the scien)fic scenario: innovave medicines in ibd ... - … · the scien)fic scenario: innovave...
TRANSCRIPT
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TheScien)ficScenario:
Innova)veMedicinesinIBD&LatestNews
AlessandroArmuzzi
IBDUnit-ComplessoIntegratoColumbus
GemelliHospitalCatholicUniversityFounda@on-Rome
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Medicinalproductsthathavebeenproducedbytheuseoflivingorganisms:
● Proteins
-Hormones(growthhormones,insulins,erythropoie@ns)-Enzymes-Monoclonalan(bodies
● Bloodproducts● Immunologicalmedicinalproducts
-Sera-Vaccines-Allergens
● Advancedtechnologyproducts-Genetherapies-Celltherapies
Whatarebiologictherapies?
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Biologicsarefarmorecomplexthanconven)onalmedicines
• Biologicsdifferinsize,manufacturingcomplexity,andinthewaytheyinteractwithcellsandotherproteinsinthebody
• Differentsystemsofapprovalarenecessaryforsmallmoleculegenericsandsubsequententrybiologics
Aspirin HumanGrowthHormone MonoclonalAn5body
Biologics
180DaltonsandZeroAminoAcids
22,125Daltonsand191AminoAcids
Non-GlycosylatedProtein
148,000Daltonsand1,330AminoAcids
availableathHp://www.healio.com/orthopedics/arthri5s/news/online/%7B7bfa55f8-fffe-4d03-bbe7-049421dbbdf9%7D/two-drugs-combined-beHer-for-ra-than-methotrexate-alone.AccessedOctober2015
Conven5onalMedicine(“small-molecule”)
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4
ManufacturingofBiologicsInvolvesMul)pleStepsandIsInhererentlyComplex
FigureadaptedfromMellstedtetal.AnnOncol.2008;19:411.
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ManyBiologicsHaveUndergoneMul)pleManufacturingChangesDuringTheirLifeCycle
Number of Manufacturing Changes for Biologics from Time of First Approval in Europe
DatafromtheEuropeanMedicinesAgency.www.ema.eu.Seenotesfordetailedreferences.AllfilesaccessedOctober12,2014.
0 10 20 30 40 50 60 70 80
Benlysta™(belimumab)
Ilaris™(canakinumab)
Cimzia™(certolizumabpegol)
RoActemra™[Actemra™](tocilizumab)
Orencia™(abatacept)
Humira™(adalimumab)
Enbrel™(etancercept)
Remicade™(infliximab)
MabThera™[Rituxan™](rituximab)
number of manufacturing changes
2/6/1998
13/8/1999
3/2/2000
8/9/2003
21/5/200716/1/20091/10/200923/10/200913/7/2011
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EMA Guidelines
TheEMAUsesaComparabilityExercisetoEvaluateManufacturingChangestoApprovedBiologics1,2
1. EMA Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1). 2014. 2. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp#Otherguidelinesrelevantforbiosimilars.
“The demonstration of comparability means that the quality attributes of the pre-change and post-change product are
highly similar and existing knowledge is sufficiently predictive to ensure that any differences in quality attributes have no
adverse impact upon safety or efficacy of the drug product”1
Comparability ≠ Identical
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Source:IMSMIDAS,09/2012,IMSPatentfocus,AdaptedfromG.Morelli,IMSHealth*RaderRA,Biosimilarsmarkets.BioProcessInterna)onal2013;11(6)suppl:16-23
An)-TNFsontheTopofBiologicalSales
INN EUpatentexpdate
USpatentexpdate
Biosimilarsindevelopment*
Adalimumab 2018 2016 13
Etanercept 2015 2028 21
Infliximab 2014 2018 9
InsulinGlargine 2014 2014 5
Rituximab 2013 2016 30
Bevacizumab 2019 2017 14
InterferonB-1a Expired Expired N/A
Trastuzumab 2015 2015 N/A
InsulinAspart 2014 2019 N/A
Gla5rameracet 2017 2015 N/A
Pegfilgras5m 2015 2014 14
Ranibizumab 2016 2016 24
4.3
4.3
4.9
5
5
5.3
5.9
6.2
7.1
7.3
8.1
0 2 4 6 8 10
TotalUSD67billion
Globalsales,USDbillion
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PutrikP,etal.AnnRheumDis2014;73:198–206.
