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Introduction of European priority review vouchers to encourage development of new medicines for neglected diseases

Authors:

Abstract

Every year 1 billion people worldwide are affected by traditionally neglected diseases, such as malaria, tuberculosis, leishmaniasis, and lymphatic filariasis, which impose tremendous public health burdens. Governments, foundations, and drug manufacturers have, however, started to support development of new treatments. European Union Member States have been leaders in implementing so-called push mechanisms (payment for drug development) and pull funding (reward for output), such as the advance market commitment, which creates a market for vaccines by guaranteeing prices. We propose an additional step that could be taken to encourage development of medicines for neglected diseases. A priority review voucher scheme, as is already in place in the USA, would reward a manufacturer that developed a new medicine for neglected diseases with a voucher that could be redeemed for priority review of a future medicine, probably a potential blockbuster drug. Unlike the US system a European voucher would also accelerate pricing and reimbursement decisions. This scheme would be likely to provide substantial benefits to voucher holders, society, and public health organisations.
IntroductionofEuropeanPriorityReviewVo ucher stoEncourage
DevelopmentofNewMedicinesforNeglectedDiseases
DavidBRidley
DukeUniversity,Durham,NC,USA,david.ridley<at>duke.edu
AlfonsoCallesSánchez
DukeUniversity,Durham,NC,USAandSpanishPatentOffice,Madrid,Spain
Abstract:Everyyear1billionpeopleworldwideareaffectedbytraditionallyneglecteddiseases,
suchasmalaria,tuberculosis,leishmaniasis,andlymphaticfilariasis,whichimposetremendous
publichealthburdens.Governments,foundations,anddrugmanufacturershave,however,
startedtosupportdevelopmentofnewtreatments.EuropeanUnionMemberStateshavebeen
leadersinimplementingsocalledpushmechanisms(paymentfordrugdevelopment)andpull
funding(rewardforoutput),suchastheadvancemarketcommitment,whichcreatesamarket
forvaccinesbyguaranteeingprices.Weproposeanadditionalstepthatcouldbetakento
encouragedevelopmentofmedicinesforneglecteddiseases.Apriorityreviewvoucherscheme,
asisalreadyinplaceintheUSA,wouldrewardamanufacturerthatdevelopedanewmedicine
forneglecteddiseaseswithavoucherthatcouldberedeemedforpriorityreviewofafuture
medicine,probablyapotentialblockbusterdrug.UnliketheUSsystemaEuropeanvoucher
wouldalsoacceleratepricingandreimbursementdecisions.Thisschemewouldbelikelyto
providesubstantialbenefitstovoucherholders,society,andpublichealthorganisations.
Notice:thisistheauthor'sversionofaworkthatwasacceptedforpublicationinTheLancet.
Changesresultingfromthepublishingprocessmaynotbereflectedinthisdocument.Changes
mayhavebeenmadetothisworksinceitwassubmittedforpublication.Adefinitiveversion
wassubsequentlypublishedinTheLancet,Vol.376,No.9744,September2010.

Introduction
Diseasessuchasmalaria,tuberculosis,leishmaniasis,andlymphaticfilariasisimposesubstantial
healthburdensbutarewidelyneglectedbecausethereislittleincentiveintheprivatemarket
todevelopnewtreatments.1Mostofthe1billionpeopleaffectedbyneglecteddiseaseslivein
lowincomecountries.2Improvementofhealthconditionsindevelopingcountriesisamongthe
UNMillenniumDevelopmentGoals.
Governmentsandfoundationshaverecognisedthedearthofprivatesectorincentivesand
haveprovidedsocalledpushfundsforresearchanddevelopment(fundingfordrug
development)3andpullmechanisms(rewardsforoutput)torewardsuccessfuldevelopment.4
Oneimportantpullmechanismistheadvancemarketcommitment,whichcreatesamarketfor
vaccinesbyguaranteeingprices.5Throughsuchefforts,governmentsoftheEuropeanUnion
(EU)MemberStateshavebeenleadersinencouragingdevelopmentoftreatmentsfor
neglecteddiseases.HereweproposeanewincentivemechanismfortheEU.
Priorityreviewvouchers
Thepriorityreviewvoucherschemeisamarketdrivenincentivethatrewardsdevelopersof
newmedicinesforaneglecteddisease.TheschemeisalreadyavailableintheUSA,with
decisionsbeingmadebytheFoodandDrugAdministration(FDA).ItwasproposedbyDuke
Universityfacultymembers(DBR,HenryGrabowski,andJeffreyMoe)in2006,6becamelawin
2007,andthefirstvoucherwasawardedtoNovartisin2009afterFDAapprovalofCoartem
(artemetherandlumefantrine)forthetreatmentofmalaria.
Inexchangeforregistrationofanewdrugforaneglecteddisease,themanufacturerreceivesa
voucherforpriorityregulatoryreviewofanothermedicine.Thevouchercanbetransferredto
anothercompany.Thedrugtowhichthevoucherisappliedislikelytobeapotential
blockbustertreatment,suchasanLDLcholesterolloweringdrug.Thebenefitofearlier
approvalofsuchadrugcouldbeworthseveralhundredmilliondollarstothevoucherholder.
