assessmentsmteam

AMatterofRecord(301)890-41881FOODANDDRUGADMINISTRATION1CENTERFORDRUGEVALUATIONANDRESEARCH2345PSYCHOPHARMACOLOGICDRUGS6ADVISORYCOMMITTEE(PADAC)MEETING78910Tuesday,January12,2016118:06a.
m.
to4:56p.
m.
121314151617FDAWhiteOakCampus18Building31,TheGreatRoom19WhiteOakConferenceCenter20SilverSpring,Maryland2122AMatterofRecord(301)890-41882MeetingRoster1ACTINGDESIGNATEDFEDERALOFFICER(Non-Voting)2JenniferShepherd,RPh3DivisionofAdvisoryCommitteeandConsultant4Management5OfficeofExecutivePrograms,CDER,FDA67PSYCHOPHARMACOLOGICDRUGSADVISORYCOMMITTEE8MEMBERS(Voting)9ThomasA.
Grieger,MD10StaffPsychiatrist11MarylandDepartmentofHealthandMentalHygiene12ThomasB.
FinanCenter13Cumberland,Maryland1415DavidPickar,MD16AdjunctProfessorofPsychiatry17JohnsHopkinsMedicalSchool18UniformedServicesUniversityofHealthSciences19202122AMatterofRecord(301)890-41883TEMPORARYMEMBERS(Voting)1WarrenK.
Bickel,PhD2Director,AddictionRecoveryResearchCenter3Professor,DepartmentofPsychology4VirginiaTechUniversity5Professor,DepartmentofPsychiatry,VirginiaTech6CarilionSchoolofMedicine7Roanoke,Virginia89KathleenT.
Brady,MD,PhD10DistinguishedUniversityProfessor11MedicalUniversityofSouthCarolina12StaffPsychiatrist13MentalHealthServiceLine14RalphH.
JohnsonVAMedicalCenter15Charleston,SouthCarolina16171819202122AMatterofRecord(301)890-41884MelindaCampopiano,MD1MedicalOfficerandBranchChiefforRegulatory2Programs3DivisionofPharmacologicTherapies4CenterforSubstanceAbuseTreatment5SubstanceAbuseandMentalHealthServices6Administration7Rockville,Maryland89KathleenM.
Carroll,PhD(viaphone)10AlbertE.
KentProfessorofPsychiatry11YaleUniversitySchoolofMedicine12WestHaven,Connecticut1314LoriE.
Dodd,PhD15MathematicalStatistician16BiostatisticsResearchBranch,DivisionofClinical17Research,NationalInstituteofAllergyand18InfectiousDiseases19NationalInstitutesofHealth(NIH)20Bethesda,Maryland2122AMatterofRecord(301)890-41885AdamJ.
Gordon,MD,MPH,FACP,FASAM1Professor,MedicineandClinicalandTranslational2Sciences3UniversityofPittsburghandVAPittsburgh4HealthcareSystem5Pittsburgh,Pennsylvania67JenniferHiggins,PhD8(ActingConsumerRepresentative)9Director,StrategicPlanningandBusiness10Development11CenterforHumanDevelopment12Springfield,Massachusetts1314DawnF.
Ionescu,MD15DepressionClinicalandResearchProgram16MassachusettsGeneralHospital17HarvardMedicalSchool18Boston,Massachusetts19202122AMatterofRecord(301)890-41886MargaretKotz,DO1ProfessorofPsychiatryandAnesthesiology2CaseWesternReserveUniversitySchoolof3Medicine4Director,AddictionRecoveryServices5UniversityHospital6Cleveland,Ohio78JudithM.
Kramer,MD,MS9(ActingChairperson)10ProfessorEmeritaofMedicine11DukeUniversitySchoolofMedicine12Durham,NorthCarolina1314LauraF.
McNicholas,MD,PhD15ClinicalAssociateProfessor16DepartmentofPsychiatry17PerelmanSchoolofMedicine18UniversityofPennsylvania19Philadelphia,Pennsylvania202122AMatterofRecord(301)890-41887RajeshNarendran,MD1AssociateProfessorinRadiologyandPsychiatry2UniversityofPittsburghSchoolofMedicine3Pittsburgh,Pennsylvania45KenzieL.
Preston,PhD6Chief/SeniorInvestigator7ClinicalPharmacologyandTherapeuticsResearch8Branch9IntramuralResearchProgram10NationalInstituteonDrugAbuse11NationalInstitutesofHealth12Baltimore,Maryland1314JamesTroendle,PhD15MathematicalStatistician16OfficeofBiostatistics17NationalHeart,Lung,andBloodInstitute18NationalInstitutesofHealth19Bethesda,Maryland202122AMatterofRecord(301)890-41888MichaelYesenko.
MDiv1(PatientRepresentative)2Laytonsville,Maryland34ACTINGINDUSTRYREPRESENTATIVETOTHECOMMITTEE5(Non-Voting)6RobertRussellConley,MD7GlobalDevelopmentLeader,PainandCore8TherapeuticsandDistinguishedScholar9EliLillyandCompany10Indianapolis,Indiana1112FDAPARTICIPANTS(Non-Voting)13SharonHertz,MD14Director15DivisionofAnesthesia,Analgesia,andAddiction16Products(DAAAP)17OfficeofDrugEvaluationII(ODEII)18OfficeofNewDrugs(OND),CDER,FDA19202122AMatterofRecord(301)890-41889RigobertoRoca,MD1DeputyDirector2DAAAP,ODEII,OND,CDER,FDA34CeliaWinchell,MD5ClinicalTeamLeader6DAAAP,ODEII,OND,CDER,FDA78DavidPetullo,MS9StatisticalTeamLeader10DivisionofBiostatisticsII(DB-II)11OfficeofBiostatistics(OB)12OfficeofTranslationalSciences(OTS),CDER,FDA1314KimberlyLehrfeld,PharmD15TeamLeader16DivisionofRiskManagement(DRISK)17OfficeofMedicationErrorPreventionandRisk18Management(OPEPRM)19OfficeofSurveillanceandEpidemiology(OSE)20CDER,FDA2122AMatterofRecord(301)890-418810CONTENTS1AGENDAITEMPAGE2CalltoOrderandIntroductionofCommittee3JudithKramer,MD124ConflictofInterestStatement5JenniferShepherd,RPh186FDAOpeningRemarks7CeliaWinchell,MD218ApplicantPresentations–BraeburnPharm.
9Introduction10BehshadSheldon3411PublicHealthNeed12FrankYoung,MD,PhD4113MedicalNeed14MichelleLofwall,MD4415Efficacy16SonnieKim,PharmD5117TrainingProgramandSafety18StevenChavoustie,MD,FACOG7019202122AMatterofRecord(301)890-418811CONTENTS(continued)1AGENDAITEMPAGE2RiskManagement3BehshadSheldon834Benefit/Risk5MichaelFrost,MD,FACP,FASAM946ClarifyingQuestionstoApplicant1017FDAPresentations8EfficacyandSafetyofProbuphineforthe9MaintenanceTreatmentofOpioid10DependenceinClinicallyStablePatients11RachelSkeete,MD,MHS12412JamesTravis,PhD15413RachelSkeete,MD,MHS17114ClarifyingQuestionstoFDA19315OpenPublicHearing21216ClarifyingQuestions(continued)27717ChargetotheCommittee18SharonHertz,MD29919QuestionstotheCommitteeandDiscussion30220Adjournment4222122AMatterofRecord(301)890-418812PROCEEDINGS18:00a.
m.
2CalltoOrder3IntroductionofCommittee4DR.
KRAMER:Ithinkwe'regoingtogoahead5andgetstarted.
Goodmorning.
Iwouldliketo6firstremindeveryonetosilenceyourcellphones,7smartphones,andotherdevicesthatyouhaveif8you'venotalreadydoneso.
Thatwouldbevery9helpful.
I'dalsoliketoidentifytheFDApress10contactinthebackraisinghishand,EricPahon.
11Thankyou.
Ifyouhaveanyquestions,Ericisthe12persontotalkto.
13MynameisJudithKramer,andI'mtheacting14chairpersonofthePsychopharmacologicDrugs15AdvisoryCommittee.
I'dliketocallthismeeting16toorderandstartbygoingaroundthetableand17havingeveryoneintroducethemselves.
Let'sstart18attheright.
19DR.
CONLEY:Goodmorning.
I'mRobConley.
20Iamtheindustryrepresentativetoday.
I'm21distinguishedscholarinneuroscienceatEliLilly22AMatterofRecord(301)890-418813andanadjunctprofessorofpsychiatryinpharmacy1scienceattheUniversityofMaryland.
2DR.
BICKEL:Hi.
I'mWarrenBickel.
I'm3directoroftheAddictionRecoveryResearchCenter4attheVirginiaCarilionResearchInstituteof5VirginiaTech.
6DR.
DODD:I'mLoriDodd.
I'ma7biostatisticianattheNationalInstitutesof8HealthatNIAID,theinfectiousandallergy9institute,andI'mprimarilyfocusedonclinical10trials.
11DR.
TROENDLE:IamJamesTroendle.
I'ma12statisticianattheNationalHeart,Lung,andBlood13Institute.
14MR.
YESENKO:MichaelYesenko,patient15representative.
16DR.
HIGGINS:JenniferHiggins,consumer17representative.
18DR.
PRESTON:KenziePreston.
I'mthechief19oftheclinicalpharmacologyandtherapeutics20researchbranchattheNationalInstituteonDrug21AbuseIntramuralResearchProgram.
22AMatterofRecord(301)890-418814DR.
McNICHOLAS:LauraMcNicholas,1UniversityofPennsylvania.
2DR.
GRIEGER:TomGrieger,psychiatrist3workingforthestateofMarylandandalsoadjunct4professoratUniformedServicesUniversity.
5DR.
PICKAR:DavePickar,formerchiefof6experimentaltherapeutics,intramuralresearch,7NIMH,andadjunctprofessoratHopkinsand8UniformedServices.
9DR.
KRAMER:AsIsaid,I'mJudithKramer.
10I'mprofessoremeritaatDukeUniversity.
11LCDRSHEPHERD:JenniferShepherd,12designatedfederalofficer.
13DR.
IONESCU:DawnIonescu,psychiatristat14MassachusettsGeneralHospital.
15DR.
NARENDRAN:RajNarendran,psychiatrist,16UniversityofPittsburgh.
17DR.
KRAMER:Ifwecouldholdjustamoment.
18KathleenCarrollisillbutisabletojoinusby19phone.
Sowe'regoingtohaveKathleenintroduce20herselfsowecanrecognizehervoicebeforeAdam21introduceshimself.
22AMatterofRecord(301)890-418815Kathleen1DR.
CARROLL:Hi.
ThisisKathleenCarroll,2professorofpsychiatry,YaleUniversitySchoolof3Medicine--notmyrealvoice.
4DR.
KRAMER:Theconnectionwasalittle5spottythere.
Idon'tknowifanyonecouldworkon6that.
ItsoundedlikeKathleen'svoicebrokeupa7coupletimes.
8Okay.
Goahead,Adam.
9DR.
GORDON:Goodmorning.
AdamGordon,10professorofmedicine,clinicalandtranslational11sciences,healthservicesresearcher;Universityof12Pittsburgh,VAPittsburghHealthcareSystem.
13DR.
KOTZ:MargaretKotz.
I'mprofessorof14psychiatryandanesthesiologyatCaseWestern15MedicalSchoolanddirectorofAddictionRecovery16ServicesatUniversityHospitalsinCleveland.
17DR.
LEHRFELD:KimLehrfeld,FDA,Division18ofRiskManagement,andI'mteamleader.
19DR.
PETULLO:DavidPetullo,FDA,Officeof20Biostatistics.
21DR.
WINCHELL:CeliaWinchell.
I'mthe22AMatterofRecord(301)890-418816medicalteamleaderforaddictiondrugproductsat1FDA.
2DR.
HERTZ:SharonHertz.
I'mdirectorof3theDivisionofAnesthesia,Analgesia,and4AddictionProducts.
5DR.
ROCA:I'mRigoRoca.
I'mdeputy6divisiondirectorintheDivisionofAnesthesia,7Analgesia,andAddictionProducts.
8DR.
KRAMER:Thankyouverymuch.
I'mgoing9toreadastatementthatIhopeyouallwilllisten10toandpayattentionto.
11Fortopicssuchasthosebeingdiscussedat12today'smeeting,thereareoftenavarietyof13opinions,someofwhicharequitestronglyheld.
14Ourgoalisthattoday'smeetingwillbeafairand15openforumfordiscussionoftheseissuesandthat16individualscanexpresstheirviewswithout17interruption.
Thus,asagentlereminder,18individualswillbeallowedtospeakintothe19recordonlyifrecognizedbythechairperson.
We20lookforwardtoaproductivemeeting.
21InthespiritoftheFederalAdvisory22AMatterofRecord(301)890-418817CommitteeActandtheGovernmentintheSunshine1Act,weaskthattheadvisorycommitteemembers2takecarethattheirconversationsaboutthetopic3athandtakeplaceintheopenforumofthe4meeting.
Weareawarethatmembersofthemedia5areanxioustospeakwiththeFDAaboutthese6proceedings.
However,FDAwillrefrainfrom7discussingthedetailsofthismeetingwiththe8mediauntilitsconclusion.
9Also,thecommitteeisremindedtoplease10refrainfromdiscussingthemeetingtopicsduring11breaksorlunch.
Thankyou.
12Now,I'llnowpassittoLieutenant-13CommanderJenniferShepherdatmyleft,whowill14readtheConflictofInterestStatement.
15Actually,IthinkKathleenBradyjustjoined16us.
Kathleen,doyouwanttointroduceyourself17andgiveyourinstitution18DR.
BRADY:I'mKathleenBradyfromMedical19UniversityofSouthCarolina.
20DR.
KRAMER:Thankyou.
Gladyoucomemake21it.
22AMatterofRecord(301)890-418818ConflictofInterestStatement1LCDRSHEPHERD:Goodmorning.
TheFoodand2DrugAdministrationisconveningtoday'smeetingof3thePsychopharmacologicDrugsAdvisoryCommittee4undertheauthorityofFederalAdvisoryCommittee5Actof1972.
Withtheexceptionofindustry6representative,allmembersandtemporaryvoting7membersofthecommitteearespecialgovernment8employeesorregularfederalemployeesfromother9agenciesandaresubjecttofederalconflictof10interestlawsandregulations.
11Thefollowinginformationonthestatusof12thiscommittee'scompliancewithfederalethicsand13conflictofinterestlaws,coveredbybutnot14limitedtothosefoundat18USCSection208,is15beingprovidedtoparticipantsintoday'smeeting16andtothepublic.
FDAhasdeterminedthatmembers17andtemporaryvotingmembersofthiscommitteeare18incompliancewithfederalethicsandconflictof19interestlaws.
20Under18USCSection208,Congresshas21authorizedFDAtograntwaiverstospecial22AMatterofRecord(301)890-418819governmentemployeesandfederalregularemployees1whohavepotentialfinancialconflictswhenitis2determinedthattheagency'sneedforaparticular3individual'sservicesoutweighshisorher4potentialfinancialconflictofinterest.
5Relatedtothediscussionoftoday's6meeting,membersandtemporaryvotingmembersof7thiscommitteehavebeenscreenedforpotential8financialconflictsofinterestoftheirown,as9wellasthoseimputedtothem,includingthoseof10theirspousesorminorchildrenand,forpurposes11of18USCSection208,theiremployers.
These12interestsmayincludeinvestments,consulting,13expertwitnesstestimony,contracts,grants,14CRADAs,teaching,speaking,writing,patentsand15royalties,andprimaryemployment.
16Today'sagendainvolvesNewDrugApplication17204442,Probuphine,buprenorphinehydrochlorideand18ethylenevinylacetate,subdermalimplant,19submittedbyBraeburnPharmaceuticals,onbehalfof20TitanPharmaceuticalsfortheproposedindication21ofmaintenancetreatmentofopioiddependence.
22AMatterofRecord(301)890-418820Thisisaparticularmattersmeetingduringwhich1specificmattersrelatedtoTitanPharmaceuticals2newdrugapplicationwillbediscussed.
3Basedontheagendafortoday'smeetingand4allfinancialinterestsreportedbythecommittee5membersandtemporaryvotingmembers,noconflict6ofinterestwaivershavebeenissuedinconnection7withthismeeting.
Toensuretransparency,we8encourageallstandingcommitteemembersand9temporaryvotingmemberstodiscloseanypublic10statementsthattheymayhavemadeconcerningthe11productatissue.
12WithrespecttoFDA'sinvitedindustry13representative,wewouldliketodisclosethat14Dr.
RobertConleyisparticipatinginthismeeting15asanonvotingindustryrepresentative,actingon16behalfofregulatedindustry.
Dr.
Conley'sroleat17thismeetingistorepresentindustryingeneral18andnotanyparticularcompany.
Dr.
Conleyis19employedbyEliLillyandCompany.
20Wewouldliketoremindmembersand21temporaryvotingmembersthatifthediscussions22AMatterofRecord(301)890-418821involveanyotherproductsorfirmsnotalreadyon1theagendaforwhichanFDAparticipanthasa2personalorimputedfinancialinterest,the3participantsneedtoexcludethemselvesfromsuch4involvement,andtheirexclusionwillbenotedfor5therecord.
FDAencouragesallotherparticipants6toadvisethecommitteeofanyfinancial7relationshipsthattheymayhavewithTitan8PharmaceuticalsandBraeburnPharmaceuticals.
9Thankyouverymuch.
10Dr.
Kramer11DR.
KRAMER:Wewillnowproceedwith12Dr.
Winchell'sintroductoryremarks.
13FDAOpeningRemarks–CeliaWinchell14DR.
WINCHELL:Goodmorning.
Dr.
Kramer,15membersofthePsychopharmacologicDrugsAdvisory16Committee,andinvitedguests,thankyouforyour17participationinthisimportantmeeting.
Today,we18willaskforyourassistanceinourevaluationof19TitanandBraeburn'sapplicationtomarket20Probuphine,animplantableformulationof21buprenorphine,asatreatmentforopioiddependence22AMatterofRecord(301)890-418822inapopulationofpatientswho'vebeen1successfullyandstablytreatedontransmucosal2buprenorphineatmoderatetolowdoses.
3Buprenorphinewasoriginallyapprovedin41981asaninjectableanalgesic.
Itisapartial5agonistatthemureceptor,unlikemostopioid6analgesics,whicharefullagonists.
Agonist7maintenancetherapyofopioiddependenceisa8well-establishedparadigm.
9Intheseveraldecadessincemethadone10maintenancetreatmentwasintroduced,11epidemiologicalstudieshaveestablishedthat12participationinmethadonetreatmentreduces13mortalityinHIVseroconversion.
However,to14controltherisksofdiversionandaccidental15overdose,methadonetreatmentislimitedbylawto16speciallyregisteredopioidtreatmentprogramsor17OTPs.
PatientsmustreporttotheOTPdailyfor18supervisedmedicationadministrationuntilthey're19sufficientlystabletobegintoearntake-home20dosesaccordingtoaspecificschedule.
21Buprenorphinewasdevelopedasatreatment22AMatterofRecord(301)890-418823foropioiddependencebecausesomeofits1pharmacologicalpropertiessuggesteditcouldserve2asasaferalternativetomethadonethatwouldbe3lessattractivefordiversionandabuse,andas4such,itcouldbemadeavailableinphysicians'5officesratherthanbeinglimitedtosupervised6dosingintheOTPsetting.
7Unfortunately,inthedecadessincethe8introductionofsublingualbuprenorphineforthe9treatmentofopioiddependence,buprenorphine10sublingualproductshavebeenincreasingly11identifiedintheillicitdrugmarket,anditis12knownthattheyarediverted,abused,andmisused.
13Additionally,theyhavebeenimplicatedinanumber14ofcasesofaccidentalpoisoningsofsmall15children.
Therefore,adepotinjectionoran16implantableproduct,whichwouldbedifficultto17divertorabuseandwouldbelesslikelytobe18accidentallyingestedbysmallchildren,offers19potentialadvantages.
20Probuphinewasdevelopedtoprovidethese21advantagesaswellastoprovideenhancedadherence22AMatterofRecord(301)890-418824totreatmentandtooffersomeconvenienceto1patientsintermsoftheneedforofficevisitsand2fillingofprescriptions.
Thedivisionagreeswith3thesponsorthatanimplantableformulationof4buprenorphinehasthepotentialtomeetan5importantpublichealthneed.
6WhenTitanfirstsubmittedthisapplication7in2012,theclinicaltrialsexploredtheefficacy8ofProbuphineforpatientsnewlyenteringtreatment9foropioidaddiction.
Wefoundthattheresultsof10thestudy,takentogetherwiththecomparative11pharmacokineticstudyfindings,pointedtothe12conclusionthattheplasmabuprenorphinelevel13associatedwithProbuphinewassimplytoolowtobe14effectiveinthatpopulation.
15WerecommendedthatTitanstudyahigher16dose.
However,Titanandtheirmarketingpartner17Braeburnelectedinsteadtoexplorewhether18Probuphinewouldbeeffectiveinmaintaining19stabilityinpatientswhohavebeensuccessfully20treatedwithsublingualbuprenorphineandhavebeen21tapereddowntomoderate-to-lowdoses,meaning22AMatterofRecord(301)890-418825dosesthattheplasmalevelofbuprenorphine1producedbyProbuphinecanreasonablymatch.
2Itwasachallengetodeterminethe3appropriatedesignofthisstudy.
Typicallyin4addictiontreatmentstudies,fullystablepatients5arenotenrolledintrialsinwhichthey're6withdrawnfromamedicationthat'sworkingfor7them.
Thisformulationdoesoffersomeconvenience8tothepatient,andweunderstoodtherewasa9demandandinterestfrompatients,andtheymaybe10willingtoparticipate.
Butaplacebo-controlled11trialdidn'tseemappropriatebecauseitwould12placepatientsatriskofrelapsethatmightbe13difficulttoreverse.
14Ontheotherhand,anactivecontrolled15trialpresentedchallengesforanalysis.
Youmight16expectthatapassivecomplianceformulationthat17ensuresmedicationadherencecouldbeshowntobe18superiortoamedicationthatmustbetakendaily,19butitcouldbedifficulttoshowsuperiorityin20non-relapserateinstablepatients.
Thisisa21populationinwhichnon-relapseoveramatterof22AMatterofRecord(301)890-418826monthsismoreorlessexpected.
1Sothisledustoconcludethatatrialof2thetypecallednoninferioritytrialwouldbethe3mostappropriate.
Activecontrolnoninferiority4trialsareintendedtoshowthatthenewtreatment5isnotinferiortoanunacceptableextent;thatis6thatanydifferencebetweenthetwotreatmentsis7smallenoughtoallowaconclusionthatthenew8drugcanbeexpectedtobeeffective.
9Nowhistorically,thedivisionhasbeen10reluctanttoagreetononinferioritydesignsfor11trialsofdrugstotreatopioiddependencebecause12therereallyhasnotbeengoodinformationabout13theexpectedresponserate.
Thisisbecausetrials14havebeenquiteheterogenouswithrespecttothe15studydesigns,thepopulations,thetreatments,the16treatmentsettings,thewayresponsewasdefined.
17ButinthissituationwithProbuphine,wefeltit18wasappropriateforustobeflexible,andwe19reallydidseethepotentialpublichealthbenefit20ofanimplantableformulationlikethisin21addressingthisgrowingproblemofmisuse,abuse,22AMatterofRecord(301)890-418827anaccidentalexposure.
1Weencouragedthesponsortoseekout2sourcesofinformationabouttheexpectedrateof3non-relapseinstable,successfullytreated4patientswhocontinueonbuprenorphineovera5six-monthperiodtosupportthisstudy,whichthey6did.
Butbecauseoftheremaininguncertainties7aboutconductingastudylikethis--a8noninferioritytrialinthisclinical9setting--becausewecouldnotanticipateallof10thepotentialfactorsthatcouldinfluenceoutcome11inthisparticularstudy,wedidletthesponsor12knowwecouldn'tjustsayupfrontthathavingthe13studymeetitsproposedendpointswouldbeenough14evidencetosupportafindingofefficacy;andthat15itwouldbeamatterforreview;andthatwe're16goingtolookquantitativelyandqualitativelyat17theanalysisandclinicalmeaningfulnessofthe18findings.
19Therearemanydifferentwaysthatonecould20choosetodefineasuccessfulpatientinatrial21likethis.
Wedidagreetoonebecausetherehas22AMatterofRecord(301)890-418828tobeasingle,agreed-uponanalysisfor1statisticalreasons.
Butwebelievethat2reasonablepeoplecouldholdmanydifferent3opinionsaboutwhatconstitutessuccess,andthat's4oneofthethingswewanttodiscusstoday.
5Certainaspectsofthequalityofthetrial,6whichareimportantinanysetting,are7particularlyimportantinnoninferioritytrials.
8Someissuesinstudyconductcanmaketreatment9armslookmoresimilar.
Inasuperioritytrial,10poorstudyconducttendstoreducethe11between-treatmentdifferences,whichintroducesa12biastowardthenull,meaningthestudy'smore13likelytofail.
Butinanoninferioritytrial,14anythingthatreducestheabilitytodetecta15differencebetweenthetreatmentsactuallybiases16thestudyforsuccess.
17So,someaspectsofstudyconductthatmight18makeithardertoshowadifferencewouldbe19enrollmentofpatientswhodidn'tquitemeetentry20criteria,missingdata,anduseofrescue21medication.
Andwedidseesomeoftheseissuesin22AMatterofRecord(301)890-418829thestudy,andwe'llaskyoutodiscusshowthey1affectinterpretation.
2We'llbeaskingyoutoconsiderwhetherthe3applicanthassucceededinidentifyingapopulation4forwhomProbuphineiseffective,andthiswould5involvediscussingwhetherthesubmittedstudy6providesevidenceofefficacyfortreatmentwith7Probuphineinthestudypopulation.
Andifso,8we'llaskyoutocommentonwhatfactorsdefinea9patientwhowouldbeacandidateforthistreatment10andtodiscusstheimpactthatfactorssuchasuse11ofrescueormissingresultsfromurinesamples12couldhaveonexpressingaresponder-basedoutcome.
13Thetopicofrescuemedicationdeserves14particularcomment.
Thestudycriteriacalledfor15enrollmentofpatientswhowereconsidered16clinicallystableandonasublingualdoseofno17morethan8milligramsadayforatleastthelast1890daysbeforeenteringthetrial.
19Rescueuseduringthetrialwasexpectedto20bearareoccurrenceifithappenedatall.
Butas21itturnsout,itwasn'tatalluncommonfor22AMatterofRecord(301)890-418830patientstoneedextradosesduringthetrial.
Of1particularnoteisthatnoneofthepatientswho2neededrescueduringthetrialhadrequiredextra3dosesofmedicationinthesixmonthspriortothe4trial.
5Ofcourse,clinicallyitisn'tnecessarilya6concernifpatientsrequireanoccasionaldose7adjustmentinordertomaintainstability,butthe8problemisthatProbuphineisn'ttitratable.
