©) Cochrane
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`Library
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`xf
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`Cochrane Database of Systematic Reviews
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`degeneration (Review)
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`steele lecCe deerme tieCeair]
`ACWARE)mlm elmeet Clay. elem allel
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`Li E, Donati S, Lindsley KB, Krzystolik MG,Virgili G
`
`Li E, Donati S, Lindsley KB, Krzystolik MG,Virgili G.
`Treatment regimens for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular
`degeneration.
`Cochrane Database ofSystematic Reviews 2020, Issue 5. Art. No.: CD012208.
`DOI: 10.1002/14651858.CD012208.pub2.
`
`www.cochranelibrary.com
`
`Treatment regimensfor administration of anti-vascular endothelial growth factor agents for neovascular age-
`related macular degeneration (Review)
`Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`WI LEY
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`TABLE OF CONTENTS
`1
`HEADER ou...csscsescsssscesessesescesessesescsscssessssescescseeecssesescescsessescessscsceasseeseseescscescssescsccsescescuaescescssesesceecssescsseseseescsasacesessuacscesesceeeneceeseeaceaceceaeaaeaes
`1
`ABSTRACT ou...csscesesssesesseeeeeeeeees
`see
`
`PLAIN LANGUAGE SUMMARY_.u.....ccccsscsecssesssecssescsssscessesssssesssscessescessessessessessesseesesececesseseescessesseaeeeseseeecesseseeaeeseeseessescesseascaseseeaeesacaeeaseoeees 2
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`SUMMARY OFFINDINGS ou....ccccccesecsecsceseesssecssesseseseseescesecseesssecsesseeseecesesceescesssecscescseseeceesesceecasecsasceceseesesescseceaseecaseeceesaeeesescsaeeesnecees
`BACKGROUND o1......1.1..ccccscsscsccecssccessosesssseseososcessssoseseesnsoessessssvessonccessescessocessoscsessssesnesscecscoessssssseesssesssoesseooossooesseesoccessecscssossssessoosssoseseeesees
`VS annosesessscsssscsssscssssssnsssssnscssosusscsssessessossssesussssnssessasessssssensssesesssassssesessussssesessssessssesssssassssssessesessesssesssssessossses
`METHODS...
`one
`eewcsecenasnaesen
`RESULTS
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`
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`oun....esccsesscescsseesceseesessessesseseessessescessesecenseseesssesssecessesaeeenseseeseeeesseesessceeescsaseesesssaeseeeseseesaseecaaseusesceaseseessaaeeeseseeseceseaeeneceseasee
`REFERENCES.
`CHARACTERISTICS OF STUDIES ou...ececsccssesssseessesccsssecessesesssesesssesseecessesceseeecesseesssseseesccsseecnsceesesseuseesessesessesenseeeseseeasseseaseesesseseeaeeaseasensenseese
`DATA AND ANALYSES .....cseccsccsssscesesscsssesesssescescessescessescessescsssesseecessescesscesesseassesesseecessesccasensessesseeceaseaccaseascasensesecaeesceseeaseaseassaeenseacenseeeensenes
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`Analysis 1.1. Comparison 1: As needed (PRN) versus monthly injections, Outcome 1: Mean changein best-corrected visual acuity
`ATL YOCAL
` oeeeeccceseesesssesceseescesessesecessesessseseeseeseeseeseseeesssseseseesesecesescesesecaseeeseseasseeesenecceseeseaesaeseseaseeeesseecessesseasensesseasenseaseacesceaseasensneseaseases
`Analysis 1.2. Comparison 1: As needed (PRN) versus monthlyinjections, Outcome2: Gain > 15letters visual acuity at lyear ...
`Analysis 1.3. Comparison 1: As needed (PRN) versus monthly injections, Outcome 3: Mean changein best-corrected visual acuity
`AT 2 YCATS
`eaeeecesecsecscesseseesseseeseescessssesssesesseesseseesesscessesesesesesscesseecessescesseeseesesseseessescessescesseaceseeaseeeesseeeessesceasesseseeaseacesseaecesesseaeenseseeaseaseasee
`Analysis 1.4. Comparison 1: As needed (PRN) versus monthly injections, Outcome4: Gain > 15 letters visual acuity at 2years ...
