上海CMC培训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课件

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