The9mainpublichealthbenefitofProbuphineisthat10themedicationisn'tinthemedicinecabinetorthe11kitchencupboardwhereit'svulnerabletobeing12stolen,orgivenaway,orriskofaccidentally13poisoningahouseholdcontacttothepatient.
14Ifnearly20percentofProbuphinepatients15requiresupplementalsublingualbuprenorphinefrom16timetotime,we'llaskyoutodiscusshow17cliniciansshouldaddressthis.
Wouldevery18patienthaveaprescriptionforas-needed19buprenorphineinthemedicinecabinetorthe20kitchencupboardMaybeitdoesn'treallymatter21ifit'sanewbottleeverymonth,asapatienton22AMatterofRecord(301)890-418831sublingualbuprenorphinewouldhave,oronebottle1sittingthereforsixmonths.
Theriskscouldbe2similar.
3Iftheremustbeasupplyofsublingual4buprenorphineinthehome,doestheproductprovide5thepurportedbenefitwithrespecttodiversion,6abuse,andaccidentalpediatricexposureAndwhat7ifthepatientactuallyneedstotaketherescue8medicationAtwhatpointdoesthatpatientnot9adequatelytreatedonProbuphinebemanagedwitha10differentmedicationWe'llaskforyourthoughts11onthistopic.
12Fromasafetystandpoint,370patientshave13beentreatedwiththisproduct.
Mostofthemonly14haveonesix-monthtreatmentcycleinwhatcould15potentiallybealifelongtreatment.
Wedidnot16identifysystemicrisksthatdifferedfrom17currentlyavailablesublingualbuprenorphine18products.
Butwedohavesomeconcernsaboutthe19risksassociatedwiththeinsertionandremoval20proceduresandpotentialcomplicationssuchas21devicemigration,expulsion,andextrusion.
22AMatterofRecord(301)890-418832Aproductthatwassimilarinformatandthe1proceduresnecessaryforinsertionandremovalis2Norplantimplantablecontraceptive.
Norplanthas3beenassociatedwithsomeproceduralcomplications,4eventhoughNorplantproceduresareperformedby5surgicallytrainedphysicians.
Complicated6removalsmayrequireimagingequipmentandsurgical7exploration.
Andphysicianswhoarecurrently8involvedinprovidingbuprenorphinetreatmentof9addictionhavenotcommonlyhadsurgicaltraining.
10Toaddressthis,theapplicanthasproposed11ariskevaluationandmitigationstrategy,aREMS,12consistingofatrainingandcertificationprogram13forhealthcareprofessionalswhowillprescribe14Probuphineandforthehealthcareproviderswho15willinsertorremoveProbuphine.
16Additionally,theREMSwillrestrict17distributiontoREMScertifiedprescribers,and18we'llbeaskingthecommitteetodiscusswhether19theproposedREMSisadequatetoaddresstherisks20ofpotentialcomplicationsassociatedwithimproper21insertiononremoval,aswellasabuse,misuse,and22AMatterofRecord(301)890-418833accidentaloverdoseifanimplantprotrudesfromor1completelycomesoutoftheskin.
2Yourdeliberationsandrecommendationswill3playanimportantroleinourdecision-making4process,andI'dliketothankyoufortakingtime5fromyourotherextensiveresponsibilitiesto6participateinthisprocess.
7DR.
KRAMER:Thankyou,Dr.
Winchell.
8We'llnowgoonwiththesponsor9presentations.
BoththeFoodandDrug10Administrationandthepublicbelieveina11transparentprocessforinformation-gatheringand12decision-making.
Toensuresuchtransparencyat13theadvisorycommitteemeeting,theFDAbelieves14thatitisimportanttounderstandthecontextof15anindividual'spresentation.
Forthisreason,the16FDAencouragesallparticipants,includingthe17sponsor'snon-employeepresenters,toadvisethe18committeeofanyfinancialrelationshipsthatthey19havewiththefirmatissue,suchasconsulting20fees,travelexpenses,honoraria,andinterestin21thesponsor,includingequityinterestsandthose22AMatterofRecord(301)890-418834basedupontheoutcomeofthemeeting.
1Likewise,theFDAencouragesyouatthe2beginningofyourpresentationtoadvisethe3committeeifyoudonothavesuchfinancial4relationships.
Ifyouchoosenottoaddressthis5issueoffinancialrelationshipsatthebeginning6ofyourpresentation,itwillnotprecludeyoufrom7speaking.
8Wewillnowproceedwiththesponsor's9presentations.
10ApplicantPresentation-BehshadSheldon11MS.
SHELDON:Goodmorning.
Thankyou,12MadamChair.
ThankyoutothecommitteeandFDA13membersfordevotingyourtimetodayforthis14discussion.
I'mBehshadSheldon,presidentandCEO15ofBraeburnPharmaceuticals.
I'veworkedinthe16developmentandcommercializationofmedicinesin17chronicdiseasesforover20years,including18glucophagefordiabetes,Plavixforheartdisease,19andAbilifyforseriousmentalhealthdisorders.
20Braeburnisaneuropharmaceuticalcompany21dedicatedtodevelopinglong-actingtreatmentsfor22AMatterofRecord(301)890-418835patientssufferingfromaddiction,pain,and1seriousmentalhealthdisorders.
Whilelong-acting2treatmentscanbehelpfulinalmostanychronic3disease,theycanbeessentialintheareasweare4focusedonduetothesignificantpersonaland5publichealthimpactofadherenceissues.
6Peoplewithopioiddependencerepresentan7underservedpopulationthatisgrowingrapidlyas8theepidemicofopioidabuseprogresses.
From9publicperceptionofthediseaseasamoral10failing,tothelimitsonhowmanypatientscanbe11treatedbyanindividualphysicianandinsurance12coveragelimitationsonmedicinesthatwork,tothe13paucityofresearchanddevelopmentofnew14treatmentoptions,nothingseemseasyinthe15addictionmedicinefield.
16Wehavehadourchallengesaswell.
Thisis17thesecondsubmission,asDr.
Winchellmentioned,18ofProbuphineandaddressesthetwokeyissuesthat19FDAidentifiesintheoriginalsubmission:the20demonstrationofclinicalbenefitinaspecific21populationandthevalidationofthetraining22AMatterofRecord(301)890-418836programforinsertionandremovalprocedures.
1FDAsuggestedwecouldeitherincreasethe2dosedeliveredbyProbuphineorexaminethe3potentialbenefitsofProbuphineinastable4populationrequiringlowerdosesofbuprenorphine.
5Asitmadeclinicalsensetotreatpatientswitha66-monthimplantonlyoncethey'verespondedwellto7buprenorphineandhaveprogressedintheir8treatment,wechosethetargetpopulationdosewho9arealreadystabilized.
Patientsrequiring108milligramsSubutexequivalentorlesswere11selectedbecause,againasDr.
Winchellmentioned,12theplasmaconcentrationsdeliveredby4implants13approximatethosedeliveredbylowerdosesof14sublingualdailybuprenorphine.
15Importantly,theobjectiveofthestudywas16nottoshowthatProbuphineisequivalenttoa17particulardoseofsublingualbuprenorphinebutto18demonstratethatpatientsonaslowas2milligram19andashighas8milligramofsublingualdaily20buprenorphinecanbesafelyandeffectively21transferredto4Probuphineimplants.
22AMatterofRecord(301)890-418837Butwedidnotforgetabouttheneedfor1higherdosesinsomepatients.
Inordertoaddress2theneedsofpatientswhoareinitiatingtreatment3orrequirehigherdosesofbuprenorphine,we4licensedtwoadditionaldepotinjectionproducts.
5Sooursuiteofinvestigationalproductsnow6includehighlytitratableweeklyandmonthly7injectablebuprenorphineproductsinadditionto8the6-monthbuprenorphineimplant.
Wehopetobe9abletooffertreatmentoptionsthathelp10personalizedoseandfrequencydependingonthe11patient'sstageoftreatment.
12Westandherewithgreathumilitytowards13allofyouwhohavedevotedyourcareerstopeople14withopioiddependence,whetherinthetreatment15communityorinpublicservice,hopingtobring16forwardthefirstofourproducts,Probuphine,to17helpmakeadentinthisdevastatingdisease.
18Today'sdiscussiononProbuphinewillfocus19onaspecificinvestigationonpatientswhoare20alreadystableonbuprenorphineatdosesof218milligramsorless.
EachProbuphineimplant22AMatterofRecord(301)890-418838contains80milligramsofbuprenorphine,4implants1insertedsubdermallyintheupperarminasimple2officeprocedure,anddelivercontinuousblood3levelsofbuprenorphinefor6months.
Theimplants4havebeenstudiedintrialsinvolving647subjects5overthepast12years,andProbuphinewasgranted6priorityreviewbyFDAin2012duetoitspotential7toreducetherisksofdiversion,misuse,and8accidentalpediatricexposure.
9WithguidancefromFDAandglobaladdiction10experts,wedesignedaninnovative,double-blind,11double-dummytrialtodemonstratethatclinically12stablebuprenorphinepatientscanbesafelyand13effectivelytransitionedtoProbuphineandmaintain14stabilityovertime.
Thismethodologically15rigoroustrialdemonstratedunequivocallythe16efficacyoflong-termuseofbuprenorphinein17stablepatients.
Thedatafurtherdemonstratedthe18clinicalbenefitofProbuphineinthetarget19population,thosestableon8milligramsorless.
20Wecertainlyanticipatedthatthestudy21woulddemonstratenoninferiorityandwere22AMatterofRecord(301)890-418839pleasantlysurprisedthatthestudyresultsmet1criteriaforsuperiorityeventhoughthemoderately2sizestudywasnotprospectivelypoweredtodetect3superiority.
Whywearenotseekingaclaimfor4superiority,wedolookforwardtothecommittee's5commentsonthesedata.
6Weareverygratefulfortheclose7collaborationwithFDAandouradvisorsin8addictionmedicinethathavebroughtustothis9pointandfortheopportunitytopresentand10discussthisnewtreatmentoptionwiththe11committee.
Followingthisintroduction,Dr.
Frank12Young,Braeburn'sexecutivevicepresidentof13regulatoryandmedicalandformercommissionerat14FDA,willdescribethegrowingpublichealthneed15foreffectiveandsafetreatmentsinopioid16addiction.
17ThenDr.
MichelleLofwall,associate18professorofpsychiatryatKentuckyUniversity,19willdescribetheunmetneedsinthisunderserved20populationofstablepatientswhofacechallenges21ofadherence,drug,supply,andstigmatizationthat22AMatterofRecord(301)890-418840areonlyworsenedbytheneedfordailydosing.
1Dr.
SonnieKim,Braeburn'svicepresidentof2clinicaldevelopmentandmedicalaffairs,will3presenttheresultsfromtheefficacystudythat4showbyeveryparameterProbuphineisatleastas5efficaciousassublingualbuprenorphineandthat6stablepatientscanbetransitionedeffectivelyto7Probuphine.
8ThenDr.
SteveChavoustie,volunteer9assistantprofessorofOB/GYNatUniversityof10MiamiMillerSchoolofMedicine,willshow11Probuphinehasasafetyprofilesimilartothatof12sublingualdosageformsandthatthecurrent13trainingandcertificationforimplant14insertion/removalassuresthesafetyofthese15procedures.
16Iwillthenreturntodescribetherisk17managementprogramthatprovidespatienteducation18andassuresthatonlytrainedandcertified19healthcareprofessionalsareabletoobtain20Probuphine.
21Dr.
MichaelFrost,medicaldirectorat22AMatterofRecord(301)890-418841EaglevilleHospital,a300-bedinpatientaddiction1treatmentfacility,andpresidentofFrostMedical2Group,astateaccreditedoutpatientaddiction3treatmentcenter,willthenshowthatthe4benefit-riskprofileofProbuphineishighly5favorableforthemanagementofstablepatientsin6needofbuprenorphinemaintenancetreatment.
7I'dnowliketowelcomeDr.
FrankYoung8ApplicantPresentation-FrankYoung9DR.
YOUNG:Thankyou,Behshad.
10MynameisFrankYoung.
I'vedevoted1160yearstohealthcareinvariouspositionsasan12academicscientist,deanofamedicalschool,13chairmanofanexecutivehospitalcommittee,14governmentofficialinthepublichealthservice,15andamemberoftheexecutivecommitteeofthe16WorldHealthOrganization.
Intheseroles,I've17livedthroughimportantpublichealthcrises.
18Ournation'sabuseofopioidshasreached19epidemicproportions.
4.
3millionAmericansabuse20opioidseachyear,and2.
4millionofthese21Americansaredependentonopioids.
Unfortunately,22AMatterofRecord(301)890-418842onlyasmallpercentageofAmericansdependenton1opioidsreceivetreatment.
Thishasdire2consequences.
3Over26,000Americansdiedfromopioid4relatedoverdosesin2014,andtheproblemis5gettingworse.
TheCDCrecentlyreportedthatfrom62013to2014,therewasa9percentincreasein7deathsfromprescriptionopioidsanda26percent8increaseindeathsfromheroinoverdose.
Therate9ofheroindeathshastripledsince2010.
10Let'stakealookatageasoneexampleof11thebreadthofthisaddiction.
Herearethe12sudden,unexpecteddeathsfromprescriptionopioids13byage.
WhenIlookatthisslide,Idon'tsee14data.
Iseeinsteadgapingholesinthefabricof15ourfamilies,ourcommunities,followingthedeaths16ofourchildren,ourspouses,andourparents.
17I'mheretodaybecauseI'vecommittedthe18remainingofmylifetodosomethingaboutthis19crisis,whichisworsethananythingthatIhave20seenbeforeinthetimethatIhavebeeneitherin21publicserviceorintheprivatesectordealing22AMatterofRecord(301)890-418843withhealth.
Thisisagrowingcalltoactionat1alllevelsofgovernmentonabipartisanbasis,2includingthepresident,membersofCongress,3governors,andlocallawenforcement.
Wecansee4themagnitudeofopioidaddictioninthewayithas5emergedinthe2016presidentialrace.
6Nevertheless,ifthiscalltoactionisnot7translatedintopolicyandimplementedatall8levels,itisfornaught.
9AsI'veseenbeforeinpublichealthcrises10likeAIDS,whereIhelpedspeedtheaccessto11investigationaldrugs,wemakeprogresswhenwe12reachapointofgenuineurgency.
Complexpublic13healthchallengesdonothavesimplesolutions.
14Butstepbystep,translatingwordsintoaction,we15canresolvethiscrisisthewayI'vesucceededand16seenussucceedintacklingothers.
17IhopethatProbuphinewillprovetobean18importantadditiontothetherapeuticresources19patients,doctors,andcommunitieshaveattheir20disposal,andIbelieveProbuphinecouldplaya21partinhelpingtoaddresstheopioidabuse22AMatterofRecord(301)890-418844epidemic.
1I'mnowpleasedtointroduceDr.
Michelle2Lofwalltopresentherinformation.
3ApplicantPresentation-MichelleLofwall4DR.
LOFWALL:Thankyou,Dr.
Young.
I'm5Dr.
MichelleLofwall.
I'maphysicianboard6certifiedinpsychiatryandaddictionmedicine,and7I'manassociateprofessorofbehavioralsciencein8psychiatryattheUniversityofKentuckyinthe9CenteronDrugandAlcoholResearch.
10Ihaveanactiveoutpatientaddiction11treatmentclinicwhereItreatmanyadultswith12opiatedependenceandteachresidentsandother13healthprofessionalsaboutsubstanceusedisorders.
14Ialsoconductresearchaimedatimprovingthe15treatmentofopiateaddictionandwastheprincipal16investigatorforstudy814.
Ihavereceived17consulting,honorariaformytime.
Idonothave18anyfinancialinterestinthecompanyorthe19outcomeofthismeeting.
20Kentuckyisoftenconsideredtheepicenter21oftheprescriptionopiateepidemic,although22AMatterofRecord(301)890-418845heroinusehasalsoincreasedsubstantiallyinthe1lastseveralyears.
Asinmostotherstates,we're2oftenfacedwithmorepeoplewhoneedandwant3treatmentthanthereistreatmentavailable,andwe4routinelyareturningpeopleaway.
5Somepatientshavetowaitaverylongtime6toinitiatetreatment,andthehurdlesaremuch7higherforthesepatientsthanforpatientswith8othermedicaldisorders.
Thereareoftennot9enoughproviders,andmanyprovidershavewait10listsduetopatientlimits.
Reimbursementislow,11andsomeinsurancescreatesignificantbarriersto12care.
Therearealsofewmedicationoptionsin13contrasttootherchronicconditionslike14schizophreniaordiabetes,andnolong-acting15formulations.
16Medicationdiversionisalsoanimportant17issue.
InaNIDAfundedstudy,Iresearchedthe18relationshipbetweenbuprenorphinediversionand19treatmentaccessamongadultsabusingprescription20opioidswhowereoutoftreatmentinAppalachia,21andresultsshowedthatthosewhotried22AMatterofRecord(301)890-418846unsuccessfullytoenterbuprenorphinetreatment1were7timesmorelikelytousediverted2buprenorphineatfollow-upthanthosewhodidnot3trytoaccesstreatment.
4Thisisconsistentwithotherstudies5reportingthatpeopleoftenusediverted6buprenorphineforself-treatmentofopiate7addiction.
Thisdoesnotjustifydiversion.
This8suggeststhatfindingnovelmedicationsthat9minimizediversionandexpandingtreatmentaccess10matchedtopatients'needsmaybeoneofthemost11effectivepublichealthstrategies.
12Patientshavedifferentneedsandchallenges13duringopiatedependencetreatment.
Manyhavebeen14addictedalongtimeandhavesignificant15psychosocialproblemsorcomorbiduntreated16psychiatricandmedicaldisorders.
17Therearealsochallengeswiththecriminal18justicesystem.
It'snotuncommonforprovidersto19beplacedinapositionwiththecourts--for20instance,familyordrugcourts--wherebythe21courtsarerequiringthatthepatientscomeoffof22AMatterofRecord(301)890-418847theirbuprenorphinetreatment.
Thiscanextendto1jailsaswell.
I'vehadexperienceswhenpatients2havebeenjailed,andthejailsrefusedtoallow3thepatienttotaketheirmedicationthatI4prescribed.
5Otherpatientshavefewercomorbidities,and6manystarttreatmentalreadyholdingjobsand7havingthesupportoftheirfamilyandfriendswho8don'tusedrugs,sotheircarecanbeless9complicated.
Thesearepatientswhooftenbecome10stablequitequickly.
11Theliteraturedoesnothaveaclear12definitionofstability,buttherearecommonly13understoodgeneralcharacteristicsofstable14patients.
Stablepatientsaredoingwellin15treatment,althoughstabledoesnotmeanperfect.
16Theyhavealowrateofpositiveurinetestsand17haveabstinencefromillicitopioidsforlonger18durationsoftime.
19Stablepatientsareregularlyattending20theirclinicvisits.
They'readherenttotheir21treatmentplan,andtheyhavemuchimproved22AMatterofRecord(301)890-418848psychosocialfunction.
Theytendtohave1consistentdosesofbuprenorphine,whichmaybe2lowerthantheirinitialmaintenancedose.
3However,doseadjustmentsstillremainpossible,4especiallywheninsurancechangesformulations.
5Thisisnotuncommon.
6Treatmentisdynamicanddoseadjustments7canoccurforavarietyofreasons.
Thisisnot8synonymouswithtreatmentfailureortreatment9rescue.
About40percentofmypatientsatthe10clinicarestableon8milligramsperdayorless.
11Mystablepatientsneedtreatmentstailoredtosuit12theirneedsandchallenges,whichoftenaremore13practical.
14Onechallengeisadherence.
Theyworry,15whatifsomehowIlosemymedicationorsomeone16takesitAndifapatientdoesn'ttaketheir17medicationforseveraldaysandthenusesafull18opioidagonist,thiscanbefatal.
Opiate19dependenceisaveryunforgivingdisorder.
20Anotherchallengeisretaining21confidentialityandavoidingbeingstigmatized.
As22AMatterofRecord(301)890-418849apatient,theyworry,whatifsomeonefindsout1thatIhaveopiatedependence,likemyemployer,2andIlosemyjobThisisarealisticconcern,so3ourclinicoftenopensat5:30inthemorningso4thatourstablepatientscancomeforappointments5beforetheirworkdaybegins,sotheydonotneeda6workexcusedabsence.
7Otherchallengesarelogistical.
Forsome8patients,thelogisticalchallengesareparamount9andgettingtothephysician'sofficeisareal10burden.
Forinstance,IOpatientswhoarethe11primarybreadwinneroftheirfamily,theyhave12spousesandchildrenwhodependuponthemtowork13fulltime.
They'reoftenworkingmorethan1440hoursaweek.
Wealsoservearuralpopulation,15andtheyliveoveranhourawayfromtheclinic,16andtheywanttobeabletocomelessthanmonthly.
17Otherpatientshavejobsthatrequirethem18totraveloutofstate,andthisisgoodbecausewe19encourageworkandbecomingtax-payingproductive20citizens.
Buttheyworrythatthey'regoingtorun21outoftheirmedicationwhileonalast-minute22AMatterofRecord(301)890-418850businesstrip,andthenslipintowithdrawal.
They1worryaboutthebestplacetopacktheirmedicine2whentraveling.
Dotheykeepitintheirjacket3andriskitfallingout,ordotheypackitinthe4suitcaseandrisktheftorlostbaggageReducing5theseconcernsthatarerealandstressfulmay6allowforfurtherimprovementinrecovery.
7Stablepatientsworkhardtobein8treatment.
Noteveryonecandothis,butthere9certainlyisapopulationthatcanandisdoing10thiscurrently.
Itmakessensethatourmost11successfulpatientswantmore.
Theywantmore12convenienceandconfidentialtreatment,andthey13wantmedicationthatworksreliablytokeepthem14wellforwhichtheycancontrolandnotworrythat15itwillbetakenaway.
16Providersandthepublicclearlywant17treatmentthat'slesslikelytobediverted,18misused,andresultinunintentionalpediatric19exposures.
Withimplantablebuprenorphine,these20wantscanbemet.
Otheraspectsofthetreatment21canstillbedeliveredtailoredtoeachstable22AMatterofRecord(301)890-418851patient'sneeds.
Butthedoctorandpatientwill1nolongerhavetoworryaboutthefateofthe2prescriptionfordailyingestion,whetheritwill3rightlyremainwiththepatientandbetakenas4prescribed.
Thankyou.
5ApplicantPresentation-SonnieKim6DR.
KIM:Goodmorning.
I'mSonnieKim,7vicepresidentofclinicaldevelopmentandmedical8affairsatBraeburn.
StudyPRO814demonstrated9thatProbuphinedeliverssubstantialclinical10benefitinpatientswhohavebeenclinicallystable11onamaintenancedoseof8milligramsorlessof12sublingualbuprenorphine.
Thisdouble-blind,13double-dummystudydemonstratedthatProbuphineis14atleastasefficaciousassublingualbuprenorphine15andthatpatientscansuccessfullytransitionto16Probuphineformaintenancetreatment.
17Additionally,patientsonProbuphinehad18higherresponseratesthanpatientsonsublingual19buprenorphineeventhoughtheratesofresponsewas20highforthesublingualgroup.
814wastheseventh21clinicalstudyforProbuphine.
Thesevenstudies22AMatterofRecord(301)890-418852includedonePKstudyandonecomparative1bioavailabilitystudy.
2Inaddition,thereweretwophase3,3randomizedplacebo-controlledstudiesandtwoopen-4labelextensionstudies.
Thesestudieswere5conductedinpatientswhoarenewentrantsto6buprenorphinetreatment.
Thefocusoftoday's7presentationisstudy814,whichlookedat8Probuphineinpatientswhoarealreadystableon9sublingualbuprenorphine.
10Thedefinitionofthispopulationwas11criticalforthedesignofthestudy.
Stable12patientsweredefinedasbeingonbuprenorphine13treatmentforatleast6monthsonadoseof148milligramsorlessforthe90dayspriorto15enrollment.
Theyhadtohavenoevidenceof16illicitopioiduseinthe90dayspriorto17randomizationandbefreefromsymptomsof18withdrawal.
19Inaddition,treatingphysicianshadto20attesttotheclinicalstabilityoftheirpatients21basedontheirownclinicaljudgment,considering22AMatterofRecord(301)890-418853thefollowinglistofcharacteristicsidentifiedby1addictionexperts:stablelivingenvironment;2participationinastructuredactivityorjob;3consistentparticipationincognitivetherapyor4peersupport;compliantwithclinicvisits;no5reporteddesireorneedtouseillicitopioidsfor6thepast90days;ornohospitalizations,ER7visits,orcrisisinterventionsinthepast890days.
9Giventheneedsofthesepatients,itwould10beunethicaltoconductaplacebo-controlledstudy11inthispopulation.
Literatureshowsthatwhen12stablepatientsareremovedfrommaintenance13treatment,thevastmajoritywillrelapse.
Since14thesewerestabilizedpatients,itwasessentialto15provideanactivecontrol.
Tocomparethetwo16treatmentarms,thestudyusedadouble-blind,17noninferioritystudydesignwithadouble-dummyand18anactivecontrol.
19Asdescribedinthebriefingdocument,we20wereinagreementwiththeagencyinthe20percent21noninferioritymarginbasedondatafromthe22AMatterofRecord(301)890-418854literatureandexternaladdictionexperts.
In1addictiontreatment,thisaninnovativeapproach2appliedtoapopulationnotusuallyincludedin3randomizedclinicaltrials.
Therefore,the4developmentofanoninferioritymarginrequired5inputandinvolvementofaddictionexpertsin6additiontoreviewofanyrelevantliterature.
7Theseanalysesdeterminedanappropriate8effectsizeofsublingualbuprenorphineversus9placeboinstablepatientstobeapproximately1075percent,whiletheFDAguidancedocumentson11noninferioritydesignallowsforpreserving1250percentofeffectsizeinwhichthemarginwould13havebeen37.
5percentagepoints.
Inagreement14withtheagency,wechoseaconservativemarginof1520percentagepointsthatpreservesgreaterthan1670percentoftheeffectsize.
17Theresultsofthestudyshowedthat18Probuphinemetthecriteriafornoninferioritywith19thelowerboundoftheconfidenceintervalwell20abovethemarginandalsometcriteriafor21superiorityinthisdouble-blind,double-dummy22AMatterofRecord(301)890-418855design.
1Patientswereenrolledandrandomizedto2either4Probuphineimplantsplusplacebo3sublingualtabletsorsublingualbuprenorphine4tabletsplus4placeboimplants.
Thedoseof5sublingualbuprenorphinewasbasedonpatients'6baselinedoseofbuprenorphinepriortoenrollment7inthetrial,whichhadtobe8milligramsorless.
8Thestudydurationwas6monthswithmonthly9visitsduringwhichpatientsunderwentall10assessments,includingurinetoxicology.
Patients11alsohad4randomurinesamplesduringthecourse12ofthestudyforatotalof10urinesamples.
13Urinetoxicologyresultswereanalyzedusinga14highlysensitivequantitativemethodofliquid15chromatography,tandemmassspectrometry,whichcan16detectconcentrationsaslowas50nanogramspermL17foropiates,6timesmoresensitivethanthe18standardimmunoassaymethodology.