AccesstobiologicDMARDsinRAintheEUandGDPpercapita
Threemajordimensionsofaccesstomedicalcare
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● WHOdefini5on:A“similarbiotherapeu5cproduct”isabiotherapeu5cproductthatissimilarintermsofquality,safety,andefficacytoanalreadylicensedbiotherapeu5cproduct1
● EMAguidance:abiosimilarsponsoristo“generateevidencesubstan5a5ngthesimilarnature,intermsofquality,safetyandefficacy,ofthenewsimilarbiologicalmedicinalproductandthechosenreferencemedicinalproductauthorisedintheCommunity”2
● USFDA(BPCIA)defini5on:afollow-onbiologicmeans:– Thebiologicproductishighlysimilartothereferenceproduct,notwithstandingminor
differencesinclinicallyinac5vecomponents;and– Noclinicallymeaningfuldifferencesexistbetweenthebiologicproductandthereference
productintermsofthesafety,purity,andpotency3
Whatarebiosimilars?
1. hHp://www.who.int/biologicals/areas/biological_therapeu5cs/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdfAccessedOctober20152. EMA:CHMPGuidelineonSimilarBiologicalMedicinalProducts(October2005)3. FDADrakGuidances–QualityandScien5ficConsidera5onsinDemonstra5ngBiosimilaritytoaReferenceProteinProduct(Feb2012)–USGuidance)
BPCIA:BiologicsPriceCompe55onandInnova5onAct
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Biosimilardevelopmentparadigmisdifferentfromtheorignatorpathway
Originaldevelopment
Proofofefficacy&safetyby
clinicalstudies
Benefit>risk
Biosimilardevelopment
Comparabilityexercise
Noclinicalevidence
Originaldevelopment
Proofofefficacyandsafety
Biosimilardevelopment
Proofofcomparability
Clinicalprogram=proof
PhaseI
Pre-clinical
Physical,Chemical&Manufacturingcontrols
Clinicalprogram=confirma5on
PhaseI
Pre-clinical
Physical,Chemical&Manufacturingcontrols
Time&effortspentTime&effortspentForreference:EMA,FDA,WHO,Biosimilarguidelines,EPARofCT-P13
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Evalua)onofaBiosimilarAstepwise«comparabilityexercise»
1. Physicochemicalcharacteris)cs
2. Biologicalac)vity(comparisontotheRMP)
3. Pharmacodynamicsandpharmacokine)csstudies
4. Pre-clinicaltoxicologystudies
5. Clinicaltrials
-Pharmacodynamicsandpharmacokine)cs
-Safetyandefficacystudies
GuidelineonSimilarBiologicalMedicinalProducts.CHMP/437/04Rev1.Guidelineonsimilarbiologicalmedicinalproductscontainingmonoclonalan)bodies–non-clinicalandclinicalissues.EMA/CHMP/BMWP/403543/2010.