WeproposetheintroductionofapriorityreviewvoucherschemefortheEU,tobeawardedby
theEuropeanMedicinesAgency(EMA)orEuropeanCommission.Foreachnewneglected
diseasetherapyapproved,thedeveloperwouldbeawardedavoucherforprioritymarketing
authorisationandacceleratedpricingandreimbursementproceduresforamedicineofthe
developer’schoice.ThepricingandreimbursementfeaturediffersfromtheUSversionofthe
programme,whichonlyacceleratesFDAscientificreview;theUSGovernmentplaysasmallpart
innegotiatingpriceswithmanufacturers,whereaspricingandreimbursementnegotiationsin
Europeareimportantandtimeconsumingfeaturesofgovernmentinvolvement.7
Wesuggestthateachawardedvouchercouldbetransferredbetweencompaniesand
organisationsmultipletimes.Thus,theoriginalvoucherrecipientwouldnotneedtodevelop
boththeneglecteddiseasemedicineandthemedicineforwhichthevoucherisused.For
instance,thedeveloperoftheneglecteddiseasemedicinemightbeasmallbiotechcompany,a
foundation,oranacademicinstitution.Thesenonprofitdeveloperscouldusetheproceeds
fromtransferofthevouchertofundadditionalneglecteddiseaseresearchorsupportaccessto
existingmedicines.Thevoucherwouldbereturnedtotheregulatorifthefinalbearerdidnot
fulfillacceleratedassessmentrequirementsattheEMA.TheEMAcouldchargeasupplemental
fee(e.g.,€1–2million)tocoveradditionaladministrativecostsofacceleratedreview.We
estimatethattheaveragevalueoftheEUpriorityreviewvoucherswouldbesimilartothatof
theUSvouchers.6,8,9Theseincentivesshouldatleastmotivatefirmstoensurethatmedicines
forneglecteddiseasesreachlatestageclinicaltrials.
Marketingauthorisation
TwotypesofmarketingauthorisationaregiveninEurope:thatgrantedbymedicinesagencies
atthenationallevel,andEUwideauthorisationgrantedbytheEuropeanCommissionafter
receiptofapositivescientificopinionfromtheEMAandcentralisedscientificassessmentofan
applicationfromthemanufacturer.10Thecentralisedprocedureiscompulsoryforspecific
medicinalproductslistedintheAnnextotheRegulation(EC)726/2004,includingthose
developedundercertainbiotechnologyprocesses,newactivesubstancesfortreatmentof
AIDS,medicinesdevelopedforcancer,diabetes,neurodegenerativedisorders,andviral
diseases,andmedicinesdesignatedorphanstatus.10Forotherproductsthecentralised
procedureisoptionalforsomeandunavailableforothers.10
Accesstothecentralisedapprovalprocessandacceleratedassessmentforthevoucherbearer’s
drugofchoicewouldbegranted,evenifthemedicinewouldnototherwisebeeligiblefor
centralisedoracceleratedassessmentunderArticle10(9)ofRegulation726/2004.Accelerated
assessmentiscurrentlyrareandgenerallyappliesonlytoinnovativemedicinesofmajorpublic
healthinterest.Inthesecases,theEMA’sCommitteeforMedicinalProductsforHumanUse
rendersascientificopinionwithin150days.Inaddition,upto30daysofsocalledclockstops
areallowedduringtheprocesstoenablethesubmissionofadditionalinformationbythe
applicantifitisrequestedbythescientificcommittee.Bycontrast,nonaccelerated
assessmentsmustbecompletedwithin210days,butthereisnolimitontotalclockstoptime.
Theaverageclockstoptimefor1996–2007was151days(table1).
ThecurrentregulatorytimelinesindicatethatacceleratedassessmentatEMAshouldsavethe
manufacturerabout2months.Inpractice,however,thereductionmightbebetween1month
and7months(table1).11,12From1996to2007theaverageactivetimesavedbyaccelerated
medicineswas67daysexcludingclockstoptime,and202daysincludingclockstoptime.
Acceleratedproductsseemconsistentlytorequirelessclock–stoptime,whichhelpsto
maintainacceleratedstatus.
Ifthecentralscientificassessmentispositive,furthertimeisrequiredforcertainadministrative
procedurestobecompletedattheEMAandtheEuropeanCommissionbeforemarketing
authorisationcanbegranted.Thispartoftheprocessdoesnothaveafasttrackprocedure,but
forthemedicinesapprovedfrom2006to2008,administrativetimewasconsistentlylessthan
70days.12
Pricingandreimbursement
Afteradrugreceivesmarketingauthorisation,manufacturersenterthepricingand
reimbursementprocess,whichtakesplaceonacountrybycountrybasis.InEUMemberStates
individualgovernmentsareexpectedtodeterminepricingandreimbursementwithinthe
frameworkoftheTransparencyDirective(Directive89/105/EEC),whichrequiresthatdecisions
betakenwithin180daysofsubmission.13Thisdeadlineisfrequentlyunmet,accordingtothe
EuropeanFederationofPharmaceuticalIndustriesandAssociations.7Manufacturersofgeneric
productshavealsocomplainedaboutdelays,althoughgenericdrugsseemtoreceivepriority
decisionsinmanyEUMemberStates(table2).