`Analysis 1.5. Comparison 1: As needed (PRN) versus monthly injections, Outcome 5: Mean changecentral retinal thickness at
`L YCar eecececcscsscssessecseesesseescssesscescssesscessesssssescsssessescesseecessesesesescescesensceseceseaseaesesesseecessesseaseacesseaseecesseasessesseasessusseaseeceaseaseaseascaseesuaeensaess
`Analysis 1.6. Comparison 1: As needed (PRN) versus monthly injections, Outcome 6: Mean changecentral retinal thickness at
`2 YCATS ceeescesessecscesessesssesesseessesecsesscesseseessesesseessesccsssecesseseseseseseeecseeceaseecessessesseasensesseecesseseesceusescecsessesseaceasescescesseseessseecseeaseaeesssaeegaeeenseees
`Analysis 1.7. Comparison 1: As needed (PRN) versus monthlyinjections, Outcome 7: Mean numberof injections during 2 years
`Analysis 1.8. Comparison 1: As needed (PRN) versus monthly injections, Outcome 8: Endophthalmitis .........cesesseseseseeeeeee
`Analysis 1.9. Comparison 1: As needed (PRN) versus monthly injections, Outcome9: Serious systemic adverse events.
`...........
`Analysis 1.10. Comparison 1: As needed (PRN) versus monthly injections, Outcome 10: Death oo...eeeseseeteeeeeeseseeeeneeseseeeeee
`Analysis 1.11. Comparison 1: As needed (PRN) versus monthly injections, Outcome11: Arterial thromboembolic events.
`........
`Analysis 1.12. Comparison 1: As needed (PRN) versus monthly injections, Outcome 12: Mean numberofinjections during 1
`YOAT eeeccecccceeseseseseseseetseenssseessssesessescscscsesesescecsesesescsesesesesesesssesesecsescscsescscscscsnscsesesnsesnsesnsessusesusiesssesesescesessssesesesnseseseseseseseseseseseseseceeecees
`
`4
`8
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`9
`12
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`15
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`31
`70
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`Analysis 1.13. Comparison 1: As needed (PRN) versus monthly injections, Outcome13: Sensitivity analysis excluding high-risk
`of bias: mean changein best-corrected visual acuity at 1 year
`.o...eeccececscsseseeeseseeeseeeeeseseseseseetetsnseessssesessescscsesesessscsesesesesesesnseeeseee
`Analysis 1.14. Comparison 1: As needed (PRN) versus monthly injections, Outcome 14: Sensitivity analysis using fixed effects:
`meanchangein best-corrected visual acuity at 1 year oo.eeesseseseseseseseesesesesescescseseseseeeeseseseseesesescseeeseseseseeseseseseseaeacseeeeeeaeataees
`Analysis 2.1. Comparison 2: Extended-fixed versus monthly injections, Outcome1: Mean changein best-corrected visual acuity
`ATL YOAL eeeeeeecceeeseescssesseeseeseesesesesesseeseesscsusssesesseessesessececesesseseceseeseeesesesseesseecceeeecesessesesesesesesseeecssesceasescueseassecesseseesaeaseasesaneseasseees
`Analysis 2.2. Comparison 2: Extended-fixed versus monthlyinjections, Outcome2: Gain = 15 letters visual acuity at lyear .....
`Analysis 2.3. Comparison 2: Extended-fixed versus monthly injections, Outcome 3: Mean changeof central retinal thickness at
`L YCar ecceccceccccssecscseeesesseescssessceecssececeesesececesceesescesceseeecesseeesesesceecesseecesseeceesesesecesseecessesseseescessesesecesseeeessescesuessuscesesecesseeeseaeeeseseeseeeeaseess
`Analysis 2.4. Comparison 2: Extended-fixed versus monthly injections, Outcome 4: Mean changein quality of life scores at 1
`JOA ceccececesesseseseeeesesesessesesesnesesessessesssssssesussssesesessesesueseseseseesesessesesessussesesussnsesussesesesesesesessesesuseesesusessesesesessesussesessessesesesseseseseseseeeeeeses
`Analysis 2.5. Comparison 2: Extended-fixed versus monthly injections, Outcome 5: Endophthalmitis 0.0...eeeeseeeseeeeeeeeeeees
`Analysis 2.6. Comparison 2: Extended-fixed versus monthly injections, Outcome6: Serious systemic adverse events ............++
`Analysis 2.7. Comparison 2: Extended-fixed versus monthly injections, Outcome7: Sensitivity analysis excluding high risk of
`bias: mean changein best-corrected visual acuity at 1 year oe...esesesessssesesesesesesesesescesesesesescecesesssescseeseseseaeeeesseseseeeseasateeeeeees
`82
`Analysis 2.8. Comparison 2: Extended-fixed versus monthly injections, Outcome8:Sensitivity analysis using fixed effects: mean
`changein best-corrected visual acuity at 1 year oo...eeseseseeessesesesesesesesesesesesesescscsseaeseseseesesesesessssesesescaeseeseasseneseeseasseseeeeesseaseeeees
