentionwastodeveloponecountryplanafterthe

globalstrategywascompleted.Thisdidnotprovetobearealisticexpectation.Therewere

delaysindevelopmentoftheglobalplanuponwhichthecountryplandependsforstrategic

guidance.Alsorelatedtotiming–itquicklybecameclearthattheintentiontocompletea

countryplanwouldnotberealisticgiventhesignificantamountoftimeremainingto

productlaunchandcriticalmilestonesthatremained,leastofwhichwasresultsfrom

clinicaltrialsthatwouldconfirmthespecificproductprofile.Moreover,theideaof

immediatelystartingtoworkonacountryplanaftertheglobalplanoverlookedtheeffort

requiredtodefineauniversaltemplateforallcountryplans.Italsodidnotaccountforthe

coordinationneededtoensuretherewereadequateresources,plansandtimeallocatedfor

Strategic Direction 1. Travel Markets

2. Endemic, high

readiness

3. Endemic, with some gaps

4. Donor Markets

Pillar 1: Evidence Generation

1.1 [title]

1.2 [etc.]

1.3

Pillar 2: Pricing and Funding

2.1

Pillar 3: Health Initiatives and Services

2.1

2.2

2.3

2.4

Pillar 4: Supply Chain and Logistics

4.1

Pillar 5: Policy and stakeholder approach

5.1

5.2

Pillar 6: Vaccineesand communities

6.1

6.2

6.3

6.4

SD applies to archetype

Potentially relevant

Not Applicable

Legend:

59

allcountryplanstobedeveloped(notjustonethatwouldbethefocusoftheDELTA

project).

Theemphasisofthecountry-levelplanningshiftedtoaddresstheserealizations.Thework

forcountry-levelmarketaccessplanninginvolved:i.)confirmingthedeliverabletemplate

thatallcountryplanswouldfollow;ii.)establishingaworkstreamforthecompletionofall

nationalmarketaccessplans,andiii.)beginningonenationalstrategybasedonavailable

information,andusingtheexperiencetoinformtheoverallapproachtocountryplanning.

Tofollowisanaccountofresultsandreflectionsforeachactivity.

Countryplantemplates

Theimportanceofastandardtemplateforcountry-levelplansshouldnotbe

underestimated.Itsvalueliesinensuringthatcountrieswillreceiveequalattentioninall

necessaryareasofmarketaccessstrategy.Theconsistentformatalsofacilitateseasy

comparisonoffindingsandgapsbetweencountrieswhenlookingacrossthecohortof

launchcountries.ItwasstructuredasaPowerPointdocumentwithtables,figuresand

chartsthataretobepopulatedwithcountry-leveldata.

Carefulattentionwaspaidtotheconnectionbetweentheglobalmarketaccessstrategyand

thestructureforeachcountryplan.Wheretheglobalplanwasnecessarilyahighlevel

document,providingbroadStrategicDirections,thecountryplansaretheplacetocapture

detailedmarketinsightsandtacticsforstrategyexecution.Thecountrytemplateconsists

of3sections.Thefirst,“Set-up”,describestheglobalTakeda-wideobjectivesandproduct

characteristics.Thesecondtrackistheexternalenvironmentanalysis.Thefinalsectionis

60

thedetailedlocalmarketaccessapproach.AccordingtoVBU’smarketaccessmethodology,

thissectioniswherethelinkbetweentheguidancefromtheglobalstrategyandthelocal

tacticsoccurs.Figure6illustratesthestructureofacountrytemplateandhighlightsthis

cruciallink.

Figure6.Structureoflocalmarketaccesstemplate

Althoughthisconnectionbetweentheglobalstrategyandcountryplanswasstructurally

accountedforinthemethodology,amoreimportantquestionmustbeconsidered.Thatis

thedegreetowhichtheincentivesofacountryteamareexpectedtobealignedorin

contestwiththegoalsoftheglobalteamfoundinthestrategy.Thefullextentcanonlybe

learnedandaddressedoverthecomingmonthsasplanningprogressesand

implementationbegins;atthisstagethedynamicscanbereflectedontoanticipate

potentialareasofalignmentandtension.Someinitialreflectionsonthisimportanttheme

areofferedinSection3.3.5.

Establishingaworkplan

Thesecondactivityfocusedonestablishinganoverarchingworkplanforthecreationof

eachindividualcountryplan.Thiswasnotanovelorparticularlynoteworthyactivity–but

Local strategic framework

Evidence generation and synthesis

Pricing, reimbursement and funding

Health initiatives and services

Supply and logistics

Policy and stakeholder approach

Vacinees & their communities

Global Takeda strategy

Vaccination environment

Stakeholder mapping

Competitive landscape

Disease environment

Public health context C1

C2

C3

C5

C6

C7

A1

B2

B3

B4

B5

B1

C4

A. Set-up

Integrated Value PropositionC7

B. Local Environment Analysis

C. Local Market Access Approach

Based on Strategic Directions of the Global Market Access Strategy

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itismentionedherebecauseitwasanactivitythatwasinitiallyoverlookedwhen

establishingthescopeoftheDELTAassignment.Itincludesstandardcomponentsof

timelinesandresponsibilities.Ofnoteistheimportanceofarrangingforsufficientlocal(i.e.

nationallevel)andregional(i.e.AsiaPacific,LatinAmerica,etc.)expertiseinthe

developmentofeachcountrymarketaccessplan.Settinginternalexpectationsthatthe

country-levelplanswillnotbecompleteuntilaftertheclinicaltrialresults,forthesame

reasonsasdescribedabovefortheglobalstrategy,wasalsoanimportantfactor.

Developingacountrystrategy

Thefinalcomponentofthecountryplanningworkwastobeginpopulatingthetemplatefor

onecountryinLatinAmericabasedoncurrentlyavailabledataandinputfromin-country

stakeholders.Theideawastousethisexperienceasa‘pathfinder’thatcouldinformthe

overalltemplatestructureandplanningforallcountryplans.Itwasahighlyvaluableeffort

inthisregard,andseveralkeyinsightsemergedfromthisexperience.First–similartothe

experienceofdefiningcountryarchetypesfortheglobalstrategy–theglobalteamquickly

appreciatedthecomplexityandunfeasibilityofsomeoftheinformationrequestedinthe

initialtemplate.Therefore,sometimewasspenttoreviewthetemplatesandidentifya

subsetofslidesandcontentthatwouldbevaluableandfeasibletocollect.Aspartofthis

exercise,theteamalsoflaggedsectionsofthetemplatethatcouldnotbecompletedinthe

neartermbecauseofoutstandingdatadependencies.Thisadditionalstepintheprocess

wasadirectresponsetothebroaderrealitytheprojectoperatedwithin,i.e.theneedto

progressandbepreparedtotheextentpossiblewhileappreciatingthedown-stream

dependenciesanduncertaintywithoutdefinitivetrialresults.

