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ProposalforaThesis
intheFieldofBiotechnology
inPartialFulfillmentofRequirementsfor
theMasterofLiberalArtsDegree
HarvardUniversity
ExtensionSchool
February 1, 2015
MichaelJones
Address
City State Zip
Phone Number
Email address
ThesisDirector:
StuartSimpson,Ph.D.
Address
City State Zip
Email address
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II.
ResearchProblem
Overthepastthreedecades,significantstrideshavebeenmadeintheareaof
drugdevelopment,particularlyinthedevelopmentofbiologics.Withadvancesin
geneticsandbiotechnologyimprovingthedevelopmentofbiologicaldrugs,many
drugcompanieshavetakenadvantageoftheseadvancesandareusingthemto
createlife-changingtherapeuticsforthetreatmentofvariousdiseases.However,
despitetheireffectiveabilitytotreatdisease,thesebiologicscomewithasignificant
costburdentothepayer(e.g.,healthcaresystem,insurancecompanies,and
patients).Whilemosttraditionalpharmaceuticalscostapproximately$730peryear
(Emerton,2013),biologicscancostanywherebetween$15,000and$150,000per
year(Epstein,Ehrenpreis,&Kulkarni,2014).Withtheuseofbiologicsincreasingin
theclinicandcostoftreatmentreachinganall-timehigh,thereisaconsiderable
demandforlow-costalternativesthatcanprovidethesameefficacyandsafetyas
thesebiologics.
Unlikesmall-moleculedrugs,genericbiologicdrugs,alsoknownas
biosimilars,arenotyetavailableintheUSmarket.However,thisisexpectedto
changeoverthenexttenyearsasseveralofthefirstbiologicstoenterthemarket
areexperiencingpatentexpirations.Withmorethan$60billionworthofbiologic
saleslosingpatentprotection(Emerton,2013),manyanalystspredictbiosimilarsto
beaprofitablebusinessventure.Thissentimentofoptimismhasbeenechoedinthe
pharmaceuticalindustryasbiosimilardealsbetweendrugcompaniesandContract
ManufacturingOrganizations(CMOs)havecontinuedtoincreasesince2000
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(Bourgoin,2011).Withanotionthatabrandedbiologicwithlargesalescanresult
inlargerevenuegainsforacounterpartbiosimilar,manydrugcompanieshave
alreadybeguntodevelopbiosimilarsforsomeofthetop-sellingbiologics.Someof
thesebiologicsincludeHumira,Remicade,Enbrel,Rituxan,HerceptinandAvastin,
whichalreadyhave16,9,21,34,30and16biosimilarsrespectively,indevelopment
(Thayer,2013).
WhiletheUSbiosimilarmarketexhibitstremendouspotentialasan
investment,noteverygenerictoareferencebiologicwillbeaworthyinvestment.
Sincethedevelopmentofabiosimilarrequiressignificantcapital,adrugcompany
interestedinthebiosimilarventurewillneedtohaveastrategyinplacewhen
selectingthebiosimilar(s)itwouldliketodevelopandadvancetotheUSmarket.
Whilethetrendappearstofavorbiosimilarcandidatesforthosereferencebiologics
experiencinghighsales(Rader,2013),thiscasestudywillexploretheinvestment
opportunityofbiosimilarsbyevaluatingtwobiosimilarcandidateswithcontrasting
marketprofiles.Ratherthanrelyingonevaluationscenteredongeneralsalesasa
projectionoffuturevalue,suchastheNickischandBode-Greuel(2013)study,this
casestudywillexpandtheNickischandBode-Greuelevaluationtoincludeamore
thoroughandindividualizedanalysisofthebiosimilarmarket.Byapplyingthis
model,Ibelievethisapproachwillprovideamoreconclusivemeasureofvaluefora
biosimilarcandidateinthecurrentmarketthantheevaluationmadebyNickisch
andBode-Greuel.Furthermore,itismyhypothesisthatabiosimilarcandidatefora
referencebiologicwithfewersalesbutapromisingmarketoutlookwillbeabetter
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investmentopportunitythanabiosimilarforreferencebiologicexperiencing
blockbustersales.
Oneofthemostimportantelementsintheevaluationofaninvestmentis
determiningvaluecreation.Althoughtherearevariousmethodstoassessvalue,
whenevaluatingaproduct,itiscommontodeterminevaluecreationbyanalyzing
futurecashflows(revenueandcost)throughquantitativemodels,suchasanet
presentvalue(NPV)model(Brealey,Myers,&Allen,2008;Higgins,2009;Harris,
1997).Sincethedevelopmentofadrugiscontingentonmanyfactors,theNPV
modelcanbeadjustedtospecificallyevaluatethepotentialofadrugdevelopment
candidate(Nickisch&Bode-Greuel,2013;Bode-Greuel&Greuel,2005).Bytailoring
theNPVtoreflectthebiosimilarbusinessmodelandthemarketofeachbiosimilar
candidate,thevalueofeachcandidatecanbedeterminedandcompared.Usingthis
approach,thehypothesiswillbetestedbycomparingtheoutcomeofthefollowing
twoscenarios:(1)thevalueofabiosimilarmonoclonalantibodycandidateforatop-
sellingbiologicand(2)thevalueofabiosimilarmonoclonalantibodycandidatefor
abiologicwithbothfewersalesandamorefavorablemarketoutlookthanthe
biologicpresentedinscenario1.Someprospectivebiologicswithfewersales(under
$2billionworldwidein2013)includeTysabri,Synagis,Xolair,andSoliris
(GlobalData,2014).
