FDA 临床评估范本Word格式文档下载.docx
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FDA 临床评估范本Word格式文档下载.docx
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TheMedicalReviewerhasthefollowingconcernsregardingthepivotalPhase3study:
1.TherewasnostatisticallysignificantdifferenceinsurvivalbetweenthetwostudyarmsofRT-009intheintenttotreatpopulation.
2.Thesponsor’sfindingofasurvivaldifferencebetweenthetwostudyarmsofRT-009inthebreastcancersubgrouprepresentsanon-prespecifiedsubgroupanalysiswhichshouldbeconsideredexploratory.
3.ThemarginalfindingsregardingresponserateinthebraininRT-009cannotbeconsideredreasonablylikelytopredictclinicalbenefitsincetumorshrinkagecouldbeattributedtoradiationtherapygiveninbothtreatmentarms.Anotherfactorintheuncertaintyofthisfindingisthatmostdeathswereattributedtonon-neurologicalorindistinguishablecauses.OtherconcernsregardingtheassessmentofresponseinRT-009includethefollowing:
∙Confirmatoryscanswerenotrequired.
∙ThedesignationofCR/PRwasgivenwhetherornotanewbrainparenchymallesionwasdocumentedonaparticularevaluation.Seebriefingdocumentforotherconcerns.
SeeSectionIVofthisbriefingdocumentforthesafetyanalyses,whichwillbepresentedinmoredetailattheAdvisoryCommitteemeeting.
TABLEOFCONTENTSFORBRIEFINGDOCUMENT
I.IntroductionandBackgroundp.3
II.DescriptionofClinicalDataandSourcesp.8
III.Efficacyp.10
ProtocolReview(RT-009)
TrialResults
EfficacyResults–Sponsor’sAnalysis
EfficacyResults-FDAAnalysis
ProtocolReview(RT-008)
TrialResults
IV.ReviewofSafetyp.61
A.Introduction
B.Exposure
C.AdverseEvents
ClinicalReview
I.IntroductionandBackground
A.DrugEstablishedandProposedTradeName,DrugClass,Sponsor’sProposedIndication(s),Dose,Regimens,AgeGroups
GenericName:
EfaproxiralSodium
ProposedTradeName:
Excelar
EstablishedTradeName:
RSR-13
ChemicalName:
2–[4-[2-(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propanoicacidmonosodiumsalt
PharmacologicCategory:
Radiation-sensitizingagent
DrugClass:
Syntheticallostericmodifierofhemoglobin
RouteofAdministration:
Intravenous
DoseandRegimen:
75or100mg/kgdailyover30minutesthroughacentralvenouscatheter,MondaythroughFriday,for2weeks.Concurrentsupplementaloxygenisalsoadministeredatarateof4L/minvianasalcannulaorfacemaskbeginning5minutespriortoinitiationofinfusion,duringinfusionandwholebrainradiationtherapy(WBRT),andforatleast15minutesaftercompletionofdailyWBRT.WBRTmustbeadministeredwithin30minutesoftheendoftheExcelarinfusion.
PopulationStudied:
Patientswithbrainmetastasesoriginatingfromhistologicallyconfirmedsolidprimarymalignancies,excludingsmallcellcarcinoma,lymphoma,andgermcelltumors.
ProposedIndication:
Adjunctivetherapytowholebrainradiationtherapyforthetreatmentofbrainmetastasesoriginatingfrombreastcancer.
B.StateofArmamentariumforIndication
Approximatelyone-thirdtoonehalfofalladultbraintumorsresultfromhematogenousdisseminationofmalignantcellsfromanextracranialsourcetothecentralnervoussystem.Themostcommonsitesoforiginarethelung,breast,ormelanomaskincancers.Themediansurvivalfollowingtreatmentisonly3–6monthswhenmultiplemetastaticlesionsarepresentandabout12monthsforthosewithasolitarymetastaticdeposit.