62

Oncethetemplatewasrefinedanditsscopewasprioritized,theefforttopopulateits

contentbegan.Thisworkinvolvedreviewinginternalandexternalreportsavailableabout

thespecificmarketandmeetingwithin-countrystakeholderstogatherinsightsonmarket

conditions.

Severalkeyinsightsemergedfromthisprocess.Aboveall,itservedtoputthemarket

accessplanningintothecontextofacountry’sbroaderpublichealthpriorities.Theprocess

todevelopamarketaccessmethodologyandglobalstrategydevelopmentwas,by

definition,focusedondengue.Theexperienceofunderstandingalocallandscape,andin

particular,meetingwithlocalstakeholders,helpedtocharacterizethecompetingpriorities

thatcountriesfacewhenconsideringadiseaselikedengue.Ontheonehand,thescaleof

thedengueproblemandneedforasafeandefficaciousvaccinewasclear.Atthesametime,

though,workingonthecountryplanhelpedappreciatetheunfortunaterealitythat,while

hugelyproblematic,dengueisalso‘common’andpartofdailylifeforsomeinendemic

countries.Thatdoesnotmakeitacceptable,butitwasaprofoundlesson,particularlyfor

thosefortunatetonotliveinadengue-endemicregion.Thisinsighthasimplicationsforthe

developmentoflocalcountrymarketaccessplans.Aboveall,itistoacknowledgethemany

otherpotentialpriorities–e.g.othervaccines,andevennon-vaccinepreventablediseases–

thatareimportanttoin-countrystakeholdersandessentiallycompetingforthesamefinite

resources.The‘realitycheck’fromthisrealizationhasadirectbearingontheglobal

strategiesandmanyofthepillarsofmarketaccess–inparticulartheexpectationsarounda

pricingapproachandfunding.Italsoopensinterestingopportunitiestoexploresector-

63

basedcollaborationsandpartnershipsthatmayincludedenguebutbebroaderthanit,

suchasmomentumaroundeffortstoachieveuniversalhealthcareinagivencountry.

Importantnuancesaboutmarketstructuresthatwerenotclearattheglobalstageinthe

planningalsocameintofocus.Forexampleintheglobalmarketaccessstrategy,equal

considerationwasgiventobothpublic(i.e.governmentfundedandadministered)and

private(i.e.outofpocket)markets.Thecountryplanningexperiencepointedoutthatthere

couldbeaclearemphasisofoneortheotherinagivencountrycontext.Giventhatapublic

orprivatemarketcouldreachpeopleandcommunitiesindifferentways,adequately

reflectingthisdifferentialemphasisinacountry’smarketaccessplancouldhavesignificant

implicationsforthepotentialpublichealthimpactofavaccine.Similarly,amoregranular

appreciationforcomplexitycameintofocus.Inoneexample,therewaseffectivelynosingle

publicmarket–butrathermultiplenationalagenciesandtenders.Thissignificantlyadds

tothelogisticalandpoliticalcomplexitybeyondwhatwasinitiallypresumedintheglobal

guidancedevelopmentandtemplate.Lastly,andperhapsmostsignificantly,therewasan

appreciationforhowdynamicacountrycontextcanbeandthesignificantimpactthatlocal

politicscanhave.Planningatthegloballevelcan’tcompletelyavoidtreatingasituationas

static–indeed,itisnecessaryinordertocapturerequirementsandmarketfeatures.But

therealityonthegroundishighlyfluid–takeforexampleacountrythatmightbeentering

anelectionyear.Insuchascenario,theprioritiesandpersonalitiesdominatingthecurrent

healthlandscapeasitrelatestodenguecouldbeverydifferentaftertheelections.The

experiencewiththecountryplansurfacedinsightsthatinhindsightseemobvious,andwill

beincorporatedintotheevolutionoftheglobalmarketaccessstrategy.

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3.1.3Organizationalandstakeholdercontext

Theglobalmarketaccessmethodologywasnotatheoreticalexercisethatwas

implementedinisolation.Rather,itwasdevelopedamidacomplexenvironmentthat

underwentsignificantexternalandinternalchanges.

Externaldevelopments

ForemostamongthesedevelopmentswasSanofi’s29November2017recommendation

thathealthauthoritieschangethelabelindicationforDengvaxia®sothatitwouldonlybe

prescribedtoindividualsthathadpreviouslybeeninfectedwithdenguevirus(111).This

requestwasbasedonnewanalysisbythecompanythatconfirmedahighernumberof

severedenguecaseswereobservedinthelongtermamongindividualsthathadnever

beenexposedtotheviruspriortovaccination.Giventhedebateandinitialhesitations

surroundingtheincreasedrateofhospitalizationthatwasobservedinDengvaxia®’sinitial

phaseIIIdata(describedaboveinsection2.2.2),Sanofi’supdateinNovemberwasahighly

significantdevelopment.

Theupdatetriggeredarangeofswiftreactionsfrommanyconcernedstakeholders,andthe

responsesarestillunfolding.WHOprovidedinterimguidancelessthanonemonthafter

Sanofi’supdate,anditisduetoreleaserevisedrecommendationsinApril2018(112).

WHO’sinterimguidancedidnotlosesightofthepotentialpopulation-levelbenefitsthat

Dengvaxia®canhaveinhighseroprevalancesettings,butitdidalignwithSanofi’srequest

byrestrictingtherecommendedusetoindividualswithdocumentedpastdengueillness

(112).

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Arangeofreactionswerealsoobservedincountriesthathadbegunvaccinationprograms

withDengvaxia®.MostextremeisthecaseofthePhilippines.Afterthedisclosurefrom

Sanofi,thegovernmenthaltedthedengueimmunizationprogram(whichhadalready

beguntovaccinate830,000children),demandedarefundandispresentlypursuingcivil

andpotentiallyevencriminalrecourseagainstSanofi(113).Othercountries,suchasBrazil,

recommendedrestrictionsbutdidnotsuspendtheprogram(114).Academicsandexperts

havealsoweighedin;atthetimeofdrafting,acallforabalancedapproachwasemerging.

Sucharesponsewouldappropriatelyaddresssafetyrisksbutnotlosesightofthepotential

population-levelhealthimpactthatthisoranydenguevaccinemighthave(115).