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`79
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`Treatment regimensfor administration of anti-vascular endothelial growth factor agents for neovascular age-related macular
`degeneration (Review)
`Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
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`Analysis 3.1. Comparison 3: As needed (PRN) orextended-fixed versus other extended-fixed injections, Outcome 1: Mean change
`in best-corrected visual ACUIty oo...esesesesessesesescsessesssesesescescseseseeesesssesessesesesescscusesescseeseaeaescssussesesencuaeseacseusesesesescuceseseasacueeaeaeaeaes
`Analysis 3.2. Comparison 3: As needed (PRN) or extended-fixed versus other extended-fixed injections, Outcome 2: Gain = 15
`letters Visual ACUITY oo...eseeteeeeseseseseeeseseseseseesscsescscsssescsesseaesescscecesesescscususeseseseusesescssuceceaescscuseceseseaeseesesssesesceceaeseseeeeseseaeaeeeeeees
`Analysis 3.3. Comparison 3: As needed (PRN)orextended-fixed versus other extended-fixed injections, Outcome 3: Mean change
`In Central retinal thickMess
`......c.cccessseesesesesesssesesesenescesessscseececesesescseeseseseseseesesssesesceseseseseseesesesesessseseseseeceseseseseeceseaeseseeaeaeseseaceaeanenee
`
`Analysis 4.1. Comparison 4: No loading versus loading injections, Outcome 1: Mean changein best-corrected visual acuity at
`L YCar eececceccccccsesscssesseeseescsssesceecssesecessesesesescsssescescssesecesseseeesesceecesseeceseescessesesecesseesessescessescescesseeseaseesesseseeseeseesseaesecesseassaeeascasessneeeeasess
`Analysis 4.2. Comparison 4: No loadingversusloading injections, Outcome2: Gain > 15 letters visual acuity at lyear .............
`Analysis 4.3. Comparison 4: No loading versus loading injections, Outcome 3: Mean changein centralretinalthickness.
`.........
`ADDITIONAL TABLES.
`...........ccseeeeee
`suseseseseseesescsesesceseseseseseeseseseseesescsesesessesesesceceaeaeseseeeeeeseacaeanaeeeeenees
`seseeeseaeseeeeeeeeaee
`
`APPENDICES oo..eeceeccccecsccesssesesscesssceseccessseeesaeseseeeseecesssesesaecesaesesceseeseeseseseaeenseaceeseesesesecaesecsaessaaeensceceaceesaecueaeeseaaseeseceueeessasecseeeeeaeeeseeeeaeenees
`HISTORY wiececccccccscscessecssceesccesssesesseeseccessseeessceesacsesseceeasessecsesesecaesesseeeeseesesaeeeseceeaaseceeseessecesacecseeeeaaeceseeeeeecesececseesesaeeeseeeeeeessececeeeeeaeeeseaees
`
`CONTRIBUTIONS OF AUTHORS ou....eeeececeseseesesesesesssesnsesescesesesesesceseseseseseusesescseessseansssceseeesssceseeeesescsesesaessscseseeseseseseseeseseseseeseanseseeeeeeaeaneees
`DECLARATIONSOFINTEREST oui...seecsccessscsescesesesescscesesesescsescecessscssssusscscscuessssesesescesesssesescueesesesessesesesesesceseseseseceseassesceceaesesesenaeasaeeeeeeaeanes
`
`sone
`SOURCES OF SUPPORT
`DIFFERENCES BETWEEN PROTOCOL AND REVIEW .u......csssssssssssssssesesesesscesescseseseesssesescscesesesesesceseseseseusesesesescsaeaeseseeceaeasseseeaaeseseneeaeanenee
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`83
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`90
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`90
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`Treatment regimensfor administration of anti-vascular endothelial growth factor agents for neovascular age-related macular
`degeneration (Review)
`Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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`ii
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`[Intervention Review]
`Treatment regimensfor administration of anti-vascular endothelial
`growthfactor agents for neovascular age-related macular degeneration
`
`Emily Lil, Simone Donati2, Kristina B Lindsley3, Magdalena G Krzystolik*, GianniVirgili5
`
`1Transitional Year Residency Program, Signature Healthcare Brockton Hospital, Brockton, MA, USA. 2Departmentof Surgical and
`Morphological Sciences, Section of Ophthalmology,University of Insubria, Varese-Como,Varese,Italy. 3Life Sciences, Oncology, &
`Genomics, IBM Watson Health, Baltimore, Maryland, USA. 4Department of Ophthalmology, Retina Service, Mass Eye and EarInfirmary,
`Providence, RI, USA. SDepartmentof Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA),University of Florence,
`Florence,Italy
`
`Contact address:GianniVirgili, gianni.virgili@unifi.it.
