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1、WhyBioequivalenceofHighlyVariableDrugsisanIssueCharlesE.DiLibertiVicePresident,ScientificAffairsBarrLaboratories,Inc.PresentationtotheAdvisoryCommitteeforPharmaceuticalSciencesApril14,2004April14,20041DefinitionofHighlyVariableDrugs(HVDs)Anydrugwhose
2、rateandextentofabsorptionshowslargedose-to-dosevariabilitywithinthesamepatientCommonlyunderstoodtoincludethosedrugswhoseintrapatientcoefficientofvariation(Cmaxand/orAUC)isapproximately30%ormoreApril14,20042CurrentBioequivalenceCriteriaComparisonbetwe
3、entestandreferenceproductUsenaturallogtransformationofCmaxandAUCCriterion:90%confidenceintervalsaboutgeometricmeantest/referenceratiosforbothCmaxandAUCmustfallwithin80–125%Appliestoallsystemicallyactingdrugs(i.e.,notlocallyacting)withmeasurablebloodo
4、rurinelevelswithoutregardtothedrug’sinherentvariabilitySamecriteriausedbypioneerfirmstosupportformulationchangesApril14,20043April14,20044WhyAlternativeAcceptanceCriteriaAreNeededforHVDsReducehumanexperimentation(numberofparticipants)inBEstudiesProhi
5、bitivesizeofBEstudiesforsomeHVDsmeansnogenericisavailable–manyAmericanpatientsgountreated/undertreatedChangingcriteriatoreducenumberofparticipantsinBEstudiesonHVDscanbeaccomplishedwithoutcompromisingsafety/efficacy80–125%BEcriterianotuniversallyimple
6、mentedworldwideApril14,20045ForeignBECriteriaCountry/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
7、%Somedrugswiderthan80–125%Worldwide(WHO)80–125%“acceptancerangeforCmaxmaybewiderthanforAUC”April14,20046TypesofDrugsThatAreHighlyVariableIncludesmanytherapeuticclassesIncludesbothnewerandolderproductsPotentialsavingstopatientsinthebillionsofdollarsif
8、genericsareapprovedExamples:atorvastatin,esomeprazole,pantoprazole,clarithromycin,paroxetine(CR),risedronate,metaxalone,itraconazole,balsalazide,acitretin,verapamil,atovaquone,disulfiram,erythromycin,sulfasalazine,etc.April14,20047FedBEStudiesConfide