19Theincreasedsensitivityextendsthe20durationofdetectionofpossibleopioiduse.
21Urinesamplesweretestedforallavailableopioid22AMatterofRecord(301)890-418856analytesandtheirmetabolites.
Thismethodwas1usedasscreeningtodetermineeligibilityfor2entryintothestudy.
3Baselinecharacteristicsweresimilarin4bothgroupswithameanageofaround40.
Fifty-5eightand60percentweremalesinProbuphineand6sublingualbuprenorphinegroup,respectively.
The7majoritywereCaucasians.
Approximately80percent8ofthesubjectshadatleastahighschooldegree.
9Additionally,mostsubjectshadajobor10participatedinastructuredactivity.
11Themajorityusedprescriptionopioidsas12theirprimaryopioidofabusewithameantime13sincefirstabuseofopioidbeing11years.
Mean14timesincefirstdiagnosiswas6years.
Themean15durationofbuprenorphinetreatmentwas3.
5and163.
4yearsforProbuphineandsublingual17buprenorphine,respectively.
Thedistributionof18buprenorphinedoserangedfrom2milligramsto198milligramsperdaywith70to75percenton208milligramsatenrollment.
Thestudyenrollment21periodwasveryshortandhadahighrateof22AMatterofRecord(301)890-418857completion.
1Atotalof21sitesparticipatedinthe2study,andenrollmentwascompletedin4months,3demonstratingaveryhighlevelofpatient4interest.
Ofthe211patientsscreened,177were5randomizedtoeitherProbuphineorsublingual6buprenorphine.
176subjects,87inProbuphineand789insublingualbuprenorphinearms,wereincluded8inthesafetydatasetdefinedasallsubjectswho9receivedanystudymedication.
173subjects,84in10Probuphineand89inthesublingualbuprenorphine11arms,wereincludedintheintent-to-treatdataset12definedinthestatisticalanalysisplanas13randomizedsubjectswhoprovidedatleastonepost-14baselineassessment.
15TheITTdatasetdidnotinclude3subjects16duetobeinglosttofollow-upafterday1andnot17providinganystudyassessments.
Ofthe1118subjectswhodidnotcompletethestudy,7were19losttofollow-up,1wasincarcerated,2withdrew20consent,and1hadanadverseeventleadingto21discontinuation.
Completionrateswerehighand22AMatterofRecord(301)890-418858similaracrosstreatmentarms,93percentin1Probuphineand94percentinsublingual2buprenorphine.
3Theprimaryefficacyanalysiswasthe4differenceofresponderratesbetweenProbuphine5andsublingualbuprenorphine.
Thedefinitionofa6responderwasdeterminedtobeatleast4outof7the6monthswithnoevidenceofillicitopioiduse8bybothurinetoxicologyandself-reporteduse.
9Eachmonthwasdeterminedtobeeitherpositiveor10negativeforillicitopioidusebasedonscheduled11urinetoxicologyresults,self-reporteduse,andif12itoccurredinthatmonth,randomurinetoxicology13collection.
Withthisresponderdefinition,the14primaryefficacyanalysisdemonstratedthat15Probuphinemetcriteriafornoninferiorityaswell16asmeetingcriteriaforsuperiority.
17Thisisanillustrationoftheprespecified1820percent,noninferioritymargin.
Inorderto19achievenoninferiority,thelowerboundofthe20confidenceintervalneedstobetotherightof21negative0.
2.
Alloftheseexamplesmeetcriteria22AMatterofRecord(301)890-418859fornoninferiority.
1Theredexamplemeetsnoninferiority2criteriabuthasapointestimatetotheleftof3thezero,favoringthecomparator,meaningthatthe4investigationaldrugdidnotperformaswellasthe5comparator.
Theyellowexamplemeets6noninferioritycriteriaandhasapointestimate7thatisnodifferentfromthecomparator.
8Thegreenexamplemeetsnoninferiority9criteriaandhasapointestimatethatis10numericallygreaterthanthecomparatorbutdoes11notachievesuperioritybecausethelowerboundis12crossingzero.
Inordertoachievesuperiority,13thepointestimateandthelowerboundofthe14confidenceintervalneedtobetotherightofthe15zero.
16TheprimaryanalysisresultsforProbuphine17meetbothnoninferioritycriteriaandsuperiority18criteriabecausethepointestimateandthelower19boundoftheconfidenceintervalarerighttothe20zero.
Theprimaryefficacyresultsinthisstudy21demonstratedproportionofresponderstobe22AMatterofRecord(301)890-41886096.
4percentinProbuphinegroupand87.
6percent1insublingualbuprenorphine.
Thedifferencewas2statisticallysignificantinfavorofProbuphine3withachisquarep-valueof0.
034demonstrating4superiorityforProbuphine.
5Whilerespondersneededtohavenoevidence6ofillicitopioidusefor4outofthe6monthsin7thestudy,asecondaryendpointlookedat8cumulativeevidenceofnoopioidusethroughoutthe96months.
Thecumulativeproportionofsubjects10withoutevidenceofillicitopioiduseforeach11monthofthestudyfavoredProbuphine,reaching12statisticalsignificanceatmonth3andall13subsequentmonths.
14Atmonth6,86percentofProbuphine15patientshadnoevidenceofillicitopioidusefor16theentiredurationofthestudycomparedto1772percentofthesublingualbuprenorphine18patients.
Similarly,thetimetofirstuseof19illicitopioidwassignificantlylongerfor20Probuphine.
21Theseparationisapparentbymonth3witha22AMatterofRecord(301)890-418861statisticalsignificancedifferenceintimeto1illicitopioiduseinfavorofProbuphinewitha2hazardratioof0.
49,a51percentrelativerisk3reductionintheriskoffirstillicitopioiduse4versussublingualbuprenorphinewithalogrank5p-valueof0.
037.
6Ifwelookattheactualrateofuse,there7were31totaleventsinProbuphineand64eventsin8thesublingualbuprenorphinegroups.
Therateof9illicitopioidusewassignificantlymoreinthe10sublingualbuprenorphinegroupversusProbuphine,11withahazardratioof0.
52andap-valueof0.
003.
12Therefore,cumulativeevidenceofnoopioidusein136months,timetofirstillicitopioiduse,andthe14numberofrecurrentusesallcorroboratethe15resultsofprimaryendpointandcontributetothe16totalityofevidenceforProbuphine'sbenefit.
17Objectiveandsubjectivemeasuresof18withdrawalremainstableonbothtreatmentarms.
19TheClinicianOpioidWithdrawalScale,COWS,20capturesclinicians'assessmentsofobjectivesigns21ofwithdrawal.
Itdemonstratedthatpatients22AMatterofRecord(301)890-418862remainedstableanddidnotexperiencesymptomsof1withdrawalintransfertoProbuphine,andinfact2maintainedthesameresultsbeforeandafter3transitiontoProbuphine,showingthatpatientshad4noclinicalsymptomatologyassociatedwiththe5change.
Similarly,patient-reportedSubjective6OpioidWithdrawScalealsoremainedstable7throughoutthestudywithnoapparentdifferences8betweenthetreatmentarms.
9Consistentwiththeseresults,patientsalso10showedlowscoresunderneedanddesiretouse11illicitopioidsonbotharms,demonstratingthat12patientsremainstablethroughoutthetrialinboth13groupswithnoincreasesinneedordesiretouse14opioids.
15Severalsensitivityanalysesdemonstrated16therobustnessoftheclinicalefficacyresults.
17Theprimaryendpointwas4outof6monthswithno18evidenceofillicitopioiduse.
Sensitivity19analyseslookingat5outof6monthsfreeof20illicitopioiduseandall6monthsfreeofopioid21usesupporttheoutcomesoftheprimaryefficacy22AMatterofRecord(301)890-418863endpoint.
Thesemorestringentdefinitionsof1responsedemonstratefavorablepointestimatesand2confidenceintervalforProbuphine.
3Additionalsensitivityanalysesexaminedthe4impactofthethreesubjectswhowerenotincluded5intheITTdatasetbecausetheyhadnoefficacy6data.
Priortothedevelopmentofthestatistical7analysisplan,theprotocoldefinedtheITT8populationtoincludeallrandomizedsubjectswho9receivedatleastonestudydose.
Ourstatistical10analysisplan,finalizedapproximately6months11priortounblindingofthestudy,definedtheITT12populationasthoserandomized,receivedtreatment,13andprovidedatleastonepost-baselineassessment.
14Thedivisionconsiderstheearlier15definitionfromtheprotocoltobeapplicable.
16Therefore,wealsoconductedtheprimaryanalysis17withthethreesubjectsnotincludedintheSAP18definedITTpopulation.
Usingprimaryimputation19methods,thisanalysiswasconsistentwiththe20primaryprespecifiedITTdatasetwiththepoint21estimateandconfidenceintervalfavoring22AMatterofRecord(301)890-418864Probuphine.
1Imputingthethreesubjectswithnoefficacy2dataasnon-responderssoyieldedaresultthat3meetsnoninferioritycriteria,thoughnolonger4meetingsuperioritycriteria.
Thus,eventhemost5conservativeapproachofimputingpatientswithno6dataasnon-respondersstillsupportsthepositive7resultsfortheprimaryendpoint.
Thisistruly8conservativebecausethesewerestablepatients,9andthereisananecdotalreportthat1ofthe310subjectswaslikelytobearesponder.
11Additionalsensitivityanalysesexaminedthe12impactofmissingurinetoxicologydata.
In13studiesofopioiddependence,missingurine14toxicologyvalueshavebeenhandledinvarious15ways.
Inclinicallyunstablepatients,these16missingvaluesaregenerallyimputedaspositive17forillicitopioiduse.
However,inclinically18stablepopulations,itwouldbeexpectedthatmost19ofthemissingvalueswouldbesimilartonon-20missingvalues.
21Forthesublingualbuprenorphinearm,the22AMatterofRecord(301)890-418865missingvalueswereimputedconsistentwiththis1expectation,i.
e.
,theproportionofpositiveurine2samplesforeachsubjectwascomputedforeach3treatmentgroup,andthentheaverageofthese4proportionsacrosssubjectsinthisgroupwas5computedasgroupspecific,probabilityofpositive6urinetoxicology.
7However,tobeconservative,apenaltywas8appliedtothemissingurinevaluesinthe9Probuphinearmbyusinganadditional20percent10penalty.
Inthisgroup,themaximumestimatesof11thetwogroup-specificprobabilityofpositive12urine,multipliedby1.
2,wasusedasabasisfor13imputation.
Therefore,thismethodofclassifying14patientswithmissingvaluesasnon-respondersor15respondersintheprimaryanalysisimplementsa16penaltyintheProbuphinegrouprelativeto17sublingualbuprenorphine.
18Only3percentinbothtreatmentarmshad19missingurinesamples.
Thenumberofrandomand20scheduledsamplesthatweremissingweresimilarin21bothgroups.
Eachurinetoxicologytestcomprises22AMatterofRecord(301)890-41886622urinetoxicologypanelitems,andapproximately11.
5percentofthenearly40,000totalpanelitems2werenotreported.
Thesepanelitemsaffected37percentoftheProbuphineurinesamplesand44percentofthesublingualbuprenorphineurine5samples.
6Althoughmissingdatawereminimal,7sensitivityanalyseswereconductedtoassessthe8impactofthesemissingdata.
Multipleanalyses9assesstheimpactofdifferentapproachesof10imputingmissingdata.
Sensitivityanalysesusing11conservativeapproachesofimputingallmissing12urinetoxicologyresultsaspositivefortheITT13dataset,andthesameanalysiswiththeinclusion14ofthethreesubjectswithoutanypost-baseline15data,demonstratethatthepointestimatesfavor16Probuphine.
17Additionally,imputingmissingsamplesand18missingpanelitemsaspositivealsoshowthatthe19pointestimatefavoringProbuphinewiththelower20boundoftheconfidenceintervalarewellwithin21themarginatnegative6.
2percentagepoints.
22AMatterofRecord(301)890-418867Theseresultssupporttherobustnessoftheprimary1result.
2Supplementalusewasanotherfactorassessed3foritspotentialimpactontheprimaryendpoint.
4Evenstablepatientsareexpectedtohaveperiods5whentheyrequiretemporarydoseadjustments.
The6studyallowedinvestigatorstoprovidesupplemental7buprenorphineasneededbytheirclinicaljudgment.
8Patientsweretoldthatthedoseofbuprenorphine9theywerereceivingwasexpectedtobeadequate,10butanyadditionalsupplementaltreatmentswere11allowedinadditiontosupplementalcounselingand12supplementalpharmacologictreatment.
13Ratesofuseofsupplementalbuprenorphine14werelowandsimilarinbotharms,13subjectsin15sublingualbuprenorphineand15subjectsin16Probuphine.
It'simportanttonotethat5ofthe17subjects,one-thirdofthetotalintheProbuphine18group,onlyrequiredonedispensingepisode.
All1913subjectsinthesublingualbuprenorphinearmwho20usedsupplementalbuprenorphinehadtwoormore21dispensingepisodes.
Therewasonesubjectwhowas22AMatterofRecord(301)890-418868anoutlierintheProbuphinegroupwith21total1episodes.
2Thisslideillustratesthatalthough3supplementalbuprenorphinewereusedinboth4treatmentgroups,themajorityofthesubjects,5overall84percent,didnotrequireany6supplementalbuprenorphine.
Acloserreviewofthe7subjectswithsupplementalbuprenorphineuseshows8thattheusewassimilarinbothgroupswithno9specificpatterntothetimingofuse.
10Clinicaloutcomesforthe28subjectsthat11receivedsupplementalbuprenorphinedemonstrate12thatallsubjectswererespondersexceptforonein13thesublingualbuprenorphinegroup.
Eighty-seven14percentwerefreeofillicitopioidusethroughout15the6monthsintheProbuphinegroupcomparedto1669percentinthesublingualbuprenorphinegroup.
17Buprenorphinedosepriortostudyentrywere18similarinbothgroups,andveryfewhadmissing19urinesamplesorevenmissingpanelitems.
20Theseoutcomesmirrorclinicalpracticeand21dosemodulationisnotequivalenttolackof22AMatterofRecord(301)890-418869responsetotreatment.
Therefore,thesesubjects1shouldnotbecharacterizedasnon-responders.
2However,aconservativeapproachwasusedto3analyzesubjectswhotooksupplementals,andwe4imputedpatientswhotooksupplementalsas5non-responders.
Thisanalysisisconsistentwith6alltheothersensitivityanalyses.
Thepoint7estimatefavorsProbuphinecomparedtosublingual8buprenorphinewithalowerlimitofconfidence9intervalwellwithinthemarginofnegative8.
610percentagepoints.
11StudyPRO814mettheprimaryendpoint12demonstratingnoninferiorityofProbuphinerelative13tosublingualbuprenorphine.
Theconfidence14intervalwaswellabovetheprespecified15noninferioritymarginandinfactmetcriteriafor16superioritywithap-valueof0.
034.
Additionally,17themajorsecondaryendpointanalysesstrongly18supporttheprimaryfindingandcontributetothe19totalityofevidence,showingthebenefitof20Probuphine.
Further,allsensitivityanalyses21demonstratedtherobustnessoftheseresults.
22AMatterofRecord(301)890-418870IwillnowintroduceDr.
SteveChavoustie,1whowillpresenttheProbuphineinsertionand2removalprocedureandProbuphinesafety.
3ApplicantPresentation-StevenChavoustie4DR.
CHAVOUSTIE:Thankyou,Sonnie,andgood5morning,everyone.
MynameisSteveChavoustie.
I6amaprincipalinvestigatorwiththeSegal7Instituteforclinicalresearch.
Iamboard8certifiedinobstetricsandgynecologyandhave9extensiveexperienceimplantingandremoving10contraceptiveimplants.
11Ihavereceivedhonorariaformytime.
Ido12nothaveanyfinancialinterestinthecompanyor13theoutcomeofthismeeting.
Iwasa14sub-investigatorinthephase2PKstudy,all15phase3studies,andservedasanadvisortohelp16developtheProbuphineapplicator,surgical17procedures,andtrainingprogram.
18Duringtheclinicaldevelopmentprogramof19Probuphine,subdermalimplant,development,20equipmentproceduresevolved.
Norplantwas21approvedin1990.
The6silasticNorplantimplants22AMatterofRecord(301)890-418871wereinsertedusingatrocharandwereremovedbya1techniquedevelopedbythePopulationCouncil2referredtoasthestandardtechnique.
3Thetechniqueinvolvedpullingtheimplant4outbyitsendusingahemostatfromanincisionat5thebase.
Sincefibrosisformsaroundthe6implants,removingthemutilizingthestandard7techniquewasdifficultandtimeconsuming.
Anew8removaltechniquereferredtoastheU-technique9waspublishedbyDr.
Praptohardjoin1993to10enhancetheremovalprocedureanddealwiththe11fibroticimplants.
Itwasconsideredmore12convenientandpreferabletocliniciansandtothe13patients.
Subsequently,severalotherimplantable14medications,includingImplanon,Vantas,and15Supprelinwereapproved.
16Inresponsetolessonslearnedfromthe17NorplantexperienceandfromProbuphine'sfirst18double-blindstudy805anditsextensionstudy807,19wemodifiedtheequipment,procedures,andtraining20relatedtotheimplantinsertionandremoval.
21Let'sstartbytalkingabouttheequipmentand22AMatterofRecord(301)890-418872proceduremodifications.
1Instudies805and807,weuseda2blunt-tippedapplicatoranda5to10-millimeter3incisionforimplantinsertions--soaboutyour4fingernailbreadth--andthestandardremoval5techniqueforNorplant.
Forstudies806,811,and6814,wemodifiedtheprocedurestouseasharp,7bevel-tippedcannulaanda3-millimeterincision8forimplantinsertionsandutilizedthemodified9U-techniqueforremoval.
10Thistechniqueinvolvesgraspingtheimplant11inthemiddleusingamodifiedvasectomyclampand12removingitthroughamidlineincisionparallelto13theimplanttracks.
Themodifiedvasectomyclamp,14orX-clamp,hasa2.
5millimeteropeningtograsp15theimplantatraumatically.
16Thetrainingprogramalsoevolved.
For17studies805and807,weprovidedimplanting18physicianswithaninstructionalDVD,written19instructionsforself-guidedtraining.
Ifneeded,20ourimplantmedicalmonitorprovidedadditional21trainingatthestudysites.
22AMatterofRecord(301)890-418873Instudies806,814,and811,weintroduced1theCompetencyBasedTrainingprogramconsistingof2atrainingmanual,aninstructionalvideo,andan3half-dayinteractiveclassroomsessioninvolving4reviewingthebrachiumofthearm,managing5complicationssuchasfibrosis,protrusions,6extrusions,bleeding,andinfections.
Participants7fromvariousmedicalspecialtiesreceivedhands-on8trainingwheretheypracticedimplantinsertionand9removaltechniquesusingameatsimulationmodel.
10Themastertrainersobservedeachtraineecarefully11duringthissessiontoconfirmthattheyhad12achievedcompetency.
Wedidnotstopevolvingthe13trainingprogramattheendofthe814clinical14trialeither.
15ThisisaProbuphinetrainingclassroom16setupattheNationalCenterforHumanFactorsin17HealthcarewithinMedStarHealth.
MedStarwas18engagedtodesignandexecuteathoroughandrobust19humanfactorsstudy.
Theyvalidatedallsteps20involvedwiththeproceduresandassociated21trainingcomponentstoequipuserswiththe22AMatterofRecord(301)890-418874knowledgeandskillstosafelycompleteboththe1insertionandremovalprocedureswhileminimizing2riskofharmtopatients.
3Thefinaltrainingprogramisdesignedto4havea5to1ratiooftraineestomastertrainers5toallowformoreintensiveobservationand6education.
Thetrainingincludesthreeprimary7components.
Firstistheimplantprocedure8training,whichincludesaslidepresentationand9livedemonstrationoftheproceduresona10meat-simulatedhumanarmpresentedbyamaster11trainer.
12Next,asshowninthisphotograph,isinthe13insertionandremovallivepracticum.
Thisis14wheretraineespracticetheinsertionandremoval15proceduresusingthemeatmodel.
Themeatmodelis16preimplantedwithadeepimplant,anormalimplant,17afracturedimplant,andanimplantdesignedto18representfibrosis,theadheredone.
19Tosimulatethis,SuperGluewasinjected20aroundthatimplanttocreatethefibrosis.
21Actually,it'stechnicallymoredifficulttoremove22AMatterofRecord(301)890-418875thatimplantthanitisinthehumanarm.
This1givesthetraineespracticalexperiencedealing2withdifficultremovals.
Thetrainersare3availabletoguideparticipantsthrougheachstep4andansweranyquestionstheymayhave.
5Finally,there'sacertificationexam.
6Traineesmustbothsuccessfullyansweraseriesof7knowledge-basedquestionsanddemonstrate8proficiencyof21criticaltasksforinsertionand918criticaltasksforremoval.
I'veshownyouhow10wehaveenhancedtheequipmentproceduresand11trainingduringthedevelopmentprogram.
Let'snow12reviewanactualinsertionandremovalprocedure.
13ThefirststepinProbuphineinsertionisto14setupalocationthatisappropriatefor15performingasterileprocedureandassuringaseptic16techniqueispracticedthroughouttheprocedure.
17Identifytheproperinsertionsite,preferablyon18thenon-dominantarmabout8to10centimeters19abovethemedialepicondyleofthehumerus,and20thenpreptheskin.
21Theskinprepisatwo-stepprocess.
First,22AMatterofRecord(301)890-418876wewipetheskinoffwithalcoholtoremoveany1debris,orsurfacedirt,oranyoils,andthenwe2markthesitewithasinglemarker.
Thenthe3secondpartoftheprepinvolvesusingChloraPrep4triplesticksinthreesequentialswipes.
5Injectlocalanestheticundereachmarked6trackandmakea3-millimeterincision.
Insertthe7beveledcannulaalongthefirsttrack.
Important.
8Bymaintaininglessthana20-degreeangleand9tentingtheskin,youinsertsubdermallyjustunder10theskintoavoidthelargebloodvesselsand11nervesthatliedeeperbelowthesubdermalplane.
12Loadtheapplicatorandinserttheimplants13undereachmarkedtrackintothesubdermalplane.
14ApplySteri-Stripstoclosetheincision.
Palpate15theimplanttoconfirmproperlocationandapplya16pressuredressing.
Instructthepatientonproper17woundcareandremindthemtonotifytheirdoctor18immediatelyiftheyseeanysignsorsymptomsof19infection,includingpain,swelling,redness,20fever,drainageorpusorincisionalopening.
21Theinsertionprocesstakesabout10to22AMatterofRecord(301)890-41887715minutes.
Afteratreatmentdurationof16months,theimplantswillberemoved.
The2removalprocessisalsoaminoroffice-based3procedureutilizingaseptictechniquethroughout.
4Beginbylocatingalloftheimplantsbypalpation5andmarkeachonebeforepreppingtheskin.
Inject6localanestheticbeneaththeimplants;thisway7theylifttheimplantstowardstheskin.
8Youmakea7-to10-millimeterincision9length-wisebetweenthesecondandthirdimplant.
10Yougentlygraspthemiddleoftheimplantwitha11modifiedvasectomyclamp,thusutilizingthe12U-technique.
Youdissectthefibroustissuearound13theimplant,liftandremovetheimplantthrough14theincision,andensurethatall4implantshave15beenremovedintheirentirety.
Oncethe164implantshavebeenremoved,suturetheincision,17applyanadhesivebandage,andapressuredressing18wrap.
Emphasizeproperwoundcaretothepatient19aswehavepreviouslydiscussed.
20Theimplantremovalistypicallycompleted21in20minutes.
Itisimportanttostressthatall22AMatterofRecord(301)890-4188784implantsneedtobepalpatedbeforebeginningthe1procedure.
Iftheyarenot,referthepatientfor2implantlocalizationbyultrasound.
3I'llnowpresentandoverviewofimplanting4physiciansintheclinicaldevelopmentprogram.
5Withintheclinicalstudies,theimplanting6physicianscamefromavarietyofbackgrounds,7includingsurgeryandsubspecialties,family8medicine,internalmedicine,obstetricsand9gynecology,anesthesiology,andpsychiatry.
10Thesafetydatabaseconsistsof7Probuphine11clinicalstudies.
Theprimarysafetyevaluationis12basedonpooleddatafromthethreedouble-blind13studies805,806,and814.
Thisisunlikethe14discussionofclinicalefficacy,whichwasfocused15ontheresultsofstudy814.
16Iwillfirstdiscussbuprenorphine,whichis17containedinmultipleFDA-approvedtransmucosal18formulationsandbrieflyitssafetydataasan19implantableformulation.
Wewillthenfocusonthe20safetyprofileoftheimplantitselfandthe21insertionandremovalprocedures.
22AMatterofRecord(301)890-418879370patientswereexposedtoProbuphine1duringtheclinicaldevelopmentprogram;1512subjectswereexposedfor6monthsorlongerand385subjectswereexposedfor12monthsormore.
4Additionally,inarecentcase,astudy[sic]5returnedtotheclinicalinvestigator'ssite6approximately7yearsaftertheinsertionprocedure7andhadtheimplantsremovedwithoutdifficulty.
8Thesafetydatabasefortheprocedure9includessubjectswhoreceivedplaceboimplants.
10Anadditional198subjectsreceivedplacebo11implantsinthecontrolledclinicaltrialsfora12totalof568subjectswhowereexposedtoeither13Probuphineorplaceboimplants.
14Hereisanoverviewofsubjectswhoreported15adverseeventsduringthedouble-blindstudies.
16Youwillnotethatratesofadverseeventsdeclined17fromtheearlieststudy,805,tothemostrecent18study,814.
Thenextrowshowsratesofadverse19eventsleadingtostudydiscontinuation.
Serious20adverseeventratesweresimilarbetweenstudyarms21acrossthe3double-blindstudies.
22AMatterofRecord(301)890-418880Therewasonedeathinthesublingual1buprenorphinegroupduringthedevelopmentprogram.
2Thisdeathoccurredinasublingualbuprenorphine3controlarm806.
Thesubjectwasa29-year-old4womanwhosufferedafatalheroinoverdose3days5aftershevoluntarilywithdrewfromthestudy.
6Lookingmorecloselyatthemostrecent7study,814,thereareseveraleventsofinterestto8consider.
A2-year-oldchildofasubjectinthe9sublingualbuprenorphinegroupwasadmittedtothe10ICUafterconsuminganunknownnumberofsublingual11buprenorphinetabletsthatwereaccidentally12droppedandscatteredonthefloor.
Shewas13dischargedhomefromthehospitalthefollowingday14instablecondition.
15Inaddition,2subjectsinthesublingual16buprenorphinegroupenteredrehabfacilitiesdueto17relapse.
Thesesubjectsremainedinandcompleted18thestudy.
Alsoinstudy814,2subjectshad19incidentsrelatedtoallegedtheft.
Onesubjectin20thesublingualbuprenorphinegroupreportedthata21relativestoleherstudymedication.