`
`Editorial group: CochraneEyes and Vision Group.
`Publication status and date: New,published in Issue 5, 2020.
`
`Citation: Li E, Donati S, Lindsley KB, Krzystolik MG,Virgili G. Treatment regimensfor administration of anti-vascular endothelial growth
`factor agents for neovascular age-related macular degeneration. Cochrane DatabaseofSystematic Reviews 2020,Issue 5. Art. No.:
`CD012208. DOI: 10.1002/14651858.CD012208.pub2.
`
`Copyright © 2020 The CochraneCollaboration. Published by John Wiley & Sons,Ltd.
`
`ABSTRACT
`
`Background
`
`Age-related macular degeneration (AMD)is one of the leading causes of permanent blindness worldwide. The current mainstay of
`treatment for neovascular AMD (nAMD)is intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents: aflibercept,
`ranibizumab,andoff-label bevacizumab.Injections can be given monthly, every two or three months(‘extended-fixed'), or as needed (pro
`re nata (PRN)). A variant of PRNis 'treat-and-extend' wherebyinjections are resumed if recurrence is detected and then delivered with
`increasing intervals. Currently, injection frequency varies amongpractitioners, which underscores the need to characterize an optimized
`approach to nAMD management.
`
`Objectives
`
`To investigate the effects of monthly versus non-monthly intravitreous injection of an anti-VEGF agentin people with newly diagnosed
`nAMD.
`
`Search methods
`
`We searched CENTRAL, MEDLINE, Embase,LILACS,and three trials registers from 2004 to October 2019; checked references; handsearched
`conference abstracts; and contacted pharmaceutical companies to identify additionalstudies.
`
`Selection criteria
`
`Weincluded randomized controlled trials (RCTs) that compared different treatment regimensfor anti-VEGF agents in people with newly
`diagnosed nAMD.Weconsidered standard doses only (ranibizumab 0.5 mg, bevacizumab 1.25 mg,aflibercept 2.0 mg, or a combination
`of these).
`
`Data collection and analysis
`
`We used standard Cochrane methodsfortrial selection, data extraction, and analysis.
`
`
`
`Treatment regimensfor administration of anti-vascular endothelial growth factor agents for neovascular age-related macular
`degeneration (Review)
`Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`1
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`Mainresults
`
`Weincluded 15 RCTs. The total numberofparticipants was 7732, ranging from 37to 2457in eachtrial. Thetrials were conducted worldwide.
`Of these,six trials exclusively took place in the US, and three included centers from more than one country.Eight trials were at high risk of
`bias for at least one domain andall trials had at least one domainatunclearrisk of bias.
`
`Seventrials (3525 participants) compared a PRN regimen with a monthly injection regimen,of whichfive trials delivered four to eight
`injections using standard PRN andthree delivered nine or 10 injections using a treat-and-extend regimenin thefirst year. The overall
`meanchangein best-corrected visual acuity (BCVA) at one year was+8.8letters in the monthly injection group. Compared to the monthly
`injection, there was moderate-certainty evidence that the meandifference (MD) in BCVA changeat one year for the standard PRN subgroup
`was-1.7 letters (95% confidenceinterval(Cl) -2.8 to -0.6; 4 trials, 2299 participants), favoring monthly injections. There was low-certainty
`evidence of a similar BCVA changewith the treat-and-extend subgroup(0.5 letters, 95% Cl -3.1 to 4.2; 3 trials, 1226 participants).
`
`Compared to monthly injection, there was low-certainty evidence that fewerparticipants gained 15 or morelines of vision with standard
`PRN treatmentat oneyear (risk ratio (RR) 0.87, 95% Cl 0.76 to 0.99;4 trials, 2299 participants) and low-certainty evidenceof a similar gain
`with treat-and-extend versus monthly regimens (RR 1.11, 95% Cl 0.91 to 1.36; 3 trials, 1169 participants).