Whilethebiosimilarbusinessisbelievedtobeaprofitablebusinessfortop-
sellingbiologics,thiscasestudywillquestionthisnotionbychallengingtheNickisch
andBode-Greuelstudy.Ratherthanrelyingonpeaksalesofthereferencebiologic
tomeasurethevalueofabiosimilarcandidate,asdonebyNickischandBode-
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Greuel,thiscasestudywillimplementamorerobustevaluationapproachthatwill
takeintoaccountboththecurrentbiosimilarlandscapeandmarketprofileofthe
twobiosimilarcandidatesofinterest.Inadditiontoprovidingacompellingbusiness
argumentintheevaluationofabiosimilarcandidate,thiscasestudywillintroduce
andexplainthebusinessmodelofbiosimilarsforthoseinterestedinpursuingthe
biosimilarbusiness.
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III.
DefinitionofTerms
“Biologics”:aclassofdrugsderivedfromlivingorganismsthatarecomposedof
biologicalentitiessuchasproteins,peptides,nucleicacids,orcells(Wang&Singh,
2014).
“BiologicsPriceCompetitionandInnovation(BPCI)Act”:Passedaspartofthe
PatientProtectionandAffordableCare(PPAC)ActtoallowtheFDAtocreatea
regulatorypathwayfortheapprovalofbiosimilars(Wang&Singh,2014).
“Bioreactor”:avesselthatisusedtocultivatecellsforthepurposesofproducingthe
drugofinterest.
“Biosimilar”:abiologicthatishighlysimilarincomparisontothereference
biologicalproduct(Chow,2014).
“Biotechnology”:technologybasedonthefundamentalsofbiologythatuseliving
organismsorbiologicalsystemstoidentify,sequence,andmanipulateDNAforthe
purposesofproducingtherapeuticandmedicalproducts(Simoens,2011).
“Cloning”:ThebiotechnologyprocessofintroducingDNAintoacelltobeusedfor
theproductionofaproteinofinterest.
“Hatch-WaxmanAct”:AcommonreferencetotheDrugPriceCompetitionand
PatentTermRestorationActof1984,thisstatuteallowstheFDAapprovalofgeneric
drugs(i.e.,small-molecules)viaanabbreviatedpathway(Wang&Singh,2014).
“Invivo”:Studiesthattakeplaceusingalivingorganism.
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“Monoclonalantibody”:Anengineeredtherapeuticantibodyusedtotargetan
antigenofinterest.
“NetPresentValue(NPV)model”:Aforward-lookingquantitativemodelthattakes
intoaccountbothcashinflowsandoutflowstodeterminethepotentialvalue
generationofaninvestment(Bode-Greuel&Greuel,2005).
“Processdevelopment”:Theprocessinvolvedintheproductionofatherapeuticvia
clonedcells.
“Referencebiologic”:Thebrandedbiologic(createdbytheoriginator)forwhichthe
biosimilariscomparedto.
“Small-molecule”:“adrugwithalowmolecularweightthatischemically
synthesized.
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IV.
Background
Whatisabiologic?
Biologicaldrugproducts,alsoreferredtoasbiologics,aretherapeutics
manufacturedthroughlivingorganismsusingbiotechnologymethods.Composedof
abiologicalentity,biologicsaremadeupofpeptides,proteins,nucleicacids,orcells
(Wang&Singh,2014).Firstdevelopedintheearly1980’s,biologicsarewellknown
intheclinicfortheirabilitytodiagnose,prevent,andtreathumandiseases.
Drasticallydifferentthanthetraditionalpharmaceuticaldrugs(i.e.,small-
molecules),biologicsarelargerinsize,heterogeneous,anddifficulttocharacterize
(Table1)(Chow,2014).Asaresult,thedevelopmentofabiologicismorecomplex
andcostlyasitisinvolvesintensiveengineeringandmanufacturing.Despitethese
hurdles,biologicsareconsideredsomeofthemosteffectiveandpreferred
therapeuticsforthetreatmentofseverediseases,suchascancer,rheumatoid
arthritis,multiplesclerosis,hepatitis,andmanyothers.AccordingtoWang&Singh
(2014),therearecurrentlyover200differenttypesofbiologicsinthemarketwith
approximatelyonethirdofpharmaceuticalpipelinesconsistingofabiologic.
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Small-molecule Vs. BiologicChemicallysynthesized Production Livingorganism
Defined Composition Complex/HeterogeneousLow MolecularWeight High
Lowcomplexity Characterization HighcomplexityLow Immunogenicity HighHigh Stability LowLow ManufacturingRisks High
Lowtomedium Cost(topayer) HightoveryhighOral Administration Injection
Table1:Differencesbetweensmall-moleculedrugsandbiologicaltherapeutics.
Source:AdaptedfromChow,2014.
MonoclonalAntibodies:ATypeofBiologic
Ofallthevariousbiologicscurrentlyinthemarket,oneofthemostsuccessful
andlargestgrowingclassesoftherapeuticsaremonoclonalantibodies.Antibodies
areproteinssecretedbywhitebloodcellsthatareusedbythehumanimmune
systemtoprotectthebodyfromforeigninvaders.Inprotectingthebody,the
antibodyrecognizestheantigenexpressedbythepathogen–thebodyhasadiverse
panelofantibodiesthatrecognizedifferentantigens–andtriggerstheimmune
response.Likeantibodiesgeneratedbytheimmunesystem,therapeuticmonoclonal
antibodiesfunctioninasimilarfashion.Producedfromlivingorganisms(usually
mammaliancells)throughelaboratemanufacturingprocesses,theseantibodiesare
engineeredtohaveaffinitytowardsanantigenofinterest,inthiscase,thebiological
entitycausingthedisease(Ansar&Ghosh,2013).Asaresultofdetailed
engineering,therapeuticmonoclonalantibodiesareabletoreproducesimilar
immuneresponseinhumansbytargetingtheantigenofinterest.Duetotheirstrong
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bindingcapabilitiesandstability,theseantibodiesareabletoprovidelessoff-target
effectsandareamoreeffectivetreatmentfordiseasethanmostsmall-molecule
drugs(Wang&Singh,2014).Inadditiontotheirtherapeuticapplication,theUS
FoodandDrugAdministration(FDA)hasapprovedtheuseofmonoclonal
antibodiestowardsotherapplications,includingdiagnosisandbioterrorism(Ansar
&Ghosh,2013).