Asecond22AMatterofRecord(301)890-418881subjectreportedthatherstudymedicationwas1stolenfromhervehicle.
2Non-implantsiteadverseeventsweresimilar3betweentreatmentgroups.
Thesearetheevents4thatoccurredingreaterthan5percentofsubjects5inthepooled,double-blindstudies.
Themost6frequentadverseeventswereheadache,insomnia,7nasalpharyngitis,upperrespiratoryinfection,8nausea,anxiety,andbackpain.
Whileafewevents9weremorefrequentonProbuphine,theoverallrate10ofadverseeventswasthesameinbothgroups,1164.
7percent.
12WhatisuniqueaboutProbuphineisthe13safetyrelatedtotheimplantandtheassociated14procedures.
Theimplantsiteadverseevents15decreasedsubstantiallywhenwecomparethefirst16double-blindstudy,805,theyellowcolumn,with17thelaststudy,814,theblue.
Thesechanges18correlatewiththerefinementoftheequipment,19proceduresandtraining.
20Bythetimewegottothestudy814,implant21siterelatedeventsaremuchlessfrequent.
We22AMatterofRecord(301)890-418882combinedallimplantsiteadverseeventtermsthat1couldindicateinfection.
Theoverallinfection2ratesacrossall7clinicalstudieswas4percent.
3TheinfectionrateinPRO814was3.
4percent.
Only46subjectsdiscontinuedfromtheclinicalstudies5duetoimplantsiteadverseevents.
Allofthese6discontinuationeventsoccurredinstudy805and7itsextensionlabelstudy807whenwewereusing8theoriginaltechniqueandthestandardtechnique9forremoval.
Therewerenoimplantsiteadverse10eventsthatledtodiscontinuationfromstudies80611or814.
12TheoverallsafetyprofileforProbuphinein13theclinicaldevelopmentprogramwascomparableto14approvedformsofbuprenorphineforthetreatment15ofopioiddependenceandapprovedtypesof16subdermalimplants.
Nounexpectedadverseevents,17basedontheknownsafetyprofileofbuprenorphine,18wereidentified.
19Theimplantsiteadverseeventsthat20occurredwereminorandmanageable.
Moreover,21implantsiteadverseeventratesdeclinedduring22AMatterofRecord(301)890-418883thedevelopmentprogramaftertheequipmentandthe1insertionandremovalprocedureswererefinedand2thetrainingprogramenhanced.
Thankyou.
3ApplicationPresentation-BehshadSheldon4MS.
SHELDON:Thankyou,Dr.
Chavoustie.
5Probuphineriskmanagementprogramisa6comprehensiveapproachtoensuringthesafetyof7patients,whichwedesignedincollaborationwith8ouradvisors,bothinaddictionmedicineandin9implementationprocedures.
BecauseProbuphine10administrationrequiresaprocedurenotcommonto11addictionmedicine,weagreewithFDAthatarisk12evaluationandmitigationstrategy,orREMS,is13required.
14We'vedesignedaREMSinkeepingwith15guidancealsofromtheDEAandSAMHSAbecausethe16REMSmustcomplywiththeapplicablelawsrelating17tocontrolledsubstancesaswellastothose18relatingtooffice-basedprescribingof19buprenorphine.
Aswe'vereachedagreementwiththe20FDA'sDivisionofRiskManagementontheproposed21REMS,weareprovidingthisoverviewoftheREMSon22AMatterofRecord(301)890-418884behalfofFDAaswell.
1ThegoaloftheProbuphineREMSisto2mitigatetheriskofcomplicationsofmigration,3protrusion,expulsion,andnervedamageassociated4withtheimproperinsertion/removalofProbuphine5andalsotheriskofaccidentalexposure,misuseor6abuseifanimplantcomesoutorprotrudesfromthe7skin.
Thisisdonebyeducatingproviders,8informingpatientsabouttheriskofcomplications,9anddistributingProbuphineonlytotrainedand10certifiedhealthcareproviders.
11Dr.
Chavoustie'salreadyexplainedthe12educationalprogram,the4-hourcompetency-based13trainingprogramthatwewillbeusingtoensure14thattheprocedureismanagedifProbuphineis15approvedandisonthemarket.
We'llprovidethese16REMStrainingprogramsatsitesthroughoutthe17nationsothatallinterestedhealthcareproviders18willhaveanopportunitytobecertifiedasa19prescriberoranimplanter.
20Theprogramincorporateswhatwe'velearned21fromthehumanfactorstudyandincludesadidactic22AMatterofRecord(301)890-418885lecture,livedemonstrationusingtheporkmodel,1andapracticumusingthesameporkmodelwill2provideuspracticeandnecessaryskills.
Then,3participantswhointendtobecertifiedas4implantersneedtocorrectlyperform21critical5tasksforinsertionand18criticaltasksfor6removalaspartoftheproceduralcompetency7assessment.
8Sowhodowethinkwilllikelyparticipate9orwanttoparticipateinthistrainingand10certificationprogramCurrentbuprenorphine11prescribersrepresentavarietyofdisciplines.
12Thelargesttwogroupsareprimarycarephysicians13andpsychiatrists.
Thesegroupsrepresent1444percentand23percentofprescribers,and1549percentand24percentofprescriptions.
Other16prescribersincludespecialistsinemergency17medicine,painmanagement,anesthesiology,OB/GYN,18surgery,andotherswhoalsoprovideaddiction19treatment.
20Basedonsurveystodate,weexpectthatthe21majorityofpotentialProbuphineprescribersplan22AMatterofRecord(301)890-418886tofilladualroleofbothprescriberand1implanter.
Butwealsorecognizethatsome2potentialProbuphineprescribersarelikelytohave3limitedexperienceperformingsterilesurgical4proceduresandmayneedtheassistanceofother5colleaguesfortheirpatients.
6Basedonthehumanfactorystudy,weexpect7thatproviderswho'vecompletedamedicalresidency8orfellowshipinaproceduralspecialty,orwhodo9proceduresmoreregularly,aremostlikelytobe10abletopasstheproceduralcompetencyassessment11tobecertifiedtobeabletobeimplanters.
12WeinitiallyproposedtoFDAthatthe13participationevenintheREMStrainingprogramfor14implantersbelimitedtohealthcareproviderswho15haveproceduralbackgroundsorspecialties.
16However,wesubsequentlyagreedwithFDA'sDivision17ofRiskManagementthatproviderswhoareableto18passtherigorousproceduralcompetencyassessment,19regardlessoftheirbackgroundsorspecialties,20shouldbeabletoimplantandremovesafely.
This21isparticularlyimportantforpsychiatristswhoare22AMatterofRecord(301)890-418887criticaltotheadoptionofanynewmedicinebut1whomaynothavepriorproceduralexperience.
2Braeburnwillnotexcludenon-proceduralists3fromseekingtobecertifiedtoperforminsertion4andremovalprocedures.
Rather,westrongly5recommendthatprovidersseekingtobecertified6haveproficiencyinaseptictechniqueinsuturing7andremovalofforeignbodiespriorto8participatinginthetrainingprogram.
9Weexpectthatpsychiatristswill10appropriatelyself-selectbasedontheirownprior11clinicalexperiences.
Somepsychiatristsmaybe12abletodemonstrateproceduralcompetencyand13performthedualroleofprescriberandimplanter.
14Inthehumanfactorsstudy,forexample,wesaw15thatseveralpsychiatryresidentswhohadpretty16recenttrainingdidextremelywellinlearningthe17procedureandpassingthecompetencytest.
18Thepsychiatristswhodeterminethey're19unabletoimplantorunabletopasstheprocedural20competencytestwillhavetwooptions.
Thosewho21arepracticinginamulti-specialtyenvironment22AMatterofRecord(301)890-418888whereanimplantercancometothepsychiatristto1providetheprocedurewilldosointhe2psychiatrist'soffice.
Thosepsychiatristswitha3solopracticeorwhootherwisedonothavethe4correctfacilityfortheimplantationwillbeable5toreferouttoanimplanterwho'seither6DATA-2000waivedorpracticesatanOTP.
7AlthoughourproposedREMSprogram8distinguishesbetweenhealthcareproviderswho9prescribeversusimplant,allhealthcareproviders10mustparticipateinthelivetrainingprogram.
As11aconditionalcertification,bothprescribersand12implantersmustattestthattheywillcounsel13patientsonthepotentialriskofProbuphine,14completethedidacticandlivepracticumtraining,15passtheProbuphineREMSknowledgetest,and16documentthecompletedProbuphineinsertion/removal17inthepatientlog.
18Prescribershaveanadditionalobligationof19ensuringthattheinsertion/removalproceduresare20onlyperformedunderthesupervisionofa21healthcareproviderwho'scertifiedtoimplant22AMatterofRecord(301)890-418889Probuphineunlesstheyreferthepatientouttoa1certifiedimplanter.
Inaddition,implantersmust2passtheproceduralCompetencyAssessmentTestand3ensurethatthefacilitywheretheprocedurewill4beconductedhastheappropriateequipmentto5safelyperformtheprocedure.
6Certifiedhealthcareproviderswillreceive7aseriesoftake-homematerialsandthe8insertion/removalchecklist,whichhighlightskey9componentstoensureeffectiveinsertionand10removalofProbuphineisintendedforuseatevery11procedure.
Healthcareproviderswillalsoreceive12theinstructionsforusebooklet,theslidesfrom13thetrainingprogram,thepackageinsert,14medicationguide,thepatientcounselingtool,and15insertion/removallogthatthey'llalsoneedtouse16foreveryprocedure.
17Thesecondmaincomponentofachievingthe18REMSgoalrelatestopatienteducation.
TheREMS19programisdesignedtoensurethatpatientsare20awareofthegeneralrisksassociatedwith21insertionandremovalofProbuphineandthat22AMatterofRecord(301)890-418890seriousriskcanoccurifProbuphineimplantis1expelled.
TheREMSprogramisalsodesignedto2ensurethatpatientshaveadequateguidanceabout3woundcareandpreventingfurthercomplicationsand4accidentalexposuresintheunlikelyeventofan5expulsion.
6Bothprescribersandimplanterswillbe7requiredtoprovidelivecounselingtopatients.
8Implanterswillusethemedicationguidepriorto9performingtheinsertionprocedure.
Inadditionto10themedicationguide,prescriberswillalsousethe11patientcounselingtool,whichconfirmsawareness12ofallpotentialrisksandcouldbesignedbyboth13patientandprovider.
14TheProbuphinewebsitewillprovidean15overviewoftheREMSprogramandrequirementsas16wellasthetrainingslides,themedicationguide,17andpatientcounselingtool.
Thewebsitewill18includeadverseeventreportinginformation.
It19willalsoincludealocatortoolthatwillenable20prescriberstosearchfornearbycertified21implanters.
22AMatterofRecord(301)890-418891ThefinalcomponenttoachieveProbuphine1REMSgoalsisacloseddistributionsystem.
2Probuphinewillonlybedistributeddirectlyto3providersthroughaspecialtydistributorhubunder4abuyandbillmodel.
Onlycertifiedprescribers5willbeeligibletoorderProbuphine,andthehub6willverifythattheprescribingphysicianis7eitherDATA-2000waivedorpracticesatanOTP;8thattheprescribingphysicianisREMScertified,9andthatthereisacertifiedproviderwhowill10insertandremoveProbuphine.
11Healthcareproviderswillberequiredto12storeProbuphineinaccordancewiththeControlled13SubstancesAct.
Followingtheremovalprocedure,14providerswillberequiredtodisposethe15Probuphineimplantsaspharmaceutical,biohazardous16waste.
Thus,underthissystem,thereisno17mechanismforobtainingProbuphinethrougha18prescriptionthatpatientsfillataretail19pharmacy.
Probuphineisneverinthehandsof20patients.
21TheProbuphineREMSalsoincludesongoing22AMatterofRecord(301)890-418892assessmentstoensurethattheprogramisworking1aswellasintended.
TheFDAisstillreviewing2theassessmentplans,sothesummarypresentedhere3representsBraeburn'scurrentproposal.
We'll4recordandreporttheaggregatenumberofcertified5prescribersandimplanters.
Wewillreview6evaluationsoftheREMSprogramdidacticandlive7practicumtrainingsubmittedbyprogram8participantsandmakequalityimprovementsas9needed.
10We'llmonitorandevaluatetheclosed11distributionsystembytrackingordersthatare12filledbythespecialtyhub,byreviewingorders13thatarerejectedbytheverificationhub,14includingidentifyingreasonsforrejectionand15investigatinganysuspiciousorders.
We'll16investigateanyimpropershipmentsofProbuphineas17determinedthroughsemi-annualauditsofall18shippedorders.
19Finally,we'llinvestigateany20irregularitiesandthird-partyreportssuggesting21thatthere'sbeenanykindsofdiversionof22AMatterofRecord(301)890-418893Probuphineandcollaboratewithanylicensing1boardsorlawenforcementasnecessary.
2InadditiontotheelementsoftheREMSthat3we'vealreadydiscussed,wewillalsoprovide4additionalsupportforhealthcareproviders.
Upon5request,insertion/removaltoolkitswillbe6available.
Thesewillincludeallmaterials7necessaryfortheinsertion/removalprocessexcept8forlidocaine.
Additionally,uponrequest,9Braeburn'sclinicaleducatorswillbeavailablefor10thefirstinsertion/removalproceduressubjectto11compliancewithHIPAAregulations.
Probuphine12mastertrainerswillbeavailablefor13consultations,andcliniciansmayattendadditional14trainingprogramsatanytime.
15TheProbuphineriskmanagementprogramisa16comprehensivesystemtoassurethesafeuseof17Probuphineandoftheprocedure.
Itincludes18patientandprovidereducation,mandatorytraining19andcertificationforprescribersandimplanters,20andacloseddistributionsystemthatlimits21distributiontoonlycertifiedproviders.
Weare22AMatterofRecord(301)890-418894committedtoassuringthesafeuseofProbuphine1andwillcontinuetomonitortheeffectivenessof2thisprogramandtoimproveallaspectsofthe3programbasedonhealthcareproviderfeedback.
4I'dnowliketowelcomeDr.
Frosttodiscuss5thebenefit-riskconclusions.
6ApplicantPresentation-MichaelFrost7DR.
FROST:Thankyou.
I'mDr.
Michael8Frost.
I'maphysician,boardcertifiedinboth9internalmedicineandaddictionmedicine.
I'mthe10medicaldirectoratEaglevilleHospital,whichisa11300-bedinpatientaddictiontreatmentfacility12outsideofPhiladelphia.
Ialsoserveaspresident13ofFrostMedicalGroup,whichisastateaccredited14outpatientaddictiontreatmentcenter.
15I'vereceivedconsultinghonorariaformy16time,butIdonothaveanyfinancialinterestin17thecompanyortheoutcomeofthemeeting.
Ihad18theopportunitytoactbothasaprincipal19investigatorinthe814studyaswellasan20implanter,andIhaveexperiencewithboth21insertionandremovalofProbuphine.
22AMatterofRecord(301)890-418895We'veprovidedsubstantialevidencethat1Probuphineiseffectiveforclinicallystable2patients.
Thesearepatientsthataremaintained3at8milligramsorlessofbuprenorphineandhave4beentakingthesamedoseforatleastsixmonths.
5Itreatpatientslikethiseverydayinmy6practice.
Theyareengagedintheirtreatmentand7demonstrateacommitmenttotheirlong-term8wellness.
9Study814comparedProbuphinetosublingual10buprenorphineinclinicallystablepatients11maintainedondosesof8milligramsorless.
This12firstofitskindstudydemonstratedthat13Probuphineisnotinferiortosublingual14buprenorphine.
96.
4percentofsubjectstreated15withProbuphineand87.
6percentofpatients16treatedwithsublingualbuprenorphinehadatleast174outof6monthswithnoevidenceofillicit18opioiduse.
Strikingly,85.
7percentofsubjects19intheProbuphinegroupshowedabsolutelyno20evidenceofillicitopioiduse.
21Inthe814study,thereweretwoinstances22AMatterofRecord(301)890-418896ofsublingualtablettheftandoneinstanceof1accidentalpediatricexposuretothesublingual2buprenorphinetablets.
Probuphinereducesthese3real-worldoccurrencesthatpatientsreceiving4sublingualbuprenorphinecurrentlyface.
5Probuphinecontributestoreducingthe6numberofbuprenorphinetabletsavailablefrom7misuse,diversion,oraccidentalexposure.
Inthe8814study,patientsintheProbuphinearmreceived9onlyatotalof1,288buprenorphinetablets.
By10contrast,patientsinthesublingualbuprenorphine11armreceivedatotalof16,667tablets.
Moreover,12theseequivalentoutcomeswereobtainedwith1376percentlessmedicationoverall.
14Thereductioninpillburdencoupledwith15Probuphine'sextendedreleasecharacteristicsand16closeddistributionsystemwillhelptoreducethe17risksassociatedwithsublingualbuprenorphine.
18Probuphinecanreducetheanxietythatmany19ofmypatientsfeelaboutmedicationsupply,20dosing,andmedicationlossortheft.
Itcanalso21easethefearofaccidentalexposureofachildor22AMatterofRecord(301)890-418897othermemberintheirhousehold.
Probuphineis1moreconvenientforpatientsbyofferingincreased2discretioncomparedwithmonthlytripstothe3pharmacyorthedailyburdenofsublingual4self-administrationthatcanpullthemawayfrom5theirfamilyandworkforupto20minutesormore6perday.
Probuphineallowsthepatientsthe7freedomtoworkandplaywithoutthestressof8managingtheirmedicationsupply.
9Asaprovider,Iwelcometheflexibility10thatProbuphineoffersmeandmypatients.
Iwill11beabletospendmoretimeaddressingfactors12relatedtomypatients'recoveryandlesstimeon13issuessurroundingmedicationadherenceor14availability.
Perhapsmostimportantly,severalof15mypatientstoldmethattreatmentwithanimplant16wouldmakethemfeelmuchlessself-consciousabout17theiraddictionandmuchmorelikenormalpeople.
18Thisisreallyaboutgivingpeaceofmindto19patientsandproviders.
20Buprenorphinehasbeenwellcharacterized,21andProbuphine'sgeneralsafetyprofileis22AMatterofRecord(301)890-418898comparabletotheprofilesofvarioustransmucosal1formulations.
Therewerenounexpectedadverse2eventsandnodeathsfromProbuphineduringthe3clinicaldevelopmentprogram.
Theadverseevents4relatedtotheimplantationandremovalprocedures5werenotseriousanddidnotresultinpatients6withdrawingfromthestudy.
7Whilesomepatientsexperiencedmild,8localizedandtransientbleeding,pain,swelling,9orfibrosisandscarringfromimplantationand10removal,theseareminorrisksandarecommonto11allsurgicalprocedures.
Whileprocedurerelated12eventsarekeyriskstoconsiderforProbuphine,13theclinicalsafetydataandthevalidatedtraining14programshowthattheseriskscanbemanaged15effectively.
16Finally,whileProbuphineisdesignedand17expectedtobesufficienttomaintainclinical18stabilityamongpatientstreatedwith8milligrams19orlessofsublingualbuprenorphine,thewaxingand20waningnatureofopioiddependencemayrequire21periodicintensificationoftreatment.
Noneofthe22AMatterofRecord(301)890-418899patientsIcaredforinthe814studyrequiredor1requestedsupplementalbuprenorphine,butin2clinicalpractice,psychosocialstressorsor3biologicchangesmaynecessitateadjustmentof4pharmacologicorpsychologicaltherapies.
5Doseincreasemaybeindicatednotasrescue6therapybutasphysician-directedtemporarydose7adjustments.
Thisoccursinthemanagementofall8chronicdiseases.
Itisanalogoustoapatient9withdiabetesonalong-actinginsulin,requiring10theintermittentadditionofashorter-acting11insulintobettermaintainstablebloodglucose12levels.
13Theepisodicuseofphysician-directed14supplementalbuprenorphineinapatientwho15maintainsclinicalstabilityonProbuphineshould16stillbeconsideredatreatmentsuccess.
For17doctorsandpatientsalike,Probuphinecantake18awaytheuncertaintyaboutensuringconsistent19deliveryofmedication.
20Weknowthatbuprenorphineworkswellwhen21it'staken,butsublingualdailydosingcreates22AMatterofRecord(301)890-4188100opportunities,inadvertentornot,tomissdoses.
1Thesix-monthdosingofProbuphinehasthe2potentialtoreducethoseopportunitieswhile3offeringconvenienceandmuchgreaterdiscretion4comparedwithdailydosing.
Justassublingual5buprenorphineallowedpatientstomoveawayfrom6thestigmaofdailyclinicvisits,animplantable7formulationgoesevenfurthertoprovidepatients8greaterfreedomandsecurity.
9Opioidaddictionisachronic,relapsing10braindisease,andcliniciansneedmoretreatment11options.
Effectivetreatmentsthatareless12susceptibletodiversionandabusebenefit13patients,clinicians,andoursociety.
Asan14addictiontreatmentprovider,Ineedmoretreatment15options,andmypatientscertainlydeservethesame16rangeoflong-actingtherapiesthatareavailable17topatientswithotherchronicillnesses.
No18medicationaloneisgoingtosolvetheopioid19epidemic,butProbuphinehasavaluableroleto20playinadiseasethatclaimssomanylives.
Thank21you.
22AMatterofRecord(301)890-4188101ClarifyingQuestionstoApplicant1DR.
KRAMER:Thankyouverymuch.
We'rea2littlebitbehindschedule,soI'dliketoexplain3toeveryone,andthecommitteeinparticular,what4we'regoingtodo.
Wearegoingtopreserve515minutesaswasontheoriginalschedulejustto6receiveclarifyingquestionsforthesponsor.
7Thesearethingsyoudon'tunderstandthatyou8reallycouldn'tgetfromboththepacketandthe9presentationsthatyouneedtohavebeforewe10proceedwiththemeeting.
Afterthat,wewilltake11a10-minutebreak,sotheFDApresentationwill12start10minuteslaterthanontheschedule.
13Whatwe'dliketodoisifyouhavea14question,putyournametagverticalandalsotry15togetJenniferShepherd'seyessothatshecan16writeyouonalist,andwe'llgothroughthelist.
17Andtrytobeverysuccinctwithyourquestions.
18MS.
SHELDON:CouldIjust19have--sorry--thelastslidebackupIwanted20tointroducetheotherfolkswhoareavailableto21answerquestions,ifthat'sokay.
22AMatterofRecord(301)890-4188102DR.
KRAMER:Ithinkpeoplehavethatin1theirpacket.
2Dr.
Bickel3DR.
BICKEL:Ihavethreequestions.
Iwas4wonderingiftherewasanyqualitativeanalysisof5thestatementsthatledtosupplementaldosing6betweenthetwogroupsandwhethertheywereof7similarordissimilarstatements.
Iaminterested8toknowifpatientsareadvised,iftheyarelost9tofollow-uptechnicallyfromthestudy,whatare10theysupposedtodowiththemedicationthatisin11theirarmAretheygiveninstructionsaboutthat12Lastly,Iwanttoknowiftheywereto13extracttherodsthemselves,couldtheygetthe14medicationoutofit.
Howwouldtheyextractit15Isthatpossible16MS.
SHELDON:Sowe'llstartwiththelast17onefirst.
Itisunlikelythatpatientswilltake18rodsoutoftheirarms.
AndI'llhaveboth19Dr.
ChavoustieandDr.
Torringtondiscussthe20surgicalskillsnecessarytodothat,butalsothe21risk-benefitofgettingwhatultimatelywillbethe22AMatterofRecord(301)890-4188103equivalentof10pillsthatcouldbeavailableon1themarket.
Itispossibletoextract2buprenorphine,butletmeIguessmaybestartwith3Dr.
Torrington.
4DR.
TORRINGTON:Hi.
MatthewTorrington.
5I'mafamilymedicinedoctorwithaspecialtyin6addictionmedicine.
I'vereceivedhonorariaformy7time,butIhavenofinancialinterestinthe8outcomeofthismeetingorinthecompany.
9Yes.
Soitispossibletoextractsome10buprenorphinefromtheimplantswitheitheralcohol11orwithlikealong-termsaturationmethod.
But12theestimatesarethattheygetaverysmallamount13ofbuprenorphinefromthem.
There'sabout1480milligramstotalIthinkinthedoseof4rods.
15Soconsideringhowavailablebuprenorphineseemsto16beonthestreetfromourpatients,itjustseems17veryunlikelyconsideringthesepatientsare18incrediblyresourcefulandefficientinwhatthey19do.
Soitispossible,butitseemssomewhat20unlikelyforus.
21MS.
SHELDON:Youalsoaskedaboutthe22AMatterofRecord(301)890-4188104patientswhowerelosttofollow-up.
Allpatients1aretoldduringtheprocedurethattheyneedto2returnafter6monthsfortheimplantstobe3removed,andthatwereallydon'tknowhowmuch4longerafterthatthemedicationwillcontinueto5work.
6Thatdidhappenwithoneofourpatientswho7wasincarceratedforthedurationofthestudy.
We8madeactually--hewasoutforalittlebitof9time,andwewerereallyhopingtogetsome10assessmentsfromhim.
Wemadeactuallyevery11attempttoevenaccesshimwhilehewas12incarceratedtobeabletogetdataback,butwere13unsuccessful.
Hedidreturnafterthestudywas14completedtohavehisimplantsremovedandreported15thatwhilehewasincarcerated,hedidnotuse,and16ultimatelytaperedoffbuprenorphine.
17DR.
BICKEL:Myquestionactuallywas,are18patientsgiveninstructionsiftheyweretoleave19theabilitytogothroughwhatwouldbethe20standardprocedurefortheextractionoftherods,21whattheyshoulddo,likeiftheymovetoanother22AMatterofRecord(301)890-4188105partofthecountryorsomething.
1MS.
SHELDON:IntheREMSprogram,the2websitewillactuallyhavelocators.
Andso3they'llbeabletoclickontheirzipcodeortheir4areaandbeabletofindadifferentimplanting5physiciantohelpthemwiththeremovalprocess.
6DR.
BICKEL:Andmyfirstquestionwasabout7qualitativestatements.
8MS.
SHELDON:Onthesupplementaluse9DR.
BICKEL:Yes.
10MS.
SHELDON:Wehavenarrativesonall2811patientswhoreceivedsupplementals.
Therewerea12varietyofreasonsgiven.
Theoutlierpatient13actuallywhoreceived21--slideup,please.
I'll14giveyoujustoneexample.
Thiswasthepatient15whoreceived21episodes,actuallyaskedtocome16backforweeklypsychosocialcounselingaswellas17incrementaldosesofbuprenorphine.
18Thispatientwasexperiencingsituational19anxietyanddepression,hadsomelifestressors20goingon,andendedupactuallydoingquitewell21fromanoverallperspectiveofnothavingany22AMatterofRecord(301)890-4188106positiveurinetoxicologyandcompletingthestudy1successfully.
2Thereseemedtobesomepracticedifferences3inhowcliniciansdealwithsupplementaluse.
Some4clinicianshavetoldusandasyousawinthe5briefingbook,21outofthe28patientswho6receivedsupplementalscamefromtwosites.