`
`The meanchangein centralretinal thickness was a decrease of -166 um in the monthlyinjection group; the MD compared with standard
`PRN was21 um (95% Cl6 to 32;4 trials, 2215 participants; moderate-certainty evidence) and with treat-and extend was 22 um (95% Cl 37 to
`-81 um;2 trials, 635 participants; low-certainty evidence), in favor of monthlyinjection. Only onetrial (498 participants) measured quality
`of life and reported no evidence ofa difference between regimens, but data could not be extracted (low-certainty evidence).
`
`Both PRN regimens(standard and'treat-and-extend') used fewerinjections than monthly regimens(standard PRN: MD -4.6injections, 95%
`Cl -5.4 to -3.8; 4 trials, 2336 participants; treat-and-extend: -2.4 injections, 95% Cl -2.7 to -2.1 injections; moderate-certainty evidence
`for both comparisons). Twotrials provided cost data (1105 participants, trials conducted in the US and the UK). They found that cost
`differences between regimens were reduced if bevacizumabratherthanaflibercept or ranibizumab were used, since bevacizumab was
`less costly (low-certainty evidence).
`
`PRN regimenswere associated with a reduced risk of endophthalmitis compared with monthly injections (Peto oddsratio (OR) 0.13, 95%
`Cl 0.04 to 0.46; 6 RCTs, 3175 participants; moderate-certainty evidence). Using data from alltrials included in this review, we estimated
`the risk of endophthalmitis with monthly injections to be 8 in every 1000 peopleperyear. The correspondingrisk for people receiving PRN
`regimenswas1 in every 1000 people per year (95% Cl 0 to 4).
`
`Three trials (1439 participants) compared an extended-fixed regimen (numberof injections reported in only onelargetrial: 7.5 in one
`year) with monthly injections. There was moderate-certainty evidence that BCVAat one yearwassimilar for extended-fixed and monthly
`injections (MD in BCVA change compared to extended-fixed group:-1.3 letters, 95% Cl -3.9 to 1.3; RR of gaining 15 letters or more: 0.94,
`95% CI 0.80 to 1.10). The changein centralretinal thickness wasa decrease of 137 um in the monthly group; the MD with the extended-fixed
`group was8 um (95% Cl -11 to 27; low-certainty evidence). The frequency of endophthalmitis was lower in the extended-fixed regimen
`compared to the monthly group,but this estimate was imprecise (RR 0.19, 95% CI 0.03 to 1.11; low-certainty evidence).If we assumed a
`risk of 8 cases of endophthalmitis in 1000 people receiving monthly injections over one year, then the correspondingrisk with extended-
`fixed regimen was 2 in 1000 people (95% CI0 to 9).
`
`Other evidence comparingdifferent extended-fixed or PRN regimensyielded inconclusiveresults.
`
`Authors' conclusions
`
`We foundthat, at one year, monthly regimensare probably more effective than PRN regimensusing sevenoreightinjectionsin thefirst year,
`but the difference is small and clinically insignificant. Endophthalmitis is probably more commonwith monthlyinjections and differences
`in costs between regimensare higherif aflibercept or ranibizumab are used compared to bevacizumab.
`
`This evidence only applies to settings in which regimens are implemented as describedin thetrials, whereas undertreatmentis likely to
`be commoninreal-world settings. There are no data from RCTs on long-term effects of different treatment regimens.
`
`PLAIN LANGUAGE SUMMARY
`
`Comparingdifferent injection frequencies for neovascular age-related macular degeneration
`
`Whatwasthe aim ofthis review?
`
`The aim of this Cochrane Review wastofind outif anti-vascular endothelial grownfactor(anti-VEGF) injections for neovascular age-related
`macular degeneration (nAMD)can be given less frequently than every month.
`
`Key messages
`This review found that people receiving monthly injections hadslightly better vision (one or twoletters more on a vision test chart, less
`than half-line of vision) at one year compared with peoplereceiving injections 'as needed' (average: seven injections), but there was no
`
`
`Treatment regimensfor administration of anti-vascular endothelial growth factor agents for neovascular age-related macular
`degeneration (Review)
`Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`2
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`difference with a modified 'as needed’ regimencalled treat-and-extend (average:nine injections). People receiving monthlyinjections had
`moreinjections andthis increased the risk ofrare, but severe side effects suchasinfections.
`
`What wasstudied in this review?
`Neovascular age-related macular degeneration occurs in older people andaffects the central part of vision. In nAMD, new blood vessels
`growat the backofthe eye.
`
`People with nAMD canbenefit from injections of medicines into the eye. These ‘anti-VEGF’ medicines block the growth of new bloodvessels.