Thereactionswerenotlimitedtopublichealthauthoritiesandacademics.Italsotriggered

awaveofcoverageintheinternationalpressincludingmainstreamwesternmedia

publicationssuchastheNewYorkTimes,BBC,andCNN(116,117,118).Theheadlines

focusedprimarilyontheunfoldingstoryaboutDengvaxia®.Butthecoveragemayalso

impactthebroaderdevelopmentpipelinefordenguevaccines,andevenimmunization

beyonddengue.Regardingthepipeline:onepossiblereactiontotheSanofisituationisthat

healthauthoritieswillraisetheevidentiaryrequirements,forexamplebyrequesting

longer-termdatabeforeauthorizingavaccine.Somefearthatthiscouldharmbroader

developmentincentives–accordingtothechairofWHO’sworkinggroupthatstudied

Dengvaxia,“Mybigworryhereiswhatthiswilldotothefuturedevelopmentofsecond-

generationorevenfirst-generationdenguevaccines…it’sdifficulttoseehowany

commercialenterprisecouldtakeforwardadenguevaccineinthefutureandcommitto

thatleveloffollow-upwhenyou’renotsurethere’sacommercialreturnonthat

66

vaccine”(119).Thenewsmayalsobenegativelyimpactingimmunizationeffortsingeneral.

ForexamplethePhilippinesDepartmentofHealth(DOH)gaveapressconferenceon

February2ndtovoiceconcernoverdropsinroutineimmunizationrates–from~85%to

60%-inlightoftheDengvaxiasituation(120).ThisstoryisunfoldingandtheDOH’sclaims

ofcausalityarenotconclusive-butthebroaderpointstandsthatimmunizationisahighly

sensitivetopicandaneventthatunderminesconfidenceinoneareacanhavefar-reaching

effects.

ConcerningthedirectfocusofthisDELTA,Sanofi’snewshadseveralimpactsonthework

todevelopamarketaccessplanforTakeda’sdenguevaccine.Ifregulatoryauthoritiesdo

indeedadjustthekindordurationofdatarequired,thiswillneedtobeaccountedforinthe

tacticsofthemarketaccessstrategy.ThenewsnaturallyraisedquestionsabouthowTAK-

003mightdifferfromDengvaxia®,andtheimplicationsthismayhaveonthemarket

accessapproach.Theutmostcautionisrequiredinexploringthisquestion,becausethereis

aneedtowaitfortheTIDEStrialdataforanyconclusiveresultsaboutTAK-003’ssafety

andefficacy.Somehigh-levelobservationsarestillrelevantwiththiscaveatinmind.Most

relevantformarketaccessplanningistheclinicaltrialplansandtimelines,sincethatmay

impactthestrategyandtimingofHTAsubmissions.VBU’spresidentDr.RajeevVenkayya

gaveaninterviewtoreaffirmconfidenceinthedevelopmentplansandemphasizethe

abilityoftheTIDEStrialtobringanypotentialsafetysignalstolight,sinceitstrialdesign

accountedfortheproblemsthatDengvaxiaexperienced(119).Anotherquestionrelatesto

thescienceandthedegreetowhichTAK-003isdifferentiatedorpronetosimilar

challenges.Again,onecannotdrawanycertainconclusionsbeforephaseIIItrialresults.

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Butdirectionally,theunderstandingisthatSanofi’sresultsmaybeexplainedbythefact

thattheimmunesystemisexposedtoaninsufficientamountofdenguevirusbecausethe

vaccineusesayellowfeverbackbone(121).Onthistopic,Dr.Venkayyaexplainedhow

“We’vetakenadengue2virusbackboneandinsertedelementsofdengue1,3and4.[That

isimportant]becauseitexposesanindividualthatisimmunizedtoabroadrangeof

proteinsontheoutsideandtheinsideofthevirus,whichallowsindividualstogeneratea

broadimmuneresponse.”(121).Inthatsameinterview,Dr.Venkayyaalsoexplainshow

TakedaresearchshowsthatTAK-003generatesbothantibodiesandCD8+Tcellsthat

identifyandkilldenguevirus(121).ThiscouldalsobeanimportantattributeinTakeda’s

favour,asresearchhasrecentlyshownthebenefitofincorporatinga‘killer’Tcellresponse

inadditiontoantibodyresponseinthedesignofvaccinesfordengue(122,123).

Regardlessoftheobjectivedataandtrialresults,stakeholders’opinionsregardinga

denguevaccinehaveandwillcontinuetobeinfluencedbytheSanofistory.Forexample,

stakeholderperceptionsfrompolicyleaderspresentedabovebyDouglasetal.from2013

(89)havelikelychangedoverthelast5yearsandparticularlyfollowingtheSanofi

experience,andwouldthereforebenefitfromrefreshedanalysis.

ThenetofthisassessmentabouttheDengvaxia®updateisthatthestakeholder

environmentismorecomplex,buttheneedforasafeandefficaciousdenguevaccineis

evengreaterthanatthestartoftheDELTAproject.ThereforestakesontheTIDEStrial

resultsareevenhigherforthepublichealthcommunity,asistheneedforthe

implementationofaneffectivemarketaccessplanifthetrialresultsarefavourable.

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Internaldevelopments

AfavourabledevelopmentoccurredfortheVBUteamduringtheDELTAproject.The

originalplanwastoconductthefieldworkinsupportoftheglobalheadofvaccinemarket

access,whichwasbeingrecruitedduringthemonthsleadingtotheDELTAstart.Delays

howevermeantthatthisrolewasstillvacantatthetimetheDELTAworkbegan.Although

themainobjectivewastodeveloptheglobalmarketaccessstrategyfordengue,some

membersoftheinternalteamwerenaturallyhesitanttoinvesttooheavilyinthiswork

beforeitssustainingleaderwasidentified.Fortunately,aseasonedindustryleaderwas

identifiedandjoinedtheteamasSeniorDirectorandglobalheadofmarketaccessfor

vaccinesinSeptember2017.Theirexperienceaddedcredibilitytotheprocessandgavea

substantialboosttotheinternalmomentumforthiswork.Akeytakeawaythereforeis

relatedtothesignificanceandchangeabilityofhumanresources–hadtheheadofmarket

accessnotbeenrecruited,theeffortstodevelopthedenguestrategyasanisolated8-month

assignmentwouldhaveprobablyprogressedslowlyandwithmorechallenges.

3.2Evaluationofresults

TheprecedingsectionshavefocusedontheexperienceofimplementingVBU’smarket

accessmethodology,andkeyinsightsfromitsevolution.Thissectionaimstoconsiderthe

outcomesoftheworkbyassessingthemethodologyfromatheoreticalperspective.A

frameworkfromtheacademicliterature,describedearlierintheAnalyticalPlatform,is

usedtoguidethisreflectioninasystematicfashion.

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3.2.1AssessmentusingSmithFramework

Inresponsetoinconsistentdefinitionsofwhatconstitutesamarketaccessstrategy–let

alonewhatdifferentiatesaneffectivestrategyfromapoorone–Smith(94)proposesnine

criteriatoevaluatemarketaccessstrategiesforpharmaceuticals.Pleaserefertofigure2in

theAnalyticalPlatformforafulldescriptionofeachdimension.Theproposedcriteriaare

highlyrelevantfortheprimaryworkofthisDELTAandanassessmentofeachdimensionis

presentedinfigure7.