(1)Thecontrast-enhancedMRIisconsideredthebestimagingstudytodiagnosebrainmetastasesandwillguidethechoiceofmanagement.TherearenoFDAapproveddrugsforthetreatmentofmetastatictumorstothebrain.Acceptedtreatmentstandardsconsistofsurgicalresectionfollowedbypost-operativeradiationtherapy,wholebrainradiationtherapy(WBRT)alone,stereotacticradiosurgery,interstitialbrachytherapy,andanecdotalreportswithhormonaltherapyincasesofbreastcancersresponsivetohormones.Theuseofchemotherapyhasbeendisappointing.Corticosteroidsaidinalleviatingperitumoraledema.Thepresenceofseizureactivityinpatientswithbrainmetastasesleadstotreatmentwithanticonvulsanttherapy.Venousthromboembolicdiseasealsooccursatahigherfrequencyinpatientswithbrainmetastases,oftenrequiringinferiorvenacavalfiltersorstandardanticoagulation.
(2)
Corticosteroidswerefirstusedin1957inpatientswithbrainmetastasesoriginatingfromthebreast,followedbydexamethasonein1961.Dexamethasonehaslessmineralocorticoidactivityandhasbeenincludedinthestandardtreatmenteversince.Itsmainmechanismofactionistoreducethepermeabilityoftumorcapillaries.
(2)
Primaryradiationtherapyhasbeenthemainstayoftreatingmetastatictumordepositsinthebrainfor40years.Themediansurvivalofpatientswithbrainmetastasistreatedwithsteroidsaloneornoformoftreatmentis1to2months.Conventionalwholebrainradiationtherapy(WBRT)increasesthemediansurvivalto3-6months.Thereisnoconsensusontheoptimalirradiationscheduleforpatientswithbrainmetastasis.Typicalirradiationtreatmentschedulesconsistoftotaldosesof30-50Gyin1.5–4Gy/dailyfraction,usually30Gyin10fractionsover2weeks.Occasionally,reirradiationisemployedatthetimeofbrainrecurrenceinpatientswithpreviouslycontrolledsystemicsymptoms.
(2)
ThreerandomizedprospectivestudieshaveevaluatedtheroleofsurgeryasanadjuncttoWBRTforpatientswithasinglebrainmetastasis.Patchelletal.randomized48patientstoreceivebiopsyfollowedbyWBRT(36Gyin12fractions)orsurgicalresectionfollowedbyWBRT.(3)PatientstreatedwithsurgeryfollowedbyWBRThadfewerlocalrecurrences(20%vs.52%,
p<
0.02),improvedsurvival(40weeksvs.15weeks),andhadabetterqualityoflifeasmeasuredbytheKarnofskyPerformanceScale.Vechtetal.alsorandomizedpatientstoWBRTaloneorsurgicalresectionfollowedbyWBRTandshowedabenefitinthetreatmentarmconsistingofsurgeryfollowedbyWBRT.(4)However,nobiopsywasperformedtoconfirmthepresenceofmetastaticdiseasetothebrainandtheradiationusedwasanunconventionalschemeusing40Gyover2weeks.Conversely,Mintzetal.observednodifferenceinsurvivalorqualityoflifebetweenpatientswhounderwentsurgeryplusradiotherapyandthosehavingradiotherapyalone.(5)Theresultsfromthe43patientsrandomizedinthatstudymaynotbetrulyrepresentativegiventheirlowerbaselinemedianKarnofskyPerformanceStatus(KPS)andhigherproportionofextracranialdisease.
Stereotacticradiosurgeryisusuallyreservedforsmall(<
3cm)lesions.Itisperformedusinghighenergyroentgenogramsproducedbythelinearaccelerator,gammaraysfromagammaknife,orwithchargedparticlesproducedbyacyclotron.Theuseofthismodalityresultsinahigherconcentrateddeliveryofradiationtothetargetedvolumeandlessradiationexposuretonormalnon-targettissue.
(2)
Interstitialbrachytherapyisusuallyperformedatthetimeofsurgicalresectionwithimplantationofradioactivenuclidesintothewallofthesurgicalcavitytodeliveranadditionaldoseofradiationtherapytothetumorwhilelimitingtheirradiationtothesurroundingbrain.Althoughinterstitialbrachytherapyisrarelyperformedforsmalllesionssuitableforradiosurgery,itmayhavealimitedroleformetastasestoolargeforradiosurgery.
(2)
Thereisnowevidencethattheblood-brainbarrierispartiallydisruptedwithinabraintumor.Assuch,theconceptoftheinabilityofchemotherapytoenterthecentralnervoussystemhasbeenchallenged.Otherfactorsmaybecontributingtothedisappointingresultsofchemotherapysuchasintrinsicresista
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