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ControlsofPhysicochemicalandBiologicalCharacteris)csofCT-P13
AdaptedfromEMA/CHMP/589317/2013AssessmentreportRemsimapp16-23
Biologicalcharacteris5cs Physicochemicalcharacteris5cs
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CT-P13Clinicalstudies:PKequivalenceandclinicalefficacy
-50
0
50
100
150
200
0 4 8 12 16 20 24 28 32 36 40 44 48
Hour
Con
cent
ratio
n µ
g/m
L
600 400 1000 200 800
ParkW,etal.AnnRheumDis2013;72:1605–12YooDH,etal.AnnRheumDis2013;72:1613–20
60.973.4
58.669.7
0
20
40
60
80
100
ITTpopula)on PPpopula)onCT-P13 INX
Respon
sera
te(%
)
Treatmentdifference2%(95%CI:-6%,10%)
Treatmentdifference4%(95%CI:-4%,12%)
184/302 178/304 182/248 175/251
Clinical Pharmacokinetics
AS study: PK similar to RMP
Clinical efficacy
Primary Endpoint: ACR20 at Week 30 RA study: clinical efficacy similarto RMP
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CT-P13 Phase 3 Study in RA Patients – Adverse Events (Source: 54 Week Data 8/12)
Drug-Related TEAEs occurring in >1% of overall safety population
AdverseEvent CT-P13(N=302) INX(N=300)
Nasopharyngi)s 24(7.9%) 17(5.7%) Latenttuberculosis 21(7.0%) 19(6.3%) UpperRespiratoryTractInfec)on 10(3.3%) 5(1.7%) InfusionRelatedReac)on 10(3.3%) 11(3.7%) ALTincreased 10(3.3%) 11(3.7%) UrinaryTractInfec)on 8(2.6%) 9(3.0%) Rheumatoidarthri)s 6(2.0%) 5(1.7%) Bronchi)s 6(2.0%) 7(2.3%) ASTincreased 5(1.7%) 7(2.3%) Hypertension 5(1.7%) 3(1.0%) Headache 5(1.7%) 7(2.3%) Pyrexia 1(0.3%) 6(2.0%) Drughypersensi)vity 6(2.0%) 11(3.7%) Hepa)cenzymeincreased 5(1.7%) 2(0.7%)
YooDH,etal.AnnRheumDis2013;72:1613–20
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Whytoextrapolateinmedicine?
EuropeanMedicinesAgencyonextrapola5on
“Theprimaryra(onaleforextrapola(onistoavoidunnecessarystudiesinthetargetpopula@onforethicalreasons,forefficiency,andtoallocateresourcesto
areaswherestudiesarethemostneeded.“1
EMAConceptpaperonextrapola)onofefficacyandsafetyinmedicinedevelopment(Final).EMA/129698/2012,2013
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KeyTopicsrelatedToInfliximabBiosimilarUptake
BiosimilarUptake
Extrapola5onAcross
Indica5ons
INNNaming&PrescribingGuidelines
Inter-changeability&Subs5tu5on
(automa5c,primary,secondary)
Pricing&Reimbursement
TenderPurchasing
IBDPhysicianPercep5on
EMA approved infliximab biosimilar for all
indications of originator (June 27, 2013)
EMA decided that infliximab biosimilar should share same INN* as originator
Countries determine whether to allow, based on presumed risk to patients, switching between
biosimilar & originator
Different Countries set different guidelines for
pricing & reimbursement
* INN: International Nonproprietary Name
?
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LearnedSociety,Country
Date Limita5ons/addi5onalcomments
Efficacy Safety Extrapola5on Switchingandsubs5tu5on
BIRD,Belgium1
Jan,2015
Paediatrictrialsneeded TrialsneededinIBDpa)ents
TrialsneededinIBDpa)ents
Shouldnotextrapolate
Physician’sdecision
BSG,UK2 Aug,2015
Prescribebybrandnameonly
Efficacymaydiffer Registryforsafetydata
Nocomment Noswitching,datainIBDneeded
ANSM,France3
Sept,2013
NotspecificforIBD Trialsforspecificindica)ons
Pharmacovigilanceandtraceabilityneeded
Fulljus)fica)onneeded
Noswitchingbutsubs)tu)ononini)a)onallowed