Thisassessmentwasconductedindependentlybytheauthor.TheSmithframework

outlinescriteriaforthreepossiblelevels(“strong”,“mediocre”,and“weak”marketaccess

plans);theexperienceofworkingonthedenguemarketaccessstrategywasdrawnonto

reviewthecriteriaandinformajudgementofwhatlevelshouldbeassignedforeach

dimension.Therationaleforeachrankingisdescribedbelowfigure7.Notetheshort-hand

labelsforeachdimensionwereselectedforconvenienceinthediagram’spresentationand

werenotemployedbySmithintheoriginalarticle.Also,itshouldbeclarifiedthatthe

assessmentconcernstheVBUmarketaccessmethodology(i.e.theextenttowhichthe

processthatwasfollowedcanbeexpectedtoproduceaplanthatwouldconformtothe

criteria).Itisnotanassessmentofthespecificmarketaccessplanthatwasdevelopedfor

thedenguevaccine.Saidanotherway:inordertopromotebroadrelevanceofthisanalysis,

theevaluationisfocusedonthemarketaccessmethodology’sprocessandthefeaturesthat

followingitsdesignarelikelytoengenderoroverlook.

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Figure7.Evaluationofmarketaccessmethodology

Overall,themethodologyscoresfavorably.Alldimensionsareconsidered‘strong’,withthe

exceptionof#2and#4.Ajustificationandcommentaryforeachdimensionfollows.

Regardingthestrengths:themarketarchetypeclassificationexercise,andprovisionfor

bothprivateandpublicmarkets,helpsaccountforheterogeneousmarketenvironments

(criteria#1).Thethirdcriteria,concerning“theextenttowhichthemarketaccessstrategy

offerspayer-perceivedeconomicvalue”(94),isaccountedfornicelybyacombinationof

theEvidenceGenerationandSynthesispillarintheglobalstrategyandthedetailed

stakeholderanalysisprescribedinthelandscapesectionofacountryplantemplate.Thefit

1. Environment heterogenity

2. Resource allocation

3. Economic value

4. Change anticipation

5. Product & Org. fit6. Coherence

7. Match decision making

8. Product Lifecycle

9. Financial goals

WeakMediocreStrong

Performance of VBU Market Access Methodology

LEGEND:

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betweentheproductprofileandorganizationalstrengthsandweaknesses(criteria#5)is

accountedforinthefirstportionofacountrymarketaccesstemplate,whichfeaturesa

presentationofTakeda’sglobalorganizationalstrategyforaproductaswellasan

overviewofitsrelativestrengthsandweaknesses.Thecoherencebetweenvariouslevelsof

plans(criteria#6)isperhapsoneofthestrongestfeaturesofVBU’sglobalmarketaccess

methodology;theroleoftheStrategicDirectionsispreciselytohelpensurealignmentand

connectionbetweentheglobalmarketaccessplanandnationaltactics(seefigure6).The

abilitytomatchasubmissionwiththerequirementsofahealthauthorities’decision-

makingprocess(criteria#7)isclearlyanimportantfactorforastrongmarketaccessplan.

Again,thecombinationoftheevidencegenerationpillaranddetailedin-country

requirementsthatwouldbemappedaspartofacountryplanshouldproducestrong

dossiersforevaluationinthisregard.Intermsofthelifecycle(criteria#8):the

requirementsinVBU’smethodologyfortheevidencegenerationpillarexplicitlydefinethe

scopeasfortheproductsentirelife-cycle(i.e.includingpost-licensurestudies).Although

theyarenottheonlypriorities,thefinancialgoals(criteria#8)areincludedinthelead-in

toboththeglobalandcountryplantemplates.

Themethodology,asimplemented,didnotreceivethehighestratingintwodimensions.

Thefirstrelatestotheextenttowhichitisabletofacilitateresourceallocationchoices

betweenalternatives.Theapproachtodevelopamarketaccessplandidnotdirectly

accountforthis.Hence,theassessmentof‘weak’.Thisdoesnotmeanitisanincurable

shortcoming,andinfactthelackofamechanismtoadjudicateresourcingtradeoffsis

partiallyafunctionoftheDELTAtimingandstillbeinginrelativelyearlystagesof

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planning.Astheworkprogressesclosertolaunch(andassumingpositiveclinicaltrial

results),aproceduralmechanismcanbeincorporatedtofacilitateresourcetrade-offsfor

theactivitiesproposedbytheplan.Indeed,oneofthepiecesoffeedbackfromaroundof

internalreviewsrelatedtothisquestionofhowtheresourcessupportingthevarious

proposedactivitieswillbeallocatedandprioritizedifnecessary.

Themethodologydoesnotexplicitlyincludeaprocesstoreviewandrevisestrategy

accordingtochangesinmarketconditions(criteria#4).Thestageddevelopmentprocess

ofglobalandlocalstrategiessomewhataccountsforthis,asdoesthethoroughreviews

fromstakeholdersandultimatelytheglobalprogramteam(GPT)forthedenguevaccine

programatTakeda.Althoughitreceiveda‘moderate’score,thiscanbeimprovedby

specificallymodifyingtheframeworktospecifyprotocolsandperiodicorevent-based

reviewstomakenecessaryadjustments.

3.2.2CritiqueofSmithFramework

AssessingthemarketaccessmethodologyaccordingtoSmith’sframeworkidentified

valuableareasofimprovement.Interestingly,theexperienceofimplementingVBU’s

methodologyoffersperspectivesabouttheSmithframeworkthatmightbeconsideredfor

itsownevolution.Chiefamongtheseistheframework’sfailuretoevaluatetheextentto

whichaplanincorporatesethicalandpoliticaldimensions.Italsoonlyfocusesonan

organization’sfinancialgoals;itdoesnotproposetoholdamarketaccessplanaccountable

foritsdiseaseandpatient-levelimpact.Thisisasubstantialshortcomingforall

organizationsthatwishtocreate,andevaluate,socialimpactbeyondfinancialresults.In

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sum,considerationofthesefactorsinadditiontothoseproposedbySmithwouldproduce

anevenmoreholisticevaluationofagivenmarketaccessstrategy’sstrength.

3.3Keyinsights

Thusfar,theResultssectionfocusedontheprocessandoutcomeoftheDELTAworkto

produceamarketaccessplanforTakeda’sdenguevaccine.Hopefully,thepractical

experienceandevolutionoftheframeworkwillbeusefulforthefieldofmarketaccess

planningasaguideandreferencepointforotherrelevantefforts.Asanintensive

immersionwiththecommercializationteamofalargepharmaceuticalcompany,the

experiencealsoofferedinsightsthatmightbeofvaluetoabroaderfieldofpractice,namely

thatofaccesstomedicinesandglobalhealth.Sixkeyinsightsarepresentedbelow.

