高特異性藥物的生物等效性研究高特異性藥物的生物等效性研究第1頁April14,2DefinitionofHighlyVariableDrugs(HVDs)Anydrugwhoserateandextentofabsorptionshowslargedose-to-dosevariabilitywithinthesamepatientCommonlyunderstoodtoincludethosedrugswhoseintrapatientcoefficientofvariation(Cmaxand/orAUC)isapproximately30%ormore高特異性藥物的生物等效性研究第2頁April14,3CurrentBioequivalenceCriteriaComparisonbetweentestandreferenceproductUsenaturallogtransformationofCmaxandAUCCriterion:90%confidenceintervalsaboutgeometricmeantest/referenceratiosforbothCmaxandAUCmustfallwithin80–125%Appliestoallsystemicallyactingdrugs(i.e.,notlocallyacting)withmeasurablebloodorurinelevelswithoutregardtothedrug’sinherentvariabilitySamecriteriausedbypioneerfirmstosupportformulationchanges高特異性藥物的生物等效性研究第3頁April14,4高特異性藥物的生物等效性研究第4頁April14,5WhyAlternativeAcceptanceCriteriaAreNeededforHVDsReducehumanexperimentation(numberofparticipants)inBEstudiesProhibitivesizeofBEstudiesforsomeHVDsmeansnogenericisavailable–manyAmericanpatientsgountreated/undertreatedChangingcriteriatoreducenumberofparticipantsinBEstudiesonHVDscanbeaccomplishedwithoutcompromisingsafety/efficacy80–125%BEcriterianotuniversallyimplementedworldwide高特異性藥物的生物等效性研究第5頁April14,6ForeignBECriteriaCountry/RegionAUC90%CICriteriaCmax90%CICriteriaCanada(mostdrugs)80–125%none(pointestimateonly)Europe(somedrugs)80–125%75–133%SouthAfrica(mostdrugs)80–125%75–133%(orbroaderifjustified)Japan(somedrugs)80–125%Somedrugswiderthan80–125%Worldwide(WHO)80–125%“acceptancerangeforCmaxmaybewiderthanforAUC”高特異性藥物的生物等效性研究第6頁April14,7TypesofDrugsThatAreHighlyVariableIncludesmanytherapeuticclassesIncludesbothnewerandolderproductsPotentialsavingstopatientsinthebillionsofdollarsifgenericsareapprovedExamples:atorvastatin,esomeprazole,pantoprazole,clarithromycin,paroxetine(CR),risedronate,metaxalone,itraconazole,balsalazide,acitretin,verapamil,atovaquone,disulfiram,erythromycin,sulfasalazine,etc.高特異性藥物的生物等效性研究第7頁April14,8FedBEStudiesConfidenceintervalcriterianowrequiredforBEstudiesunderfedconditionsGeneralpaucityofinformationonvariabilityunderfedconditionsSomedrugsshowmuchmorevariabilityunderfedconditionsthanfastingconditions,makingthemHVDs(e.g.,esomeprazole,pantoprazole,tizanidine)MaybemoreHVDsthangenerallyappreciated高特異性藥物的生物等效性研究第8頁April14,9WhyCurrent80-125%CriteriaAreNotAppropriateForHVDsCurrentcriteriaareappropriatefordrugswithlowtomoderatevariabilitybecausedose-to-dosevariabilitywithinapatientiscomparabletothewidthofthecriteriaCurrentcriteriaarenotappropriateforHVDsbecausedose-to-dosevariabilitywithinapatientismuchlargerthanthewidthofthecriteriaHVDsare“widetherapeuticindex”drugs–i.e.,haveshallowdoseresponsecurves,andwidesafetymarginsModifyingBEacceptancecriteriaforHVDstoreducethenumberofparticipantsinBEstudiescanbeaccomplishedwhilemaintainingassuranceofsafetyandefficacy高特異性藥物的生物等效性研究第9頁April14,10DifferentHVDsMayRequireDifferentApproaches–