TheDrugDevelopmentProcessForaMonoclonalAntibody
Likesmall-moleculedrugs,thedevelopmentofatherapeuticmonoclonal
antibodyintheUScanbecategorizedinthreemainstages:discovery,preclinical
development,andclinicaldevelopment(Wang&Singh,2014).Priortoengineering
amonoclonalantibodyforthetreatmentofadisease,thebiologicalentity
responsibleforcausingthedisease(i.e.,drugtarget)mustfirstbeidentified.Taking
theformofagene,protein,orRNA,thedrugtargetcanbeidentifiedthroughvarious
scientificexperimentations(e.g.,genetic,invivoandcellular)thattestthe
relationshipbetweenthetargetanddiseaseofinterest(Hughes,Rees,Kalindjian,&
Philpott,2011).Forexample,incancer,therearemanycell-specificantigens
involvedinthepathogenesisofthedisease.Ifonecanidentifyanantigenlinkedto
cancer,thenamonoclonalantibodycanbeengineeredtotargetthatantigenand
modulatethedisease.Thissamerationaleappliesinthediscoveryphase.Oncea
targethasbeenidentifiedandlinkedtothepathogenesisofadisease,various
monoclonalantibodiestothattargetcanbeengineered(Wang&Singh,2014;Ansar
&Ghosh,2013;Hu&Hansen,2013).Oncealeadmonoclonalantibodyhasbeen
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identifiedandoptimized(i.e.,engineeredtohaveminimalimmunogenicity,superior
biochemicalandbiophysicalproperties,andidealpharmacokineticproperties),itis
thenpassedtoprocessdevelopmentforproduction(Wang&Singh,2014).
Priortoproducingthemonoclonalantibodythatwillbeutilizedinclinical
trials,itiscriticaltoestablishthemanufacturingprocessthatwillbeusedto
producetheantibodyofinterest.Thisistheobjectiveofthepre-clinical
developmentphase,toestablishamanufacturingprocessthatproducesadrug
productofhighqualityandsafety(Wang&Singh,2014).Sincemonoclonal
antibodiesareproducedfromlivingorganisms,manyalterationsmayoccur
throughouttheproductionprocess(e.g.,post-translationalmodification,
glycosylation,proteincleavage,andyield)(Genazzani,etal.,2007).Therefore,itis
importanttodevelopamanufacturingprocessthatisbothrobustandconsistent,to
ensurethatthetherapeuticprovidedinclinicaltrials(andthegeneralpublic,if
givenapproval)isconsistentandofthehighestquality(Wang&Singh,2014).
Thefinalstepinthedevelopmentofamonoclonalantibodyisclinical
development.Oncetheearlydevelopmentandpre-clinicalphasesdemonstrate
promisingresultsforthemonoclonalantibodycandidate,thedrugsponsorcanthen
pursuetestinginhumans.TotesthumansubjectsintheUS,itisfirstnecessaryto
receiveclinicaltrialapprovalfromtheUSFDA.Thisisinitiatedbyfilingan
InvestigationalNewDrug(IND)applicationtotheFDAthatsupportstherequest
basedondataacquiredfromearlierdevelopmentphases(Wang&Singh,2014).
OncetheFDAhasgrantedapproval,thedrugsponsorcanthenbeginclinicaltrials
(phaseI-III)todetermineifthedrugisbothsafeandefficacious(Umscheid,
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Margolis,&Grossman,2011).Dependingontheresults,thedrugsponsorcanthen
applytotheFDAforapprovalbyfillingaBiologicsLicenseApplication(BLA).Once
theBLAisapproved,thedrugsponsorcanthenmarketandsellthetherapeutic
monoclonalantibodyintheUS.
AnIntroductiontoBiosimilars
AccordingtotheFDA(2012),aUSbiosimilarisabiologicalproductthatis
highlysimilartoanFDA-licensedbiologicalproduct(thereferenceproduct)for
whichtherearenoclinicallymeaningfuldifferencesintermsofsafety,purity,and
potencyoftheproduct.WhiletherearenobiosimilarsintheUSmarket,thisis
believedtochangeoverthenextfewyears,asseveralreferencebiologicswillbegin
tolosepatentexclusivityintheUS.Withlegislativechannelsinplacetoallowthe
developmentofgenericbiologics,severalbiosimilarsareexpectedtoenterthe
marketoverthenexttenyears(Blackstone&Fuhr,2013).Asaresultofthe
demand,biosimilarstosomeofthebest-sellingbiologics,suchasHerceptin,Humira,
AvastinandEnbrel,areexpectedtoentertheUSmarketby2020(Bourgoin,2011).