3.3.1TherelativedefinitionsofMarketAccessandAccesstoMedicines

TheAnalyticalPlatformestablishedtheworkingdefinitionsforthesetwoconceptsin

section2.1.Inshort,marketaccesstypicallyfocusesonwhatacompanymustdotobringits

producttomarket,whileaccesstomedicinesisconcernedwithenablingotherwise

marginalizedpeopletobenefitfromamedicalproductorservice.Theproceedingsections

offersomethoughtsontheimplicationsandinteractionofthesenotionsafterhavingthe

benefitofcompletingtheDELTAfieldwork.Forconvenienceandclarity,fromhereafterthe

abbreviation“A2M”willbeusedforaccesstomedicines.Alsoinkeepingwiththis

shorthand,theword“medicine”willbeusedasastand-inforthebroadrangeofproducts

(i.e.drugs,diagnostics,vaccines)andmedicalservicesthatfallwithinthescopeofthese

definitions.

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First,someobservationsabouttheirrespectivedefinitionsandhowpotentialareasof

confusionorconflictmightbereconciled.ThedefinitionofA2Mrestsonanexpectation

aboutthestatusquo.Itisfocusedonhowtonarrowagap–eitherreal,oranticipatedin

thecounterfactualwithoutA2Mactivities–thatpreventscertainpeoplefrombenefiting

fromthemedicineinquestion.Incontrast,theconceptualizationofmarketaccessbegins

witha‘blankslate’;itisconcernedwiththedecisionsandactionsacompanycanchooseto

takeinordertomakeitsmedicineavailable.Ifmarketaccesssucceeds,theintendedpeople

willreceivethedrugandotherswillnot.A2Mthereforedependsonthesuccesses,and

failures,ofamarketaccessstrategyinordertodefineitsownobjectives.Thus,A2Mrelies

onmarketaccessandseesitsaimsasfillingintheshortcomingsofmarketaccess.Inthis

light,A2Mcanbeseenasonepartofabroaderandholisticapproachtomarketaccess.This

theoreticalplacementofdefinitionswasconfirmedbytheDELTAwork,whereinA2M

initiatives(suchaspotentialproductdonationsorinitiativestostrengthenbroaderhealth

systems)sitwithintheirdesignatedpillarsaspartofthebroadermarketaccess

methodology.

3.3.2IsMarketAccessjustaprocess?

Anotherimportantinsightarisesfromattentiontohowtheconceptsarepresentedinboth

thefieldofpracticeandacademicliterature.Atfacevalue,A2Mappearsoutcome-oriented

whilemarketaccessisconsistentlypresentedasmoreofaprocess(e.g.“marketaccessis

theprocessbywhich...”).Toresttheinquiryherewouldleaveanimportantrealityhidden.

BothA2Mandmarketaccessareultimatelyconcernedwithoutcomes,andbothhave

significantvaluesandassumptionsassociatedwiththoseoutcomes.Theprocess-oriented

descriptionofmarketaccessispotentiallyproblematicandrequiressomeefforttounpack.

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Thefollowingparagraphselaboratethispointandexploresomeofitsimplicationsforthe

fieldofpractice.

SinceA2Misconcernedwiththegapbetweenaperceivedneedandtheextentofa

medicine’savailability,theoutcomeisreadilyunderstoodtobethenarrowingofsaidgap.

Thisframingquicklydrawsattentiontothevaluesinvolvedwiththisgoal–e.g.whothe

peopleareandthebasis,oftenethical,thatjustifiestheappealfortheiraccesstothe

medicine.Butmarketaccessisalsoconcernedwithoutcomes,regardlessofhowitmaybe

commonlydescribedasaprocess.Inthefinalanalysis,somepeoplewillbenefitfromthe

medicineandotherswillnot–perhapsbecauseacompanydecidesnottotargetthem,a

nationalauthoritywillnotallowregistration,orweaknessandbarriersinthehealth

systempreventitfromreachingtheintendedpeople.Bydescribingmarketaccessasa

process,thecrucialvaluejudgmentsanddecisionsthataremadealongthewaytothese

outcomesrest‘beneaththesurface’,andtheyareprotectedfromcloseexamination.But

theyarestillthere.Tooverlookthesevaluesandtheirresultingoutcomesisparticularly

problematicforafieldsuchasvaccinesbecauseoftheconsequentialhealtheffects;the

outcomesofmarketaccesstovaccinesstandtoimpactthewellbeingofmillionsandeven

billionsofpeople.

Thispointcanbeillustratedbyusingfoodasananalogy.Accordingtotheprevailing

notionsoftheseconcepts,anA2Mapproachwouldessentiallyseektoensurethathungry

peoplecangetnutritiousfood.Whothosepeopleare,howtheirhungerwillbemeasured,

thekindofnutritionthattheyshouldreceive,etc.areallthekindsofquestionsthatmust

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necessarilybeaddressedinordertopursuethisA2Mgoal.Ifmarketaccesswereonly

regardedasaprocess,inthisanalogyitwouldfocusonthevariousstepsinvolvedin

establishingarestaurant.Seenonlyasaprocess,marketaccesswouldeffectivelybea

seriesofstepsthattherestaurantownershoulddo–e.g.runsometastetests,getalicense

fromthelocalfoodinspector,establishacontractwithsuppliers,hirestaff,etc.These

activitiesareimportant,buttheyoffernothingaboutthetypeofrestaurantthatwillor

shouldbeestablished.Forexample,whatistherestaurant’sgoal?Isittoproducehigh

volumefastfood,ortowinaMichelinstar?Theanswermustsuittheenvironmentwithin

whichtherestaurantisestablished.Misalignmentcanleadtotroublingexamplessuchas

‘fooddeserts’,orcountriesthatexportagriculturewhilecarryingadomesticburdenof

malnourishment3.Notethepurposeofexploringthisanalogyisnottoofferanyvalue

judgmentononetypeofrestaurantoranotherinabsoluteterms;rathertheintentionisto

illustratetheimportanceofdistinguishingaprocessfromitsoutcome.Onemustkeepthe

ultimateoutcomeinsightsothatitcanbeunderstood,discussedandsupportedinorderto

bestmeetsociety’sneeds.

ReturningtothespecificworkoftheDELTAprojectwiththisanalogyinmind,aflawless

executionofVBU’smarketaccessmethodologywouldnotinitselfguaranteeanoptimal

marketaccessplan,regardlessofhowsuccessisdefined(e.g.profitability,publichealth

impact,etc.).Indeed,characterizingeachessentialpillarofmarketaccessandgoing

throughtheremainingstepsofthemethodologywouldhelpmaketheresultingstrategy

3Theauthorwishestoacknowledgeandthankprof.PeterBermanforsuggestingtoextendtheanalogyand

illustratethepointwiththesetwoexamples

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comprehensiveandcohesive.Butitdoesnotinitselfdeterminewhattypeofmarketaccess

planwillbedevelopedforthedenguevaccine.Itwastheoreticallypossibletohave

followedthestepsandproducedaplanthatmakesthevaccineonlyavailabletoselective

populationsinhigh-incomecountries.Similarly,thesameapproachcouldhavebeenused

todevelopaplanthatenvisionsaccessforthepoorestpeopleacrossallendemicregions.