And7whatwe'veheardfromcliniciansissomeofthem8believebuprenorphinehasotherbenefitsbeyond9treatingopioiddependence.
10Soifsomebodyhassomesymptomsrelatingto11anxietyordepression,theydon'tmindincreasing12thedoseabitinordertomanagethat.
Other13clinicianswouldusespecificmedicationsthatare14forthosediseases.
Theywouldgiventheman15anxietymedicationoranSSRIinstead.
Wethink16thatthat'spartofwhyweseesomevariation17acrosspractices.
18DR.
KRAMER:Okay.
We'regoingtogoon19becausewehavealotofpeoplethathave20questions.
DawnIonescu21DR.
IONESCU:Hi.
Justaveryquick22AMatterofRecord(301)890-4188107question.
I'mDawnIonescu.
Forstudy807,there1weretwopatientsthathadsomeimplantsiteAEs2thathemorrhaged,infection.
Anditwasnot3relatedtotheprocedure.
I'mjustcurious.
What4wasitrelatedto5MS.
SHELDON:Dr.
Chavoustie6DR.
CHAVOUSTIE:Wecanputthatslideup.
7That'sactually--slideup.
Oneofthesubjects,8asIrecall--andI'dhavetomaybeafterthe9sessionpullthatslidefor807.
Butthereisa10subjectthathadaninfectionthatwasacellulitis11thatwasinthecontralateralarmtotheimplant.
12Andthatwasfromself-injecting,anditgot13infected.
Ithadnothingtodowithimplant.
14Anyincreaseamountofhemorrhageor15bleedingduringthat805-807trialis--remember,16Imentionedabouttheincisionwas5to1710millimetersforputtingtheseimplantsin,which18wasmuchtoolarge.
It'snow3millimeters.
So19that'swhyyou'llseethattherateofbleedinghas20markedly--almostnilinthe814trial.
21DR.
KRAMER:Dr.
Narendran22AMatterofRecord(301)890-4188108DR.
NARENDRAN:Ihaveacouplequestions.
1Iknowyouguysdidn'tdoPETstudiestolookat2thereceptoroccupancy.
Now,pharmacokinetically,3yousaylike50percentbasedontroughlevelsand430percent,16-milligramdosageequivalent,based5onareaunderthecurve.
Sowheredoyou6think--whatpercentagereceptorsareyou7occupyingHaveyoudoneanykindofsimulations8toestimatePK/PDdata9MS.
SHELDON:SoI'dliketoaskDr.
Sharon10Walshtocomeandaddressyourquestiondirectly.
11Butit'simportanttorememberthatthiswasa12clinicaltrial.
Essentially,nottryingtoequate13doses,butansweringtheempiricalquestionwith14clinicaldata,showingthatyoucouldtransfer15patientseffectivelywho'vebeenstabilizedon168milligramsorless.
17DR.
NARENDRAN:Butthatrange,itseemsto18bequiteimportanttoknowifyou'recloserto4or19you'recloserto8.
YouknowwhatImeanAnd20thenthatalsorelatestotheamountofsublingual21dosingthey'regetting.
22AMatterofRecord(301)890-4188109DR.
WALSH:Goodmorning,everybody.
My1nameisSharonWalsh,andI'mfromtheUniversity2ofKentucky.
AndIwillreceiveconsultingfees3fortimetoday,butIhavenofinancialinterestin4thecompanyortheoutcomeofthisstudy.
5Slideup,please.
Thisslideillustrates6datafromastudythatwaspublishedbyDr.
Mark7Greenwald,inwhichheexaminedthereceptor8occupancyfrommuopioidreceptorsfollowing9maintenanceonbuprenorphineacrossarangeof10dosesthatcoverlargelytheclinicalrange.
And11youcanseethatatadoseof2milligrams,there's12about41percentreceptoroccupancy,andat1316milligrams,thisisincreasedtonearly1492percent.
15Nextslide.
Inasubsequentstudythat16Dr.
Greenwaldandcolleaguespublishedthispast17year,theyexaminedtheimagingdataalongwith18pharmacokineticdataandclinicaloutcomestotry19andgetexactlyatthequestionthatyou'reasking.
20Andwhattheyestimatedwasthattherewasadose21neededofabout4milligramsofsublingual22AMatterofRecord(301)890-4188110buprenorphineorabout50percentoccupancyfor1adequatewithdrawalsuppression,amuchhigherdose2neededforblockade.
3BaseduponFDA'sclinicalpharmacologyteam4andtheirassessmentoftheProbuphineproduct,it5isexpectedthattheconcentrationofbuprenorphine6wouldbe--I'mgoingtoestimatesomewherearound7the6-milligramdoseforthecoveragefortherange8from8orlowerseemstobeappropriateand9practicable.
10Inthenextslide--slideup,please--you11canseetheoutcomesfortheresponderratesbythe12dosesthatthepatientswereonatthetimethat13theycameintotreatment.
Intheupperpartofthe14panel,you'relookingatthoseindividualswhoare15stabilizedon8milligramsbeforestarting,andin16thelowerpart,you'relookingatthosewhowereon17lessthan8milligrams.
Andtherewerepatients18whowereon2,4,and6milligrams.
19Whatyoucanseeisthatiftheconcernis20thatthere'sinadequateplasmaconcentration,that21thosepeoplewhowereon8milligramswhenexposed22AMatterofRecord(301)890-4188111toProbuphine,theyhada98percentresponserate1reallysupportingtheefficacyofthisplasma2deliveryconcentrationinthisgroupofpatients.
3DR.
NARENDRAN:Mysecondquestionkindof4relatestothis.
The814trial,itseemslike5theseweren't--Imean,70percentofthemwere6usingprescriptionopiates.
Lessthan15or720percentwereusingreallyheroin.
AndIassume8thatmostofthesepeopleareinhaledusersand9wereusingIVheroin,becauseyouhavealow10fractionofIVheroin.
11Soisthisfairtosaythatthisisamore12clinicallylessillsamplecomparedtotheprevious13trialsAndcouldthatrelatetowhyyourimplant14sideeffectsarelowerBecauseIwouldassumefor15yourIVdruguser,you'reprobablygoingtohave16morecomplicationswithinfectionsstilland17fibrosis.
18MS.
SHELDON:WedidhavesomeIVdrug19users,andwecangetyoutheexactnumbersafter20thebreak.
Certainly,thefactthatthesepatients21wereclinicallystable,thattestedtobe22AMatterofRecord(301)890-4188112clinicallystablebytheircliniciansandhadnot1beenabusingforatleast--thattheywere2abstinentforthelast3monthsandhadbeenin3treatmentfor6monthswouldsuggestthatthey4were,inoverall,betterhealthandcertainly5clinicallystable.
6DR.
WALSH:IfIcanjustaddonethingto7that.
Theywereontheirstabledosefor6months,8buttheaveragetimeintreatmentwasactually39andahalfyears.
Sothesepatientshadprobably10beendoingprettywell.
Andwedon'treally11know--obviously,theywerehavingdifficulty12beforetheyhadinitiallyenteredtreatment--13DR.
NARENDRAN:Sure,sublingual.
14DR.
WALSH:--sotheyhadalongperiodof15treatmentbeforetheycameintothestudy.
16DR.
NARENDRAN:Thankyou.
17DR.
KRAMER:Ifcommitteememberscouldtry18tobereallyconciseandlimityourquestionsto19thingsyouthinkthesponsorcouldprovidequickly,20wecouldhavelongerdiscussionduring--wehave21plentyoftimethisafternooninourdiscussion22AMatterofRecord(301)890-4188113period,andwecancallthembackupifweneedbe;1becausewe'renotgoingtogetthrougheveryoneat2theratewe'regoing.
3LoriDoddisnext.
4DR.
DODD:Yes.
Ihaveasimplequestion5relatedtothethreeearlyterminationsinthe6Probuphinearm.
Canyoutellmewhathappenedto7thosethree8MS.
SHELDON:Wedon'tknowwhathappenedto9twoofthem.
Well,weknowwhereonepatientended10up.
HeleftandwenttoKeyWestanddidnot11return.
12DR.
DODD:I'msorry.
Thiswaspriortoany13treatment,receiptofanytreatment14MS.
SHELDON:Afterreceivingthe15implant--16DR.
DODD:Aftertheimplantreceived.
17MS.
SHELDON:--aftertheimplant18was--yes.
AndthenonewastheonethatI19describedthatwenttojailfortheduration,and20wehavenoinformationonthethirdpatient.
21DR.
DODD:Butallthreedidreceive22AMatterofRecord(301)890-4188114implants--1MS.
SHELDON:Theydid.
2DR.
DODD:--andthenwentmissing.
Okay.
3Thankyou.
4DR.
KRAMER:Tothesponsor,your5terminologytocallthatgroupintenttotreat,6includingpeoplethat--andexcludingpeoplewho7receiveddrugisnotstandardandveryconfusing.
8SoIthinkthat'sanimportantquestion.
Ihope9everyoneheardthat.
Threepeoplewhoreceivedthe10implantwerenotincludedintheanalysis.
11Dr.
Higgins12DR.
HIGGINS:I'mparticularlyinterestedin13thecorrelation,ifany,betweenthosewhoare14olderadultsandtheProbuphine.
Iknowit's15probablyhardtodothisanalysisbecauseyouhave16fewerpeoplewhoareolder,butI'mwonderingif17therewereanycorrelationsbetweentheProbuphine18andanyadverseeffects,rescuemedicationused,19woundcontrol,andanymissingurinesamples.
20MS.
SHELDON:Theaverageage,asyounoted,21wasbelow40,andwedidnothavemanyolder22AMatterofRecord(301)890-4188115subjectsinourtrial.
Butoverall,wehavenot1seenanimpactonanydemographics,includingage,2intermsofsafetyorefficacyforProbuphine.
3DR.
KRAMER:Dr.
Grieger4DR.
GRIEGER:Justaquickquestion.
5ComparingslidesCE-54,inwhich15ofthe6Probuphineindividualsreceivedsomesupplemental7sublingualbuprenorphinewithslideCB-106,where8itsays1288pills--Ipresumethoseareactually9thesublingual--10MS.
SHELDON:Theywerethesupplemental.
11DR.
GRIEGER:--sublingualversion.
12MS.
SHELDON:Yes.
13DR.
GRIEGER:WhatwasthedistributionIt14wouldseemlikesomeofthoseindividualsare15receivinghundredsofpills,andothersmaybea16handful.
Isthatcorrect17MS.
SHELDON:Exactlycorrect.
Therewas18quiteavariationaslowas1single2-milligram19pillandashighas210pills.
Sotherewasthe20variationofdispensingepisodes,andeach21dispensingepisodereallydependedonthe22AMatterofRecord(301)890-4188116clinician'sjudgment.
Wewantedtomakesurewe1werenotrestrictiveatall,artificially,in2directingsupplementalusesothatthiscouldmimic3wouldcouldhappenintherealworld.
Sowe're4veryliberal,givingnoguidancewhatsoever.
5Slideup,please.
Soyoucanseetherange6ofnumberof2-milligramdosesthatweregiven.
7DR.
GRIEGER:Okay.
Thankyou.
Witha8concernforpotentialdiversionintherealworld,9inaclinicalworld,wouldyouconsiderimplant10withdrawalatsomepointifsomeone'saskingfor11hundredsofsupplementals12MS.
SHELDON:Certainly,wewouldthinkthat13thatwouldbebasedontheclinicaljudgmentand14therelationshipbetweentheclinicianandtheir15patient.
Fromourperspective,ifapatientdoes16notappeartobedoingwellonProbuphineafterone17setofimplants,itisadecisionthatwouldbe18logicaltoreconsider.
19DR.
KRAMER:DavidPickar20DR.
PICKAR:Yes.
Aquickpharmacology21question.
ItplaysoffofwhatRajeshwastalking22AMatterofRecord(301)890-4188117about.
Inthelowerdoserange,itactsasan1agonist,theclassicbuprenorphine,mixed2agonist/antagonist.
Thedoserangethatwillbe3deliveredbythisimplantwouldbeintheagonist4categorybutnottheantagonistcategory.
Isthat5correct6DoIunderstandthatrightItdoesnotact7asanantagonist,asopposedtothemix,naloxone8buprenorphine,whichisSuboxoneandsoforth,9whichisverycommonlygiven.
DoIunderstandthis10right,thatinthebloodlevelsyou'regetting11here,itwouldseemtobeina50percentoccupancy12ofthemureceptor,anditwouldbeconsidered13pharmacologicallyasanagonist,notanantagonist14Isthatcorrect15DR.
WALSH:Soletmetrytoclarify.
16Buprenorphineisonlyconsideredamixed17agonist/antagonistbecauseithasagonist18propertiesatonereceptorandantagonist19propertiesatanotherreceptor,whichis--asthe20kappaantagonist.
Peoplefrequentlyrefertoitas21amixedagonist/antagonistandthinkofitas22AMatterofRecord(301)890-4188118havingantagonistpropertiesathigherdoses.
But1that'sactuallybecauseit'sapartialagonist.
2Soasapartialagonist,you'refamiliarI'm3surewiththeceilingeffect.
Butwhathappensat4higherdosesisthatitcanbehavelikean5antagonistinsomeonewho'sopioiddependent6becauseitcanprecipitatewithdrawal,justasif7youhadsomeone,say,onmethadone,andthey8receivedaninjectionofnaloxone,andtheywent9intowithdrawal.
10Weknowthatifyouhavesomeoneon11methadone,andyougivethembuprenorphinebecause12ithaslowerefficacy,itwillessentiallyknock13themethadoneoffthereceptor,anditcanalso14precipitatewithdrawal.
Andweknowthatthat'sa15dose-relatedphenomena.
Itdependsonwhatpeople16havehad.
17SoIthinkwhatIthinkyou'rereallyasking18aboutisblockadeandtheideathatyouget19cross-toleranceorblockadewithantagonist-like20features.
Isthat--21DR.
PICKAR:Therealquestionbehindit--22AMatterofRecord(301)890-4188119DR.
WALSH:Yes.
1DR.
PICKAR:--istheagonistproperties.
2Isthatadditivetomuagonistspropertiesof3heroinofexogenousopiatesAndinthatcase,4doesitmakeyoumoresensitivetooverdose.
5That'swhereIwasgoingwithit.
Becauseit'snot6goingtobeanantagonist.
7DR.
WALSH:Right.
8DR.
PICKAR:Andacomment.
Inanaddiction9population,anindividualonoralsublingualdose10arecertainlycleverenoughtostoptheirmedicine11foradayiftheywanttoexpandintoother12opiates.
13DR.
WALSH:Yes.
14DR.
PICKAR:Itjustis.
I'msorry,butit15is.
16DR.
WALSH:Yes.
17DR.
PICKAR:Here,youdon'thavethe18option.
Soifyouwanttoexperimentinexogenous19opiates,you'regoingtoaddittowhatyouhave.
20Sothequestionisalittlesimple.
Isitsagonist21propertiesatthemureceptoradditivetoexogenous22AMatterofRecord(301)890-4188120mureceptoragonistsfromanoverdosepointof1view2DR.
WALSH:Yes.
3DR.
PICKAR:I'mjust--errorofsafetyat4thispoint.
5DR.
WALSH:Thankyou.
Yes.
It'snot6additive.
Maintenanceonbuprenorphine,evenat7lowerdoses,willproducesomeprotectionagainst8overdose.
That'soneofthereasonsthatit's9effective.
Willitproduceasmuchblockade10againstanillicitlyuseddrugas32milligrams11Theanswerisnotothat.
Weknowthatit'sa12dose-dependentphenomena,andthatthehigherthe13doseis,thebetterblockade.
14Weactuallyhavesomedatathatillustrate15this.
IsitpossibletoseetheComerdataWhile16they'refindingthat--andiftheydon't,wecan17doitafterthebreak.
Butwhatweknowthat18is--evenatdosesthatwethinkare--slideup,19please--higherthantheProbuphinedose--so20thesearedatafromSandyComer'slabthatshow21peoplewhoaremaintainedonbuprenorphineat8and22AMatterofRecord(301)890-4188121then16milligrams.
Andwegenerallythinkof116milligramsandhigherasablockingdose.
2Inthiscase,theseindividualsareina3laboratorysetting,andthey'remaintainedon4buprenorphine,andthenthey'rebeinggiventhe5opportunitytotakeheroin.
Andthey'rebeing6askedintheleftpanelhowmuchdoyoulikethe7drugiftheychoosetotaketheheroin,andonthe8rightside,you'relookingattheactualheroin-9takingbehaviorinaself-administrationprocedure.
10Whatyoucanseeisthatat8milligrams,11youdon'tseegoodblockadefortakingheroinat12thesedoses,andthatbydoublingthedoseof13buprenorphineto16milligrams,youseesome14reduction,butit'snotacompletereduction.
15Nextslide.
Inthisslide,thisisastudy16thatwedidanumberofyearsago,basicallydoing17thesamething,lookingattheefficacyof18methadone,whichwehavealotmoreclinical19experiencewith.
Andinthisstudy,wemaintained20peopleondosesofmethadone,andthenalsogave21themopportunitytotakeheroininthelaboratory.
22AMatterofRecord(301)890-4188122Inthiscase,patientsweremaintainedon150,100,and150milligramsperdayofmethadone.
2Andifyouareamethadonetreatmentprovider,you3knowthatthesearesubstantiallyhighdoses.
And4thesurprisingfindingaboutthisstudyisthatwe5alsothinkthatmethadoneproducesthesamekindof6cross-toleranceorblockade.
7Inthisstudy,evenat100milligrams,which8ismuchhigherthantheaveragedose,wedon'tsee9completeblockadeofheroinontopofthe10methadone.
Andinfact,weneededtogotoadose11ofnearly150,whichveryfewpatientsareon,to12seenearlycompleteblockades.
Soweknowthat13methadoneandbuprenorphinearebothefficacious,14buttheydon'tactuallyneedtohavecomplete15opioidblockadeinordertobeso.
16DR.
PICKAR:Physiologically--you're17showingbehavior.
Butintermsofrespirationsand18soforth,whenyouputheroinontopofthelower19doseofbuprenorphine,doyougetanyenhancement20ofrespiratorydepression21DR.
WALSH:Itwoulddependonthedoseof22AMatterofRecord(301)890-4188123heroin.
Ifyouwere--you'regoingtogetsome1blockadewhereyou'renotgoingtogetadditive2effectsbecausereceptorsarealreadyoccupied.
3It'sacompetitivereceptorphenomenon.
Soifyou4pushthedosehighenough,you'regoingtostartto5seeadditiveeffects.
It'skindofthesame6situationwhereyou'vegotsomebody,say,onahigh7doseofbuprenorphineandmaintenance,andthen8theyneedanalgesia.
Youwanttobeableto9surmountthatinordertogetananalgesic10response.
11DR.
PICKAR:Atdosesthatdon'tblockade,12yougetanaddedphysiologiceffect--13DR.
WALSH:No.
14DR.
PICKAR:--okay.
That'sthequestion.
15DR.
WALSH:No.
16DR.
KRAMER:Okay.
Ithinkwe'regoingto17havetointerruptourquestions.
Wewillcomeback18toallthepeoplethathad--wehaveyournames19down.
Wewillreturntotheclarifyingquestions20aftertheFDApresentation.
Wewillhavea2110-minutebreaknow.
We'regoingtoreturnat22AMatterofRecord(301)890-418812410:25,quickbreak.
We'regoingtostartexactly1at10:25.
2(Whereupon,at10:17a.
m.
,arecesswas3taken.
)4DR.
KRAMER:Okay.
We'realreadypastour5scheduledtime,soifeveryonecouldtaketheir6seats.
7IsFDAreadytostarttheirpresentations8Wewillcomebacktothepeoplewhohavequestions9forthesponsor.
Andforthesponsor,the10clarifyingquestionsarereallyimportant,andwe11willcomebackwiththeadditionalonesandgive12youachancetoanswer,aftertheFDA.
13FDAPresentation-RachelSkeete14DR.
SKEETE:Goodmorning,everyone.
My15nameisRachelSkeete,andI'mamedicalofficerin16theDivisionofAnesthesia,Analgesia,and17AddictionProducts.
I'mtheprimaryclinical18reviewerfortheProbuphinenewdrugapplication19resubmission,andtoday,IalongwithDr.
James20Travis--he'sastatisticalreviewer--willbe21presentingontheefficacyandsafetyfindingsfor22AMatterofRecord(301)890-4188125Probuphineforasubpopulationofpatientswith1opioidaddiction.
2Specifically,we'llbepresentingthese3findingsforProbuphineforthe4maintenance/treatmentofopioiddependencein5patientswhoareconsideredclinicallystableby6theirtreatinghealthcareprovider.
7Duringthistalk,we'llbeproviding8backgroundinformationonbuprenorphineinthe9transmucosalformscurrentlyusedfortreatmentof10opioiddependence,theProbuphinedrugproduct,and11asummaryoftheregulatoryhistoryleadingupto12thepresentnewdrugapplicationsubmissionbeing13discussedtoday.
14Theefficacydiscussionwillfocusonthe15resultsofthePRO814trial,thesingletrial16conductedinpatientsdeemedclinicallystable,and17onlowtomoderatedoses,upto8milligrams,ofa18transmucosalbuprenorphineproduct.
Dr.
Travis19willdiscussthesefindings.
Finally,the20discussionofsafetywillfocusonthesafetyof21theindividualindwellingrodsandtheprocedures22AMatterofRecord(301)890-4188126toinserttherodsandremovethemattheendofa1treatmentcycle.
2Probuphineisanimplantableformulationof3buprenorphine.
Andaswediscussedsofartoday,4thedrugsubstancebuprenorphineisapartialmu5opioidreceptoragonist.
Currently,thereare6transmucosalsspecifically,bothsublingualand7buccalformulations,thatareapprovedforthe8treatmentofopioiddependence.
9Thesetransmucosalformscanbeusedfornew10entrantstotreatment.
Andwhenusedfornew11entrantstotreatment,thetypicalmaintenancedose12is16milligrams.
AndthisisSubutextablet13equivalents,andthat'sasasingleingredient.
14Whenusedinthecombinedbuprenorphinenaloxone15forms,thedoseis16/4andasaSuboxonetablet16equivalent.
17Buprenorphinehasdose-dependentactivity.
18Ittakesonlysmallamountstostaveoffwithdrawal19symptoms.
Thesearedosesapproximatelyinthe20rangeof2to4milligrams.
Toachieveblockade21however,higherdoses,approximately16milligrams22AMatterofRecord(301)890-4188127andabove,aretypicallyneeded.
1Comparedtofullagonists,buprenorphine2safetyandtolerabilityprofileisnotablefor3withdrawalsyndromethatisdelayedandreducedin4intensityaswellasaso-calledceilingeffect,in5thatthere'saplateauoftheagonisteffectsuch6asrespiratorydepression.
7Asmentioned,transmucosalformsof8buprenorphineareavailableforthetreatmentof9opioiddependence.
Thissummarizesthelandscape10ofthetransmucosalproducts.
Theseinclude11SuboxoneandSubutextabletformulations,which12wereapprovedin2002andwerethefirstproducts13approved.
Theyarenolongermarketed,butgeneric14formsareavailable.
15Thesublingualfilmwasapprovedin2010,16andlaterasupplementforabuccaladministration17wasapprovedforthefilmlastyear.
Morerecently18Zubsolvsublingualtabletwasapprovedin2013,and19Bunavailbuccalfilmwasapprovedthefollowing20yearin2014.
21Sooverthecourseoftheevaluationof22AMatterofRecord(301)890-4188128Probuphineforclinicallystablepatientsonlowto1moderatedosesoftransmucosalbuprenorphine2product,additionalproductshavecomeonthe3marketinrecentyears.
Acrosstheproducts,there4aredifferencesinthebioavailabilityand5buprenorphineplasmaexposuresatparticulardoses.
6Bothofthesepointsareimportantforproviding7guidanceonappropriateadministrationprocedures8forProbuphine.
9Thistableprovidesanoverviewofthe10correspondingdosesforthetransmucosal11buprenorphinecontainingproducts.
Thereisalot12ofdetailonthisslide,buttherearetwomain13pointsthatI'dliketohighlightfromthisslide.
14ThefirstisthatthedosesofZubsolvandBunavail15arelowerthanthedosesfortheSuboxoneproducts,16asyoucansee.
17ZubsolvandBunavailaremorebioavailable,18soonlylowerdosesarenecessarytoachieve19comparableplasmaexposurelevelstotheSuboxone20products.
Anotherimportanttake-homefromthis21slideisthatalthoughthecorrespondingdosesfor22AMatterofRecord(301)890-4188129Suboxonetablets,includingthegenericequivalents1andSuboxonefilm,arenominallythesameforeach2strength,Suboxonesublingualfilmsaremore3bioavailable,particularlythetwohighest4doses--that'sthe8-milligram/2-milligram,and5the12-milligram/3-milligramdoses--andthey6providehigherbuprenorphineexposuresthantheir7tabletcounterpartsatthesamedose.
8Again,thearrayoftransmucosalproducts9andthedifferencesinbioavailabilitywouldhave10bearingonanyguidanceontransitioningstable11patientsonatransmucosalproducttothefixed12doseProbuphineproduct.
13Nowthatwehavesomebackgroundonthe14availabletransmucosalproductsandasthe15potentialroleofProbuphineintheaddiction16treatmentisbeingconsideredviatransferfrom17thesetypesofproducts,thedrug-usepatternsfor18theseproductsbearmention.
Membersofthedrug19utilizationanalysisstaffwithintheOfficeof20SurveillanceandEpidemiologyprovided2014drug21utilizationdata,whichisanupdatetothedrug22AMatterofRecord(301)890-4188130utilizationdataprovidedinFDA'sbackground1documentation.
2In2014,1.
3millionpatientsreceived3dispensedprescriptionsoftransmucosal4buprenorphinecontainingproductsfromU.
S.
5outpatientretailpharmacies,whichisamodest6increasefromthe2012data,whilethetotalnumber7ofprescriptions,10.
6million,remainedrelatively8stable.
9Aswasthecasein2012,prescriberswhose10specialtyisidentifiedasgeneralpractice,family11practice,orosteopathicmedicinewroteforthe12largestnumberofbuprenorphineprescriptions.
13Thiswasfollowedbyprescriberswhosespecialtyis14definedaspsychiatryandinternalmedicineto15roundoutthetopthreegroupsofprescribers.
16Withthebackgroundonthetransmucosal17formsinmind,we'llshifttodiscussing18Probuphine,theimplantableformandthepurpose19forourdiscussiontoday.
Theapplicanthas20alreadydescribedtheirproductintheir21presentation,soIwon'trepeatthefull22AMatterofRecord(301)890-4188131discussion.
Here,I'llonlyhighlightafewpoints1pertinenttoourdiscussiontoday.
2Thefirstisinregardtoterminology.
3Duringthepresentation,you'llhearmereferto4theindividualProbuphineimplants,that's1of4,5aseitherrodsorasimplants.
Theotherpoints6I'llmentionhavetodowiththeapplicant's7indicationandproposeddosageandadministration8proceduresastheyrelatetowhatwasstudiedin9thePRO814trial,whichsupportsthisresubmission.