Currently,biologicsareoneofthemostexpensivetherapeuticsintheUS
market.Rangingbetween$15,000and$150,000peryear(Epstein,Ehrenpreis,&
Kulkarni,2014),biologicshavecreatedafinancialstrainonboththeUShealthcare
systemandpayers.Withpotentialcostsavingsinthebillion-dollarrange(Bourgoin,
2011)andbiosimilarsalreadyapprovedintheEuropeanmarket,thedemandfor
biosimilarsissteadilyincreasingintheUS.Asaresult,Congresshaspassed
legislationtoallowbiosimilarstoentertheUSmarket.WiththeHatch-WaxmanAct
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openingthedoorforgenericchemicaldrugs(Blackstone&Fuhr,2013),Congress
hasrecentlypassedtheBiologicsPriceCompetitionandInnovationAct(BPCIA)
(underSubtitleVIIofthePatientProtectionandAffordableCareAct)toallowthe
FDAtocreatearegulatorypathwayforbiosimilarsseparatetothegenericdrug
pathwayobservedbysmall-molecules(Bourgoin,2011).Throughthischannel,drug
companiescannowreceiveregulatoryguidanceonthescientificissuessurrounding
biosimilarity(Chow,2014).
ChallengesintheDevelopmentofGenericDrugs:BiosimilarVersusSmall-Molecule
Asdiscussedearlier,unlikesmall-moleculegenerics,theproductionofa
biosimilarisdifficultandcomplex.Producedviaalivingorganism,theengineered
biosimilarisexposedtoseveralalterationsthatoccurwithinthecell(e.g.,
glycosylation,acylation,sulfation,phosphorylation,andproteolysis)andthroughout
theproductionprocess(e.g.,oxidation,deamination,denaturationandaggregation)
(Kresse,2009).Withoutknowingallthedetailsinvolvedintheproductionand
manufacturingoftheoriginalbiologic(someofitisusuallykeptasatradesecret),it
maybeimpracticalforabiosimilartobeidenticaltothereferencebiologic.Asa
result,regulatoryguidelinesregardingtheassessmentofsimilarity(e.g.,structural,
functional,andclinical)arenotasclearandestablishedasitisforsmall-molecule
generics.Sincethereareonlyahandfulofcompanieswiththeexperienceand
capabilitytodevelopbiosimilars,thebarriertoentryisanticipatedtobehigh
(Blackstone&Fuhr,2013).
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Inadditiontothedevelopmentchallengesintheproductionofabiosimilar,
therearechallengesinthebusinessmodelofbiosimilars.Withalimitednumberof
expertsintheareaofbiologics,thecostofdevelopingabiosimilarisexpectedtobe
morecostlythanthedevelopmentofagenericsmall-molecule.Accordingto
NickischandBode-Greuel(2013),thecostofdevelopingagenericsmall-moleculeis
between$1and$3million,whileabiosimilarcanrangebetween$50and$200
million,dependingonthemolecule.Inadditiontocost,developmenttimesarealso
longerforbiosimilarswithanaverageof7to9years(Nickisch&Bode-Greuel,
2013).Lastly,thedevelopmentriskofabiosimilarisgreaterthanthedevelopment
ofagenericsmall-molecule.Althoughtheriskindevelopingabiosimilaris
inherentlylessthanthedevelopmentofanewbiologic–abiosimilargetstobypass
thehigh-riskdrugdiscoveryphaseaswellasphaseIIclinicaltrialssincethe
referencebiologichasalreadydemonstratedefficacyintheclinic–abiosimilaronly
hasa50to75percentprobabilityofsuccesscomparedtothe95percentobserved
forasmall-moleculegeneric(Nickisch&Bode-Greuel,2013).Thisriskcombined
withcost,time,andthechallengesinmanufacturing,makethedevelopmentofa
biosimilaramorecomplicatedbusinessthanthetypicalgenericdrugbusiness.
TheEuropeanBiosimilarExperience
TheEuropeanMedicinesAgency(EMA)isoneofthefirstregulatoryagencies
toapprovebiosimilarsinthegenericdrugmarket.With14approvedbiosimilars,
someofwhichincludeepoetins,somatropins,andfilgrastims(Epstein,Ehrenpreis,
&Kulkarni,2014),Europeaccountsfor80percentoftheglobalspendingin
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biosimilars(IMSHealth,2011).Currently,thegreatestchallengewithbiosimilarsin
theEuropeanmarketisthevarieduptakeobservedacrosscountriesanddrug
classes(IMSHealth,2011).Duetodifferencesinpricingandsentimentacross
differentcountriesintheEuropeanUnion,theuptakeofabiosimilarcanvaryfrom
countrytocountry.Forexample,thebiosimilarfilgrastim(brandname:Neupogen)
ispricedat€149.7inGermany,whileintheUKthesamebiosimilarispricedat
€74.1(Rovira,Espin,Garcia,&Labry,2011).Asaresultofthisinequity,asizeable
uptakedifferenceisobservedbetweenbothcountries,withtheUKexperiencing
greateruptakeovertimecomparedtoGermany(IMSHealth,2011).Inadditionto
pricevariations,theuptakeofthebiosimilarfilgrastimhasalsobeeninfluencedby
sentiment,specificallytheopinionofphysicians.Sincetheeffectsoftreatmentin
filgrastimarereadilyapparent,physiciansfeelmorecomfortableprescribinga
biosimilarthatcanbechangedquickly;ratherthanabiosimilarthathasalonger
timetableintreatment,suchassomatropin(IMSHealth,2011).