Inourproposal,thepriorityreviewvoucherwouldconferacceleratedpricingand
reimbursementdecisionsinEUMemberStates.TheEuropeanCommissionhasexpressed
confidenceinthefeasibilityoffasttrackdecisionsonpricingandreimbursement.14,15SomeEU
MemberStatesalreadygiveprioritytogenericmedicinesororphanmedicinesduringpricing
andreimbursementprocedures.AmendmentoftheTransparencyDirectiveornational
legislationwouldenabletheintroductionofafasttrackprocedure.14InFrance,medicinesales
totalroughly€25.5billion,oraround19%oftheEuropeanmarket.Orphanmedicinesreceive
conditionaldecisionswithin15days,decisionsforgenericmedicinestakeanaverageof75days
andthoseforbrandedmedicinestakeanaverageof312days(table2).Aprioritydecisionof30
daysassociatedwithareviewvoucherwould,therefore,saveanaverageof282daysfor
proprietarydrugs(table2).Alternatively,theaveragetimesavedifthedecisiontimeforgeneric
productswereappliedtoproprietarydrugswouldbe237daysinFrance.AcrossEurope,the
weightedaveragetimesaved(wheretheweightrepresentstheshareofsalespercountry)
wouldbe176daysunderthevoucher30daysystem,or123daysifthereviewtimeforgeneric
productswereappliedtoproprietarydrugs.
Amanufacturerwithapriorityreviewvouchercouldstillchoosetopursuepricingand
reimbursementsequentiallyindifferentcountries.Forexample,themanufacturermightseeka
fasttrackdecisionincountrieswherehigherpricescanbechargedbeforesubmitting
paperworkincountrieswherepricesarelowertomitigatepriceoverspillfromparalleltrade
andreferencepricing.16
Wehavecalculateddifferencesbetweenstandardreviewandacceleratedreviewtimesfor
registrationandreimbursementdecisions.Weusedatafromregistration(table1)andpricing
andreimbursement(table2)toestimatetwoscenarios(table3).
Effectivepatentlife
Apatenttermtypicallybeginslongbeforeamedicineisapproved.IntheUSA,theHatch
WaxmanActrestorestimelostattheFDAupto5years,andtheeffectivepatenttermis
extendedupto14years.EUMemberStatesalsoextendthepatentprotectiontimetoaccount
fortimelostindevelopmentandreview.ThelimitofextensionintheEUis5years,andthe
combineddurationofthepatentandsupplementaryprotectionrarelyexceeds15years;17
termsmightbeextendedto5.5yearstorewardmanufacturersthathavetestedapatented
medicineinchildren.18Unlikepatenttermextensions,priorityreviewvoucherswillnotdelay
thegenericentrydatebutwillextendtheeffectivepatentterm.
Giventhecapontimerestored,medicinesthattakealongtimeinclinicaltestingwillstillhave
5yearsofpatentliferestoredandthevoucherwillnotchangethedateofgenericentry.By
contrast,drugswithfastclinicaltestingwillhavefewerthan5yearsofpatentliferestored.By
speedingregulatoryreviewfordrugswithfastclinicaltesting,thevoucherwouldtypicallybring
forwardthedateofgenericentry.
UnderourproposedschemesometimesavedinacceleratedreviewbytheEMAcouldbe
addedtotheeffectivepatenttermofthemedicine.Alltimesavedfromexpeditiouspricingand
reimbursementdecisionswouldbeaddedtotheeffectivepatentterm.
Valueofacceleratedassessment
Manufacturershighlyvalueacceleratedassessmentbutitisrare.Forinstance,in2006
manufacturersfiled13requestsforacceleratedassessmentatEMAbutonlyfourweregranted
accesstotheacceleratedsystem,andtwoofthesefourwerelaterrevertedtostandard
procedure.19Manufacturersdesirefastdecisionsbecauseearlyentrybringsforwardavailability
inrelationtocompetitors'drugs,enablesearliersales,andlengthenstheeffectivepatent
protectedtimeonthemarket(figure).8Genericentryisnot,however,delayed.Apriority
reviewvoucherschemewouldmaketheadvantagesoffastdecisionsavailabletomore
manufacturers.
