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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JimWei,MD,PhDx.AAPS/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:testdrugvs.IVreference-BAofanIVdrugisassumedtobe100%,orF=1.00amountreachingcirculation=FxDoserelative:testdrugvs.SLNorSUSPreferencePointstoConsider–BA
生物利用度PK指标
Forbioavailabilitystudies,ourprimary“metric”ofinterestis:areaundertheconcentration-timecurve(AUC)AUCisaderivedparameter,itisnotobservedTypes:AUCt=tothelastdetectableconcentrationAUC=fromzerotoinfinity(singledose)AUC=betweendosingintervalsatsteady-stateApproachestoDeterminingBioequivalence(21CFR320.24)
检测生物等效性试验的各种方法
InvivomeasurementofactivemoietyormoietiesinbiologicfluidInvivopharmacodynamiccomparisonInvivolimitedclinicalcomparisonInvitrocomparisonAnyotherapproachdeemedappropriatebyFDAFeV1AlbuterolBlanchingStudyTopicalCorticosteroidTopicalsNasalSuspensionsQuestran-BindingStudiesNasalSolutions-SprayerEvaluationPropofol-DropletSizeSingle-dose,two-waycrossover,fastedSingle-dose,two-waycrossover,fedAlternativesSingle-dose,parallel,fastedLongHalf-Life(wash-out):Amiodarone,EtidronateSingle-dose,replicatedesignHighlyVariableDrugsMultiple-dose,two-waycrossover,fastedLessSensitive:Clozapine(PatientTrials);ChemotherapyTrialsClinicalendpointstudyTopicals:NasalSuspensionsBEStudyDesigns
生物等效性试验的设计
BiopharmaceuticsClassification
System(BCS)生物药剂学分类体系TheBCSisascientificframeworkforclassifyingdrugsbasedontheiraqueoussolubilityandintestinalpermeabilityAppliestodrugsubstancewithhighsolubilityandhighpermeability(BCSClass1)WaiversofInVivoBEstudiesforBCSClass1drugsinimmediatereleasesolidoraldosageformsthatexhibitrapiddissolutionWaiverofinvivoBEstudiesbasedonaBiopharmaceuticsClassificationSystem(BCS)
生物药剂学分类体系和生物等效性试验豁免
RecommendedforasolidoralTestproductthatexhibitsrapid(85%in30min)andsimilarinvitrodissolutionunderspecifiedconditionstoanapprovedReferenceproductwhenthefollowingconditionsaresatisfied:ProductsarepharmaceuticalequivalentsDrugsubstanceishighlysolubleandhighlypermeableandisnotconsideredhaveanarrowtherapeuticrangeExcipientsusedarenotlikelytoeffectdrugabsorptionHighlyVariableDrugs(HVD)
高变异药物DefinitionUseANOVARootMeanSquareError(RMSE)toestimatewithin-subjectorintra-subjectvariability:DrugisclassifiedashighlyvariableifRMSE≥0.3or30%TwomaintypesorsourcesofvariabilityHighlyvariablePK(inherentdrugcharacteristic)Highlyvariableformulation•StandardBEstudyapproachmayneedmorethan100subjectsReasonsforInconsistentVariabilityinBEStudies
生物等效性试验中不一致变异的原因
DifferencesinformulationsImproperlyhandlingofBioanalyticalassaysSubjectswithirregularplasmaconcentrationsNumberofstudysubjectsUncontrolledfoodstatus90%CIs&BELimits
90%可信区间和生物等效性试验界线
GreenLowWSV(~15%)Narrow90%CIPassesRedHighWSV(~35%)Wide90%CILowerbound<80%Fails125%100%80%GMR&the#ofsubjectsarethesameinbothcasesBEStudiesinHighlyVariableDrugs(HVD)
高变异药物的生物等效性试验