DespitethechallengesintheuptakeofabiosimilarinEurope,theEuropean
marketisbeginningtoadapttothepresenceofbiosimilars.Withbiosimilarsales
increasingfrom€3.3millionin2007to€65millionin2009,andthesalesof
respectivereferencebiologicsdecreasing,theEuropeanbiosimilarmarketis
evolvingintoamorefavorablemarketforpayers(Rovira,Espin,Garcia,&Labry,
2011).Asphysiciansandpatientscontinuetogainexperiencewithbiosimilars,and
thepoliciessurroundingbiosimilarscontinuetomature,theEuropeanbiosimilar
marketisexpectedtoexpand.Thisisalreadyapparentinthenumberof
applicationsfiledtotheEMA.In2012,theEMAreceivedanall-timehighofseven
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biosimilarapplications,comparedtotheonebiosimilarapplicationfiledin2009
(Dalgaard,Evers,&Silva,2013).
TheMarketOutlookforBiosimilarsintheUS
Asthepatentcliffclosesinonseveraltop-sellingbiologicsandthedemand
forlow-costalternativescontinuestoincrease,thebiosimilarmarketintheUSis
expectedtodevelopoverthenextdecade.Currently,thefollowingissuesaredriving
afavorableoutlookforbiosimilars:(1)USaccountsforthemajorityofglobal
spendinginbiologics(IMSHealth,2011),(2)expendituresinbiologicshave
increasedovertime(Blackstone&Fuhr,2013)and(3)over$50billioninsalesfrom
biologicswhicharelosingpatentprotectionwillbeavailableforcounterpart
biosimilars(GrantThornton,2013).Asaresult,theUSbiosimilarmarketis
forecastedtobethebiggestopportunityinthegenericdrugindustryby2020(IMS
Health,2011).
Oneofthemaindriversinthemarketoutlookforbiosimilarsisdemand.
Withincreasingexpendituresandloftypricesobservedinthebiologicindustry,
thereisagrowingdemandacrossthespectrumofstakeholders(includingCongress,
payers,etc.)forthedevelopmentofbiosimilars.Althoughpharmaceuticaldrugs
accountfor8to10percentofthetotalhealthcarecostinthemajormarkets,the
costofbiologicscontinuetoescalatebeyondthe$10,000range(Nickisch&Bode-
Greuel,2013).Withtheriseofcostexceedingtheoverallinflationrate–in2010,
biologicsexperiencedanapproximate9percentincreaseovertheConsumerPrice
Index(Blackstone&Fuhr,2013)–theUShealthcaresystemisalreadybeginningto
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feelthefinancialburden,specificallyMedicare.SinceMedicarecoversallspecialty
drugs,therehasbeenlittleincentiveforinnovatorbiologiccompaniestoimplement
apricereduction(Blackstone&Fuhr,2013).However,withthetopsixbiologics
consuming43percentofthepharmaceuticalbudgetforMedicarePartB(Nickisch&
Bode-Greuel,2013),healthcareofficialsareadvocatingforbiosimilarsinhopesof
reducinghealthcarecostsintheUS.
Oneoftheotherfactorsinfluencingthebiosimilarmarketisthebarrierto
entry.Althoughmostgenericsarefacedwithhighlevelsofcompetition,whenit
comestobiosimilars,thecompetitivelandscapeisexpectedtobesignificantlyless
thanthoseseeninthegenericdrugindustry.Withseveralchallengesinthe
productionandmanufacturingofbiologics,onlyafewdrugcompanieswillhavethe
capabilitiestodevelopbiosimilars.Withamarketinthebillion-dollarrangefor
somebiologics,particularlymonoclonalantibodies,thehighbarriertoentrywill
allowbiosimilarcompaniestocaptureasignificantportionofthereferencebiologic
market(Blackstone&Fuhr,2013).Withbiosimilarsexpectedtocost10to30
percentlessthanreferencebiologics(USFederalTradeCommission,2009),
biosimilarsareexpectedtocapturegreatermarginsthantypicallyseeningenerics.
Thisiswillbeevengreaterinthosecaseswherethebiosimilarexpandstheaccess
oftreatmenttothosepatientswhowereunabletoaffordthetherapeutic
beforehand.
Whilebiosimilardevelopmentcostsareexpectedtobegreaterthansmall-
moleculegenerics,comparedtonewdrugs,biosimilarsexhibitreduced
developmentcost,time,andrisk.AccordingtoBlackstoneandFuhr(2013),the
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averagecostofdevelopinganewbiotechnologydrugisapproximately$1.9billion.
Thisissignificantlylessthantheaverageinvestmentinthedevelopmentofa
biosimilar,whichisestimatedtobebetween$50and$200million(Nickisch&
Bode-Greuel,2013).Apartofthisisattributedtodifferencesindevelopmenttime,
withbiosimilarsembracing2to6yearslessdevelopmentthannewbiologics
(Nickisch&Bode-Greuel,2013;Wang&Singh,2014).Lastly,biosimilarsexhibit
greaterlikelihoodofsuccessthannewdrugs.With95percentofallnewdrugsinan
R&Dpipelinenevermakingittomarket(Blackstone&Fuhr,2013),biosimilars
embraceagreaterchanceofreachingmarketwitha50to75percentprobabilityof
success(Nickisch&Bode-Greuel,2013).
UncertaintiesintheUSBiosimilarMarket
Whiletherearevariousfavorablecomponentsintheinvestmentofa
biosimilar,therearealsoafewissuesofuncertaintythatcanimpacttheUS
biosimilarmarket.Oneofthebiggestissuesofuncertaintyinthebiosimilarmarket
isuptake.Giventhenoveltyofbiosimilars,theUSisexpectedtoexperienceaslow
uptakeinbiosimilarsduringitsfirstfewyearsinmarket.However,thisisexpected
tochangeasbiosimilarscontinuetoentertheUSmarketandestablishapresencein
theclinic.WithEurope’srecentincreaseinbiosimilaruptakeandtheirlackofissues
aroundsafety(Blackstone&Fuhr,2013),analystsbelievetheuptakewillsurgeby
2020,whentheUSwillbetheleadingmarketforbiosimilars(IMSHealth,2011).