Assessingtheattractivenessofthesepossibilitiesdependsonthegoalsthatonemighthold

forthevaccine(e.g.profitability,reducingdiseaseburden,etc.).VBUadoptedaprogressive

approachtomarketaccessbyanchoringitsdefinitionofthetermwiththe“ultimategoalof

achievingapositiveimpactonpublichealth”(99).Butthemethodologytodevelopa

marketaccessstrategydoesnotspecifytheextentofpositiveimpactorincludeprovisions

toweighonecriteriaagainstanotheriftrade-offsmustbemade.

ItshouldbeemphasizedthattheselimitationsarenotacritiqueofVBU’sapproach.Far

fromit.Rather,thepurposeistosetexpectationsforwhatanymethodologytodevelopa

marketaccessplanshouldbereliedontoaccomplish,andwhatisnotreasonabletoexpect.

Theexamplesposedabovefordengueillustratethekindsofquestionsthatdefineamarket

accessstrategy:whatistheobjectiveofthevaccine?Willroll-outfocusononegroupof

peoplemorethananother?Willitprioritizepublichealthimpact,orprofit?Andif

necessaryhowwilltradeoffsbetweenthetwobeevaluated?TheexperienceofthisDELTA

assignmenthasledtothefollowingconclusion:itisnottheroleofamethodologytodefine

whatkindofstrategyitwillproduce.Thatistheroleofleadershipandorganizational

values.

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3.3.3Theroleofleadershipandorganizationalvalues

Itisunreasonabletoexpectamethodologytoguideallofthecomplexethical,strategicand

value-basedtradeoffsthatmustbemadeinordertodecidetheultimateaimforanew

vaccine.Therearefundamentaltenantsandinputsthatshoulddrivethemarketaccess

planningprocess.Torelyontheprocessitselftoproducetheseanswerswouldbecircular;

theymustbedefined,inspiredandhonedbythosewiththevisionforwhatshouldbe

accomplished.Thisisespeciallyimportantfortheleaderswithinanorganizationbutit

doesnothavetoexclusivelycomefromthem.Atitsbest,amethodologycanelucidatethe

tradeoffsbuttheteamandparticularlyitsleadersmustprovidetheguidanceandbe

accountablefortheresults.

Insummary,VBUfollowedasystematicprocesstodevelopitsmarketaccessstrategy.This

dissertationisfocusedonanexplorationofthatprocessbydescribingandanalyzingthe

stepsthatwereinvolvedinitsimplementation.But‘marketaccess’itselfshouldnotbe

regardedasjustaprocess,andtheplanningandexecutionofitsaimsisnotvalue-neutral.

Thefundamentalaimsofmarketaccessareestablishedbytheorganizationanditsleaders.

Asanaside,theexperienceconductingmarketaccessplanningforTakeda’sdenguevaccine

isencouraginginthisregardifonehappenstofavorpublichealthpriorities.Startingfrom

thetop,theTakeda-wideorganizationalvaluesfocusingonthepatient,trust,reputation

andbusiness(105)setthestageforthegoalsofthevaccinetobebalancedandnotover-

emphasizeoneobjectiveattheexpenseofothers.Morespecifically,theprofilesofVBU’s

leadershipandtheorganization’sspecificvisionto“protectthehealthofpeople

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everywherethroughvaccinesthataddressthemostimportantinfectiousdiseases”(21)isa

furtherdeterminantinfavorofamarketaccessstrategyalignedwithpublichealth

priorities.Moreover,themarketaccessmethodologystartswiththerequirementto

articulatethevaccine’sgoals,whichinthecaseofdengueincludemakingasubstantial

publichealthimpact.

Oneexampleshouldsufficetoillustratethepoint,sincethetacticaldetailsofthestrategy

arebeyondthescopeofthisdocument.Ithastodowiththecountriesthatwereidentified

tolaunchthedenguevaccine.RecallthatthesecondstepofVBU’smarketaccess

methodologyistoclassifycountriesintocommonarchetypes.Butthemethodologyitself

doesnotdeterminewhichcountriesshouldbeassessed.Thisstarting-pointwasaninput

fromtheglobalprogramteam(GPT)fordengue.Theabove-mentionedsenseofoptimism

aboutTakeda’sapproachisbasedonthefactthatlowandmiddle-incomecountriesacross

LatinAmericaandAsia-Pacificwereassessedinadditiontothetraditionalmarketsin

EuropeandNorthAmerica.Thisisfavourablefromapublichealthperspectivebecauseit

alignswiththeburdenprofile,anditfollowsthepro-globalhealthtrendforlaunch

sequencingdescribedintheAnalyticalFramework.Thepurposeinhighlightingthis

exampleistoestablishthattheselectedcountrieswerenotdestinedapriori;aseriesof

decisionsandleadershipinputwasinvolvedinordertoarriveatthelistwhichthemarket

accessmethodologythenclassifiedintoarchetypes.

Finally,recallthattheAnalyticalPlatformhighlightedthedifferencebetween‘market

access’and‘accesstomedicines’,andthepotentialforconfusionamongstakeholdersif

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‘access’isusedasashorthand.Thatpossibilitydidnotprovetobeasignificantproblem

duringtheDELTAproject.Althoughthephrase‘access’wasoftenused,itwasforthemost

partclearlyusedandunderstoodtohavetheintendedmeaningof‘marketaccess’.Thisis

likelybecausetheworkatthisstagewaspredominantlyinternaltoVBU–theneedfor

precisionandpotentialformisunderstandingwithexternalstakeholdersremainstobe

seenasimplementationprogressestoincludemoreexternalpartners.

3.3.4Thesignificanceoflanguage

Therelativedefinitionsandtendencytodescribemarketaccessasaprocessarenotthe

onlyimportantnuancesinvolvingthemarketaccessandA2Mconcepts.Despitethe

positioningofA2Masonepartofabroadapproachtomarketaccessestablishedabove,the

fieldsaresometimesconsideredatoddswithoneanother.Tofollowisaseriesof

comparisons,withafocusontheterminologythatistraditionallyusedbytheirrespective

proponents.Eachfieldadoptsacertainvocabularytodiscussitsimportanttopics,andin

somecasestherearedifferencesinhowthesameunderlyingconceptisdescribed.These

differentchoicesindicateimplicitassumptionsandvaluesthateachfieldmightholdabout

itselforhowitperceivestheotherdomain.Theexamplesinfigure8areempiricallybased

ontheexperienceoftheDELTAprojectwithTakedaand5yearsofworkingintheA2M

fieldbeforethat.