`Currently, there is variation in how often these injections are given. A greater numberof injections mayresult in better vision but also
`increase harm,such as endophthalmitis, a sight-threatening infectionofthe eye. More injections are also more costly forthe health service.
`
`Whatwere the mainresults of the review?
`Cochraneresearchers identified 15 studies (7732 participants) comparing non-monthly and monthly injections. Six out of 15 studies were
`funded by drug manufacturers.
`
`The review found:
`
`People whohadless frequent anti-VEGF injections may havehadslightly worse vision at one year compared with people having monthly
`injections wheninjections (seven on average) are delivered 'as needed’. This wasa difference of 1 or 2 more letters read on a vision test
`chart and an approximate 10% increased chanceofgaining 15 or moreletters of vision with monthly injections. There was no evidence of
`difference between monthly injections and treat-and-extend (nine injections on average).
`
`There wasanincreased chanceof endophthalmitis with monthly injections. Endophthalmitis is rare, occurring in approximately 8 in 1000
`people having monthlyinjections for one year, and in approximately 1 per 1000 people (range0 to 4) having less than monthlyinjections
`‘as needed’.
`
`How up-to-date wasthis review?
`The search wasupdated on 18 October 2019.
`
`
`
`Treatment regimensfor administration of anti-vascular endothelial growth factor agents for neovascular age-related macular
`degeneration (Review)
`Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`3
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`JUaLU}eaI| SUMMARY OF FINDINGS
`Je}Newpa}eyas-ase1e]NIsPAOAUJO}SJUdTE10}2}YIMOIS}eNayROPUAJE}NISeA-1UEJOUONE4}SIUILUPeOJSUdLUIZAI
`
`
`
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`
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`°
`8
`o
`2og
`a
`o
`S
`g
`a
`3
`=
`®
`
`=5
`
`Test for sub-
`group differ-
`ences
`
`P=0.26
`
`Test for sub-
`group differ-
`ences
`
`P=0.04
`
`Test for sub-
`groupdiffer-
`ences
`P=0.97
`
`2299
`(4 RCTs)
`
`®86O
`Moderate 2
`
`Standard PRN
`
`MD1.68 letters lower
`(-2.81 to -0.55)
`
`Treat-and-extend
`
`MD 0.51 higher(-3.14 to 4.16)
`
`_
`
`—
`
`Standard PRN
`
`256 per 1000
`(223 to 291)
`
`RR 0.87
`
`(0.76 to 0.99)
`
`1226
`
`(3 RCTs)
`
`2299
`(4 RCTs)
`
`Treat-and-extend
`
`RR1.11
`
`1169
`
`(0.91 to 1.36)
`
`(3 RCTs)
`
`326 per 1000
`(268 to 400)
`
`Standard PRN
`.
`MD20.8 um higher
`(5.8 to 35.9)
`
`Treat-and-extend
`
`MD 22.0 pm higher
`
`_
`
`=
`
`2215
`(4 RCTs)
`
`®BeO
`Moderate 27
`
`635
`
`(2)
`
`®8O0
`Low 4.c
`
`600
`Low a,b
`
`S600
`Low 4,¢
`
`®6O0
`Low 2.¢
`
`SamsungBioepis Exhibit 1034 - Page 7
`Biocon Exhibit 1034 - Page 7
`
`Changein BCVA at 1 year
`(ETDRSletters score, the
`higherthe score the better)
`
`The meanchangein BCVA at 1
`year was+8.8 letters
`
`Gain of 2 15letters visual
`acuity at 1 year
`
`294 per 1000
`
`Changein centralretinal
`thicknessat 1 year (um, the
`thinner the better on average)
`
`The mean changein central
`retinal thickness at 1 year was —
`165.5um
`
`
`
`(MalAay)UOeaUadap
`
`Summary of findings 1. As needed compared to monthly injections for administration of anti-vascular endothelial growth factor agents for
`neovascularage-related macular degeneration
`
`PRN compared to monthlyinjections for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular degeneration
`
`Patient or population: people with neovascular age-related macular degeneration
`
`Setting: eye services delivering intravitreal injections of anti-vascular endothelial growth factor agents
`
`Intervention: PRNinjections
`
`Comparison: monthly injections
`
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`Outcomes Certaintyof|CommentsAnticipated absolute effects* (95% Cl) Relative ef- N¢ of partici-
`
`
`
`$A fect
`pants
`the evidence
`
`Risk with monthly injections—_Risk with PRN (95% Cl) (studies) (GRADE)
`
`
`
`

`

`
`
`(mataay)UoNesauazap
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`
`“Pd‘suos°9Aay1MUYorAqpaysi|qnd‘uonesoge}}ODauesyI09AY!0207@IYy8uUAdo
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`
`e880
`Moderate 7
`‘04per
`(0.04 to 0.46)
`(6 RCTs)
`
`
`
`
`
`
`
`
`
`
`
`Changein Qolscores at 1
`year(higherwasbetter)
`
`Data could not be extracted. Author reported that measures of QoL
`(median EuroQoL EQ-5D)did not differ to a significant degree be-
`tween monthly and PRNat1 year.