However,thisforecastwillbehighlycontingentonpricing.Ifthepricedifference
betweenbiosimilarandreferencebiologicisnotsignificant,thereisapossibility
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thatpayerswillnotadoptbiosimilars.Asaresult,pricingwillbeadetermining
factorinuptake.
TheotherareaofuncertaintyiswiththeFDAanditsapprovalmethod.With
differentlevelsofbiosimilarsimilarityatplay,therecouldbeadifferenceinmarket
shareforbiosimilarsapprovedas“highlysimilar”versusthoseapprovedas
“similar”butnotinterchangeable.Thelackofinterchangeabilitycouldinfluencea
patienttoselectareferencebiologicoveritsbiosimilar,despitethetradeoffincost.
Althoughtheissueofinterchangeabilityisapotentialriskintheinvestmentofa
biosimilar,theimpactwillbeaimedatonlyafewbiosimilarssincephysicians
administerthemajorityofbiologicsdirectly(Blackstone&Fuhr,2013).With
substitutionatthediscretionofthephysicianratherthanthepharmacy,thereisan
opportunitytoinfluencephysicianstosidewithabiosimilar,shouldabiosimilar
exhibithighlysimilarsafetyandefficacyasthereferencebiologic.
Thelastmajorhurdleanduncertaintyinthebiosimilarmarketistheimpact
ofclinicaltrials.Currently,theFDAdoesnothaveamandateforclinicaltrialswhen
comparingthesafetyandefficacyofabiosimilartoitsreferencebiologic(Chow,
2014).However,inthecaseofinterchangeability,theFDAmayrequirethe
implementationofclinicaltrialstodemonstratesimilaritybetweenbiosimilarand
referencebiologic(Chow,2014).Thisuncertaintyinclinicaltrialscouldplayan
impactondevelopmentcostsforabiosimilar.Anotherpotentialchallengewith
clinicaltrials,beyondcost,isrecruitment.Sincebiosimilarstargetapopulationof
severelyillsubjects,manysubjectsmaybeinclinedtoavoidaclinicaltrialinfearof
gettingthebiosimilardrugovertheestablishedreferencebiologic(Blackstone&
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Fuhr,2013).Thisreservationcouldmakerecruitingverydifficultforbiosimilars,
especiallyinthosecaseswhenmorethanonecompanyisrecruitingthesame
patientpopulation(Blackstone&Fuhr,2013).
EnteringtheBiosimilarMarket
Asdiscussedearlier,eachbiosimilarcandidatewillneedtogothrough
developmentandanFDAapprovalprocessforthetherapeutictobemarketedasa
biosimilarintheUS.Whilethedevelopmentapproachforabiosimilarcandidate
maydifferfromcompanytocompany,thedevelopmentprocessishighlydependent
onthedrugcompany’sabilitytoexecute.However,unlikedevelopment,market
outlookofabiosimilarisnotentirelydependentonexecution.Whilesomeaspects,
suchasadvertising,canbemanipulated,therearemanyexternaldynamicsinthe
drugmarketthatcannotbecontrolled.Asaresult,foradrugcompanytobe
successfulinthebiosimilarbusiness,itwillneedtounderstandtheexternalforces
impactingthemarketofagivenbiosimilarandtakethemintoaccountwhen
analyzingthevalueofabiosimilarcandidate.Withsignificantcapitalneededto
bringabiosimilartomarket,acompanywillneedtobeprudentindecidingwhich
biosimilar(s)topursue.
Withcurrentbiosimilarsindevelopmentconsistingmostlyoftop-selling
referencebiologics(Rader,2013),thereappearstobeanotionthathighsalesfora
referencebiologicwillresultinapromisingbusinessopportunityforitscounterpart
biosimilar.Forexample,Herceptin,atop-sellingoncologybiologicwith$6.4billion
insaleshasover20biosimilarsindevelopment(Rader,2013).WhereasLucentis,an
22
ophthalmologicbiologicwithapproximatelyhalfthesales($3.7billion),hasonly2
biosimilarsindevelopment(Rader,2013).Whilesomeanalystsbelieveatopselling
biologicisafavorableproposition(Rader,2013;Blackstone&Fuhr,2013;Nickisch
&Bode-Greuel,2013),thiscasestudyaimstochallengethistheorybyimplementing
anevaluationapproachthatisfoundedontheindividualmarketprofileofagiven
biosimilarcandidateratherthanrelyingexclusivelyonsalesasageneralpredictor
ofsuccess.