DCCV,Germany4
Feb,2015
Prescribebybrandnameonly
Long-termcomparabilitydataneeded
AdverseeventsrecordedinIBDregistry
Nocomment Noswitching,long-termdatainIBDneeded
IG-IBD,Italy5 Aug,2014
Expectedcostreduc)on TrialsneededinIBDpa)ents
TrialsneededinIBDpa)ents
Shouldnotextrapolate
Noswitching,datainIBDneeded
SEPD,Spanish6
March,2013
Productlabelledasbiosimilar
Trialsneededinallphases
TrialsneededinIBDpa)ents
Shouldnotextrapolate
Subs)tu)onnotacceptedprac)ce
ESPGHAN,Europe7
Oct,2015
Concernsregardingpaediatricpopula)on
Post-marke)ngsurveillancemandatory&IBDtrials
Post-marke)ngsurveillancemandatory&IBDtrials
Withcau)onandscien)ficevidence
Noswitching,datainIBDneeded
FBG&GEDIIB,Brazil8
April,2015
Dis)nctnomenclatureneeded
Manufacturerstoprovideproofagainstreference
Pharmacovigilance(PV)shouldbemandatory
Withscien)ficproofofefficacyandsafety
Noautoma)csubs)tu)on
IBDnetSwitzerland1
Feb,2014
Paediatrictrialsneeded TrialsneededinIBDpa)ents
TrialsneededinIBDpa)ents
Shouldnotextrapolate
Physician’sdecision
Medicalsocietyposi)onstatementsforbiosimilarsinIBD
17 1. Vermeire et al. Acta Gastro-Enterol Belgica. 2015;78:26–29. 2. British Society of Gastroenterology biosimilar statement; 3. ANSM Les medicaments biosimilaires. Etat des lieux. 2013; 4. Positionspapier Biosimilars der DCCV e.V. 2015; 5. Annese & Vecchi. 2014. Digestive and Liver Disease;46:963–968. 6. Argüelles-Arias et al. Rev Esp Enferm Dig. 2013;105(1):37–43. 7. de Riddler et al. JPGN. 2015;61:503–508. 8. Azevedo et al. Autoimmunity Reviews. 2015;14:769–773
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Nopolicyforsubs)tu)onofbiologicalsinplaceinEurope
Source:EGAInternalBiosimilarMapping,dataprovidedandupdatedbyEGANa)onalAssocia)onMembers,2014.*France:LOInr2013-1203du23décembre2013definancementdelasécuritésocialepour2013,Ar)cle47.
Nopolicyforsubs5tu5onofbiologicsinplaceinanycountry(EU-EEA)
FR:'Subs)tu)on'policyunderrestrictedcondi)onslegallyadopted,butNOTimplemented*
Subs5tu5onallowedforsamebiologicalproduct(differentbrandnames)
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AuthorReference
CountryYear
CD UC SwitchCD/UC
Fail% LOR F-up(wks)
Stop% SAEs%
ADA%
KangHW28 Korea2014
8 9 3/5 12.5 11 8 6 6 ng
JungYS29 Korea2015
57 69 25/27 10.8 14 54 5.5 8 ng
GecseKB
Hungary2016
126 84 na 20.5 -- 14 7.5 171death
ng
ParkSH Korea2015 95 78 44/16 25.5 11 30 3 22 ng
SieczkowskaJ Poland2016 32 7 32/7 -- 18 12 2.5 2.5 ng
FarkasK Hungary2015 18 21 na 30 ng 8 ng ng ng
JahansenJ Norway2015 46 32 na 21 ng 14 6.5 7.5 ng
FarkasK CzechRep+Hungary2016
-- 63 na 17.5 ng 14 ng ng 11.8
HeilR CzechR2016 30 22 na 4.5 ng 14 ng 7.7 ng
GecseKGolovicsPALovaszB
Hungary2016
184 107 na 49 ng 30 ng 21.3 28
Be{eyM UK2016 134 134 1.5 0 16 1.5 41 ng
SmitsL Netherlands2016
57 24 57/24 6 0 16 6 7 8.6
KolarM CzechR2016 56 18 56/18 4 19 24 4 20.2 11.6
MurphyC
Ireland2015
14vs22IFX
-- 28.5 -- 24 28.5 ↑⬆Surg&Hosp
ng
9fullpapers7abstracts
2014-2016 1142 448 ±19%
±10%
8-54 ±7%
±15% ±11%
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ThePROSIT-BIOcohort:APRospec)veObserva)onalStudyofpa)entswithInflammatoryboweldiseaseTreatedwithinfliximabBIOsimilar
• 333pa)entsreceivedRemsima®,214pa)entsreceivedInflectra®
• Cumula)venumberof2061infusions
• Meanfollow-upof4.3±2.8(median4months,IQR:2.0-6.6months).