10Theapplicant'sproposedindicationisfor11themaintenancetreatmentofopioiddependenceand12shouldbeusedaspartofacompletetreatment13programtoincludecounselingandpsychosocial14support.
Thisindicationwouldindicatethat15all-comers,includingnewentrantstotreatment,16wouldbeappropriateforProbuphine.
However,only17asubpopulationofpatients,specificallypatients18whoareconsideredclinicallystablebytheir19treatinghealthcareprovider,wasstudiedinthe20PRO814trial.
Theproposedindicationshould,21thus,reflectthepopulationthatwaseligiblefor22AMatterofRecord(301)890-4188132studyintendedtoestablishefficacy.
1Similarly,theapplicant'sproposeddosage2andadministrationdirectionsincludeinstruction3thatProbuphineisappropriateforpatientswhoare4opioidtolerantandonadoseof8milligramsor5lessofasublingualSubutexorSuboxone6equivalent.
Althoughthesesubjectswereona7maintenancedoseof8milligramsorlessofa8SubutexorSuboxoneequivalent--andI'llstress9thatthisshouldbespecificallyatablet10equivalent--thepatientsinthistrialare11consideredclinicallystableandhavingbeenonthe12dosealonewasnotsupposedtobesufficientfor13entryintothetrials,ortrial.
Aswiththe14indication,thedosageandadministration15instructionsshouldmorecloselyreflectthe16populationstudied.
17ThefinalpointI'llmakehereisthatin18theclinicaldevelopmentprogram,therehasn'tbeen19experiencewithinsertionorremovalofProbuphine20rodsorimplantsbeyondtwoadministrationsites.
21Therearealsonodataexaminingtheefficacyand22AMatterofRecord(301)890-4188133safetyofreinsertionintoapreviously-usedsite.
1Theapplicantproposesthatthereare42administrationsites,2sitesperarm.
Soatthis3pointinthedrugproduct'sdevelopment,thereare4amaximumofonly4treatmentcyclesforthis5product,whichisintendedtobeusedforchronic6relapsingcondition.
Insomecases,evenfewer7sitewouldbeavailableiftherearecomplications8requiringearlyremovaloftheimplantsand9reinsertionintotheotherarmduringasingle10treatmentcycle.
11I'vebeendescribingthispresent12applicationasaresubmission.
Theinitial13submissionofProbuphine,oftheNDA,wasin14Octoberof2012.
Theapplicationwasanisa15505(b)(2)application,meaninginthiscasethatit16reliesinpartonagencysafetyandefficacy17findingsforSubutexandSuboxonesublingual18buprenorphinetablets.
19WhentheProbuphineapplicationwas20initiallysubmitted,itwasintendedfor21maintenancetreatmentofopioiddependencein22AMatterofRecord(301)890-4188134all-comers,includingnewentrantstotreatment.
1Tousethisproduct,apatientwouldfirstreceive2sublingualbuprenorphinewiththeintentof3reachingatargetdoseof12to16milligramsper4dayforatleast3days.
5Afterreachingatargetdose,patientswould6undergoaninitialinsertionof4rods.
Atthe7time,therewasanoptionforthefifthrodwhen8certaincriteria,basedonamountofrescueuse,9weremet.
Therearenolongerplanstomaintain10thisoptionforafifthrod.
11Tosupportthisinitialapplication,there12were2maintrialsconducted.
Thesestudies,13identifiedasPRO805andPRO806,weretwonearly14identicalsafetyandefficacytrials.
Theclinical15developmentprogramalsoincludedtwo6-month16extensiontrials,PRO807andPRO811,whichwerethe17extensionsto805and806,respectively;a18pharmacokineticstudy;andacomparative19bioavailabilitystudycomparingProbuphineto2016milligramsofsublingualbuprenorphine.
21The6-monthPRO805andPRO806trials22AMatterofRecord(301)890-4188135enrollednewentrantstotreatmentwhoinitially1received4Probuphineor4placeborodsAsI2mentionedpreviously,thereformerlywasanoption3forafifthrodthatwasplannedfortheoriginal4developmentprogram.
5Rescueorsupplementalbuprenorphineusewas6permittedandusedinatreatmentfailure7definition.
Subjectswerewithdrawnfromthetrial8iftheymetprotocol-specifiedrescue9buprenorphine-basedwithdrawalcriteria.
Although10itwasusedtodefinetreatmentfailure,11supplementalusewasn'ttakenintoaccountfor12determiningtreatmentresponse.
13Theefficacyevaluationwasbasedonurine14toxicologyandself-report.
Urinetoxicologywas15collected3timesperweek.
Thereasonforthis16frequencyinurinetestingwasthatthewindowof17detectionformanyopioidsisupto3days,sothat18thefrequenttestinghelpstoavoidurinesamples19beingclassifiedasnegativesimplybecauseuseof20anillicitopioidwasoutsideofthedetection21windowforaparticularurinesample.
22AMatterofRecord(301)890-4188136Urinetoxicologyfindingsweretakenalong1withself-reportofillicitopioiduseoccurring2aroundthetimetheurinesampleswerecollected,3toadjudicateaurinesampleasbeingpositiveor4negative.
Ifeithertheurinetoxicologyor5self-reportwaspositive,thesamplewasconsidered6positive.
7Investigatorswereblindedtourine8toxicologyfindingsduringthetrial.
Andbecause9thegoalwastoevaluateindividualtreatment10response,aresponseprofilewasusedforthe11analysis.
Inthiscase,thecumulative12distributionfunction,orCDF,ofthepercentof13opioid-negativeurineswasevaluatedtoassess14treatmentresponse.
Missingurineswereconsidered15positiveforthepurposesoftheanalysis,andonce16withdrawnfromthestudy,patients'urinesamples17wereconsideredpositivefromthepointof18discontinuationon.
19Thesearetheresultsofthetrialsbasedon20thecumulativedistributionfunction.
Ontheleft21oftheslideisthegraphicalrepresentationofthe22AMatterofRecord(301)890-4188137findingsforeachtrialshowingtheCDFcurves.
On1therightisatabularsummary.
Let'sfirstlook2atthegraphsstartingwiththePRO805graph.
3OntheX-axisistheproportionofnegative4urinesamples.
OntheY-axisistheproportionof5patients.
ThesolidcurveistheProbuphinearm.
6Thedashedcurveisplacebo.
Ifyoulookatthe70.
3mark,whichisalittlebitdifficulttosee,8ontheX-axis,thisrefersto30percentormore9urinesamplesnegativeforopioids.
Now,looking10attheproportionofsubjectsmeetingthis11threshold,between40and50percentofProbuphine12patientshad30percentormoreopioid-negative13samples,whilealittleunder30percentofplacebo14patientshad30percentormore.
15Forbothtrials,wehadhopedtoseemoreof16aseparationofthecurvesandahighernumberof17patientsontheright-handsideoftheX-axis,18representinghigherproportionsofpatients19achievingabstinenceornearabstinence.
However,20whatwesawinsteadwasthecurvesapproachingzero21towardstherightoftheX-axis,whereabstinence22AMatterofRecord(301)890-4188138andnearabstinencewererepresentedandhigher1proportionsofpatientsrepresentedtowardsthe2leftandthemiddleoftheX-axis,wherethe3changesindrug-usebehaviorwerelessconclusive,4particularlyinstudy5.
5Thetabularsummaryontherightshowsthe6samefindings.
Therewerenoabstinentpatients7andfewnearabstinentpatients.
Theplaceborates8instudy6aremarkedlylowercomparedwithstudy59andprobablyrepresentahigherdropoutrateasa10resultofstrictercriteriaforreceiving11supplementalmedicationimposedforthetrial.
12Wealsolookedatsubject-levelanalysesfor13theseearliertrials.
Again,wewereinterestedin14individualresponse.
You'llseemorepresentations15similartothisofthedataforstudyforPRO814,16andI'llspendafewmomentsorientingyoutothis17datapresentationstrategy.
18Thesearesubject-levelurinetoxicology19dataforstudy5.
Eachsubjectisrepresentedasa20pointalongtheY-axis.
Therewas2to121randomizationinthetrial,sotheProbuphinedata22AMatterofRecord(301)890-4188139pointsaretwiceasmany.
Whenyoufollowaline1across,youseeallofthatpatient'surine2toxicologyresultsoverthe24-weekperiodofthe3study.
Abluedotisanegativeurinesample,red4ispositive,andaplussignismissing.
5Asanexample,thefirstplacebopatienton6thebottomhadoneopioidnegativeurinesample,7then2positivesamples,andthenwasdiscontinued.
8Fromthatpointon,alltherestoftheurine9samplesaremissingandarerepresentedbyaplus10sign,andwouldbeconsideredpositivefromthen11on.
12Ideallyonthesegraphs,youwouldseealot13ofblue,especiallyontheProbuphineside.
But14instead,youseealotofredrepresenting15submissionofopioid-positiveurinesamples16throughoutthetreatmentperiod.
Drug-usebehavior17basedonurinetoxicologyandself-reportdatawas18usedtoevaluateefficacy,andthat'swhatyou're19seeinghere.
20Wefoundthissubject-levelurinetoxicology21resultstobesimilarforstudy6.
Andhereinthe22AMatterofRecord(301)890-4188140Probuphinearm,comparedwithstudy5,there's1arguablymoreevidenceofopioiduse.
Soinreview2oftheoriginalapplicationsubmittedinOctober32012,thereviewidentifiedconcernswithefficacy.
4BuprenorphineexposurewithProbuphineisabout50.
9ngperml,whichisenoughtomanagewithdrawal6symptoms,whereasabout3ngpermlisneededfor7blockade,raisingconcernsthatonProbuphine,a8subjectcouldpotentiallyavoidexperiencing9withdrawalsymptomsbutstillcontinueto10experienceeuphoriceffectsofillicitopioids.
11Therewerealsoconcernsaboutthe12comprehensivenessoftheevaluationofimplant13safetyatthattime.
Anadvisorycommitteemeeting14wasalsoheldinMarchof2013thataddressed15safetyconcernswiththeproceduresforinsertion16andremoval,efficacy,andtheREMS,andincluded17expertsinaddictionmedicine,obstetricsand18gynecology,riskmanagement,andstatistics.
19Althoughthemajorityofthecommitteevoted20thatefficacyhadbeendemonstrated,thatsafety21hadbeenadequatelycharacterized,andthe22AMatterofRecord(301)890-4188141risk-benefitratiofavoredapproval,thecomments1duringthediscussionandthebreakdownofvotes2revealedconsiderableambivalenceaboutthe3application.
4Basedonreviewofthetotalityof5informationsupportingtheapplication,the6applicationwasnotapproved,andtheapplication7receivedacompleteresponseinAprilof2013.
The8majordeficiencyintheapplicationwasthatitwas9uncleartousthattheclinicalbenefitofthe10seeminglyminorchangesindrug-takingbehaviorhad11beenestablished.
12BecauseProbuphineprovideslower13buprenorphineexposuresandatargetmaintenance14dosefornewentrantstotreatment,itappeared15thatthedosewastoolow.
Toaddressthese16issues,theapplicantwasadvisedtoconductan17opioidblockadestudyand/orstudyhigherdosesof18Probuphine.
Therewerealsoconcernsaboutthe19safetywithinsertionandremovalprocedures,and20theapplicantwasadvisedtoconductahuman21factorsevaluationtovalidatethetraining22AMatterofRecord(301)890-4188142program.
1InNovemberofthatsameyear,wemetwith2theapplicantafterthecompleteresponsetoaction3todiscussnextsteps.
Theapplicantproposed4limitingtheindicationforProbuphinepatients5stabilizedonadoseofnomorethan8milligrams6ofsublingualbuprenorphine.
Comparativeby7availabilitydatahadshownthatProbuphine8providesplasmabuprenorphineexposuresinthe9rangecoveredby8milligramsorlessofsublingual10buprenorphine.
Theapplicantaimedtofinda11populationforwhomProbuphinemightbe12appropriate,inlieuofstudyinghigherdosesor13demonstratingopioidblockingproperties.
14Thisrepresentedanovelindication,anew15populationneverpreviouslystudied,aswellasthe16needforanovelstudydesigninanareawhere17clinicaltrialdesignalreadyiscontinuing18evolving.
Thereisalsonosingularestablished19definitionforclinicalstability,whichcould20presentanumberofchallengesinmakingan21efficacydetermination.
22AMatterofRecord(301)890-4188143InthecaseofProbuphine,wetookinto1considerationthepotentialpublichealthbenefit2ofthisproduct,whichmayreducemisuse,abuse,3andaccidentalpediatricexposureinthefaceofa4growingpublichealthcrisissurroundingopioid5abuseandaddiction,andrecognizedthatsome6flexibilitywaswarranted.
Additionally,7Probuphineoffersthepotentialforimproved8patientadherencetotheprescribeddose.
9Wewerewillingtoconsiderthelimited10indication,butanothertrialinthisnew11populationandforthenewindicationwouldbe12neededtoestablishefficacy.
Afterward,there13wereaseriesofpost-meetingcommunicationsto14discussthestudydesignforPRO814.
Thetrial15intendedtosupportlimitedindication.
16Duringthesecommunications,theapplicant17wasinformedthatmeetingtheprimaryendpoint18wouldnotautomaticallyleadtoafindingof19efficacy,particularlygivenalltheuncertainties20andgivensomeofthelatitudethatwouldbeneeded21totakeinpermittingsuchanevaluation.
22AMatterofRecord(301)890-4188144InAugustoflastyear,theapplicant1resubmittedtheProbuphineNDA,andthePRO8142trialisintendedtoprovideevidenceofefficacy3forthelimitedindication.
Theapplicantprovided4detailsofthestudydesignintheirpresentation,5soI'llonlysummarizedafewkeypoints.
Again,6thiswasaphase3,multicentered,double-blind,7double-dummyactivecontrol,withtheactive8controlbeingsublingualbuprenorphine,efficacy9andsafetytrialthattookplacein21U.
S.
sites.
10Thestudyenrolledadultswithadiagnosis11ofopioiddependencewhowereconsideredstableby12theirhealthcareproviderandwereconfirmedby13threecriteria,includingthattheywereon14sublingualbuprenorphineforatleast24weeks.
15Althoughthiswasintendedtobeforthe2416consecutiveweekspriortostudyentry,itappears17tohavebeeninterpretedasacumulativelifetime18durationorlifetimetotalused.
Atscreening,19subjectswereasked,"Inyourlifetime,howlong20haveyoubeentreatedwithbuprenorphineandhow21manytimeshaveyouenteredbuprenorphine22AMatterofRecord(301)890-4188145treatment"1Theywerealsosupposedtobeonadoseof2sublingualbuprenorphineofnomorethan38milligramsadayforthelast90days.
Thiswas4envisionedtobeabuprenorphinesublingualtablet5equivalent,butaswesawearlier,thereareother6transmucosalformsavailablefortreatmentof7opioidaddiction.
Andsomesubjectswereonthese8othertransmucosalformswheretheymayhavebeena9bitofamismatchbetweentheirpretrialand10on-studybuprenorphineexposures.
Eligible11subjectsalsosubmittednoopioidpositiveurine12samplesinthepast90days.
13Thetreatinghealthcareproviderscompleted14andsignedaclinicalstabilitychecklistattesting15totheirpatients'clinicalstabilityand16indicatingtheclinicalstabilitycriteriaonwhich17theywerejudgingtheirpatientstobestable.
18TheClinicalStabilityChecklistis19reproducedhere,andthequestionsareexcerptedon20thenextslideforbetterreadability.
Treating21healthcareproviderswereaskedtocheckoffitems22AMatterofRecord(301)890-4188146fortheirpatientsrelatedtoself-reportedillicit1opioiduseinthepast3months,theirliving2situation'withdrawalsymptoms;participationin3recommendedpsychosocialsupportgroups;compliance4withclinicvisitsrequirements;desireorneedto5useillicitopioids;hospitalizations,ERvisits,6orcrisisinterventions;andotherindicators.
7Duringthetrial,subjectseitherreceived48Probuphinerodsorsublingualbuprenorphinealong9withtheplaceboforthecomparatortreatmentfor10thisdouble-dummytrial.
Subjectscouldalso11receivesupplementalbuprenorphine,whichIalso12willbereferringtoasrescueforshortattimes.
13Butusewasexpectedtoberare,anditwaswritten14intotheprotocolthatpatientsweretobetold15thatwhileadditionalcounselingandother16pharmacologicalinterventionswereavailable.
17Thethencurrentdoseofbuprenorphinewas18expectedtobeadequatetomaintainstabilityand19thattheywerenotexpectedtoneedsupplemental20sublingualbuprenorphine.
Becauseuseof21supplementalwasexpectedtobesporadic,ifat22AMatterofRecord(301)890-4188147all,supplementalusewasnotfactoredintothe1responsedefinition.
2Urinetoxicologyandself-reportwere3assessedfortheirefficacyevaluation.
Therewere46scheduledmonthlyurinetoxicologyvisitsat5whichtimeself-reportofillicitopioidusewas6assessed.
Andtherewere4randomurinetoxicology7visits,whereonlytheurinesamplewascollected.
8Thescheduledandrandomurinetoxicologyvisits9combinedforatotalof10samplesforthetrial.
10Recallthatintheprevioustrials,urine11sampleswerecollected3timesaweek,andin12addiction,trials,urinesamplesarecommonly13collected1to3timesaweek.
Sothisrepresents14asmallnumberofurinesamplesforatrialandfor15oneof6monthsduration.
Butbecausethiswasa16stablepopulation,lessfrequencyseemedtobemore17consistentwithclinicalpractice.
However,18likewise,becausethiswasastablepopulationand19thesamplingwasinfrequent,theapplicantwas20informedthatthereshouldn'tbeverymanymissed21urinesamples.
22AMatterofRecord(301)890-4188148Asyouwillsee,thereweren'tmanymissed1visitsforurinesamples,buttherewereanumber2ofanalyticissueswithsubmittedurinesamples.
3Theefficacyanalysisemployedaresponder4definition.
Asubjectwasconsideredaresponder5iftheyhadnomorethan2monthswithevidenceof6illicitopioiduseeitherbyurinetoxicologyor7self-report.
Theefficacyanalysiswasintendedto8establishnoninferiorityratherthansuperiority.
9Althoughit'sconceivablethataproduct10thatoffersso-calledpassivecompliancecould11potentiallybedemonstratedtobesuperior,italso12seemedreasonabletopermitanoninferiority13analysis.
Thisstrategyforanalysiswasinformed14bytheliterature,whichislimitedandasmall15surveyofaddictionspecialists.
16Thekeyquestionsinthephysiciansurvey17thatwereusedbytheapplicanttoinformthe18proposednoninferiorityanalysiswerehowoftendo19youexpecttheaveragestablepatientinyour20practicetotestpositiveforopioidsovera216-monthperiodTheresponseswereconvertedto22AMatterofRecord(301)890-4188149opioid-negativeurines,andonaverage,the1specialistsendorsedthattheirclinicallystable2patientswouldbeopioidnegativemorethan390percentofthetime.
4Theywereaskedifthesepatientswereto5continueonthesamedose,whatwouldbethe6overallaveragepercentageofopioid-negativeurine7toxicologyresultstheywouldanticipatein86months.
Theseresponseswerereportedasthe9amountofopioid-negativeurinesanticipatedover10thenext6months,andtherespondersendorsedonly11ifthey'reabitless.
12Next,theywereaskediftheirpatients'13buprenorphinetreatmentweretobestopped,what14wouldbetheaveragepercentageofrelapseinthese15patientsovera6-monthperiod.
Thisquestion16servesasaproxyforunderstandingtheplacebo17responseinthesepatients,andonaverage,18respondentsbelievedthatapproximately70percent19ofthesepatientswouldrelapseiftheir20buprenorphinetreatmentweretobestopped.
21Finally,thespecialistswereaskedto22AMatterofRecord(301)890-4188150assumethaturinetoxicologyismeasuremonthlyfor16months.
Inthatcontext,theywereaskedwhat2theyconsideredtobethemaximumreasonablechange3inastablepatient'surinetoxicologystatusfor4thepatienttocontinuetobeconsideredstable,5andtheyweregiven4choices:nochange,1outof66urine-positiveurinetoxicologies,2outof6,or73ormoreoutof6.
8Thesewereconvertedtopercentagesto9reporttheresults.
Onaverage,thespecialists10thoughtthat14percentwasareasonablechange,11whichasapercentageisclosestto1outof612positiveurinetoxicologyresultsoverthatperiod.
13Insum,withbuprenorphine,thespecialists14onaverageconsideredthattheirclinicallystable15patientswouldsubmitanopioid-positiveurine16sample1orfewertimesinthefirst6monthsand117orfewertimesinthesubsequent6monthsifthey18continuedonbuprenorphine.
Iftheyweretohave19oneadditionalpositiveurineduringa6-month20period,therespondentsonaveragethoughtthat21thosepatientscouldstillbeconsideredstablein22AMatterofRecord(301)890-4188151thatsetting.
1Giventhesefindings,aresponderwas2definedasnomorethan2monthswithevidenceof3illicitopioiduse.
I'llagainemphasizethata4certainamountofflexibilitywasappliedinthis5case.
Thetypicalconditionsneededfora6noninferioritystudyandfordefiningaresponder7werenotpresentinthissituation.
What8informationcouldbegarneredwasusedindesigning9thistrial,againwiththeunderstandingthat10carefulreviewofthefindingswouldbeundertaken11becauseofthemanyuncertaintieswithatrial12designsuchasthisone.
13ThepopulationstudiedinPRO814,aswas14discussedbrieflypreviously,wasapredominantly15male,almostexclusivelywhite,non-Hispanic,16non-Latinogroup.
Theywereabout40yearsofage17andreportedprescriptionopioidsastheirprimary18opioidofabuse.
19Incontrast,thepopulationofnewentrants20totreatmentstudiedintheearliertrials,PRO80521andPRO806fortheoriginalapplication,more22AMatterofRecord(301)890-4188152commonlyidentifiedheroinastheirprimaryopioid1ofabuse.
Onaverage,subjectshadbeenon2buprenorphinefor2yearsconsecutivelybefore3enteringthestudy,andtherewereatotalof428patientswithabuprenorphinetreatmentepisode5priortoentryoflessthan24weeks.
6I'llpointoutherethatthesedatamaynot7fullyrepresentthelengthofthetreatmentepisode8priortoentry.
Recallthatpatientswereasked9howlongtheywereonbuprenorphinetreatmentin10theirlifetime.
Sothesedataarearough11approximationindirectlyestimatedfromother12sourcesofdataavailableinthissubmission,for13example,fromtheconcomitantmedicationshistory14collectedduringscreening.
15Thespecificlengthofthetreatmentepisode16priortoentrydoesnotappeartohavebeen17captureddirectlybyaskingaquestionofeither18thepatientsand/ortheproviders.
Andinfact,19forthesesamepatients,theirreportedlifetime20buprenorphinehistorywasonaverage34months,21nearly3years,andtheshortestdurationwas22AMatterofRecord(301)890-41881536monthsforonepatient,withthelongestlifetime1durationbeingalmost10years.
2Thehighestlifetimedoseforpatientswas314milligramsonaverageforbothgroups.
The4highestlifetimeindividualdosesreportedon5averagewere8milligrams,16milligrams,and24or6more.
Atstudyentry,themajorityofsubjects7wereonthe8-milligramdose.
8Ontheclinicalstabilitychecklist,the9healthcareprovidersweretocheckalltheitems10thatappliedtotheirpatients.
Thesearethe11proportionsofsubjectsforwhoaparticularitem12wascheckedoff.
Formanyoftheitems,healthcare13providersuniversallyendorsedthemfortheir14patients.
Onlyparticipationinastructured15activityorjob,consistentparticipationina16recommendedcognitivebehavioraltherapyprogramor17supportprogram,andhospitalizations,ERvisits,18orcrisisinterventionswerenotunanimously19endorsed.
Buttheystillrepresentrelativelyhigh20proportionsofthepatients.
Theapplicantdid21notethatitispossiblethathospitalizations,ER22AMatterofRecord(301)890-4188154visits,orcrisisinterventionitemmayhavebeen1underreportedbecauseofanartifactoftheform2thatwasused.
3Now,Iwilldiscusstheresultsofthe4efficacyanalysesforthetrial,andI'llnowturn5thediscussionovertoDr.
Travis,thestatistical6reviewer,todiscusstheresultsoftheefficacy7findings.
8FDAPresentation-JamesTravis9DR.
TRAVIS:Goodmorning.
MynameisJames10Travis,andI'mthestatisticalreviewerforthis11application.
We'llbeginthissessionofthe12presentationbygivinganoverviewofthestudy13design,asthiswasanoninferioritystudy,soI14willbeginbydiscussingtheconceptof15noninferiorityandhowitrelatestothisstudy.
I16willalsodiscusstheapplicant'sdefinitionofa17responderandhowtheyincorporatedmissingdatain18theiranalysis.
19Followingthediscussionofthestudy20design,Iwilldiscusstheefficacyresults.
There21wereseveralfactors,includingthechoiceof22AMatterofRecord(301)890-4188155analysispopulation,missingdata,andtheuseof1rescuemedication,whichwerenotadequately2exploredintheprimaryanalysisoftheplanned3sensitivityanalyses.
Theeffectofthesefactors4ontheefficacyanalysiswillbeexploredinthis5presentation.
6Now,ontothestudydesign.
Thecurrent7trialenrolledpatientswhowerestabilizedon88milligramsorlessofbuprenorphine.
Itwas9thoughtthatifthesepatientsdiscontinued10buprenorphinetreatment,asignificantnumberwould11relapse.
Consequently,theagencyagreedthat12conductingaplacebo-controlledstudyinthis13populationwouldbeunethical.
14ConductingasuperioritystudyofProbuphine15comparedtosublingualbuprenorphinewouldbe16infeasiblebecausepatientsinthispopulationwere17expectedtobeclinicallystablewithalowchance18ofrelapse.
Inordertoseesuperiorityof19Probuphinecomparedtosublingualbuprenorphine,20patientsstabilizedonsublingualbuprenorphine21wouldneedtodeterioratetoagreaterdegreethan22AMatterofRecord(301)890-4188156patientsreceivingProbuphine.
Soitwasagreed1thatadouble-dummynoninferioritydesignwouldbe2utilized,wherepatientswouldberandomizedto3eitherremainonsublingualbuprenorphineand4receiveshamimplantsorreceiveProbuphineandbe5switchedtoshamsublingualtablets.
6Inthisslide,Iwillpresenttherationale7givenbytheapplicantindeterminingtheir8noninferioritymargin.
Theapplicantstatedin9theirprotocolthattheybelieveamarginthat10preservesatleast70percentoftheeffectofthe11activecontrolwouldbeconsideredclinically12acceptable.
Astherewerenohistoricalplacebo13controlledstudiesdirectlycomparingtheactive14controlsublingualbuprenorphinetoplacebointhis15population,theapplicantestimatedtheplacebo16responserateusingasurveyofaddiction17specialists.