EvaluatingaBiosimilarDevelopmentCandidate
GiventhelackofbiosimilarsintheUSmarketandthesubstantialdifference
betweenbiosimilarsandsmall-moleculegenerics,astandardapproachtothe
evaluationofabiosimilarhasnotyetbeenestablished.Asaresult,eachbiosimilar
companywillneedtodevelopitsownevaluationmodelthatwillbestinformthe
valueofabiosimilardevelopmentcandidate.Whilethelackofstandardscanmake
theevaluationprocessdaunting,anevaluationmodelcanberedesignedusing
currentfinancialmodelsinthedrugindustry.Onecommonmodelusedin
biotechnologytodeterminethevalueofdrugcandidatesandtechnologyplatforms
isnetpresentvalue(NPV)(Bode-Greuel&Greuel,2005).Aforward-looking
financialmodel,theNPVevaluatesassumptionsonfuturecashflows(gainedorlost)
foragiveninvestmentanddeterminestheoverallvalueofaventure(Bode-Greuel&
Greuel,2005).Sincethepurposeofanevaluationistodeterminevaluecreation,the
NPVcanbeusedtosatisfythisrequirement.Iftheevaluationresultsinapositive
NPV(NPV>0),theinvestmentisexpectedtocreatevalue;however,ifthe
23
evaluationresultsinanegativeNPV(NPV<0),theinvestmentisexpectednotto
createvalue(Bode-Greuel&Greuel,2005;Higgins,2009;Nickisch&Bode-Greuel,
2013).
Inevaluatingabiosimilarcandidate,theNPVmodelcanbeusedtomake
decisionsontheselectionofabiosimilardevelopmentcandidate(Nickisch&Bode-
Greuel,2013).However,priortousingtheNPVasdecision-makingtool,itwillbe
criticaltofullyevaluatethecurrentmarketofabiosimilarinordertomakecredible
assumptionsintheNPVregardingfuturecostsandrevenues(Bode-Greuel&Greuel,
2005).Sincecashflowisinfluencedbythemarket,anevaluationthatlooksatthe
individualmarketlandscapeofagivenbiosimilarcandidatewillprovidegreater
confidenceonestimatedcostandrevenue.Forexample,abiosimilarthat
experiences$1billioninsalesinagivenyear,mayexperienceasignificantdropa
fewyearslaterduetochangesinthemarketsuchas,increasedcompetition,
emergingtherapeutics,lifecyclemanagement,changesintreatmentalgorithm,and
reactionfrompayers(IMSHealth,2011).Asaresult,itwillbewiseforacompanyto
makeanevaluationbasedontheindividualmarketprofileofagivenbiosimilar,
ratherthanallowingsalesofareferencebiologictobethedecidingfactorinthe
selectionofabiosimilardevelopmentcandidate.
TheNickischandBode-GreuelStudyonBiosimilars
Whileastandardizedapproachtotheevaluationofbiosimilarsdoesnot
currentlyexist,in2013,NickischandBode-Greuelpublishedastudyonthe
evaluationofbiosimilarcandidatesviaNPVanalysis.Inthisstudy,theauthors
24
analyzedthebusinessmodelofbiosimilars,andevaluatedtheattractivenessof
biosimilarcandidatesbasedonpeaksalesofthereferencebiologics.Creating
variousscenariosforpeaksales,NickischandBode-Greueldeterminedthatsales
within$2-5billionforareferencebiologicwouldresultina“morefavorable”
biosimilarinvestment(assuminga30%marketshare)(p.30).Whilethisstudy
deservespraiseforbeingoneofthefewbusinessstudiestodiscussthebiosimilar
businessandpresentanevaluationapproachforbiosimilars,theNickischandBode-
Greuelstudyhastwomajorshortcomings.
Thefirstshortcomingwasthelackofanindividualizedmarketanalysis.
Ratherthanevaluatingbiosimilarcandidatesbasedontheiruniquemarketprofile,
theNickischandBode-Greuelstudyweightedthemarketforallbiosimilar
candidatesequallyandassessedvaluepredominantlyonthepeaksalesofthe
referencebiologic.Thesecondshortcomingwastheuseoflegacydata.Sincethe
studywaspublishedin2013,manyofthedatapointscollectedtocreatethe
evaluationdatedbackto2012andearlier.SincebiosimilarshavenotenteredtheUS
market,thebiosimilarlandscapeisconstantlyevolvingintheareasoflegal(e.g.,
patents),commercial,FDAregulations,economics(e.g.,reimbursementand
pricing),andevensentiment.Asaresult,manyoftheassumptionspresentedinthe
NickischandBode-Greuelstudywereoutdated.Tocreateanaccuratebiosimilar
evaluation,thebiosimilarlandscapemustbeanalyzedwithdatathatisreflectiveof
currentissues.Thiscasestudywillaimtoaddressboththeseshortcomingsfromthe
NickischandBode-Greuelstudy.
25
V.
CaseStudyMethods
Basedoncurrentbiosimilardealsandtheopinionsofafewanalysts,there
appearstobenotionthatbiosimilarsfortop-sellingreferencebiologicswillresultin
afavorablebusinessopportunity(Rader,2013;Nickisch&Bode-Greuel,2013;
Blackstone&Fuhr,2013).Whilethismaybethecaseinsomeoccasions,thiscase
studyaimstocounterthisviewbychallengingtheNickischandBode-Greuel(2013)
study.IntheNickischandBode-Greuelstudy,theauthorspresentedageneralized
evaluationforbiosimilarsthatfocusedprimarilyonpeaksalesofareference
biologic.Asopposedtoapplyingageneralizedmodeldictatedbysales,thiscase
studywillexpandtheevaluationmethodologyusedbyNickischandBode-Greuel
andapplyamarket-specificevaluationthatreflectsthecurrentlandscapeofagiven
biosimilarcandidate.Indoingso,thiscasestudywillanalyzethefollowingtwo
scenarios:(1)thevalueofabiosimilarmonoclonalantibodycandidateforatop-
sellingbiologicand(2)thevalueofabiosimilarmonoclonalantibodycandidatefor
abiologicwithbothfewersalesandamorefavorablemarketoutlookthanthe
biologicpresentedinscenario1.Whenselectingthetwobiosimilarcandidatesto
compare,thefollowingcriteriawillbeimplemented:(1)biosimilarreference
biologicmustdifferinsales(usingWWsalesfor2013)byatleast20percent,(2)
biosimilarreferencebiologicmusthaveanexpirypatentdateonorbefore2020,(3)
biosimilarreferencebiologicmusthaveapreliminarymarketoutlookthatsatisfies
thescenariosabove.