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Figure8.AcomparisonofthelanguageusedinPharmaceuticalAccesswork

Thepurposeoffigure8istoofferastartingpointforfurtherinquiryandinvitedeeper

analysisontheuseandpotentialimplicationsofdifferentlanguagebystakeholders

engagedintheworkofglobalaccesstopharmaceuticalproducts.Byarticulatingand

exploringthedifferencesintheirunderlyingvalues,thehopeistofacilitateaproductive

dialoguebetweendifferingperspectiveswherebysuperficialmisunderstandingsowedto

differentlanguagemightbeclarified,andgenuinetensions(ifany)canbecandidly

discussedandnegotiatedinaproductivefashion.

3.3.5Theimportanceofcountryteams

Itwasanilluminatingexperiencetocontributetothedevelopmentofacountry-level

marketaccessplanafterdengue’sglobaldeliverablehadbeendrafted.Aboveall,it

impartedastrongappreciationfortherolethatcountryteamsholdintheprocessof

enablingaccesstoavaccine.TheorientationofVBU’smethodologytowardsthecountry-

levelfortacticaldetailsandexecutionisawelcomefeatureinthisregard.Theglobalteam

triedtokeeptheneedsofthecountryteamfrontofmindthroughoutthedevelopmentof

TraditionalTerminologyA2MPerspective MarketAccessPerspective

HealthTechnology(e.g.vaccine,drug,device)

"Product" "Asset"Aproductistobeused;anassetismeanttoappreciateandhaveitsvalueextracted.

SponsorOrganization "Manufacturer" "Developer""Manufacturer"focuesontheoperationalcostsofproductionanddistrubution,"developer"isassociatedwithrisksandrewardsaccompanyinginnovationandresearch.

Price "Finalprice" "Ex-factoryprice"IfasponsoronlyfocusesontheEx-Factorypriceforitsmarketaccessplanning,thefinalpriceforconsumersmightbeunaffordableafterdistributormarginsareaccounted

FinancialFeasibility "Affordability" "Willingnesstopay"Affordabilityisorientedtowardsalowerprice,whereaswillingnesstopayseekstoidentifythemaximimumpossibleprice.

Purchaser "Buyer" "Payer"Framingasabuyerempowersthepurchaser,whereasdescribingapayerdrawsattentiononwhatisneededasapathtoreleasingfunds.

User "Person" "Patient"Personisarguablymoreempowering,albeitverygeneral;Patienthasconotationsofneedandillness

InsightsandImplicationsUnderlyingconcept

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theglobalplanaccordingtoVBU’smethodology.Anexampleofthiswastheadditionofthe

“availableresources”sectiontothestrategydocument.Itpresentedthetools,trainings

andotherresourcesthatwouldbeavailabletocolleaguesatthecountryleveltosupport

marketaccesswork.Notwithstanding,theexperienceofworkinginonecountryhelpedput

intoperspectivethenaturaltendencyforaglobalplanningexercisetoover-estimatethe

availabilityoflocalhealthdata(e.g.surveillancedata)andunder-appreciatethecomplexity

anddynamismofalocalstakeholdercontext.Thesetakeawaysofferedvaluablefeedback

forsubsequentevolutionsoftheglobalmarketaccessstrategy.

Animportantquestionrelatestothedegreetowhichthecountryteams’incentiveswillbe

alignedwiththoseoftheglobalorganizationaspresentedinthemarketaccessstrategy.It

isstillearlydaystoconcludedefinitively,butsomegeneralobservationscanbeofferedin

thisregard.Thefundamentalincentivesaredirectionallyaligned;namelytheinterestin

enablingtheuptakeofthedenguevaccine.Butthereisthepotentialfornatural

organizationaltrade-offswhenoneconsidersthespecificdetailsofthatvisionandthe

possibilitythatindividualorunit-levelincentivescoulddifferfromtheglobalteam.For

example,thinkingaheadtoprice–thereisaneedforindividualcountryteamstofollow

globalguidanceforthesakeofcoherenceandthepotentialramificationsofonecountry

usingreferencepricing.Followingthisguidancemayinvolveforgoingsomedegreeof

flexibilitytorespondtolocalmarketneedsandconditions.Theseandotherexamplesare

notuniquetodenguevaccinationorTakeda.Theyshouldbemanageablethrough

thoughtfulleadershipandestablishingclearprotocolsforhowareasofpotentialtension

aretobenavigated.Althoughthesestructuralpointswillgraduallybeidentifiedand

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addressed,onethingisalreadyclearfromthisDELTAandthatistheimportanceofcountry

teamsandtheneedforglobalteamstointeracthumblyinrecognitionofthisimportance.

ThistonewasexemplifiedbytheinteractionbetweenTakeda’sglobalteamsandin-

countrycolleaguesforthelocalmarketaccessplanning,anditscontinuationwillproveto

beakeysuccessfactor.Success–byallmetrics–isnotpossiblewithoutthefulland

effectiveengagementofcountryteams.

3.3.6Interactionsbetweenadvancedmarketplanningandclinicaldevelopment

Afinalinsightrelatestotheimportanceofsequencingandkeepingthebroadervaccine

developmentprocessinmindwhiledevelopingamarketaccessstrategy.Inthisinstance,it

relatestothecriticalityofdatafromtheTIDEStrial.Ashasbeenalludedthroughoutthis

document–withouttheconclusivephaseIIItrialresults,finaldecisionsaboutmarket

accessplanningcannotbemade.Thisissimplybecausenearlyeveryconsideration(e.g.

price,potentialimpact,policyneeds,etc.)stemsfromtheproductprofilethatwouldbe

confirmed(ornotconfirmed)bythetrial’ssafetyandefficacyresults.Thishighlightsthe

needtostrikeaninterestingbalance–ontheonehand,thecomplexityandstakesof

activitiesinvolvedinmarketaccessplanningaresosignificantthatwaitinguntilfullresults

tobeginplanningexerciseswouldinvolvedelaystowhenthevaccinewouldbeavailable

forpeople.Inthissense,itisasignofresponsibilityandcommendabledecisiontoinvestin

detailedplanningeffortsforaproductwithanuncertainfutureanddelayedresults.Todo

this,theorganizationmustacceptadegreeofrisk.Itmustalsoproceedwithadegreeof

tentativenessoncrucialareas(theexampleofpricewasofferedabove)inordertoprepare

asmuchaspossible.Itfollowsthattheresultingdeliverablefortheglobaldenguemarket

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accessstrategyisnotafinalizedstaticdocument.Indeed,itisacceptedasa‘living’

documentthatwillevolveandbeadaptedastheexternalenvironmentevolvesanddatais

available.AttheoutsetoftheDELTAprojectthesignificanceofthisdependencyonthetrial

resultswasnotfullyappreciatedandthereforeitishighlightedhereasakeytakeawayfor

considerationforpractitionersundertakingsimilarplanningexercises.