18Theaddictionspecialistsexpectedamedian19of75percentofsubjectswouldrelapseiftheir20stabledoseweretobediscontinued,andsoitwas21assumedthat25percentofthepatientswould22AMatterofRecord(301)890-4188157maintainclinicalstabilityiftheydiscontinued.
1Usingthisestimate,theapplicantthen2assumedthatthedifferenceinresponderrates,3whichisalsoreferredtoastheeffectsize,for4sublingualbuprenorphinewhencomparedtoplacebo5is75percent.
Amarginof20percentwasthen6selected,whichtheapplicantassumedwould7preserveslightlymorethan70percentofthe8assumedeffectsize.
9Noninferioritycanbeconcludedifthelower10boundofthe95percentconfidenceintervalofthe11differenceinresponseratesbetweenProbuphineand12sublingualbuprenorphineisgreaterthanminus1320percent.
14Now,movingontotheapplicant'sdefinition15ofaresponder.
Aresponderwasdefinedasa16patientwithnomorethan2of6monthswithany17evidenceofillicitopioidusage.
Evidenceof18illicitopioidusewasdefinedaseitherapositive19urinetestoraself-reportofillicitopioiduse.
20Atotalof10urinetestsweretobeconductedin21thestudy,6duringthesubject'smonthlysite22AMatterofRecord(301)890-4188158visitsand4randomlyscheduled.
Theapplicant1specifiedthatnomorethanonerandomtestbe2conductedpermonth.
3Subjectswerealsoaskedtoreportany4illicitopioidusageonlyduringthemonthlysite5visitsandnotduringtherandomvisits.
Itis6importanttonotethattheapplicant'sdefinition7ofaresponderdidnotconsideruseofsupplemental8sublingualbuprenorphine.
9Theapplicantdescribedthefollowing10procedureforimputingtheillicitopioidusage11statuswhentherewerenourinesamplesprovided12foraparticularmonth.
Theassumedproportionof13positiveswasdeterminebytakingtheaverageof14theintra-subjectpositiverateforthattreatment15arm.
Theanalysiswasmademoreconservativeby16increasingthepositiverateby20percentoverthe17higherofthetworatesfortheProbuphine18treatmentarm.
19Afinalimportantaspectoftheclinical20trialwasthechoiceoftheanalysispopulation.
21Theapplicantstatedthattheyintendedtousea22AMatterofRecord(301)890-4188159modifiedintent-to-treatpopulation,ormITT,for1theirprimaryanalysis.
However,theyprovidedtwo2differentdefinitionsforthispopulation.
3Thefirstdefinition,whichwasprovidedin4thestudyprotocol,includedallrandomized5subjectswhoreceivedanystudymedication.
The6seconddefinitionexcludedsubjectswhofailedto7provideanypost-baselineefficacydata.
This8definitionwasutilizedbytheapplicantintheir9primaryanalysis.
10Nowmovingontotheefficacyresults.
11Presentedonthisslidearetheresultsofthe12applicant'sprimaryanalysis.
Thelowerboundof13the95percentconfidenceintervalisgreaterthan14minus20percent,orminus0.
2,sononinferiority15tosublingualbuprenorphinewasconcluded.
16Further,whentheapplicanttestedforsuperiority,17thep-valuewas0.
03,andsuperiorityofProbuphine18tosublingualbuprenorphinewasalsoconcluded.
19However,therewereseveraldeficiencieswiththis20analysis,whichIwillnowdiscussfurther.
21First,Iwilldiscusstheissuewiththe22AMatterofRecord(301)890-4188160selectionoftheanalysispopulation.
Atotalof41subjectswhowererandomizedintothestudywere2excludedfromtheanalysispopulation.
Onesubject3randomizedtosublingualbuprenorphinedidnot4receivestudydrug,andIbelieveitisappropriate5toexcludethissubjectfromtheanalysis6population.
7ThreesubjectsrandomizedtoProbuphine8receivedstudymedicationbutdidnotprovideany9efficacydata.
Twowerelosttofollow-upandone10wasincarcerated.
Thesesubjectswereexcluded11fromtheapplicant'sprimaryanalysispopulation,12whichIdonotbelieveisappropriate.
13Onthenextslide,Iwillpresentmy14analysiswherethesesubjectswereincludedand15consideredtobenon-responders.
Thefirstlisting16inthistableistheapplicant'soriginalprimary17analysis,whichwaspreviouslyshown.
Thesecond18listingshowstheresultsoftheanalysiswhenthe193excludedsubjectswereincludedas20non-responders.
21Weseethatthep-valueforsuperiorityis22AMatterofRecord(301)890-4188161greaterthan.
05forthisanalysis,meaningthatwe1cannotconcludesuperiority.
However,thelow2boundoftheconfidenceintervalisstillgreater3thanminus20percent,andsoProbuphinewould4stillbeconsideredtobenon-inferiorto5sublingualbuprenorphine.
6Inadditiontotheselectionoftheanalysis7population,wenoted4deficiencieswiththe8applicant'smissingdataprocedurefortheir9primaryanalysis.
First,missingdatawasonly10imputedifallsamplesweremissingfora11particularmonth.
Forexample,ifarandomsample12wasscheduledandmissedinaparticularmonth,and13iftheregularsamplewasnegative,noimputation14wasperformed.
15Second,illicitopioidusagewasassumedto16beequallylikelyformissingandobserveddata.
17Theplausibilityofthisassumptionwasexploredin18varioussensitivityanalyses,whichIwillpresent.
19Third,asdesigned,theapplicant'smissing20dataimputationschemehasasmallprobabilityof21classifyingasubject,whoprovidedabsolutelyno22AMatterofRecord(301)890-4188162efficacydatainthestudyasaresponder.
For1example,intheprimaryanalysisforthe2imputation,itusedapositiverateof3approximately13percent,whichgivesa97percent4probabilitythatsomeonewhoprovidedabsolutelyno5efficacydatawouldbeclassifiedasa6non-responder,whichwedonotthinkisrealistic.
7Finally,thereareanumberofissueswith8inconclusivesamplesthattheapplicantmadeno9attempttoexploreintheiroriginalefficacy10analyses.
Wewilldiscusstheseissuesonthenext11slide.
12Thefirstandlargestissuewasinterference13withtheanalysisofthenorfentanylcontentinthe14urine.
Theapplicantstatesthatthisproblemcan15occurwhenthereareothercompoundsthatcould16haveinterferedwiththechromatographyofthe17lab'smethods.
Theapplicantsaidthatitwasnot18possibleatthistimetoruleouttamperingwith19thesampleinordertoconcealuse.
20Therewerealsoissueswiththesites21providingurinespecimenstothelabafterthe22AMatterofRecord(301)890-4188163applicant'sdefinedcreatinineacceptability1cut-off.
Approximatelyhalfofthesesampleswere2alsoprovidedafterthedefinedstabilitycut-offs3forthemajorityoftheopioids.
4Overall,weseethattherewere5approximatelytwiceasmanypositivetestsforthe6sublingualbuprenorphinetreatmentarmthanforthe7Probuphinetreatmentarm.
Therewerehowevermany8moreissueswithmissingdataforsubjectsinthe9Probuphinearm.
10Thisfigureshowstheresultsoftheurine11toxicologyassessmentsconductedduringthestudy12withthesubjectsreceivingProbuphineontheleft13andthesubjectsreceivingsublingualbuprenorphine14ontheright.
Eachrowinthefigurerepresents15theresultsforasinglesubject.
16Thegreencrossesrepresentthenegative17tests,theorangesquaresrepresentpositivetests,18andbluecirclesrepresenteithermissedvisitsor19testswheretheresultswereincomplete.
Theblack20opensquaresindicatethesubjectswhodidnot21provideall10urinespecimens.
Subjectsabovethe22AMatterofRecord(301)890-4188164blacklineprovidedatleast3positiveurine1toxicologyspecimensduringthetrial.
Asyoucan2see,therewereagreaternumberofrespondersin3thesublingualbuprenorphinearmwhoprovided1or42positiveurines.
5Therewereseveralsubjectsinthestudywho6repeatedlyprovidedurinespecimensthatcouldnot7becompletelyanalyzed.
Thisappearstobedueto8theissueswiththeanalysisofnorfentanyl.
9Thistableshowsasummaryofthepercentage10ofthesubjectsineachtreatmentarmwho11experiencedeachtypeofissue.
Justoverhalfthe12subjectsinbotharmscompletedthestudyand13provided10negativeurinesamples.
Theproportion14ofsubjectswhoprovidedpositiveurinetestswas15highinthesublingualbuprenorphinearmthanthe16Probuphinearm,whiletheproportionofsubjects17withmissingdataishigherintheProbuphinearm18thanthesublingualbuprenorphinearm.
19Inordertoevaluatetheextentofthe20effectofmissingdataontheconclusionofthe21study,twofurtheranalyseswereconducted.
For22AMatterofRecord(301)890-4188165thefirstanalysis,alloccasionswhereasample1wasmissedwereclassifiedaspositive.
The2non-responderdefinitionusedforthisanalysiswas3thesameasfortheprimaryanalysis,i.
e.
,the4subjectswereclassifiedasanon-responderif5therewasevidenceofillicitopioidusageor6missingdataforatleast3ofthe6monthsinthe7study.
8Thesecondanalysiswastoexplorethe9effectsofincompleteandmissingurinesampleson10theconclusion.
Inthisanalysis,anysubjectwith11amissedorinconclusivesamplewasassumedtobe12positive.
Theresponderdefinitionwasagain13unchanged.
Weseethatthelowerboundofthe1495percentconfidenceintervalisgreaterthan15minus20percentforboththeseanalyses,andso16noninferioritycanbeconcludedforboth.
17Itwasanticipatedthatsincethepatients18whoweretobeenrolledinthisstudywere19stabilizedonalowdoseofbuprenorphine,thatthe20currentdoseofbuprenorphineshouldbeadequateto21maintainstabilityandhence,thereshouldnotbea22AMatterofRecord(301)890-4188166needforanyadditionalsupplementalbuprenorphine.
1However,supplementalbuprenorphinewasrequiredby2approximately15to18percentofthesubjectsin3thestudy,withasimilarproportioninbotharms4requiringsupplementaldoses.
5Thoughtheproportionofsubjectsrequiring6rescueinthetwoarmswasfairlysimilar,the7quantityofrescuemedicationtabletsusedwas8considerablyhigherforthesubjectsinthe9Probuphinearmwithsubjectsreceiving10approximately70percentmoretabletsonaverage11thanthesubjectsinthesublingualbuprenorphine12arm.
13Thesupplementalbuprenorphinewasdispensed14asa2-milligramtablet.
Todistinguishrescue15medicationfromstudydrugandmaintainblinding,a16differentbrandofsublingualbuprenorphinetablet17wasused.
Thebluecirclesrepresentwhenthe18supplementalbuprenorphinewasdispensedtothe19patient.
Thedurationofuserepresentedbythe20bluelineswascalculatedbyassumingthatthe21patientusedasingleadditional2-milligramtablet22AMatterofRecord(301)890-4188167perdayunlessotherwisespecified.
1Asyoucansee,therewereanumberof2subjectswhoreceivedsupplementalmedicationfor3themajorityofthestudy.
Thoughthemajorityof4thesesubjectsappeartobeadequatelymanaged,the5levelofrescueusedmayindicatethatthedoseof6buprenorphinedeliveredbyProbuphine,a7non-titratableproduct,isinsufficientforthese8subjects,soweexploredadifferentdefinitionof9respondersconsideringuseofrescue.
10Inthisslide,wepresenttheresultsofthe11sensitivityanalysesweconductedtoexplorethe12impactofsupplementalbuprenorphineonthe13responderrate.
Theseanalysescorrespondtothose14previouslypresentedtoexploretheeffectof15missingdatabutwithanysubjectswhorequiredany16supplementalbuprenorphineclassifiedasnon-17responders.
18Forboththeseanalyses,theresponserate19isconsiderablysmallerthanthatseenwiththe20previousanalyses.
Inbothcases,thelowerbound21ofthe95percentconfidenceintervalisgreater22AMatterofRecord(301)890-4188168thanminus20percent,andhence,noninferiority1canstillbeconcluded.
2Thisfigurecorrespondstothefirst3analysiswhereallsubjectswithmissingurine4samplesareassumedtobepositive.
Subjectsabove5theblacklineprovidedatleast3positiveor6missingsamples.
Andthisfigurecorrespondsto7thesecondanalysis,whereallsubjectswith8missingorinconclusiveurinetestsareassumedto9bepositive.
10Accordingtotheapplicant,oneofthemain11advantagesofProbuphineisthatithasthe12potentialtoreducetheopportunityfordiversion13andtheriskofaccidentalexposureto14buprenorphinecomparedtothecurrentlyavailable15treatmentoptions.
However,ifpatientsrequire16additionalsublingualbuprenorphineinorderto17remainstable,theseadvantagesareeliminated.
18Consequently,theimpactofpatientsrandomizedto19receiveProbuphinerequiringadditionalsublingual20buprenorphinemaybemoresignificantthanfor21thosecontinuingtoreceivesublingual22AMatterofRecord(301)890-4188169buprenorphine.
1Toexaminethis,Iconductedtwoadditional2analysestoexploretheimpactontheresponder3rates.
Probuphinepatientsrequiringrescuewere4considerednon-responders.
Thefirstanalysis5showstheresponseratesifallsubjectswho6receivedrescueareconsideredtobe7non-responders.
WeseethatProbuphinewouldno8longerbeconsiderednon-inferiortosublingual9buprenorphine,andinfact,sublingual10buprenorphinewouldalsobeconsideredtobe11superiortoProbuphine.
12Thefirstanalysisconsideredanysubjects13whorequiredsupplementalmedicationtobeanon-14responder.
Thismaybeoverlyharsh,asthereare15alsoanumberofsubjectswhorequiredonlya16limitednumberofdosesforashortperiodoftime.
17However,hence,asecondanalysiswasconducted18wherethedefinitionofresponderwasconsideredto19benomorethan2occasionswhererescuemedication20isdispensedormonthswithevidenceofillicit21opioidusage.
22AMatterofRecord(301)890-4188170Weseethatunderthislessstrict1definition,Probuphinewouldbeconsideredtobe2non-inferiortosublingualbuprenorphine.
Missed3sampleswereconsideredtobepositiveinboth4analyses.
5Finally,hereistheconclusionofthe6efficacyanalysis.
Hereisasummaryofthe7analyseswehavepresented.
Inaddition,thefinal8threelinesshowtheresponderrateswhenno9positiveormissingurinesareallowedwithvarying10levelsofrescueusepermitted.
Intheseanalyses,11wehaveexploredtheimpactofseveralfactors,12includingthechoiceoftheanalysispopulation,13thehandlingofmissingdata,andtheimpactof14rescuemedicationontheresponseratefor15Probuphine.
16Fromaregulatoryperspective,inorderto17establishtheefficacyofadrug,itisimportant18toexaminearangeofplausibleassumptionsand19considertheworstcasescenarios.
However,the20analysesconsideredintheseexplorationsmaynot21beclinicallyusefulorevenrealistic.
22AMatterofRecord(301)890-4188171Now,wewillreturntoDr.
Skeete,whowill1summarizetheclinicalimplicationsoftheefficacy2findings.
3FDAPresentation-RachelSkeete4DR.
SKEETE:Thankyou,Dr.
Travis.
5Asyousawfromthediscussionofthe6efficacyresults,weidentifiedanumberof7challengesininterpretingtheefficacydata.
This8inturnpresentedchallengesfordefiningan9appropriatepopulationforProbuphineand10determiningthemostappropriatewaytopresent11theseresults.
12TheapplicantdefinedtheITTorintent-to-13treatpopulationasrandomizedsubjectswhoare14randomizedandreceivestudymedication,and15providedpost-baselineefficacydata.
Basedon16thisdefinition,3patientsintheProbuphinearm,17whoreceivedstudymedicationbutdidn'treturn18duringthetreatmentperiod,wereadmittedfromthe19applicant'sanalysis.
Theseincluded2patients20whowerelosttofollow-upand1incarcerated21patient.
22AMatterofRecord(301)890-4188172However,inapatientpopulationdeemed1stablebytheirtreatinghealthcareproviders,2discontinuationsforthesereasonsinpatientswho3justunderwentprocedurestoinsertProbuphinewas4seentohaveimplicationsforjudgingtreatment5response.
6Someurinetoxicologysamplesweremissing7becausesubjectsdidnotattendvisitstoprovide8urinesamples.
Inothercases,thesubjects9submittedthesample,buttherewereproblems10analyzingthesamples.
Ofthetotalsamples11collected,samplesthatweremissedornotproperly12analyzedoccurredmorefrequentlyintheProbuphine13armthansublingualbuprenorphinearm.
Ofthe14samplessubmittedandanalyzed,ahigherproportion15ofpositivesampleswereseeinthesublingual16buprenorphinearm.
Theurinetoxicologydata,17alongwithself-report,wereusedtodefinea18responder.
19Althoughsupplementalbuprenorphineusewas20anticipatedtobesporadicamongstablepatients,21somepatientsrequiredsublingualbuprenorphine22AMatterofRecord(301)890-4188173throughouttheentiretreatmentperiod.
Noneof1thepatientswhorequiredsupplementalsublingual2buprenorphineduringthetrialhadreceivedrescue3inthe6monthspriortoentrytothestudy.
4Althoughthetransmucosalformsofbuprenorphine5usedtotreatopioidaddictionallowfordose6titration,Probuphineisanon-titratable,7fixed-doseproductthatdoesnotofferthesame8paradigmfordoseadjustment.
9Baselinecharacteristicsofthestudy10populationforpre-trialtreatmentdurationand11transmucosalformusedwerealsoexamined.
A12treatmenteffectbasedonbuprenorphinetreatment13durationimmediatelypre-trialwasnot14demonstrated.
Butasyou'llrecall,thesedata,15however,werearoughapproximationandwerenot16themostreliable.
17ThetransmucosalformthatProbuphinehas18beencomparedtoisthesublingualbuprenorphine19tablet.
However,thereareothertransmucosal20formsonthemarket,andsome,likethesublingual21film,offerhigherlevelsofbuprenorphineexposure22AMatterofRecord(301)890-4188174atthesamenominaldoseofthetablet.
Butas1withthepre-trialtreatmentduration,atreatment2effectwasnotdemonstratedbasedontransmucosal3formulationuse,specificallyfilmuse,pre-trial.
4Dr.
Travispresentedanumberofdifferent5analyses,whichareshownheretakingintoaccount6theinterpretationissuesthatwereidentified.
7Theanalysesexploredtheeffectofthechosen8analysispopulation,thechoiceofresponder9definition,methodsforhandlingmissingdata,and10rescueuse.
Noninferioritywasestablishedfor11Probuphineineachandeverycase.
12Therearemanyapproachesthatwouldbe13consideredreasonableforpresentingthesedata,14andweareseekinginputfromthecommitteeabout15therepresentationthatwouldbemostappropriate16andmostusefulforclinicians.
I'lldiscussour17reasoningasitrelatestoeachofthesefactors18basedonourreviewofthedata.
19Fortheanalysispopulation,thefirst20column,webelievethecorrectpopulationshould21includethe3patientsadmittedbytheapplicant,22AMatterofRecord(301)890-4188175asweareinclinedtoassumethatbeingcompletely1losttofollow-uporbeingincarceratedarenot2positiveoutcomesinthiscase.
3Thesecondcolumnlooksattheresponder4definition.
Theresponderdefinitionallowed5subjectstohaveupto2monthswithevidenceof6illicitopioiduse.
Saidanotherway,asubject7couldsubmit4positivesamplesoutofatotalof810.
Thatwouldbe2monthlysamplesand2random9samplesinthesame2monthsandstillbe10consideredaresponder.
11We'renotconvincedthatallowing2months12ofopioiduseisjustifiedinapopulationthat13wasn'tusingopioidsbefore,sowethinkthatthe14analysisinwhichthereareanypositivemonths15indicatestreatmentfailureandmightcomeclosest16torepresentingtheeffectivetreatment.
17Theoriginalassumptionswehadabout18missingurinesamplesmayalsoneedtobe19reconsidered.
Weanticipatedthattheoverwhelming20majorityofpatientswouldsubmitopioid-negative21samplesandthatanimputationstrategythat22AMatterofRecord(301)890-4188176doesn'tassumemissingsamplesarepositivewould1beappropriate.
Thefactthat20percentofthe2patientsactuallyprovidedapositivesample3suggestsouroriginalassumptionswereincorrect.
4Sowe'dbeinclinedtousea5missing-equals-positiveapproach.
6Therewereanumberofsampleswherethe7patientpresentedforthevisitsubmittedasample,8butbecauseofissueswiththespecimen,they9weren'tproperlyanalyzed.
Wemightbewillingto10believethatsamplesthatwereprovidedbutnot11analyzedcorrectlyarenegativeifthepartsthat12wereanalyzedarenegative.
13Fortheexaminationoftheextentand14patternorrescueuse,weexaminedafew15permutations,includedallpermitted,non16permitted,andupto2usespermitted.
Wethink17thereisprobablysomeminimalamountofrescue18thatcouldbeattributedtoextraordinary19circumstances,butneedingrescueallalongseems20toindicatethatProbuphine,whichprovidesonlya21fixeddose,doesn'tprovideadequatetreatmentfor22AMatterofRecord(301)890-4188177thatparticularpatient.
Althoughitmayseem1overlystrict,we'reinclinedtowardthestrategy2thatallowsnomorethan2rescueoccasionsfor3Probuphinebutallowsdosageestimatefor4sublingualbuprenorphine,theproductofthetwo5thatcanactuallybetitrated.
6Takingallofthoseconditionsinto7consideration,we'reinclinedtothinkthatthe8analysisthatbestrepresentstheefficacyfindings9istheanalysisthatdefinestheanalysis10populationasallpatientswhoarerandomizedand11receivestudydrug;allowsnoopioid-positive12months;imputesamissingsamplebecauseofa13missedvisitaspositiveandanincompletely14analyzedsampleasnegativeifthoseportionsof15thesamplethatwereanalyzedwerenegative;and16allowsforupto2usesofrescueforthe17fixed-doseproductandalluseoftherescuefor18sublingualbuprenorphine,theproductthatpermits19titration.
20Theresultingresponderratesarethen2169percentforProbuphineand64percentfor22AMatterofRecord(301)890-4188178sublingualbuprenorphine,andnoninferiorityis1established.
2Insummarizingtheefficacyreviewand3findings,thiswasanoverviewofsomeofthe4conclusionsthatwe'vecometoregardinghowto5bestrepresentthesefindings.
Again,we6acknowledgethattherearemultiplereasonable7approachesthatcanbetakentopresentthesedata.
8Andalongthoselines,wesuggestedoneoptionthat9weconsidertobereasonable.
10We'llbeaskingthecommitteetoweighinon11thevariousapproachestopresentingtheseresults12andtoprovidefeedbackonwhatyouconsidertobe13anappropriaterepresentations,orrepresentations,14basedonyourexpertiseinthisarea.
This15concludestheefficacyportionofourdiscussion.
16Now,ontothediscussionofsafety.
The17applicantsummarizedtheoverallsafetydatabasein18theirpresentation.
It'sasafetydatabase,which19includessafetyexposuresfromthreephase320controltrials,themostrecentbeingPRO814,the21trialunderdiscussion,2open-labelextension22AMatterofRecord(301)890-4188179studies,and2clinicalpharmacologystudies.
1Thedevelopmentprogramincludesexposures2toProbuphine,toplaceboimplants,andto3sublingualbuprenorphine.
Acrossthesestudies,4safetyassessmentsincludedassessmentof5treatment-emergentadverseevents,implantsite6examinations,clinicallaboratoryassessments,7urinetoxicologyscreens,EKGevaluations,and8vitalsigns.
9Theframeworkweusedforthereviewof10safetywastolookatsystemicsafetyrelatedto11thedrugsubstance,buprenorphine,safetyofthe12implantsthemselves,andtheproceduralsafety13relatedtoinsertionandremovaloftheproduct.
14Thesafetyprofileforbuprenorphineisfairly15well-characterized,sowedirectedourreviewto16identifyinganyneworatypicalsystemicfindings17forthedrugsubstancewiththesenewpatient18exposuresprovidedbytheProbuphinesafety19databaseandtosystemicfindingsthatmaybe20relatedtobuprenorphineinitsnewformulation.
21Thereviewdidnotidentifynovelsafety22AMatterofRecord(301)890-4188180signalsthatemergerelatedtobuprenorphine's1systemicsafetyonreviewofProbuphinesafety2data.
Accordingly,thesafetyrelatedtothis3novelimplantableformulationwasemphasized,4includingthesafetyexperienceasitrelatesto5therodinsertionandremovalproceduresandthe6indwellingrods;foreignbodies,whichareintended7toremaininplacefor6months;andkeyfindings8fromthehumanfactorsevaluation.
9Asmentioned,therearesimilaritiesbetween10theoutpatientproceduresforinsertionandremoval11ofProbuphineandtheproceduresforthe12implantablecontraceptives,particularlyNorplant.
13Soweaskedourobstetricsandgynecologyphysician14colleaguesintheDivisionofBone,Reproductive,15andUrologicProducts,DBRUPforshort,whohave16specificexperiencewiththeimplantable17contraceptivesandwithsurgicalproceduresin18generaltoconsultativelyreviewtheprocedural19safetydataincludedinthesubmissionandto20provideaclinicalperspectivebasedontheir21expertiseinthisarea.
Thissummaryofprocedural22AMatterofRecord(301)890-4188181safetyisbasedextensivelyonDBRUP'sconsultative1review.
2Proceduralsafetydatafromthephase33studieswereevaluated.
Theseincludedthethree4phase3controlstudies,805,806,and814,and5extensionstudies807and811,whicharethe8056and806extensions,respectively.
7Thistablesummarizesthenumberofsubjects8whounderwentatleastoneinsertionprocedure9duringaparticulartrial.
Somesubjectsrequired10morethanoneinsertionprocedurewhentherewere11complicationsrequiringremovaloftheinitialset12ofrodsandinsertionofnewrodstocontinuea13treatmentcycle.
Stillothershadafifthrod14placedinthestudiespriortothemostrecent15trialandunderwentanotherinsertionprocedurefor16thedoseincrease.
17Thecumulativeexposureacrossthetrials18was654;thatistherewere654patientswho19underwentaninitialinsertionprocedure.
20Probuphineandplaceboimplantsareexamined21togetherbecausethesameprocedureisrequiredfor22AMatterofRecord(301)890-4188182insertionandremoval.
1Therewereasimilarnumberofremovals,but2therewerealsosomepatientswhowerelostto3follow-up,andtherodswereneverremoved.
Soto4placethesenumbersincontext,thescopeofthe5proceduralsafetydatabasefortheimplantable6contraceptivesisprovided.
7Norplant,theimplantablecontraceptive8where6rodswereinsertedforupto5years,is9theonemostsimilartoProbuphine.
ForNorplant,10theclinicaldevelopmentprogramincluded84911removalspriortoapproval.
ForJadelle,the2-rod12contraceptive,therewere1100removalspriorto13approval.
Therewere849forImplanon,the14single-rodcontraceptive,and296forNexplanon,15thenext-generationimplant.