Toestimatethepotentialvalueofapplyingapriorityreviewvouchertoatopsellingmedicine
intheEU,weusedsalesdataforfivetopsellingdrugslaunchedinthelate1990s:Enbrel
(etanercept,Immunex,Seattle,WA,USA),Lipitor(atorvastatin,Pfizer,NewYork,NY,USA),
Plavix(clopidogrel,SanofiAventis,Paris,France),Seretide(fluticasone,GlaxoSmithKline,
Greenford,UK),andZyprexa(olanzapine,EliLilly,Indianapolis,IN,USA).Datawereprovidedby
IMSSpaininMadrid.Weincludedsalesfiguresfrom20countries:Austria,Belgium,Czech
Republic,Denmark,Finland,France,Germany,Greece,Hungary,Ireland,Italy,Netherlands,
Norway,Poland,Portugal,Slovakia,Spain,Switzerland,Turkey,andtheUK.Thislistincludes
threenonEUMemberStates(Norway,Switzerland,andTurkey)andexcludestenMember
States,butcontributesareasonableestimateofsalesintheEU.Wecalculatedvaluesin
constantUS$bychoosingtheeuro–dollarexchangerateforMarch31,2009.
Wecalculatedthevalueofshiftingsalesforwardasfollows:
value=AP(1–tax)NPV((1+DR)^(ST–AT)–1)/(1+DR)^WT
(APmeansapprovalprobability,NPVmeansnetpresentvalue,DRmeansdiscountrate,ST
meansstandardtime,ATmeansacceleratedtime,andWTmeanswaittime).Weassumeda
68.5%probabilityofapproval,whichwastheaveragevalueforasampleof68drugssubmitted
totheFDAinthe1990s.20Thisestimateisconservativebecausethe2008EMAannualreport
suggestsahigherprobabilityofsuccessintheEU12andbecausemanufacturersarelikelytobe
confidentinthevalueandlikelihoodofapprovalformedicinessubmittedunderthevoucher
system.Weappliedan11%discountrate,whichwasderivedfromindustryresearchfindings
andreflectstheexpectedreturnthatinvestorsforegowhentheyinvestinpharmaceutical
developmentinsteadofanequallyriskyportfoliooffinancialsecurities.20Weassumedthatthe
waittimebetweenacquiringavoucherandapprovalwouldbe1year,andweassumedtaxesof
30%.Thevalueofshiftingsalesforwardwas$20millionpermonth.
Wecalculatedthevalueofextendingeffectivepatentlifeasfollows:
value=AP(1–tax)sales/(1+DR)^years
(APmeansapprovalprobabilityandDRmeansdiscountrate).Thediscountandtaxratesand
probabilityofapprovalremainedasabove.Weassumedthattheadditionalsaleswouldoccur
11yearsafterbrandedlaunchandestimatedthattheadditionalsaleswouldbe$200million
permonth,accordingtotheaforementionedsalesdata.Thenetpresentvalueofextended
patentlifewasroughly$30millionpermonth,butinrealitythefirstmonthwouldbe
somewhatmorevaluablethanthe12thmonth.
Weassumedthattheassessmenttimefallsfrom210to150days,aspertheEMA’scurrent
acceleratedschedule,andestimatedtimesavingsof2monthsforassessment.Weestimated
thatanadditional4monthswouldbesavedduringpricingandreimbursementassessmentif
vouchermedicineswerereviewedatthecurrentaveragerateofgenericmedicines(table3).
These6monthssavedwouldbeworth$120millionfromearlysalesandUS$180millionfor
additionalsalesachievedunderextendedeffectivepatentlife,yieldingatotalvalueof$300
million.
Thevaluesaboveareaveragesandthepotentialvalueofpriorityreviewvoucherswillvary
widely.Forexample,ifallreviewtimesforapplicationsapprovedin1996–2007wereusedto
calculatedifferences,acceleratedreviewwouldlowertheoverallassessmenttimebyaround
12months(table3).Iftheaverageworthofthevoucherbasedonmovingsalesforwardand
extendingeffectivepatentlifewas$50millionpermonth($20millionplus$30million),
accelerationof1yearcouldbeworthatotalof$600million($240millionforearlysalesplus
$360millionforpatentextension;table3).Conversely,intheconservativescenario(scenario2
intable3)weassumenocorrelationbetweenacceleratedreviewandclockstoptime(taking
36daysforbothacceleratedandnonacceleratedratherthanthenonacceleratedaverageof
133days)andnegligibletimesavedforpricingandreimbursement.Ifonlyapplications
approvedin2007wereused,accelerationwouldbeonly1.5monthsandthetotalworthwould
beonly$75million($30millionforearlysalesplus$45millionforpatentextension;table3).In
theUSA,thepriorityreviewvoucherhasbeenestimatedtobeworthseveralhundredmillion
USdollarsperproduct.6,8SalesinEuropeareonlyabout75%ofthoseintheUSA,butthe
expectationthatthevalueofvoucherswillbesimilarinbothregionsisreasonable,owingto
thehighpotentialforearlypricingandreimbursementinEurope.