547pa5entsenrolledin31referralCenters311pa5entswerenaïvetoan5-TNFα;139pa5entshadapreviousexposuretooneomorebiologics(31infliximab,105adalimumab,3golimumab)97pa5entsswitchedfromIFXoriginatortoCT-P13
57%50%
74%
55%43%
50%
26%
45%
0%10%20%30%40%50%60%70%80%
Overallcohort Naive Previouslyexposed
Switch
CD UC
Fiorino G, et al. Inflamm Bowel Dis 2016; in press
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Efficacyofbiosimilars:treatmentpersistency Naïve Previouslyexposed Switched Overall 8weeks* 98.4% (95.0–99.5) 97.2% (89.3–99.3) 100.0% 98.9% (97.0–99.6) 16weeks* 91.3% (84.5–95.1) 91.5% (80.3–96.4) 98.7% (91.0–99.8) 93.5% (89.6–95.9) 24weeks* 82.2% (71.9–89.0) 70.9% (52.1–83.5) 92.1% (81.9–96.7) 83.4% (77.0–88.1)
* Assessed after week 8 in 399 patients who responded Fiorino G, et al. Inflamm Bowel Dis 2016; in press
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Safety(Adverseeventsleadingtodiscon)nua)on)
4.8%2.3% 2.6%
18.0%
4.3%
13.7%
5.2%3.1% 2.1%
0,0%5,0%10,0%15,0%20,0%25,0%
AllAEs AEs(excl.Infusionreactions)
Infusionreactions
Naive Previouslyexposed Switched
AdverseEvents(excludinginfusionreac5ons)
Pvalue Infusionreac5ons Pvalue
Naivevs.previouslyexposed IRR,0.48(0.14–1.71) NS IRR:0.17(0.06–0.41) <0.001
Naivevs.switched IRR:1.10(0.25–6.58) NS IRR:1.88(0.37–18.2) NS
Previouslyexposedvs.switched IRR:2.31(0.49–14.3) NS IRR:11.0(2.65–97.3) <0.001
* *
Fiorino G, et al. Inflamm Bowel Dis 2016; in press
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Posi)on’schange
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Posi)on’schange
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43.1
67.1
89.5
6.6 16.9
27.1
92.4
3.4 0
20
40
60
80
100
They can work differently from the originator
They can have a different
immunogenicity pattern than the
originator
They will be less expensive
than the originator
There will be more indications than for
the originator
Perc
ent (
%)
2013 (N=307) 2015 (N=118)
Comparison of responses in the 2013 and 2015 ECCO surveys to the multiple choice question “What could be issues or advantages of a mAb biosimilar?”. More than one was answer possible. 1. Danese S, et al. J Crohns Colitis 2014;8:1548-50. 2. Danese S, et al. J Crohns Colitis. April 2016. Manuscript Doi:10.1093/ecco-jcc/jjw090.
Advantages and issues with biosimilars
2015ECCOPhysicianSurvey1,2
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66
84.8
5.9
22
72.3
35
89.8
44.4
27.4 39.9
0
20
40
60
80
100
Biosimilars should have different INN
Disagreement with automatic
substitution
They would switch a patient
on sustained remission
They would switch, but they would inform the
patient
They would not switch because of insufficient
data to support it
Perc
ent (
%)
2013 (N=307) 2015 (N=118)
1. Danese S, et al. J Crohns Colitis 2014;8:1548-50. 2. Danese S, et al. J Crohns Colitis. April 2016. Manuscript Doi:10.1093/ecco-jcc/jjw090.
Interchangeability and automatic substitution
2015ECCOPhysicianSurvey1,2
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5 7.6
26.4 28.7
32.3 28.8
17.8
33.9
10.2 9.3
0
20
40
Totally confident
Very confident
Enough confident
A little confident
Not confident at all
Perc
ent (
%)
2013 (N=307) 2015 (N=118)
1. Danese S, et al. J Crohns Colitis 2014;8:1548-50. 2. Danese S, et al. J Crohns Colitis. April 2016. Manuscript Doi:10.1093/ecco-jcc/jjw090.
