BioavailabilityandBioequivalenceStudyinGenericandnewDrugApplications

生物利用度和生物等效性在仿制藥和新藥申請中的法規要求JimWei,MD,PhDx.AAPS/CPAWorkshopShanghai,June28-29,2010Agenda議程GeneralBA/BE生物利用度和生物等效性內容概述Biowaiver生物等效性試驗豁免RegulatoryrequirementsforBEsupplies,samplestorageanddataanalysis生物等效性試驗的法規要求BEand505(b)(2)NDA生物等效性和505(b)(2)類新藥上市申報申請

Bioavailability–defined

生物利用度定義

“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指標

Forbioavailabilitystudies,ourprimary“metric”ofinterestis:areaundertheconcentration-timecurve(AUC)AUCisaderivedparameter,itisnotobservedTypes:AUCt=tothelastdetectableconcentrationAUC=fromzerotoinfinity(singledose)AUC=betweendosingintervalsatsteady-stateApproachestoDeterminingBioequivalence(21CFR320.24)

檢測生物等效性試驗的各種方法

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

生物等效性試驗的設計

BiopharmaceuticsClassification

System(BCS)生物藥劑學分類體系TheBCSisascientificframeworkforclassifyingdrugsbasedontheiraqueoussolubilityandintestinalpermeabilityAppliestodrugsubstancewithhighsolubilityandhighpermeability(BCSClass1)WaiversofInVivoBEstudiesforBCSClass1drugsinimmediatereleasesolidoraldosageformsthatexhibitrapiddissolutionWaiverofinvivoBEstudiesbasedonaBiopharmaceuticsClassificationSystem(BCS)

生物藥劑學分類體系和生物等效性試驗豁免

RecommendedforasolidoralTestproductthatexhibitsrapid(85%in30min)andsimilarinvitrodissolutionunderspecifiedconditionstoanapprovedReferenceproductwhenthefollowingconditionsaresatisfied:ProductsarepharmaceuticalequivalentsDrugsubstanceishighlysolubleandhighlypermeableandisnotconsideredhaveanarrowtherapeuticrangeExcipientsusedarenotlikelytoeffectdrugabsorptionHighlyVariableDrugs(HVD)

高變異藥物DefinitionUseANOVARootMeanSquareError(RMSE)toestimatewithin-subjectorintra-subjectvariability:DrugisclassifiedashighlyvariableifRMSE≥0.3or30%TwomaintypesorsourcesofvariabilityHighlyvariablePK(inherentdrugcharacteristic)Highlyvariableformulation?StandardBEstudyapproachmayneedmorethan100subjectsReasonsforInconsistentVariabilityinBEStudies

生物等效性試驗中不一致變異的原因

DifferencesinformulationsImproperlyhandlingofBioanalyticalassaysSubjectswithirregularplasmaconcentrationsNumberofstudysubjectsUncontrolledfoodstatus90%CIs&BELimits

90%可信區間和生物等效性試驗界線

GreenLowWSV(~15%)Narrow90%CIPassesRedHighWSV(~35%)Wide90%CILowerbound<80%Fails125%100%80%GMR&the#ofsubjectsarethesameinbothcasesBEStudiesinHighlyVariableDrugs(HVD)

高變異藥物的生物等效性試驗

FDAStudytoCharacterizeHighlyVariableDrugsinBEStudies:Collecteddatafrom1127acceptableBEstudies,submitted524ANDAsfrom2003-2005(3years)Mostsponsorsused2-waycrossoverstudiesUsedANOVARootMeanSquareErrortoestimatewithin-subjectvarianceDrugwasclassifiedashighlyvariableifRMSE≥0.3or30%BEstudiesofHVDenrolledmorestudysubjectsthanstudiesofdrugswithlowvariabilityAverageNinstudiesofHVD=47AverageNinstudiesofdrugswithlowervariability=33Range18–73subjects10%ofstudiesevaluatedwereHVDAdvantagesofScaledBE増寬的生物等效性試驗的優點(ReferenceScaled)Testproductwillbenefitif:Tvariability<RvariabilityThetestproductwillnotbenefitif:Tvariability>RvariabilityWhatifhighvariabilityresultsfromformulationsproblemsorpoorstudyconduct?IfTvariability>Rvariability,nobenefitinusingscaledapproachTheburdenisontheapplicanttoconvinceFDAthatproductisaHVD21CFR320.36

Requirementsformaintenanceofrecordsofbioequivalencetesting生物等效性試驗記錄保存的法規要求

Allrecordsofinvivoorinvitrotestsshallbemaintainedbythemanufacturerforatleast2yearsaftertheexpirationdateofthebatchandsubmittedtotheFoodandDrugAdministrationonrequest.

AnypersonwhocontractswithanotherpartytoconductabioequivalencestudyfromwhichthedataareintendedtobesubmittedtoFDAaspartofanapplicationsubmittedunderpart314ofthischaptershallobtainfromthepersonconductingthestudysufficientaccuratefinancialinformationtoallowthesubmissionofcompleteandaccuratefinancialcertificationsordisclosurestatementsrequiredunderpart54ofthischapterandshallmaintainthatinformationandallrecordsrelatingtothecompensationgivenforthatstudyandallotherfinancialinterestinformationrequiredunderpart54ofthischapterfor2yearsafterthedateofapprovaloftheapplication.Thepersonmaintainingtheserecordsshall,uponrequestforanyproperlyauthorizedofficeroremployeeoftheFoodandDrugAdministration,atreasonabletime,permitsuchofficeroremployeetohaveaccesstoandcopyandverifytheserecords.

BESampleRetention

生物等效性試驗樣品保存

TheguidancehighlightshowthetestarticleandreferencestandardforBAandBEstudiesshouldbedistributedtothetestingfacilitieshowtestingfacilitiesshouldrandomlyselectsamplesfortestingandmaterialtomaintainasreservesampleshowthereservesamplesshouldberetained.FDA/DSIInspectiononBEStudies

FDA對生物等效性試驗的監察

Afrequentfindingfromtheseinspectionsistheabsenceofreservesamplesatthetestingfacilitieswherethestudiesareconducted:Inmanycases,DSIfindsthattestingfacilitiesreturnreservesamplestothestudysponsorsand/ordrugmanufacturers,Inothercases,studysponsorsand/ordrugmanufacturers,SMOs,orcontractpackagingfacilitiesdesignatethestudytestarticleandreferencestandardforeachsubject,andprecludethetestingfacilitiesfromrandomlyselectingrepresentativereservesamplesfromthesupplies.Thestudysponsorand/ordrugmanufacturershouldsendtothetestingfacilitybatchesofthetestarticleandreferencestandardpackagedinsuchawaythatthetestingfacilitycanrandomlyselectsamplesforbioequivalencetestingandsamplestomaintainasreservesamples.FDA/DSIInspectiononBEStudiescont’d

FDA對生物等效性試驗的監察

QuantityofReserveSamplesSufficienttoperformfivetimesallofthereleasetestsrequiredintheapplicationorsupplementalapplicationForsolidoraldosageforms(e.g.,tablets,capsules),anupperlimitof300unitseachforthetestarticleandreferencestandardEachsiteisaskedtoretainareasonableamountoftestarticleandreferencestandardamin