Severalsourcesofadditionalvalueformanufacturersthatspentthevoucherareomittedfrom
thisanalysis.First,manufacturersmightvaluethecompetitiveadvantagefromlaunchingahead
oforclosertoarival(figure).Second,manufacturersmightvalueefficiencyassociatedwiththe
centralisedapprovalprocess,whichwouldnotbeavailableforsomemedicineswithoutthe
voucher.
Societycouldbenefitfromearlieraccesstothepotentialblockbusterforwhichthevoucheris
used.Inasimpleeconomicmodeloflineardemand,thesurplus(theamountthatconsumers
arewillingtopayminustheamountitcostsmanufacturerstosupplyadditionalunits)issplit
betweenmanufacturersandconsumersataratioof2:1.Wedonotruleoutthepossibility,
however,thatgovernmentsandprivateinsurerscouldpaypricesthatexceedaproduct’svalue,
butthisissueisbroaderthancanbeaddressedhere.Finally,theanalysisdoesnotaccountfor
theconsiderableadvantagetosocietyofdevelopingnewmedicinesthatreducetheburdenof
neglecteddiseases.
Thevalueofthevoucherissensitivetovariousinfluences,suchastheprobabilityofapproval
andrisesintaxanddiscountrates.Anyofthesefeaturescouldlowertheworthofmovingsales
forward.However,asubstantialreductionintheapprovalprobabilityisimprobable,giventhat
manufacturerswouldbelikelytoapplyvoucherstoproductswithprobabilityabovethemean.
Alternativevoucherschememodels
Weproposethatpriorityreviewvouchersbeappliedtobrandedmedicines,buttheycouldbe
extendedtogenericproducts,includingfollowonbiologics.Asanotheralternative,ratherthan
usethepriorityreviewvoucherasapullmechanism,voucherscouldbeauctionedandthe
proceedsusedtofundpushmechanisms.21Anadvantageofauctioningandpushfundingisthat
uncertaintyinoutcomesandwaitingtimescouldbediminishedforthedrugdeveloper.A
disadvantage,however,isthattheuncertaintyandwaitingwouldbetransferredtosociety.
Whetherpushorpullfundingisbetterisunclear,butbothareusefulmethodstomotivate
developmentofnewmedicinesforneglecteddiseases.
Limitations
TheproposedEUvoucherschemehaslimitationssimilartothoseintheUSsystem.6,8,22–24First,
thevalueofthevouchermightbetoogenerousifitrewardsresearchthatwouldbedone
anyway,butthisfeatureisseenwithotherincentives,suchasrewardingcharitabledonations
withtaxdeductionseventhoughsomeofthedonationswouldhavebeenmadeanyway.Policy
makerscouldconsider,amongotherthings,limitingvouchereligibilitytomoleculesthathad
notpreviouslybeenapprovedinEuropeandhadnotbeenapprovedintheUSAorJapanfor
morethan2yearsbeforethefilingoftheapplicationinEurope.
Second,andconversely,thevalueofthevouchermightbetoosmall.Diseaseswithsubstantial
publichealthburdensmeritsizeableresources.Thepriorityreviewvouchershouldnotbea
substituteforotherincentives.
Third,althoughpriorityreviewvouchersmightmotivatedevelopmentofnewtherapies,they
wouldnotpayforaccesstothetherapies.Adeveloperthatearnsavouchercouldsellthe
voucherandusethemoneytobroadenaccesstothetherapy.Alternatively,fundingfrom
governmentsorfoundationsmightbeneededtoensureaccesstomedicines.TheGlobalFund
toFightAIDS,TuberculosisandMalaria,forexample,providesbillionsofdollarsinfunding
worldwideforaccesstomedicines.
Fourth,acceleratedreviewcouldtieupEMAresources.Tocompensatefortheadditional
burdenintheUSA,voucherbearersarerequiredtogive1year’snoticeofintenttousea
voucherandmustpayauserfee.
Fifth,thereisapossibilitythatacceleratedassessmentwouldcompromisesafety.Although
acceleratedreviewwouldnotshortenorotherwiseweakenclinicaltestingrequirements,
regulatorswouldhavelesstimetoassessthepaperworkthaninstandardreviewperiods.25–27
Finally,authoritiesmightignorevouchersandstillmakeslowdecisions.IntheUSA,reviewfor
prioritydrugssometimestakesmorethan6months.Whateverthedurationoftheprocess,
however,thevoucherisstillvaluableifitshortensreviewtime.Forpricingandreimbursement
certainauthorities,suchastheFrenchGovernment,haveshownanabilitytogreatlyincrease
thespeedofdecisions.Forregulatoryreview,authoritiescouldchargeanadditionaluserfee.
Themanufacturer,theglobalhealthcommunity,andpoliticalleaderswillallbeinterestedin
seeingthatauthoritiesrespectthevoucher.
Conclusion
Europeangovernmentshavemadesubstantialcontributionstoresearchanddevelopmentof
medicinesfororphanandneglecteddiseases.Theintroductionofapriorityreviewvoucher
schemeintheEUsimilartothatintheUSAwouldbeausefuladditionalcontribution.Likethe
USversion,aEuropeanvoucherwouldaccelerateregulatorydecisionsfornewdrugs.Unlike
theUSversion,aEuropeanvoucherwouldalsoacceleratepricingandreimbursement
decisions.Theuseofsimilarsystemsinthetworegionscouldhelptoexpandincentivesfor
developingnewtreatmentsforneglecteddiseases.