Confidence in biosimilars
2015ECCOPhysicianSurvey1,2
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TheNOR-SWITCHStudyArandomized,double-blind,controlled,parallel-group,mul5center,phaseIV,non-inferioritycompara5vestudy
Popula5on:500pa)entsrandomised,100ineachindica)on(20%withdrawals)inpa)entswithrheumatoidarthri)s,spondyloarthri)s,psoria)carthri)s,ulcera)vecoli)s,Crohn’sdisease,andpsoriasis
Primaryendpoint:Percentageofpa)entsexperiencingdiseaseworsening
Controltreatment:• Innovatorinfliximab:INX(Remicade)Inves5ga5onalMedicalProduct:• Biosimilarinfliximab(Remsima®/Inflectra®):CT-P13
ScreeningStablepa5entsonINX(Remicade)
foratleast6months
Randomisa5on1:1
N=500
INX(Remicade)
DiseaseworseningW52 Follow-upW78
CT-P13 DiseaseworseningW52 Follow-upW78
PrimaryendpointWeek52
Switch
Assump5on:30%worseningin52weeksNon-inferioritymargin:15%
OpenLabelFollow-up
JørgensenK,etal.UEGW2016.Abstract#LB15.
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PrimaryEndpoint:DiseaseWorseningAcrossIndica)ons
INX(N=202) CT-P13(N=206) Adjustedratedifference(95%CI)
Diseaseworsening(allindica5ons)* 53(26.2%) 61(29.6%) -4.4(-12.7–3.9)
TheauthorsconcludedthatswitchfromINX(Remicade)toCT-P13wasnotinferiortocon5nuedtreatmentwithINX(Remicade)
An)-drugAn)bodies(ADAb)INX
(N=241)CT-P13(N=240)
IncidenceofADAb 17(7.1%) 19(7.9%)
Troughdruglevelsandfrequenciesofadverseeventsincludinginfusionreac5onsweresimilarbetweenINX(Remicade)andCT-P13
JørgensenK,etal.UEGW2016.Abstract#LB15.
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DiseaseWorseningbyIndica)on1,2
1.JørgensenK,etal.UEGW2016.Abstract#LB15.2.GollGL,etal.ACR2016.Abstract#19L.
INX(N=202)
CT-P13(N=206)
Adjustedratedifference*(95%CI)
All 53(26.2%) 61(29.6%) -12.7–3.9%
Crohn’sdisease 14(21.2%) 23(36.5%) -29.3–0.7%
Ulcera5vecoli5s 3(9.1%) 5(11.9%) -15.2–10.0%
Spondyloarthri5s 17(39.5%) 14(33.3%) -14.5–27.2%
Rheumatoidarthri5s 11(36.7%) 9(30.0%) -20.3–29.3%
Psoria5carthri5s 7(53.8%) 8(61.5%) -45.4–28.1%
Psoriasis 1(5.9%) 2(12.5%) -26.9–13.2%
Thetrialwasnotpoweredtoanalyzenon-inferiorityindiseaseworseningbyindividualindica5on,thiswasclassedasanexploratoryanalysis
*The percentage rate difference for each indication was not reported in the abstract
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Howtodealwithswitch,reverseswitch,crossswitchinthenearfuture?
Danese,S.etal.(2016)BiosimilarsinIBD:fromtheorytoprac)ceNat.Rev.Gastroenterol.Hepatol.doi:10.1038/nrgastro.2016.155
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Conclusions
1. Biosimilarsapprovaltothemarketfollowsacomprehensivecomparabilityexercise,whichisconsideredmoresensi)vetodetectBS-to-RMPdifferencesthanequivalenceclinicaltrials
2. Biosimilarsareavaluablecontribu)ontoimproveefficiencyinprovidinghealthcaretothepopula)on:theyareanintegralpartofphysicians’prescrip)ons
3. IBDspecialistsaregenerallywellinformedandeducatedaboutbiosimilars.Comparedwithin2013,therearenowfewerconcernsandmoreconfidenceabouttheiruseinclinicalprac)ce
4. Increasedknowledgefrompostgraduateeduca)onandpublishedevidencefromclinicalprac)ceareprobablythemainreasonsforthischangeofmind
5. Generaldisagreementwithautoma)csubs)tu)on:clearinterchangeabilityrulesareessen)altothisprocess,tosecurethetraceabilityofeachprescrip)onandofeachproduct
6. Worldwidepharmacovigilanceisneededtodetectearlyanysafetyorlossofefficacysignal
7. Pa)ents’knowledgeandinforma)onisessen)al