肇庆市机动车驾驶培训教练员教学质

Anti-InfectiveDrugProducts

and

DrugSafetyandRiskManagement

AdvisoryCommitteesMeetingDecember14&15,2006EdwardCox,MDMPHActingDirector,OfficeofAntimicrobialProductsOND/CDER/FDA1WelcomeWelcomeTopicfordiscussionNDA21-144Ketek®(telithromycin)TabletsOverallbenefitsandrisksbaseduponwhatweknowtodayInformationintheoriginalNDA&theadditionalinformationthatwehavesincethedrugswasapprovedinApril2004PrimarypurposeofthemeetingToseektheAdvisoryCommittee’sadviceontheoverallassessmentofrisksandbenefitsofKetekforeachofitsapprovedindicationsbaseduponwhatweknowtoday2Ketek(telithromycin)ComplexNDAReviewSpanned3reviewcyclesMarch2000toApril20042PreviousFDAAnti-InfectiveDrugProductAdvisoryCommitteesApril2001&January2003Ketek(telithromycin)Tablets-ApprovedinApril20043KetekIndicationsINDICATIONSANDUSAGE KETEKtabletsareindicatedforthetreatmentofinfectionscausedbysusceptiblestrainsofthedesignatedmicroorganismsintheconditionslistedbelowforpatients18yearsoldandabove.

AcutebacterialexacerbationofchronicbronchitisduetoStreptococcuspneumoniae,Haemophilusinfluenzae,orMoraxellacatarrhalis.

AcutebacterialsinusitisduetoStreptococcuspneumoniae,Haemophilusinfluenzae,Moraxellacatarrhalis,orStaphylococcusaureus.

Community-acquiredpneumonia(ofmildtomoderateseverity)duetoStreptococcuspneumoniae,(includingmulti-drugresistantisolates[MDRSP*]),Haemophilusinfluenzae,Moraxellacatarrhalis,Chlamydophilapneumoniae,orMycoplasmapneumoniae.4OtherDrugswithSimilarIndicationsAcutebacterialsinusitis

amoxicillin,amoxicillin/clavulanatecefdinir,cefpodoximeproxetil,cefprozil,cefuroximeaxetil,loracarbef,azithromycin,clarithromycinciprofloxacin,levofloxacin,moxifloxacinAcutebacterialexacerbationofchronicbronchitiscefaclor,cefdinir,cefditorenpivoxil,cefixime,cefpodoximeproxetil,cefprozil,ceftibuten,cefuroximeaxetil,loracarbefazithromycin,clarithromycin,dirithromycingemifloxacin,levofloxacin,lomefloxacin,moxifloxacin,ofloxacintrimethoprim/sulfamethoxazoleCommunity-acquiredpneumoniaamoxicillin/clavulanatecefdinir,cefditorenpivoxil,cefpodoximeproxetil,loracarbef,azithromycin,clarithromycin,dirithromycingemifloxacin,levofloxacin,moxifloxacinlinezolidLowerrespiratorytractinfections

(pastindication-AECB&CAP)amoxicillin,amoxicillin/clavulanate ─erythromycincefaclor ─ciprofloxacin5OtherDrugswith

“Older”RelatedIndicationsAmoxicillinInfectionsoftheear,nose,andthroatduetoStreptococcusspp.(alphaandbetahemolyticstrainsonly),Streptococcuspneumoniae,Staphyloccocusspp.,orH.influenzaeAmpicillinInfectionsoftherespiratorytract:non-penicillinaseproducing H.influenzaeandstaphylococci,andstreptococciincludingStreptococcuspneumoniaeTetracycline&DoxycyclineRespiratorytractinfectionscausedbyM.pneumoniaeRespiratorytractinfectionscausedbyH.influenzaeandKlebsiellaspp.

(whensusceptibilitytestingindicatesappropriate)UpperRespiratorytractinfectionscausedbyS.pneumoniae(formerlyDiplococcuspneumoniae)