FDAStudytoCharacterizeHighlyVariableDrugsinBEStudies:Collecteddatafrom1127acceptableBEstudies,submitted524ANDAsfrom2003-2005(3years)Mostsponsorsused2-waycrossoverstudiesUsedANOVARootMeanSquareErrortoestimatewithin-subjectvarianceDrugwasclassifiedashighlyvariableifRMSE≥0.3or30%BEstudiesofHVDenrolledmorestudysubjectsthanstudiesofdrugswithlowvariabilityAverageNinstudiesofHVD=47AverageNinstudiesofdrugswithlowervariability=33Range18–73subjects10%ofstudiesevaluatedwereHVDAdvantagesofScaledBE増宽的生物等效性试验的优点(ReferenceScaled)Testproductwillbenefitif:Tvariability<RvariabilityThetestproductwillnotbenefitif:Tvariability>RvariabilityWhatifhighvariabilityresultsfromformulationsproblemsorpoorstudyconduct?IfTvariability>Rvariability,nobenefitinusingscaledapproachTheburdenisontheapplicanttoconvinceFDAthatproductisaHVD21CFR320.36
Requirementsformaintenanceofrecordsofbioequivalencetesting生物等效性试验记录保存的法规要求
Allrecordsofinvivoorinvitrotestsshallbemaintainedbythemanufacturerforatleast2yearsaftertheexpirationdateofthebatchandsubmittedtotheFoodandDrugAdministrationonrequest.
AnypersonwhocontractswithanotherpartytoconductabioequivalencestudyfromwhichthedataareintendedtobesubmittedtoFDAaspartofanapplicationsubmittedunderpart314ofthischaptershallobtainfromthepersonconductingthestudysufficientaccuratefinancialinformationtoallowthesubmissionofcompleteandaccuratefinancialcertificationsordisclosurestatementsrequiredunderpart54ofthischapterandshallmaintainthatinformationandallrecordsrelatingtothecompensationgivenforthatstudyandallotherfinancialinterestinformationrequiredunderpart54ofthischapterfor2yearsafterthedateofapprovaloftheapplication.Thepersonmaintainingtheserecordsshall,uponrequestforanyproperlyauthorizedofficeroremployeeoftheFoodandDrugAdministration,atreasonabletime,permitsuchofficeroremployeetohaveaccesstoandcopyandverifytheserecords.
BESampleRetention
生物等效性试验样品保存
TheguidancehighlightshowthetestarticleandreferencestandardforBAandBEstudiesshouldbedistributedtothetestingfacilitieshowtestingfacilitiesshouldrandomlyselectsamplesfortestingandmaterialtomaintainasreservesampleshowthereservesamplesshouldberetained.FDA/DSIInspectiononBEStudies
FDA对生物等效性试验的监察
Afrequentfindingfromtheseinspectionsistheabsenceofreservesamplesatthetestingfacilitieswherethestudiesareconducted:Inmanycases,DSIfindsthattestingfacilitiesreturnreservesamplestothestudysponsorsand/ordrugmanufacturers,Inothercases,studysponsorsand/ordrugmanufacturers,SMOs,orcontractpackagingfacilitiesdesignatethestudytestarticleandreferencestandardforeachsubject,andprecludethetestingfacilitiesfromrandomlyselectingrepresentativereservesamplesfromthesupplies.Thestudysponsorand/ordrugmanufacturershouldsendtothetestingfacilitybatchesofthetestarticleandreferencestandardpackagedinsuchawaythatthetestingfacilitycanrandomlyselectsamplesforbioequivalencetestingandsamplestomaintainasreservesamples.FDA/DSIInspectiononBEStudiescont’d
FDA对生物等效性试验的监察
QuantityofReserveSamplesSufficienttoperformfivetimesallofthereleasetestsrequiredintheapplicationorsupplementalapplicationForsolidoraldosageforms(e.g.,tablets,capsules),anupperlimitof300unitseachforthetestarticleandreferencestandardEachsiteisaskedtoretainareasonableamountoftestarticleandreferencestandardamin
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