4.Conclusion

4.1Summary

Dengueisasubstantialglobalpublichealththreat.Asafeandeffectivevaccinewouldbea

valuabletoolinthepublichealthresponseagainstthischallenge.Withthisaiminmind,

Takedaisinlate-stageclinicaltrialsforapromisingdenguevaccinecandidate.ThisDELTA

assignmentfocusedondevelopingaglobalmarketaccessstrategyforthisvaccine.The

teamfollowedasystematicmethodologytoproducethisstrategy.Itconsistedofthree

mainsteps:i.)characterizingessentialpillarsofmarketaccess,ii.)categorizinglaunch

countriesintocommonarchetypes,andiii.)developingstrategicdirectionsforeachpillar-

archetypecombination.Adjustmentstothemethodologyweremadeduring

implementation.Thesechangesmadethecountryarchetypeexercisemorepracticaland

theresultsmoreholisticbyaddingapatient-centricdimension.Theglobalstrategy

documentforthedenguevaccineformsthebasisfordevelopingdetailedcountry-level

marketaccessplans.

4.2Proposedtopicsandquestionsforfurtherinquiry

TheDELTAfieldworkwasproductive;itledtoaglobalstrategydocumentthatispoisedto

guidetherolloutofapotentiallyveryimpactfulvaccinetofightdengue.Italsogenerated

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broaderinsightsaboutthepracticeofmarketaccessplanning.Theprogressthatwasmade

wasalsohelpfultoidentifyareasthatwouldbenefitfromfurtherinquiry.

Methodologicalworktoaddresstheshortcomingsofthemarketaccessstrategy

developmentprocess(Section3.2.1)wouldbevaluable.Namely,thiswouldinvolve

evolvingtheframeworktoexplicitlyincludefeaturesthatfacilitatetrade-offdecisionsfor

resourceallocation,anddetermininghowtomodifytheprocesssothatitisresponsiveto

environmentalchanges.

Concerningthebroaderfieldofpractice,thereflectionsontheuseandsignificanceofthe

languageemployedbyvariousstakeholders(section3.3.4)isonlythestartingpointofa

potentiallyrichlineofinquiry.Theobservationsandthemeswouldbenefitfromamore

systematicandthoroughinvestigationofthelanguagethatisusedand,moreimportantly,

howanyconclusionsfromthisworkmightimprovethestateofdiscourse.

Giventhisworkoccurredwhilethevaccinewasstillinclinicaldevelopment,therewould

bebenefitinobservinghowthemethodologyandplanthatitproducedevolvesasclinical

developmentprogressesand(hopefully)commercializationbegins.Mostcrucially,this

couldincludeprovisionstoexpandthemethodologytoevaluatespecificmarketaccess

goalsandresults.ThisexperiencefordenguewasthefirsttimethatVBU’smethodology

hasbeenappliedtodevelopaglobalmarketaccessstrategyforavaccine.Theapplication

ofthisapproachtoothervaccineswillhelpfurtherevaluatetherobustnessofthe

methodologyandaidinitsrefinement.

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6.Appendix

Appendix1:OrganizationChart

*Adaptedfrom“OutlineofNewGlobalOrganization(AsofApril2015)”,availableat

https://www.takeda.com/siteassets/system/newsroom/2014/orgcahrt20140916_en.pngandTakeda

InternalDocument.

Commercial

Medical Affairs & Policy

Operations Quality Assurance

Dev. Business Planning

Discovery

Vaccine Business Unit (VBU) Functional Leads

Legend:

=LocationforDELTAwork

=DirectReporttoglobalPresident&COO

Takeda’sGlobalOrganization*

*Adapted from“OutlineofNewGlobalOrganization(AsofApril2015)”,availableathttps://www.takeda.com/siteassets/system/newsroom/2014/orgcahrt20140916_en.png.ChangesandVBUdetailstobeconfirmedafterstartingDELTAprojectinJune2017.

JapanFinanceHR

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Appendix2:Detailedmetricsforrevisedarchetypeexercise

Variable Definition Scoring Sources

1. Disease Burden

1.1 Incidence Estimated # of dengue cases per 100,000 inhabitants

Non-endemic: < 10 cases / 100,000Endemic: > 10 cases / 100,000

IDCC, UNPD (2015)

2. Readiness

2.1 NITAG Sophistication Degree to which a country meets the 6 basic criteria established by WHO

High: All 6 criteria satisfiedMed: 5/6 criteria satisfiedLow: < 4 criteria satisfied

NITAG Resource Center (2017)

2.2 Level of child immunization coverage

Percentage of the country’s children that are immunized against DTP3 (Diphtheria-tetanus-pertussis)

High: > 95%Med: 87-94% Low: < 87%

WHO Immunization Monitoring& Surveillance (2015)

2.3 Funding Availability

2.3.1 Total Vx $ Total expenditure on vaccines from all sources (US$)

High: Top quartileMed: Quartile 2,3Low: Bottom quartile

WHO Immunization Financing Indicators (2015), UNPD (2015)

2.3.2 Total Vx $ / capita Total expenditure on vaccines from allsources divided by population

WHO Immunization Financing Indicators (2015), UNPD (2015)

2.3.3 Gov. Vx $ / Capita Government expenditure on vaccines (US$) divided by population

WHO Immunization Financing Indicators (2015), UNPD (2015)

2.4 Dengue Vaccine experience

Status of Dengvaxia rollout in the country. Note this variable will be considered as ‘upside only’.

High: Registered and LaunchedMed: RegisteredLow: Not registered

Takeda CI Report (Deallus,2017)

88

Appendix3:ListofAcronyms

Acronym DefinitionA2M AccesstoMedicines

ADE Antibodydependentenhancement

AEFI Adverseeventsfollowingimmunization

CBA CostBenefitAnalysis

CDC America'sCentresforDiseaseControl

CE Cost-effectiveness

CSR CorporateSocialResponsibility

DALY Disabilityadjustedlifeyear

DELTA DoctoralEngagementinLeadershipandTranslationforAction

DOH DepartmentofHealth

GAVI GlobalAllianceforVaccinesandImmunization

GDAC GlobalDengueandAedes-transmittedDiseaseConsortium

GDP GrossDomesticProduct

GPT GlobalProgramTeam

HSS HealthSystemsStrengthening

HTA HealthTechnologyAssessment

Hib Haemophilusinfluenzaetypeb

LMICs LowandMiddleIncomeCountries

NIP NationalImmunizationProgram

NITAG NationalImmunizationTechnicalAdvisoryGroup

PAHO Pan-AmericanHealthOrganization

PPP PublicPrivatePartnership

TAK-003 DevelopmentnameforTakeda'sdenguevaccinecandidate

TIDESTetravalentImmunizationagainstDengueEfficacyStudy

(Takeda’sPhaseIIIefficacytrialforitsdenguevaccinecandidate)

TPP TargetProductProfile

VBU Takeda'sVaccineBusinessUnit

WHO WorldHealthOrganization

89

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