Content uploaded by David B Ridley
Author content
All content in this area was uploaded by David B Ridley on May 26, 2021
Content may be subject to copyright.
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
leadersinimplementingso‐calledpushmechanisms(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
low‐incomecountries.2Improvementofhealthconditionsindevelopingcountriesisamongthe
UNMillenniumDevelopmentGoals.
Governmentsandfoundationshaverecognisedthedearthofprivate‐sectorincentivesand
haveprovidedso‐calledpushfundsforresearchanddevelopment(fundingfordrug
development)3andpullmechanisms(rewardsforoutput)torewardsuccessfuldevelopment.4
Oneimportantpullmechanismistheadvancemarketcommitment,whichcreatesamarketfor
vaccinesbyguaranteeingprices.5Throughsuchefforts,governmentsoftheEuropeanUnion
(EU)MemberStateshavebeenleadersinencouragingdevelopmentoftreatmentsfor
neglecteddiseases.HereweproposeanewincentivemechanismfortheEU.
Priorityreviewvouchers
Thepriorityreviewvoucherschemeisamarket‐drivenincentivethatrewardsdevelopersof
newmedicinesforaneglecteddisease.TheschemeisalreadyavailableintheUSA,with
decisionsbeingmadebytheFoodandDrugAdministration(FDA).ItwasproposedbyDuke
Universityfacultymembers(DBR,HenryGrabowski,andJeffreyMoe)in2006,6becamelawin
2007,andthefirstvoucherwasawardedtoNovartisin2009afterFDAapprovalofCoartem
(artemetherandlumefantrine)forthetreatmentofmalaria.
Inexchangeforregistrationofanewdrugforaneglecteddisease,themanufacturerreceivesa
voucherforpriorityregulatoryreviewofanothermedicine.Thevouchercanbetransferredto
anothercompany.Thedrugtowhichthevoucherisappliedislikelytobeapotential
blockbustertreatment,suchasanLDL‐cholesterol‐loweringdrug.Thebenefitofearlier
approvalofsuchadrugcouldbeworthseveralhundredmilliondollarstothevoucherholder.
WeproposetheintroductionofapriorityreviewvoucherschemefortheEU,tobeawardedby
theEuropeanMedicinesAgency(EMA)orEuropeanCommission.Foreachnewneglected‐
diseasetherapyapproved,thedeveloperwouldbeawardedavoucherforprioritymarketing
authorisationandacceleratedpricingandreimbursementproceduresforamedicineofthe
developer’schoice.ThepricingandreimbursementfeaturediffersfromtheUSversionofthe
programme,whichonlyacceleratesFDAscientificreview;theUSGovernmentplaysasmallpart
innegotiatingpriceswithmanufacturers,whereaspricingandreimbursementnegotiationsin
Europeareimportantandtime‐consumingfeaturesofgovernmentinvolvement.7
Wesuggestthateachawardedvouchercouldbetransferredbetweencompaniesand
organisationsmultipletimes.Thus,theoriginalvoucherrecipientwouldnotneedtodevelop
boththeneglected‐diseasemedicineandthemedicineforwhichthevoucherisused.For
instance,thedeveloperoftheneglected‐diseasemedicinemightbeasmallbiotechcompany,a
foundation,oranacademicinstitution.Thesenonprofitdeveloperscouldusetheproceeds
fromtransferofthevouchertofundadditionalneglected‐diseaseresearchorsupportaccessto
existingmedicines.Thevoucherwouldbereturnedtotheregulatorifthefinalbearerdidnot
fulfillacceleratedassessmentrequirementsattheEMA.TheEMAcouldchargeasupplemental
fee(e.g.,€1–2million)tocoveradditionaladministrativecostsofacceleratedreview.We
estimatethattheaveragevalueoftheEUpriorityreviewvoucherswouldbesimilartothatof
theUSvouchers.6,8,9Theseincentivesshouldatleastmotivatefirmstoensurethatmedicines
forneglecteddiseasesreachlate‐stageclinicaltrials.
Marketingauthorisation
TwotypesofmarketingauthorisationaregiveninEurope:thatgrantedbymedicinesagencies
atthenationallevel,andEU‐wideauthorisationgrantedbytheEuropeanCommissionafter
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,upto30daysofso‐calledclockstops
areallowedduringtheprocesstoenablethesubmissionofadditionalinformationbythe
applicantifitisrequestedbythescientificcommittee.Bycontrast,non‐accelerated
assessmentsmustbecompletedwithin210days,butthereisnolimitontotalclock‐stoptime.
Theaverageclock‐stoptimefor1996–2007was151days(table1).
ThecurrentregulatorytimelinesindicatethatacceleratedassessmentatEMAshouldsavethe
manufacturerabout2months.Inpractice,however,thereductionmightbebetween1month
and7months(table1).11,12From1996to2007theaverageactivetimesavedbyaccelerated
medicineswas67daysexcludingclock‐stoptime,and202daysincludingclock‐stoptime.
Acceleratedproductsseemconsistentlytorequirelessclock–stoptime,whichhelpsto
maintainacceleratedstatus.
Ifthecentralscientificassessmentispositive,furthertimeisrequiredforcertainadministrative
procedurestobecompletedattheEMAandtheEuropeanCommissionbeforemarketing
authorisationcanbegranted.Thispartoftheprocessdoesnothaveafast‐trackprocedure,but
forthemedicinesapprovedfrom2006to2008,administrativetimewasconsistentlylessthan
70days.12
Pricingandreimbursement
Afteradrugreceivesmarketingauthorisation,manufacturersenterthepricingand
reimbursementprocess,whichtakesplaceonacountry‐by‐countrybasis.InEUMemberStates
individualgovernmentsareexpectedtodeterminepricingandreimbursementwithinthe
frameworkoftheTransparencyDirective(Directive89/105/EEC),whichrequiresthatdecisions
betakenwithin180daysofsubmission.13Thisdeadlineisfrequentlyunmet,accordingtothe
EuropeanFederationofPharmaceuticalIndustriesandAssociations.7Manufacturersofgeneric
productshavealsocomplainedaboutdelays,althoughgenericdrugsseemtoreceivepriority
decisionsinmanyEUMemberStates(table2).