Contributors
Bothauthorscontributedtothewriting,review,andeditingofthisarticle.
Conflictsofinterest
Inthepast3yearsDBRhasreceivedconsultancyfeesfromGenentechinrelationtofollowon
biologics,experttestimonyfeesfromSandozinrelationtogenericdrugpricing,andan
honorariumfromPhRMAforparticipatingataconference.ACSdeclaresthathehasno
conflictsofinterest.
Acknowledgments
DBRwasinvolvedintheoriginalresearchfortheUSvoucher,whichwasfundedbythe
GlaxoWellcomeFoundationandDukeUniversity’sCenterfortheAdvancementofSocial
Entrepreneurship.WethankJeffreyMoe,DamonSeils,JiaYao,NinaYoshimura,andthe
reviewersandeditorsforhelpfulcomments.
References
1TrouillerP,OlliaroP,TorreeleE,OrbinskiJ,LaingR,FordN.Drugdevelopmentforneglected
diseases:adeficientmarketandapublichealthpolicyfailure.Lancet2002;259:2188–94.
2DepartmentofControlofNeglectedTropicalDiseases.Neglectedtropicaldiseases:hidden
successes,emergingopportunities.Geneva:WorldHealthOrganization,2009;
http://whqlibdoc.who.int/publications/2009/9789241598705_eng.pdf(accessedJune8,
2010).
3MoranM,GuzmanJ,RoparsAL,etal.Neglecteddiseaseresearchanddevelopment:how
mucharewereallyspending?PLoSMed2009;6:e30.
4TowseA,KettlerH.Advancepriceorpurchasecommitmentstocreatemarketsfortreatments
fordiseasesofpoverty:lessonsfromthreepolicies.BullWorldHealthOrgan2005;83:301–
07.
5BerndtE,GlennersterR,KremerM,LeeJ,LevineR.Advancemarketcommitmentsfor
vaccinesagainstneglecteddiseases:estimatingcostsandeffectiveness.HealthEcon2007;16:
491–511.
6RidleyDB,GrabowskiHG,MoeJL.Developingdrugsfordevelopingcountries.HealthAff
(Millwood)2006;25:313–24.
7PatientsW.A.I.T.Indicatorphase8Report.EuropeanFederationofPharmaceuticalIndustries
andAssociations,2007;http://www.efpia.eu/Content/Default.asp?PageID=559&DocID=4900
(accessedJuly14,2010).
8GrabowskiHG,RidleyDB,MoeJL.Priorityreviewvoucherstoencourageinnovationfor
neglecteddiseases.In:EgglestonK,ed.Prescribingculturesandpharmaceuticalpolicyinthe
AsiaPacific.Washington,DC:BrookingsInstitutionPress,2009.
9MathenyJ,SmithB,CourtneyB,MairM.Drugandvaccinedevelopmentforinfectious
diseases:thevalueofpriorityreviewvouchers.ClinPharmacolTher2009;85:571–72.
10Regulation(EC)No726/2004oftheEuropeanParliamentandoftheCouncilof31March
2004layingdownCommunityproceduresfortheauthorisationandsupervisionofmedicinal
productsforhumanandveterinaryuseandestablishingaEuropeanMedicinesAgency.
EuropeanCommission,2009;http://ec.europa.eu/health/files/eudralex/vol
1/reg_2004_726_cons/reg_2004_726_cons_en.pdf(accessedJune8,2010).
11PinheiroMH.SpecifickeyprovisionsofEUNMLfacilitatingrapidaccesstomedicines.EMEA
NMLImplementation.Feb3,2006;http://www.adediem.com/docs/03MH%20Pinheiro%20
%20ADEDIEM%20030206.ppt(accessedJune8,2010).
12AnnualreportoftheEuropeanMedicinesAgency2008.EuropeanMedicinesAgency,July,
2009;http://www.emea.europa.eu/pdfs/general/direct/emeaar/AnnualReport2008.pdf
(accessedJune8,2010).
13EuropeanCommission.EUDirective89/105/EECrelatingtothetransparencyofmeasures
regulatingthepricingofmedicinaIproductsforhumanuseandtheirinclusioninthescopeof
nationalhealthinsurancesystems.OfficialJournaloftheEuropeanUnion1989;L040:8–11.
14Paragraph1434ofthePharmaceuticalInquiryFinalReport.EuropeanCommission,July,
2009;http://ec.europa.eu/competition/sectors/pharmaceuticals/inquiry/staff_working_
paper_part1.pdf(accessedJune8,2010).
15HighLevelPharmaceuticalForum2005–2008.Finalconclusionsandrecommendations.