`
`(-37.2 to -81.1)
`
`Numberof injections at 1
`year
`
`The mean numberof injections
`at 1 year was 11.3
`
`Standard PRN
`
`MD 4.57 lower
`(-5.38 to -3.76 lower)
`
`Treat-and extend
`
`MD2.42 lower
`
`(-2.71 to -2.14)
`
`Cost of treatmentperper-
`son at lyear
`
`We could not estimatethe difference in meancost of treatment per
`personat1 yearfor different regimens. Differences betweenregi-
`menswerereduced if bevacizumabwasused.
`
`31)
`
`a8
`a>
`95
`< g
`o
`
`oss
`Soe
`238>of
`sa2
`Fae72.98
`
`498
`(1 RCT)
`
`2336
`
`(4 RCTs)
`
`1232
`
`(3 RCTs)
`
`1105
`
`(2 RCTs)
`
`Low 2.¢
`
`e860
`Moderate 2
`
`@8SO
`Moderate 2
`
`Low 4
`
`Test for sub-
`group differ-
`ences
`
`P<0.01
`
`1 per 1000
`a coal
`
`Peto OR 0.13
`
`3175
`
`
`
`Endophthalmitis (ocularad-
`verseevent)
`
`8 per 1000
`
`*The risk in the intervention group(and its 95% confidenceinterval) is based on the assumed risk in the comparison group and therelative effect of the intervention (and
`its 95% Cl).
`
`BCVA:best-corrected visual acuity; Cl: confidence interval; ETDRS: Early TreatmentDiabetic Retinopathy Study; MD: meandifference; OR: oddsratio; PRN: as needed;
`QoL:quality of life; RCT: randomized controlled trial; RR:risk ratio.
`
`GRADEWorking Groupgradesof evidence
`High-certainty: weare very confidentthatthe trueeffect lies close to that of the estimateof the effect.
`Moderate-certainty: we are moderately confident in the effect estimate: the true effectis likely to be close to the estimate of the effect, but there is a possibility thatit is
`substantially different.
`Low-certainty: our confidencein the effect estimateis limited: the true effect may be substantially different from the estimateofthe effect.
`Very low-certainty: we havevery little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate ofeffect.
`
`9Downgradedonelevel for potential risk of bias as more than half were 'unclear' or ‘high.’
`bDowngraded onelevelfor inconsistency due to heterogeneity in the treat-and-extend subgroup
`Downgraded onelevelfor imprecision as no quantitative data could be extracted: "no difference" reported butthe precision of this statement wasunclear.
`dDowngraded twolevels for indirectness as drug cost data available from two studies (CATT 2011; IVAN 2012b), and a full economic evaluation available from one study (!VAN
`2012b): data available from two countries (US and UK), not including measures of variation in total cost per regimen, with unknownapplicability to other settings.
`
`
`
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`
`SamsungBioepis Exhibit 1034 - Page 8
`Biocon Exhibit 1034 - Page 8
`
`

`

`
`
`
`
`
`
`“Pd‘suos°9Aay1MUYorAqpaysi|qnd‘uonesoge}}ODauesyI09AY!0207@IYy8uUAdo
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`JUaLU}eaI| Summary offindings 2. Extended-fixed compared to monthly injections for administration of anti-vascular endothelial growth factor agents for
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`
`
`
`
`
`
`
`Gain of > 15 letters vi-
`sualacuity at 1 year
`
`300 per 1000
`
`280 per 1000
`(240 to 330)
`
`RR0.94
`
`1441
`
`(0.80 to 1.10)
`
`(3 RCTs)
`
`Changein centralreti-
`nal thicknessat 1 year
`(um,the thinnerthe bet-
`ter on average)
`
`Changein Qolscore at
`1 year (measured with
`NEI VFQ-25 question-
`naire; the higher score
`the better)
`
`Numberofinjections at
`lyear
`
`The meanchangecentralretinal
`thickness at 1 year was -137 pm
`
`MD8.16 higher
`(-11.07 to 27.40)
`
`
`
`The meanchangein QoLscore at 1
`year was an improvementof about 5
`
`MD 0.59 lower
`(-2.22 to 1.04)
`
`1439
`
`(3 RCTs)
`
`1220
`(1 RCT)
`
`Only 1 trial (1220 participants) comparing an extended (bimonthly) with a monthly regimen:7.5 injections
`with the extended-fixed regimen (scheduled for 8 injections), 12.3 in the monthly regimen (scheduled for 13
`injections); no measures of variation reported andlimited variation in the numberofinjections within each
`arm expected.