Inourproposal,thepriorityreviewvoucherwouldconferacceleratedpricingand
reimbursementdecisionsinEUMemberStates.TheEuropeanCommissionhasexpressed
confidenceinthefeasibilityoffast‐trackdecisionsonpricingandreimbursement.14,15SomeEU
MemberStatesalreadygiveprioritytogenericmedicinesororphanmedicinesduringpricing
andreimbursementprocedures.AmendmentoftheTransparencyDirectiveornational
legislationwouldenabletheintroductionofafast‐trackprocedure.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)
wouldbe176daysunderthevoucher30‐daysystem,or123daysifthereviewtimeforgeneric
productswereappliedtoproprietarydrugs.
Amanufacturerwithapriorityreviewvouchercouldstillchoosetopursuepricingand
reimbursementsequentiallyindifferentcountries.Forexample,themanufacturermightseeka
fast‐trackdecisionincountrieswherehigherpricescanbechargedbeforesubmitting
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.18Unlikepatent‐termextensions,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.
Toestimatethepotentialvalueofapplyingapriorityreviewvouchertoatop‐sellingmedicine
intheEU,weusedsalesdataforfivetop‐sellingdrugslaunchedinthelate1990s:Enbrel
(etanercept,Immunex,Seattle,WA,USA),Lipitor(atorvastatin,Pfizer,NewYork,NY,USA),
Plavix(clopidogrel,Sanofi‐Aventis,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
threenon‐EUMemberStates(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)weassumenocorrelationbetweenacceleratedreviewandclock‐stoptime(taking
36daysforbothacceleratedandnon‐acceleratedratherthanthenon‐acceleratedaverageof
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,includingfollow‐onbiologics.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
Inthepast3yearsDBRhasreceivedconsultancyfeesfromGenentechinrelationtofollow‐on
biologics,experttestimonyfeesfromSandozinrelationtogeneric‐drugpricing,andan
honorariumfromPhRMAforparticipatingataconference.AC‐Sdeclaresthathehasno
conflictsofinterest.
Acknowledgments
DBRwasinvolvedintheoriginalresearchfortheUSvoucher,whichwasfundedbythe
GlaxoWellcomeFoundationandDukeUniversity’sCenterfortheAdvancementofSocial
Entrepreneurship.WethankJeffreyMoe,DamonSeils,JiaYao,NinaYoshimura,andthe
reviewersandeditorsforhelpfulcomments.
References
1TrouillerP,OlliaroP,TorreeleE,OrbinskiJ,LaingR,FordN.Drugdevelopmentforneglected
diseases:adeficientmarketandapublic‐healthpolicyfailure.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
Asia‐Pacific.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/03‐MH%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://eur‐lex.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.Drug‐reviewdeadlinesandsafetyproblems.NEnglJMed
2008;358:1354–61.
26NardinelliC,LanthierM,TempleR,CarpenterD.Drug‐reviewdeadlinesandsafetyproblems.
NEnglJMed2008;359:95–98.
27GrabowskiH,WangY.DoFasterFoodandDrugAdministrationdrugreviewsadverselyaffect
patientsafety?Ananalysisofthe1992PrescriptionDrugUserFeeAct.JLawEcon2008;51:
377–406.
Durationsofaccelerated
review(days)
Averagedurationsfornon‐
acceleratedreviewperyear
Yearof
scientific
opinion
Active
time
Total
clock‐stop
time
Total
review
time
Active
time
Totalclock‐
stoptime
Total
review
time
Norvir(ritonavir,Abbot,USA)199669069
184121305
Crixivan(indinavir,Merck,
USA)1996851297
Zerit(stavudine,Bristol‐Myers
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,
Hoffmann‐LaRoche,USA)200312128149191200391
Soliris(eculizumab,Alexion
Pharmaceuticals,USA)200714736183
173133306
Isentress(raltegravir,Merck,
USA)200714135176
Average1996‐2005 10912121184155339
Average2006‐2007 14436180173133306
Average1996‐2007 11516131182151333
Averagesarecalculatedwitheachyearreceivingequalweight.Thetwotimeperiodsof1996–
2005and2006–07areusedbecausetheEuropeanUnionformallyimplementedaccelerated
assessmentin2006.Sources:EMAAnnualReports1996–2007,EuropeanUnionMember
States,Pinheiro,11andthe2008EuropeanPublicAssessmentReport.12
Table1:Europeanacceleratedmarketingauthorisationreviewtimesforbrandeddrugs
versusaveragenon‐acceleratedreviewtimesin1996–2007
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),includingclock‐stop
timeandassumingapriceandreimbursementscheduleof30days.
†TakesintoaccountgrantedapprovalintheEUin2006–07(n=58)andassumesnosavingin
clock‐stoptime.
‡AssumesvouchervalueofUS$20millionpermonth.
§AssumesvouchervalueofUS$30millionpermonth.
Figure:Priorityreviewvouchervalueisgainedfromthreemainsources
(1)Earliersales.(2)Increaseddurationofsalesunderpatentprotectionowingtoearlier
introductiontothemarket.(3)Highersalesfromearlieravailabilitycomparedwithrivals'
similardrugs.
0
(2) Longer
(1) Earlier
(3) Higher
Sales
Months