OneSizeDoesNotFitAll高特異性藥物的生物等效性研究第10頁April14,11Example1:HVDsNotSubjecttoSignificantAccumulationatSteadyStateHalf-lifeshortwithrespecttodosingintervalExamples:omeprazole,tizanidine,azathioprineConsiderreference-scaledcriteriaforbothCmaxandAUCDose-to-dosevariabilitywithinapatientnotsmoothedoutatsteadystateforeitherCmaxorAUCDrugexhibitswidedose-to-dosevariationsinbloodlevelsirrespectiveofchronicdosingSamelogicappliestoHVDsnotdosedchronically高特異性藥物的生物等效性研究第11頁April14,12Example2:HVDsSubjecttoSignificantAccumulationatSteadyStateChronicallyusedandwithhalf-lifelongwithrespecttodosingintervalExamples:itraconazole,metaxalone,acitretinConsiderreferencescalingcriteriaforCmaxonlySteadystateT/RforAUCsameasundersingledoseconditions(assuminglinearkinetics)butvariabilityinAUCwillbereducedatsteadystate

drugmaynothavehighlyvariableAUCatsteadystateT/RforCmaxwillbeclosertounityatsteadystatethanundersingledoseconditions,soadjustingcriteriaforCmaxcouldbeaccomplishedwithoutimpactingassuranceofsafety/efficacy高特異性藥物的生物等效性研究第12頁April14,13Example2:HVDsSubjecttoSignificantAccumulationatSteadyState(cont’d)Alternatively,couldpermitdemonstrationofbioequivalencewithmultipledosesteadystatestudyNotsuitableforalldrugsduetosafetyconcerns,e.g.,toxicdrugs,inclusionoffemales,etc.高特異性藥物的生物等效性研究第13頁April14,14高特異性藥物的生物等效性研究第14頁April14,15高特異性藥物的生物等效性研究第15頁April14,16高特異性藥物的生物等效性研究第16頁April14,17高特異性藥物的生物等效性研究第17頁April14,18SpecialConsiderations高特異性藥物的生物等效性研究第18頁April14,19ParallelStudiesforLongHalf-LifeDrugsForlonghalf-lifedrugs,crossoverstudiesmaynotbefeasible,necessitatingparalleldesignsPoweringparallelstudiesdependsonbetween-subjectvariability,notwithin-subjectvariabilityBetween-subjectvariabilityisoftenlarge,necessitatinglargeBEstudiesonsuchproducts,asforHVDsHighbetween-subjectvariabilitydoesnotnecessarilyimplyhighwithin-subjectvariability(HVD)–insteaditmaybeduetointerindividualdifferencesinabsorption/metabolism(e.g.,geneticpolymorphism)MultipledosesteadystatestudiesgenerallynotfeasibleConsiderreference-scaledcriteria高特異性藥物的生物等效性研究第19頁April14,20PoolingDatafromMultipleDosingGroupsLargenrequiredforHVDsoftenrequirestwoormoredosinggroupsFDAcurrentlyrequiresastatisticaltestforpoolabilityofdatafrommultipledosinggroups(groupxtreatmentinteraction)Ifinteractiontermissignificant,thenthegroupsmaynotbepooledIfthegroupsmaynotbepooled,eachgroupisevaluatedonitsownforconfidenceintervalcriteria,andislikelytofailduetounderpoweringThisprocedureresultsindiscarding(andhavingtorepeat)about5%ofstudiesbasedonrandomchancealoneEvenifthereweresomeunderlyingexplanationforthestatisticalsignificance(e.g.,differencesindemographicsamongthedosinggroups),thereisnoreasonnottousethedatafromalldosinggroups(theywouldbeuseableifthesamesubjectshadbeendosedinasinglegroup)高特異性藥物的生物等效性研究第20頁April14,21ConclusionsWhilecurrentBEacce