EuropeanCommission,November,2008;
http://ec.europa.eu/pharmaforum/docs/final_conclusions_en.pdf(accessedJune8,2010).
16DanzonP,WangYR,WangL.Theimpactofpriceregulationonthelaunchdelayofnew
drugs.HealthEcon2005;14:269–92.
17Article13ofCouncilRegulation(EEC)No1768/92of18June1992concerningthecreationof
asupplementaryprotectioncertificateformedicinalproducts.EuropeanCommission,Jan26,
2007;http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:
1992R1768:20070126:EN:PDF(accessedJune8,2010).
18CallesSánchezA.ImplementingpaediatricextensionstoSPCs:marketingauthorizationin‘all
MemberStates’.OxfordUniversityJIntellectPropLawPract2009;4:305–06.
19EuropeanMedicinesAgency.EMEAconcludesfirstacceleratedassessmentforamedicine
forhumanuse.EuropeanMedicinesAgency,April27,2007;
http://www.emea.europa.eu/pdfs/human/press/pr/18487607en.pdf(accessedJune8,2010).
20DiMasiJA,HansenRW,GrabowskiHG.Thepriceofinnovation:newestimatesofdrug
developmentcosts.JHealthEcon2003;22:151–85.
21PharmaceuticalR&DPolicyProject.Fasttrackoptionsasafundraisingmechanismtosupport
R&Dintoneglecteddiseases.LondonSchoolofEconomics,January,2005;
http://www.who.int/intellectualproperty/submissions/Mary.Moran2.pdf(accessedJune8,
2010).
22KesselheimA.Drugdevelopmentforneglecteddiseases—thetroublewithFDAreview
vouchers.NEnglJMed2008;359:1981–83.
23MoeJ,GrabowskiH,RidleyD,KesselheimA.FDAreviewvouchers.NEnglJMed2009;360:
837–38.
24SonderhomJ.Indefenseofpriorityreviewvouchers.Bioethics2009;23:413–20.
25CarpenterD,ZuckerE,AvornJ.Drugreviewdeadlinesandsafetyproblems.NEnglJMed
2008;358:1354–61.
26NardinelliC,LanthierM,TempleR,CarpenterD.Drugreviewdeadlinesandsafetyproblems.
NEnglJMed2008;359:95–98.
27GrabowskiH,WangY.DoFasterFoodandDrugAdministrationdrugreviewsadverselyaffect
patientsafety?Ananalysisofthe1992PrescriptionDrugUserFeeAct.JLawEcon2008;51:
377–406.

  Durationsofaccelerated
review(days)
Averagedurationsfornon
acceleratedreviewperyear
Yearof
scientific
opinion
Active
time
Total
clockstop
time
Total
review
time
Active
time
Totalclock
stoptime
Total
review
time
Norvir(ritonavir,Abbot,USA)199669069
184121305
Crixivan(indinavir,Merck,
USA)1996851297
Zerit(stavudine,BristolMyers
Squibb,USA)19961500150
Combivir(lamivudine,
zidovudine,GlaxoSmithKline,
UK)
19971190119
182122304
Viramune(nevirapine,
BoehringerIngelheim,
Germany)
19971250125
Kaletra(lopinavir,ritonavir,
Abbot,USA)20001450145177174351
HBVAXPRO(SanofiPasteur,
UK)2001701787
184158342
Viread(tenofovir,Gilead
Sciences,USA)20018363146
Glivec(imatinib,Norvatis,
Switzerland)20011190119
Fuzeon(enfuvirtide,
HoffmannLaRoche,USA)200312128149191200391
Soliris(eculizumab,Alexion
Pharmaceuticals,USA)200714736183
173133306
Isentress(raltegravir,Merck,
USA)200714135176
Average19962005 10912121184155339
Average20062007 14436180173133306
Average19962007 11516131182151333
Averagesarecalculatedwitheachyearreceivingequalweight.Thetwotimeperiodsof1996
2005and200607areusedbecausetheEuropeanUnionformallyimplementedaccelerated
assessmentin2006.Sources:EMAAnnualReports19962007,EuropeanUnionMember
States,Pinheiro,11andthe2008EuropeanPublicAssessmentReport.12
Table1:Europeanacceleratedmarketingauthorisationreviewtimesforbrandeddrugs
versusaveragenonacceleratedreviewtimesin1996–2007
Pricingandreimbursement
period(days)Timesaved(days)
Totalmedicine
sales(€millions)
Branded
drugGenericdrug
Ifassessedin
<30days
(voucher
system)
Ifassessedas
agenericdrug
Austria3701803401902,736
Belgium5031804733233,932
Czech28990259199542
Denmark811451671,860
Finland15174121771,848
France3127528223725,501
Germany000025,241
Greece2431202131235,503
Hungary351903212611,955
Ireland833053531,902
Italy33312030321316,734
TheNetherlands180601501204,616
Norway13213010221,360
Poland214180184344,237
Portugal137111107263,490
Slovakia42640039626846
Spain2719024118113,209
Switzerland18018015002,726
UK000014,493
Total  132,731
Weightedaverage
forallcountries
(days)
19774176123
Table2.PricingandreimbursementtimeinEurope
Sources:W.A.I.T.indicator7andapresentationbytheEuropeanGenericMedicinesAssociation
(PerryG.Slide35,initialspeech.EuropeanGenericMedicinesAssociationAnnualAssembly,
Barcelona,May4,2009).