(whensusceptibilitytestingindicatesappropriate)6DemonstratingEfficacy–HistoricalPerspective-1Thescienceofclinicaltrialdesignhasadvancedovertime1938FederalFood,DrugandCosmetic(FD&C)Act-Pre-clearanceofdrugsforsafety&Pre-marketnotificationdidnotincludeevaluationofefficacy1962KefauverHarrisAmendmentsaddedarequirementthatdrugsbeshowntobeeffectiveRequiredapositiveactofapprovalbeforeanewdrugcouldbemarketedRequiredthattheFDAreviewalldrugsapprovedsince1938foreffectivenessEfficacyofearlierantibioticsapprovedfrom1938-1962wereevaluatedaspartoftheDrugEfficacyStudyImplementation(DESI)review7DemonstratingEfficacy–HistoricalPerspective-2Post1962-Efficacystudiesthatenrolledpatientswithanyofavarietyofdifferentinfectionsinthesamestudy1992PointstoConsiderand1992IDSA/FDAguidelinesinClinicalInfectiousDiseases1992--Indicationspecifictrials,includingactivecontrolledstudiesdesignedtoequivalenceorsuperiority1998DraftGuidances–similarorsuperioreffectivenesstoanapprovedproductinindicationspecifictrialsMorerecently,questionsontheabilityofnon-inferioritystudiestoprovideinformativedataonefficacyinmilder,typicallyself-limitedinfections8ClinicalStudies-KetekAnumberofclinicalstudiesincludingstudiesin:CAPAECBABSActivecontrolledtrialsdesignedtoshownon-inferiority9Adequateandwellcontrolledstudies

21CFR§314.126Adequateandwell-controlledstudies.(a)Thepurposeofconductingclinicalinvestigationsofadrugistodistinguishtheeffectofadrugfromotherinfluences,suchasspontaneouschangeinthecourseofthedisease,placeboeffect,orbiasedobservation.Activetreatmentconcurrentcontrol…Thetestdrugiscomparedwithknowneffectivetherapy;forexample,wheretheconditiontreatedissuchthatadministrationofplaceboornotreatmentwouldbecontrarytotheinterestofthepatient.Iftheintentofthetrialistoshowsimilarityofthetestandcontroldrugs,thereportofthestudyshouldassesstheabilityofthestudytohavedetectedadifferencebetweentreatments.Similarityoftestdrugandactivecontrolcanmeaneitherthatbothdrugswereeffectiveorthatneitherwaseffective.Theanalysisofthestudyshouldexplainwhythedrugsshouldbeconsideredeffectiveinthestudy,forexample,byreferencetoresultsinpreviousplacebo-controlledstudiesoftheactivecontroldrug.10ICHE-10Assaysensitivityisapropertyofaclinicaltrialdefinedastheabilitytodistinguishaneffectivetreatmentfromalesseffectiveorineffectivetreatment.ifatrialisintendedtodemonstrateefficacybyshowingatesttreatmenttobenoninferiortoanactivecontrol,butlacksassaysensitivity,thetrialmayfindanineffectivetreatmenttobenon-inferiorandcouldleadtoanerroneousconclusionofefficacyThepresenceofassaysensitivityinanon-inferiorityorequivalencetrialmaybededucedfromtwodeterminations:Historicalevidenceofsensitivitytodrugeffects,i.e.,thatsimilarlydesignedtrialsinthepastregularlydistinguishedeffectivetreatmentsfromlesseffectiveorineffectivetreatmentsandAppropriatetrialconduct,i.e.,thattheconductofthetrialdidnotundermineitsabilitytodistinguisheffectivetreatmentsfromlesseffectiveorineffectivetreatments.

GuidanceforIndustry:E10ChoiceofControlGroupandRelatedIssuesinClinicalTrials:11Inactive(e.g.placebo)ActiveControls&Non-inferiority-1marginTestActiveControlEffectCase#1:LargetreatmenteffectLowspontaneousresolutionrate12Effect

ActiveControlmarginTestActiveControls&Non-inferiority-2Inactive(e.g.placebo)Case#2:UncleartreatmenteffectHighspontaneousresolutionrate13Effect

