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1、BioavailabilityandBioequivalenceStudyinGenericandnewDrugApplications生物利用度和生物等效性在仿制药和新药申请中的法规要求魏晓雄JimWei,MD,PhDx.wei@medpace.comAAPS/CPAWorkshopShanghai,June28-29,2010Agenda议程GeneralBA/BE生物利用度和生物等效性内容概述Biowaiver生物等效性试验豁免RegulatoryrequirementsforBEsupplies,samplestorageanddataanalysis生物等效
2、性试验的法规要求BEand505(b)(2)NDA生物等效性和505(b)(2)类新药上市申报申请Bioavailability–defined生物利用度定义“Bioavailabilityisthefraction(F)ofanadministereddosethatactuallyreachessystemiccirculationwhencomparedtoasolution(SLN),suspension(SUSP),orintravenous(IV)dosageform.”--21CFR320.25(d)(2)&(3)--absolute:testdrugv
3、s.IVreference-BAofanIVdrugisassumedtobe100%,orF=1.00amountreachingcirculation=FxDoserelative:testdrugvs.SLNorSUSPreferencePlasmaConcentrationProfile血药浓度时间曲线PointstoConsider–BA生物利用度PK指标Forbioavailabilitystudies,ourprimary“metric”ofinterestis:areaundertheconcentration-timecurve(AUC)AUCisa
4、derivedparameter,itisnotobservedTypes:AUCt=tothelastdetectableconcentrationAUC=fromzerotoinfinity(singledose)AUC=betweendosingintervalsatsteady-stateApproachestoDeterminingBioequivalence(21CFR320.24)检测生物等效性试验的各种方法InvivomeasurementofactivemoietyormoietiesinbiologicfluidInvivopharmacody
5、namiccomparisonInvivolimitedclinicalcomparisonInvitrocomparisonAnyotherapproachdeemedappropriatebyFDAFeV1AlbuterolBlanchingStudyTopicalCorticosteroidTopicalsNasalSuspensionsQuestran-BindingStudiesNasalSolutions-SprayerEvaluationPropofol-DropletSizeSingle-dose,two-waycrossover,fastedSing
6、le-dose,two-waycrossover,fedAlternativesSingle-dose,parallel,fastedLongHalf-Life(wash-out):Amiodarone,EtidronateSingle-dose,replicatedesignHighlyVariableDrugsMultiple-dose,two-waycrossover,fastedLessSensitive:Clozapine(PatientTrials);ChemotherapyTrialsClinicalendpointstudyTopicals:Nasal
7、SuspensionsBEStudyDesigns生物等效性试验的设计BEStatisticalAnalysis生物等效性试验的统计分析BioequivalencecriteriaTwoone-sidedtestsprocedureTest(T)isnotsignificantlylessthanreferenceReference(R)isnotsignificantlylessthantestSignificantdifferenceis20%(=0.05significancelevel)T/R=80/100=80%R/T=80%(allda