Scenario1Scenario2
Standard
review
Accelerated
review
Standard
review
Accelerated
review
Beforemarketentry
Activetime(days)(fromTable
1)
182 115 173 144
Clockstoptime(days)(from
Table1)
151 16 36 36
Administrativetime(days)60 60 60 60
Priceandreimbursement
(days)(fromTable2)
197 30 197 180
Totaltime(days)590 222 466 420
Aftermarketentry
Valuefromearliersales
(US$m)assuming
US$20m/month
NA 240 NA 30
Valuefromlongersales
(US$m)assuming
US$30m/month
NA 360 NA 45
Table3.Timesavedandresultingvalue
*TakesintoaccountreviewtimesforallapplicationsforapprovalgrantedintheEUin1996–
2007inyearsthatatleastonedrugreceivedacceleratedreview(n=234),includingclockstop
timeandassumingapriceandreimbursementscheduleof30days.
†TakesintoaccountgrantedapprovalintheEUin2006–07(n=58)andassumesnosavingin
clockstoptime.
‡AssumesvouchervalueofUS$20millionpermonth.
§AssumesvouchervalueofUS$30millionpermonth.
Figure:Priorityreviewvouchervalueisgainedfromthreemainsources
(1)Earliersales.(2)Increaseddurationofsalesunderpatentprotectionowingtoearlier
introductiontothemarket.(3)Highersalesfromearlieravailabilitycomparedwithrivals'
similardrugs.
0
(2) Longer
(1) Earlier
(3) Higher
Sales
Months
... Discussions about introducing a PRV programme in Europe began a decade ago 109 ...
Technical Report
Full-text available
Deutsche Stiftung Weltbevölkerung (DSW) is an international development organisation, which focuses on the health, needs, and potential of the largest youth generation in history. Our objective is to empower young people, especially young women and girls, by creating demand for and access to youth-friendly health information and services, including modern contraceptives, and by securing the right to bodily autonomy. With offices in Europe and East Africa, we achieve this through a combination of youth-oriented programmes and gender transformative advocacy that also champions global health, including investments in research and innovation to fight poverty-related and neglected diseases and to foster women's health. For more information please visit www.dsw.org/en/eu/ Deutsche Stiftung Weltbevölkerung (DSW)
... 6 Our proposition is a contemporary adaptation of earlier proposals presented for the USA in 2006 2 and for the EU in 2010. 7 An update is warranted due to four critical developments. First, the EU's augmenting involvement in health policies facilitates updated strategies. ...
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Introduction Neglected diseases are a significant global health challenge. Encouraging the development of therapeutics and vaccines for these diseases would address an important unmet medical need. We propose a priority review voucher programme for the European Union (EU). The developer of a drug or vaccine for a neglected disease would receive a voucher for accelerated assessment of a different product at the European Medicines Agency (EMA). Methods This study uses retrospective observational data to estimate the potential commercial value of the proposed voucher programme using a five-step approach: (1) estimating the time saved in the EMA accelerated regulatory review; (2) gauging time reductions in accelerated pricing and reimbursement decisions by EU member states; (3) selecting 10 high-revenue products launched between 2015 and 2020 representing typical voucher users; (4) analysing IQVIA MIDAS sales data for the selected products and (5) calculating the net present value (NPV) of the voucher based on the 10 products. Results The accelerated EMA review would reduce regulatory time by an average of 182 days. Additionally, products could save more than a year in many member states through an expedited 120-day pricing and reimbursement review. The estimated NPV of regulatory acceleration by two quarters would be €100 million. In addition, if France, Italy and Spain reviewed pricing and reimbursement in only 120 days, then the value would double. Conclusion An EU voucher estimated at more than €100 million, coupled with a US$100 million counterpart, offers a meaningful incentive for novel product development. However, the voucher programme should be part of a comprehensive strategy for tackling neglected diseases, rather than a standalone solution.
... Supporters (mostly sponsors and patient advocacy groups), argue that the program has given patients therapeutics that otherwise may not have made it to market [11][12][13][14]. There is even a push to develop a similar program in Europe and to extend the program to other disease areas such a neonatal therapies [14,15]. Detractors (mostly the FDA and some academics) believe the program is a burden on the FDA, disrupts the government's ability to set public health priorities, does not incentivize the development of novel drugs, and has a high potential for misuse [16][17][18][19][20][21]. ...
... Instead, they have tended to focus on the value of one effect, such as having earlier sales [1,11] or capturing market share from competitors. [12] Furthermore, we updated previous research that based the value of the voucher on standard FDA regulatory review times that exceed recent observations. ...
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