26
Oncethebiosimilarcandidateshavebeenselected,thiscasestudywill
analyzeandcomparebothcandidatesusinganNPVmodelsimilartotheBode-
GreuelandGreuel(2005)model.InadditiontotheBode-GreuelandGreuelmodel,
thiscasestudywillusetheNickischandBode-Greuelevaluationmodelthatwas
tailoredtobiosimilars.However,unliketheNickischandBode-Greuelmodel,the
evaluationinthiscasestudywillincludeanindividualizedmarketanalysisthatis
reflectiveofthetwobiosimilarcandidatesofinterestandthecurrentbiosimilar
landscape.Thismarketanalysiswillinvolvethefollowing:(1)clinicaloutlookof
drug(e.g.,mechanismofaction,therapytype,indications,presentations,placement
intreatmentalgorithm,etc.),(2)competitivelandscape,(3)disruptivetherapies
(e.g.,newemergingdrugsorbiosimilarsofadifferentreferencebiologic),(4)
referencebiologicsalesand(5)annualcostoftreatment.Basedonthisanalysis,an
accuratebasecaseassumptionforcost,revenue,andprobabilityofsuccesscanbe
determinedforeachbiosimilarcandidateandappliedtotheNPVcalculation.Based
ontheNPVresults,thehypothesiscanthenbetested.
Note:Dataneededtosupporttheselectionofthebiosimilarcandidatesaswellas
themarketanalysiswillbeacquiredviasecondarysources,suchasanalystsreports,
literature,andmarketresearchdatabases(e.g.,GlobalDataandEvaluatePharma).
28
VI.
CaseStudyLimitations
Oneofthelimitationsofanevaluationbasedonfutureassumptions,suchas
anetpresentvalue(NPV)model,istheneedtopredictfuturecashflows.While
calculatedprojectionscanbemadeonfuturecashflows,theseforecastsare
contingentoncurrentknowledge–theydonottakeintoaccounttheuncertainties
ofthefuture.Asaresult,theNPVmodelissubjecttochange.Whilethesechanges
canimpactthefinalevaluation,theimpactagivenchangehasonanevaluationcan
bemitigatedbyestablishingcredibleassumptions(Bode-Greuel&Greuel,2005).
Thisisoneofthemaineffortsofthiscasestudy.Ratherthanrelyingheavilyonthe
currentsalesofareferencebiologicasapredictoroffuturecashflowsforthe
counterpartbiosimilar,thiscasestudywillanalyzethecurrentmarketoutlookof
eachbiosimilarcandidateandwilltakeintoaccountpotentialuncertaintiesthatcan
impactthefuturevalueofabiosimilarcandidate.
29
VII.
TentativeSchedule
Submission of proposal to research advisor…………………………...December 15, 2014
Proposal returned for revision…………………………………………..…January 2, 2015
Submission of final proposal…………………………………………..…January 15, 2015
Proposal accepted by research advisor……………………………...…....February 1, 2015
Thesis director agrees to serve………………………………………..….February 2, 2015
First draft returned by thesis director………………………...…………..….June 15, 2015
Revised draft completed…………………………………….…………………July 1, 2015
Revised draft returned by thesis director…………………..…………..……..July 15, 2015
Final text submitted to thesis director and research advisor………....…….August 1, 2015
Final text approved…………………………………………….…….…September 1, 2015
Final approved thesis uploaded to ETD……………………….……...….October 15, 2015
Graduation………………………………………………………………...November, 2015
30
VIII.
Bibliography
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32
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• ApresentationbytheFDAthatdiscussesguidelinesspecifictotheassessmentofbiosimilarity.
• OutlinesconsiderationthatshouldbemadewhenseekingFDAapprovalforabiosimilar.
Kresse,G.-B.(2009).Biosimilars-Science,status,andstrategicperspective.EuropeanJournalofPharmaceuticalsandBiopharmaceuticals,72,479-486.
• Overviewontheregulatoryandmarketframeworkforbiosimilarsaswellasthescientificconsiderationsthatmayimpactbiosimilars.
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• Afinancialassessment(viaNPV)onthefinancialattractivenessofbiosimilarsbasedonpeaksalesfromthereferencebiologic.
33
• Emphasisonsalesofreferencebiologicasakeydeterminantofvaluecreationforacounterpartbiosimilar.
Rader,R.A.(2013).AnanalysisoftheUSbiosimilarsdevelopmentpipelineandlikelyevolution.BioProcessInternational,11(6),16-23.
• Aglobalanalysisonthedevelopmentofbiosimilarsandtheirevolutioninthemarketplace.
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Rovira,J.,Espin,J.,Garcia,L.,&Labry,A.O.(2011).Theimpactofbiosimilars'entryintheEUmarket.Granada:AndalusianSchoolofPublicHealth.
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• Ananalysisonthepricingeconomicsofbiosimilars.• Thedegreeofsimilaritybetweenabiosimilarandreferencebiologicwillbe
criticalindeterminingthecost-effectivenessofthebiosimilar(i.e.,thepriceatwhichonewouldselectoneovertheother).
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34
• Outlinesvariousareasofimpact,specifically,competitionbetweenreferencebiologicsandtheircounterpartbiosimilars.
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