`
`Cost of treatment per
`person at 1 year
`
`Noneof the trials in this comparison category measured treatmentcost.
`
`
`
`(MalAay)UOeaUadap
`
`neovascularage-related macular degeneration
`
`Extended-fixed compared to monthly injections for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular degener-
`ation
`
`Patient or population: people with neovascular age-related macular degeneration
`
`Setting: eye services delivering intravitrealinjections of anti-vascular endothelial growth factor agents
`
`Intervention: extended-fixed injections, such as injections every 2 or 3 months
`
`Comparison: monthly injections
`
`Outcomes
`
`Anticipated absolute effects* (95% Cl)
`
`Change in BCVA at 1
`year(ETDRSletters
`score, the higher the
`score the better)
`
`Risk with monthly injections
`
`Risk with extended-fixed
`
`The mean changein BCVAat 1 year
`was9 letters' improvement
`
`MD 1.32 letters lower
`
`(-3.93 to 1.29)
`
`
`
`Relative effect
`(95% Cl)
`
`Ne of partici-
`pants
`(studies)
`
`1439
`
`(3 RCTs)
`
`Certainty of
`the evidence
`(GRADE)
`
`S860
`Moderate 7
`
`Comments
`
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`Moderate 7
`
`Notapplica-
`ble
`
`Notapplica-
`ble
`
`SamsungBioepis Exhibit 1034 - Page 9
`Biocon Exhibit 1034 - Page 9
`
`

`

`
`
`(mataay)UoNesauazap
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`lar adverse event)
`
`8 per1000
`
`2 per1000
`
`(0 to 9)
`
`RR0.19(0.03to
`1.12)
`
`1132
`
`(3 RCTs)
`
`S600
`Low a,b
`
`—
`
`*Therisk in the intervention group(and its 95% confidenceinterval) is based on the assumed risk in the comparison groupandtherelative effect ofthe intervention (and
`its 95% Cl).
`BCVA: best-corrected visual acuity; Cl: confidence interval; ETDRS: EarlyTreatmentDiabetic Retinopathy Study; MD: mean difference; NE! VFQ-25 : NationalEye Institute
`25-Item Visual Functioning Questionnaire; QoL: quality of life; RCT: randomized controlled trial; RR:risk ratio.
`
`GRADEWorking Groupgradesof evidence
`High-certainty: weare very confidentthatthe trueeffect lies close to that of the estimateoftheeffect.
`Moderate-certainty: we are moderately confident in the effect estimate: the true effectis likely to be close to the estimate ofthe effect, but there is a possibility thatit is
`substantially different.
`Low-certainty: our confidencein the effect estimateis limited: the true effect may be substantially different from the estimate of the effect.
`Very low-certainty: we havevery little confidencein the effect estimate: the true effect is likely to be substantially different from the estimate ofeffect.
`
` Endophthalmitis (ocu-
`
`2Downgraded onelevel for potential risk of bias as more than half were ‘unclear’ or ‘high.’
`bDowngraded onelevel for imprecision due to wide confidence intervals aroundestimate.
`
`SamsungBioepis Exhibit 1034 - Page 10
`Biocon Exhibit 1034 - Page 10
`
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`Trusted evidence.
`Coch rane
`Informeddecisions.
`:
`=
`Cochrane Database ofSystematic Reviews
`Better health.
`Library
`i
`
`
`BACKGROUND
`
`Description of the condition
`
`its efficacy and safety, ANCHOR and MARINA (ANCHOR 2009;
`MARINA2006). Bevacizumab,a monoclonalantibody against VEGF-
`A, has been used alongside ranibizumabas a cheaperanti-VEGF
`alternative. Although it is FDA approved only for the treatment
`a_ progressive,
`is
`Age-related macular degeneration (AMD)
`of colorectal cancer, non-small cell lung cancer, cervical cancer,
`degenerative disease of the central retina, known as the macula,
`glioblas