Inactive(e.g.placebo)ActiveControlmarginTestActiveControls&Non-inferiority-3Inactive(e.g.placebo)marginTestActiveControlEffectCase#1:LargetreatmenteffectLowspontaneousresolutionrateCase#2:UncleartreatmenteffectHighspontaneousresolutionrate14TrialDesign–ABS&ABECBABSAIDACOct2003–GeneraldiscussionontrialdesigninABSrecommendationforsuperioritytrialsinABSplacebo-controlledoradjunctivetherapycontrolledwithclosefollow-up&safetyprovisionsAIDACSept2006–productspecificmeetingonafluoroquinoloneforABSusingactivecontrollednon-inferioritystudiesOnthequestiononefficacy(alone)baseduponnon-inferioritythecommitteevotedYes:4andNo:10ABECBAIDAC2002–generaldiscussiononplacebocontrolledstudiesinnon-severelyillpatientsCDERRegulatoryBriefingJuly2005–ForABECBtherewasnotadequatebasisfornon-inferioritytrials15ClinicalTrials-ConsiderationsPerspectiveAntibacterialdrugswerefirstdiscoveredmanyyearsagoRepresentedamajoradvanceAntibacterialtherapyIncorporatedintoclinicalpracticebeforesophisticatedclinicaltrialdesignsdevelopedConsiderationsRiskofprogressionorextensionofinfectionRiskofadversereactionstoantimicrobialClinicalTrialsshouldnotexposepatientstosignificantriskbeinformativebeethical&acceptablebaseduponIRBreviewStudydesignprobablycanimpactuponpopulationenrolledinclusion/exclusioncriteriaandinvestigatorpatientselectionprovisionsfor“rescuetherapy”considerroleofDSMB16KetekLabel–Safety(selected)CONTRAINDICATIONSprevioushistoryofhepatitisorjaundiceassoc.withKetekoranymacrolideConcomitantadministrationofKetekwithcisaprideorpimozideiscontraindicatedWARNINGSHepatotoxicity–acutehepaticfailureandsevereliverinjury,insomecasesfatal(June2006)Exacerbationofmyastheniagravis(strengthenedJune2006)QTprolongationPseudomembranouscolitisPRECAUTIONSVisualdisturbancesandsyncopeHepaticdysfunction–increasedliverenzymesandhepatitisDrugInteractions–CYP4503A4inhibition;CYP4503A4&2D6substrate

17KetekLabel–Safety(additional)seepreviousslideCONTRAINDICATIONShistoryofhypersensitivitytootelithromycinand/oranycomponentsofKetektabletsoranymacrolideantibioticWARNINGSPRECAUTIONSDosereductioninsevererenalimpairmentseeproductlabelforcompleteinformation18Safety–OtherAntimicrobials(selected)-1clarithromycinCONTRAINDICATION–co-administrationwithinteractingdrugs-postmarketingreportsofcardiacarrhythmiasWARNINGSre:useinpregnancyPseudomembranouscolitisDruginteractions–CYPP4503AADVERSEREACTIONS:Post-MarketingExperienceHepaticeffectsQTprolongation&arrhythmiaserythromycinCONTRAINDICATEDInpatientstakingterfenadineorastemizoleWARNINGSprolongedQTingeriatricpatientshepaticdysfunctionpseudomembranouscolitisPRECAUTIONSaggravateweaknessofpatientswithmyastheniagravisDruginteractionsazithromycinWARNINGSRareseriousallergicreactionsForoutpatientmildseverityCAPnotformoderateorsevereCAPpseudomembranouscolitisPRECAUTIONSmacrolidesandQTADVERSEREACTIONSliverandbiliaryadversereactions19Safety–OtherAntimicrobials(selected)-2Beta-lactamsCONTRAINDICATIONSAllergytoCephs/PCNsWARNINGSHypersensitivitytoCephs/PCNsPseudomembranouscolitisTetracyclinesWARNINGSEffectontoothdevelopmentpregnancy,childrenPseudomembranouscolitisphotosensitivityFluoroquinolonesWARNINGSPeds–arthropathyjuvenilleanimalsCNSdisordersHypersensitivityreactionsanaphylacticrash,fever,↑Eos,jaundice,hepaticnecrosis,fataloutcomes(rarelyreported)PeripheralneuropathyTendoneffectsPRECAUTIONSEffectsonQT-arrhythmia20PediatricsOnlyapprovedforuseinadultsPediatricstudiesinacutebacterialotitismedia,tonsillopharyngitiscommunity-acquiredpneumoniaSanofiAventisvoluntarilypausedthePediatricstudiesonJune8,2006Pediatricpatientsarenotbeingenrolled21AgendaDay1Respiratorytractinfections–treatmentandepidemiologyPremarketdataPostmarketingdataEMEADataminingHepaticAEsDay2PostmarketingDataVisualAEsDisturbancesofconsciousnessExacerbationsofMyastheniaGravisSummaryOpenPublicHearingCommitteeDiscussionandVoteReturntoagenda22DiscussionCommitteeDiscussion PleasediscusswhetherthebenefitsoutweightherisksforeachoftheapprovedindicationsforKetek(community-acquiredpneumonia,acutebacterialexacerbationofchronicbronchitis,andacutebacterialsinusitis).Pleasetakeintoconsiderationthecurrentsafetyinformation(specificallyincludinghepatic,visual,lossofconsciousness,andexacerbationofmyastheniagravisadversereactions).Pleasealsoconsidertheinformationsupportingefficacyfortheseindicationsaswellastherecentefficacydiscussionsontheuseofnon-inferi