16Theapplicantdescribedtheseproceduresin17theirpresentation.
Duringthepreviousreview18cycle,therehadbeenconcernsabouttheuseofthe19U-techniqueforremoval,whichisnotcommonlyused20intheU.
S.
DBRUPfoundevidencesupportingthe21useofthismethodforNorplantremoval.
Therewas22AMatterofRecord(301)890-4188183anadditionalmodificationtotheprocedurefor1Probuphineinthatalongerincisionisused7to210millimetersseparatefromtheoriginalincision,3versus4millimetersformakingsuturingnecessary4forclosureinthecaseofProbuphine.
5Comparedtotheimplantablecontraceptives6ingeneral,Probuphinerequiresanewincisionto7continuetreatment.
Incontrast,forcontraceptive8implants,asingleincisioncanbeusedforthe9rodsthataretoberemovedandfortheinsertion10ofthenewrods.
Whenrodsareremovedattheend11ofatreatmentcycle,thenewrodsarecommonly12insertedthroughthesameincisionintheopposite13directionfromtherodorrodsthatarebeing14removed.
15I'llnowdiscusstheimplantrelatedsafety16findings.
Thenumbersandproportionsofpatients17whohadanimplantsiteadverseeventare18representedherebystudy.
Adverseeventsthat19occurredinatleast5percentofallpatientswho20underwentinsertionandremovalproceduresina21studyarelisted.
Notethattheseareallthe22AMatterofRecord(301)890-4188184implantsiteadverseeventsthatoccurredand1includedthefullspectrumofeventsfrom2non-seriousadverseevents,likeerythemaandpain,3thatarenotunexpected,tothemoreimportant4proceduralcomplications.
5Becauseimprovementsweremadetothedevice6andthetrainingandcertificationprogramduring7theclinicaldevelopmentprogram,wesoughtto8comparesafetyfindingsbeforeandafterthese9changeswereintroduced,andthat'srepresentedby10thatredline.
11Somorethanhalfthepatientsinstudy805,12whichpre-datestheequipmentandtrainingand13certificationimprovements,hadanadverseevent.
14In811,theextensionto806,therewereno15patientswithanimplantsiteadverseeventthat16wasreportedbyatleast5percentofthepatients.
17Inthelaststudycompleted,PRO814,18percentof18patientsreportedatleastoneevent,andpainwas19theonlyadverseeventreportedbymorethan205percentofpatients.
Thisisanotabledecrease21inevents,suggestingthattheimprovementsinthe22AMatterofRecord(301)890-4188185device,theprocedures,andtrainingprogrammay1havecontributedtoanimprovedproceduralsafety2profileforProbuphine.
3Onthepreviousslide,yousawasummaryof4theincidenceofallimplantsiteadverseevents5thatoccurred.
Here'samorefocusedsummary6demonstratingthekeyprocedurerelatedadverse7eventsasidentifiedbyourDBRUPcolleagues.
8Theseeventsincludeimplantexpulsions,implant9siteinfection,woundcomplications,complication10ofremovalorrequiringmultipleattempts,and11bleeding,includingimplantsitehemorrhageor12hematomaandincisionsitebleeding.
13Incomparingthesafetyfindingsbeforeand14afterimplementationofimprovementstothedevice15andatrainingprogram,theresultsforstudies80516and807,whichpre-datethesechanges,are17demarcatedtodistinguishthemfromtheother18studies,whichoccurredafterthechanges.
Sowhen19comparingtheearlierandthelaterstudies,fewer20keyprocedure-relatedadverseeventswerereported21followingthechanges.
Forexample,removal22AMatterofRecord(301)890-4188186complicationswerereportedinabout9percentof1patientsinstudy805andinnosubjectsin806,2thesubsequentcontroltrialafter805.
3Despitetheseimprovements,itmustbenoted4thatintheProbuphinedevelopmentprogram,rates5ofbleeding,complicatedremovals,andimplantsite6infectionwerehigherthanratesseenin7implantablecontraceptivedevelopmentprograms.
8Theapplicantdescribedthehumanfactors9evaluationthatwasperformedinaneffortto10validatethetrainingprogram.
OurDBRUP11colleaguesassisteduswiththereviewofthehuman12factorsstudy,lendingourproceduralists'13perspectivetotheinterpretationofthefindings.
14AnumberofcaveatsidentifiedbyDBRUP,15particularlyasitrelatestothelivepracticum16portion,shouldbenoted.
Alivepracticumof17proceduresuseaporktenderloinasasimulated18humanarm.
Althoughtheporktenderloinmaybea19suitablemodelfordemonstratingtechnical20proficiencyfortheinsertionprocedures,itisnot21suitableforpredictingwhethercertaineventslike22AMatterofRecord(301)890-4188187infectionandbleedingcanbemitigatedby1training.
2Also,theremovalproceduresandpotential3complicationsdonotlendthemselvestomodeling.
4Theporktenderloin,oranartificialarmforthat5matter,can'tprovideanadequaterepresentationof6thescarringthatwoulddevelopafteraforeign7bodyhasbeenindwellingfor6months.
8Additionally,situationsthatmayarisewhen9performingtheproceduresonapatient,suchasa10patientmovingorhavingpainthatmayrequiremore11anesthesiacannotbesimulated.
Forthis12evaluation,onlycliniciansfromspecialtiesthat13involveperformingproceduresorsurgery14participateinasimulationcomponent,sothe15resultsmaynotbegeneralizabletocliniciansfrom16non-surgicalspecialties.
17Overall,thesubtasksandcriticalsubtasks18forthelivepracticumappearedappropriate.
Most19ofthe15proceduralists,whichincluded820physiciansand7mid-levelpractitioners,could21adequatelyperformthetasksrequiredtomitigate22AMatterofRecord(301)890-4188188theriskofinfection,bleeding,andfibrousscar1formationaroundimplants.
2Notwithstandingthisoverallfinding,review3ofthenarrativesofthetaskfailuresreveal4importantissuesrelatedtoproceduralsafety.
The5applicantappearedtoequatereceiptofknowledge6withabilitytoperformatask.
Itwasan7assumptionthatonceaproviderrecognizesatask8failure,theywouldbeabletoperformthetaskthe9nexttimearound.
However,thestudyprovidesno10datatosupportthisnotion.
Therewerealso311taskfailuresrelatedtomitigatinginfection.
12Thisisnoteworthy,asinfectionrelatedAEsinthe13Probuphineclinicaldevelopmentprogramhave14alreadybeenseenathigherratesthanthosefor15implantablecontraceptives.
16Notallparticipantscouldremoveallthe17implants,eveninthepracticesession,and18postmarketingdataforimplantablecontraceptives19haverevealedthatsomeimplantsarenever20localizedorremoved.
Considerationshouldjustbe21giventohowthesesituationsaretobemanagedin22AMatterofRecord(301)890-4188189areal-worldsetting.
1Finally,10percentoftheclinicians2insertedtherodsbeyondadesireddepth;thatis3morethan5to7millimeters,butlessthan10.
4Althoughaninsertiondepththatisstilllessthan510millimetersisunlikelytoresultininjury,the6findingssuggestthatthetrainingprogramtasks7relatedtoinsertiondepthmayneedtobe8reinforced.
9ProbuphinewillhaveaREMS.
Theapplicant10describedtheirproposedriskevaluationand11mitigationstrategy.
Briefly,thegoalsareto12mitigatetheriskofcomplicationsofmigration,13protrusion,expulsion,andnervedamageassociated14withtheimproperinsertionandremovalof15Probuphine.
Itisalsointendedtomitigatethe16riskofaccidentaloverdose,misuseandabuseifan17implantcomesoutorprotrudesfromtheskin.
And18thisisthroughprescriberandpatienteducation.
19Theproposedelementsincludeatrainingand20certificationprogramforhealthcareprofessionals21whoinsertorremovetheproductinarestricted22AMatterofRecord(301)890-4188190distributionsystem.
Becauseoftheimprovements1inthesafetyprofilewiththeimplementationof2thetrainingprogramandotherimprovements,we3considertheproposedstrategytobereasonable.
4Wewillaskthecommitteetoconsiderthe5appropriatenessoftheREMSforaddressingthe6attendedrisksinclinicalpractice.
7Inclosing,efficacydatafromthis8evaluationofProbuphinecomparedwithsublingual9buprenorphineinclinicallystablepatientsshowed10thatnoninferioritywasestablished.
However,as11describedinthepresentation,therewereanumber12ofissuesthatpresentedchallengesininterpreting13andpresentingthedataonwhichweareseeking14advisorycommitteeinput.
15Morethanafewepisodesofsupplementaluse16wereunanticipatedinthispopulation,however,we17sawsomepatientsreceivedrescuethroughoutthe18entiretreatmentperiod,andnoneofthesepatients19whoreceivedrescueduringatrialhadreceivedit20in6monthspriortoentryintothetrial.
This21hasimplicationsforclinicalpracticewiththis22AMatterofRecord(301)890-4188191non-titratablefixed-doseproductandimplications1forthetoutedpublichealthbenefitofdecreased2abuse,misuse,andpediatricaccidentaloverdoseif3transmucosalbuprenorphineuseisstillrequired.
4Urinetoxicologyresultswereusedforthe5evaluationofefficacy.
Thereweremissedvisits6forurinesamplesandimproperlyanalyzedsamples7amongthealreadysmallnumberofsamplesthatwere8collectedoverthecourseofthetrial.
9Additionally,onreviewofthedata,theresponder10definitionthatincorporatestheurinetoxicology11findingsmaybetoopermissive,patientswhoare12submittingopioid-negativesamplespriortoentry.
13Soallowing2monthswithevidenceofillicit14opioidusemaybetoopermissive.
15Definingtheappropriatepopulationfor16Probuphinealsopresentedachallengeconsidering17theuseofrescue,boththeamountandpatternof18use,inlightofthefixeddosing,andwhen19incorporatingboththeurinetoxicologyfindings20andthesupplementaluse.
Theappropriate21populationforanalysiswasalsoamatterto22AMatterofRecord(301)890-4188192carefullyconsiderininterpretingthesedata.
1Finally,Probuphinerequiresanoutpatient2surgicalprocedureforbothinsertionandremoval.
3Atrainingandcertificationprogramisinplace4forProbuphine,includingtrainingonremovals,the5morechallengingofthetwoprocedures.
Training6onremovalsandcomplicatedremovalscannotbe7fullymodeled,however.
8ProbuphinewillhaveaREMS,andthe9trainingandcertificationprogramarepartofthe10REMSwhoseobjectivesaretomitigateprocedural11complicationsandtheriskofabuse,misuse,and12pediatricaccidentalexposure.
13ThisconcludestheFDApresentationofour14reviewoftheProbuphineefficacyandsafetydata15inaclinicallystablepopulationon8milligrams16oflessofsublingualbuprenorphine.
Withthat,17I'dliketothankallthosefromtheCenterfor18DrugEvaluationandResearchandtheCenterfor19DevicesandRadiologicHealthwhocontributetothe20efficacyandsafetyreviewforthisapplication.
21AndI'dliketothankthecommitteemembersfor22AMatterofRecord(301)890-4188193yourattentionandfortheopportunitytopresent1thisinformationandgainyourperspectiveonthe2efficacyandsafetydatasubmittedinthis3resubmissionapplication.
Thankyou.
4ClarifyingQuestionstoFDA5DR.
KRAMER:Thankyouverymuch.
Weare6recalibratingtime-wiseandarethinkingthatwe7shouldtrytoadjournforlunchby12andbeback8hereat12:45fortheopenpublichearing.
Sothat9makesit,again,verychallenging.
10I'mgoingtostartbyjustaverysimple11questionfortheFDA.
We'veseenthepresentations12ofopioid-positiveurinesandrescuemedication13amongthegroups,andwe'veseentheplotswithall14ofthedots.
Buthasanyonejustdoneasimple15thingofsayingwhat'sthenumberandpercentof16patientsbytreatmentgroupwhoused--eitherhad17opioid-positiveurinesorself-reportofopioidand18hadrescuemedicationuse19DR.
SKEETE:Souseofself-reported--I20mean,somebodywho--21DR.
KRAMER:Eitheropioidusebyurine22AMatterofRecord(301)890-4188194positiveorself-report,orrescuemedicationuse.
1DR.
SKEETE:Orrescuemedicationuse.
2DR.
KRAMER:Hasanyonejustdonethat3simplecalculation,soweseehowmanypeoplehad4sometypeofevidenceofneedSomebodyelsehas5ananswerIthink,someonefromthecommittee.
6DR.
TRAVIS:Idon'thavetheslidenumber,7butitwas--8DR.
KRAMER:Slide47Isthat--itwasa9slideofdots,butithadalineon--sawit10quickly.
Ithoughtthatwassimpleandquick,but11maybenot.
12DR.
TRAVIS:Ifyougototheprevious13slide.
Thatwouldbeanymissingor--andgoto14thepreviousslideagain.
Sorry.
These15percentageshereshowthepercentagewhohave16eithermissedorsupplementalrescuemedicationuse17ofacertainnumber.
18DR.
KRAMER:Okay.
19(Pause.
)20DR.
KRAMER:Perhapsweshouldgoon--21DR.
TRAVIS:Ihavetheslideshere.
Sorry.
22AMatterofRecord(301)890-4188195DR.
KRAMER:--andyoucould--shouldwe1goontoanotherquestionandyoucouldprovide2that3DR.
TRAVIS:Yes.
4DR.
KRAMER:LauraMcNicholas5DR.
McNICHOLAS:Thankyou.
DidI6understandyouthatwehavedocumentedinthe7subject'srecordthattheyhavehad90daysof8buprenorphinetreatment,not6months,not9180days,consecutively10DR.
SKEETE:Right.
Consecutively,theyall11atleasthave90daysbecausetheyhad--theyalso12hadtohavetheurinepositive--theurine13positives--urinenegativesforthe90daysand14thesublingualbuprenorphineuse.
Thequestion15theywereaskedwas,whatwasyourlifetime16durationWhatIwantedtopointoutwiththat17slidewasthatthereappeartobe--theremaybe18onepatientwhohadlessthan6months.
But19overall,basedononedataset,itlookslikethere20wereafewpatientswhohadit,butthosedatawere21notreliablebecausetheywereusing--theywere22AMatterofRecord(301)890-4188196beingusedtoapproximateitfromanothersource.
1Theyweren'tactuallyeverdirectlyasked2consecutively,butthosesamepatientshadon3averageabout3yearsofbuprenorphinetreatment4overtheirlifetime.
5DR.
McNICHOLAS:Okay.
Becausethere'sa6differencebetweenapatientstabilized3months7versusapatientstabilizedfor6months--8DR.
SKEETE:Exactly.
9DR.
McNICHOLAS:--andyou'reonlylooking10atthelast3months.
That'swhatIwaswondering.
11Soweactuallydonothavedatathateverybodywas12consecutivelytreatedforatleast6monthswith13buprenorphineandonlyon8milligramsorlessfor14thepast3months.
15DR.
SKEETE:Sotheywere--thepatientsto16beenrolledwere--right.
Sotheyweresupposed17tobeonbuprenorphinefor6months.
Theintent18forthatwas6consecutivemonths.
Asfaraswe19cantell,themajorityofpatientswereonitfor620consecutivemonths.
Wedohavesomedatathatare21averyroughapproximationthatsuggeststhatsome22AMatterofRecord(301)890-4188197maynothavebeen.
Butwhenyoulookattheir1lifetimebuprenorphinetreatmenthistoryasbeing210yearsforsomepatients,it'sunlikelythatthat3wouldhavebeenthecase.
4DR.
KRAMER:Dr.
Dodd5DR.
DODD:Thesewillprobablyrequire6longerdiscussion,soIwillputtheminnow,and7perhapswecancomebacktothemduringthelater8discussion.
Myfirstquestiontothestatistician9is,whatdoweknowaboutthereasonfor10missingness11AsfarasIcantell,thehandlingofthe12missingdataassumesthatthingsweremissingat13random.
AndIcanimaginescenarioswherethe14missingnessmaydependonthetreatmentarm,which15wouldbeparticularlyconcerningifI'mnot16adequatelytreatedandgooffanduseopioids,and17don'tcomeinbecauseI'musingopioidsononearm.
18Andontheotherarm,thepatternofmissingnessis19different,thatI'mnotcominginforreasonsnot20associatedwithhavingapotentiallypositiveurine21test.
DidyouexaminethatDidyoulookinto22AMatterofRecord(301)890-4188198whatweknowaboutthereasonsformissingness1DR.
TRAVIS:Therewasn'tmuchdetailonthe2dataset.
Usually,itwas--therewereroughly3threetypes.
Thereweretheissueswiththe4analysis,whichwethinkmostlywouldbemissingat5random.
Therearethediscontinuations,sothere6wereseveral--thenumbersweresmall.
Therewere7severalthatdiscontinuedearlyon,andthen--we8certainlydon'tthinkit'sappropriatetotreatthe9informationafterthediscontinuationismissingat10random.
Thenthereareintermittentlymissing,11whichwewouldagreeneedstobeevaluatedfurther,12butnoreasonsweregiven.
Sowedon'tknow.
13DR.
DODD:Thenasafollow-up,werethere14any--itlookstomeasifallthesensitivity15analysesfollowthesamesortoflogic.
WhenIdo16sensitivityanalyses,Itrytoevaluatetheextent17towhichthestudyweaknessesmighthavebiasedthe18resultstowardsthenullhypothesis.
Andwhen19we'rethinkingaboutanoninferioritytrial,the20nullhypothesisisdifferentbecausewe'resaying21thatthetreatmentsaredifferent,thatthe22AMatterofRecord(301)890-4188199Probuphineisnoninferior.
1SowhatIreadofthesensitivityanalyses2thatI'veseenpresentedwouldtendtobiastowards3thenoninferiorityhypothesisorthealternative4hypothesis.
AndIdon'tknowiftherewereany5alternativesensitivityanalysesthatwere6conductedthatwouldbemoreinlinewithwhatwe7wouldthinkofasasensitivityanalysisthatwould8evaluatetheextenttowhichthingswerebiased9towardsthealternative.
10DR.
TRAVIS:Ithinkthefinalsensitivity11analysesIconducted,whereIexploredtheuseof12rescueonlyintheProbuphinearm,wouldcertainly13addressthat,sincethat'sonlybeing--the14penalty'sonlybeingappliedtotheProbuphinearm15ratherthanbotharms.
Thatwasoneofour16concerns,andthat'swhatwetriedtoevaluatewith17thoseanalyses.
18DR.
KRAMER:Dr.
Brady19DR.
BRADY:Yes.
Iwasjustwonderingif20youhaddoneanyfurtherexploration--Iknowit's21asmallgroup,butstillthatgroupthatrequired22AMatterofRecord(301)890-4188200rescuemedications,particularlymaybethosethat1tookmorethan2doses,justintermsofthings2likeage,orwhattheirmaintenancedosewas,or3howlongtheyhadbeenon--orhistoryof4psychiatricillness,anythinglikethat,arethey5characterizedinanyway.
6DR.
TRAVIS:Iknowtheapplicantintheir7presentationlookedatitbythepreviousdose.
We8didn'tlookatit,andwedidn'tlookatanyofthe9otherbaselinefactors.
10DR.
KRAMER:Dr.
Grieger11DR.
GRIEGER:Twohopefullybriefquestions.
12Thefirstone,I'mnotsureIunderstandthe13rationaleforallowinganunlimitednumberof14rescuesinthesublingualarm,butonlytwointhe15implantarm.
Whywouldyoucomparethemtwo16differentwaysif,infact,you'relookingatthe17sameevent,somebodywho'shavingdifficultyasking18formoremedication.
19DR.
SKEETE:I'mgladyoubroughtthatup.
20That'sactuallyoneofthethingsthatweare21askingyouallherefortohelpusthinkthrough22AMatterofRecord(301)890-4188201someofthesethings.
Butthethinkingbehindthat1waswe'recomparingatitratableanda2non-titratableproduct.
Soyoucanimaginethat3someone,whenthey'rejustswitchingoverfromthe4transmucosalformtoProbuphine,maybetheyneeda5fewdosesofextratransmucosalproductsatthe6outsetoftreatment,forexample,asthey're7gettingstabilized.
8Butifyouareplacingyourpatienton9fixed-doseproduct,andyouthinkthatyoumight10needtogivethemsublingualbuprenorphineallthe11waythroughthetreatmentperiod,forexample,12we'rewonderingifthat--isthatanappropriate13waytomanagethatpatient,forexample.
14Theotherthingisthatitalsotakesinto15accountthetoutedpublichealthbenefit.
Soif16youhavetocontinueapatient,say,forexample,17allthewaythroughthetreatmentperiod,andyou18havetosendthemhomewithabottle--sosomeof19thesethingsthatwe'retalkingaboutwithmisuse,20abuse,forgottenormissedpills,oraccidental21pediatricexposure,wouldstillbeevidenceinthat22AMatterofRecord(301)890-4188202case.
1DR.
GRIEGER:Okay.
Wecancoverthatin2discussionlaterIguess.
Thesecondquestionisa3littlebit--Imeanttoaskthisoftheindustry4representatives.
ArethesethingsradiopaqueYou5mentionedthatoneoftheserodsdisappearedand6wasneverfound.
IknowNexplanon'simprovement7wasthatitisactuallyradiopaque.
8DR.
SKEETE:Right.
9DR.
GRIEGER:Somaybeindustrycanprovide10informationthisafternoon--they'redone--on11whethertheycouldmakeitradiopaqueorputtracer12dotsonitorsomething.
13DR.
SKEETE:Ican--14DR.
HERTZ:Well,Rachel,whydon'tyougo15ahead16DR.
SKEETE:Sothey'renotradiopaque.
So17currently,ifyouarelookingtofindit,it's18generalviaultrasoundorMRI.
Asyounote,19Nexplanonis,butthat'sbeenmultipleiterations20ofvariousimplantablecontraceptiveproducts.
I21canopenituptothecompanyifyouwantto22AMatterofRecord(301)890-4188203mentionanything.
1MS.
SHELDON:Atthispoint,giventhe2concentrationofbuprenorphineineachimplant,3it'sverydifficulttoaddanythingelsetothe4implant.
Soitwouldtakeanotherreformulationin5ordertobeabletodothat.
However,whatwe've6alsoheardfromourexpertsisthatx-rayisnot7necessarilythebestmethodforboth--becauseof8exposuretoradiation,butalsobecauseofthe9numberofx-raysyou'dhavetotakeinordertobe10abletocorrectlyimagebecauseyou'renotgoingto11getdepthfromanx-ray,whatyoureallyneedin12ordertobeabletofindtheimplant.
Butyoudo13getdepthwithMRIorotherimaging.
14DR.
GRIEGER:IguessIgobacktoyoucan15loseanimplantandhavenoideawhereitis.
16That'sthebottomline.
Becausetheremaybe17peoplewhocan'tgetanMRIbecausetheyhavemetal18frombeingweldersorgrinders,orsomething.
19Therearepeoplewhocan'tgetMRIs.
20DR.
SKEETE:Right.
Therehavebeensome21casesinthedevelopmentprogramwherethey'vebeen22AMatterofRecord(301)890-4188204unabletolocateanimplantevenafterultrasound1orMRI.
2DR.
KRAMER:Onthatsametopic,thesponsor3suggestedthatyouneedtopalpateall4implants4beforeyoustarttheremoval.
Ifbychance5somebodyjustdoesn'tdothatfirst,andthey've6gotanopenwound,youcan'treallydoan7ultrasoundoveranopenwound,canyou8DR.
SKEETE:Well,thatisaquestionI9wouldprobablywanttoaskourDBRUPcolleaguesto10beabletohelpout.
11DR.
KRAMER:It'sasmallpoint,butall12right.
13DR.
SEWELL:Hi.
CatherineSewellfrom14DBRUP.
Youcanuseanultrasoundoveranopen15wound.
Ideally,you'dprobablyputsomesortof16steriledrapeoverit.
17DR.
KRAMER:Thanks.
NextwehaveJames18Troendle.
19DR.
TROENDLE:Yes.
Ijustwantedto20clarify,wheywe'retalkingaboutthedifferent21formulationsofsublingualuse,itsoundedlikeyou22AMatterofRecord(301)890-4188205wantedthem--doyouwantthesponsortocompare1ittoadifferentformulationItsoundslikeyou2were--3DR.
SKEETE:No,no,no.
4DR.
TROENDLE:--hintingthatthisisn't5therightcomparison,andyouwantacomparison6againstsomethingelse.
7DR.
SKEETE:Oh,no.
Sorry.
Ifthatis8whatcameacross,that'snotwhatwasintended.
9Whatwasintendedwasthatatthetimeofthe10study--orIshouldsayevenatthetimeaswe11werethinkingabouttheevaluationofthisdrug12productforourclinicallystablepatients,there13wereSuboxonetabletsonthemarket.
Thenin201314and2014,BunavailandZubsolv--Zubsolvandthen15Bunavailcameonthemarket.
16ThepointofwhatIwassayingtherewas17thatifwe'rethinkingabouttransferringapatient18fromatransmucosalformtoProbuphine,thereneeds19tobeguidanceaboutthedifferencesinthe20variabilitythatyoumightseeinsublingualform.
21SoevennowwiththeSuboxonefilm,there'ssome22AMatterofRecord(301)890-4188206mention--they'rementionedinthere1that--there'smentioninthelabelthatthere's2somedifferenceinthebioavailability.
Soyou3needtobeabletoconsiderthatwhenyou're4transferringapatientover.
5Inotherwords,it'smoreforcliniciansto6beabletokeepinmindthattherearevarious7forms,variousdoses,andtobeabletotransfer8thepatientappropriatelyovertoProbuphineif9theysodesire.
10DR.
WINCHELL:IfImightvery11quickly--thisisCeliaWinchell--it'salmosta12matterofthedifficultyofexpressingtothe13clinician.
Eightmilligramsisnot8milligrams.
14Sowhenwestartedthestudy,wesaidthisisfor15patientswhoareon8milligramsorless,butit's16becomemuchmorecomplicatedtocommunicatewhat17thatmeansbecause8milligramsofSuboxonetablet,185.
7milligramsofZubsolv,it'sjustgottenamore19complicatedwaytoexpressthetargetpopulation.
20Ithinkthatwasthepointofshowingthatthe21landscapehaschanged.
22AMatterofRecord(301)890-4188207DR.
KRAMER:Dr.
Kotz1DR.
KOTZ:I'mwondering,whatisthe2maximumnumberoftimesapatientcanhave3continuousimplantsIknowyoumentionedinone4ofthetalksthatitwas4treatmentcyclesat54times,2inonearmand2intheother.
What6happensafterthat7DR.
SKEETE:Well,that'sactuallysomething8thatweneedtothinkaboutaswellbecause,9actually,wedon'tknow--becauseonly4sitesare10identified.
Oncethose4sitesareusedup,we11won'tbeabletosayanythingmoreaboutcontinued12usebeyondthose4sitesbecauseithasn'tbeen13evaluatedforeithersafetyorefficacyatthis14point.
15DR.
HERTZ:Ithinkthatwouldbeagood16questionfordiscussionlateronbecauseit17probablyrequiresabitmore,andIseethesponsor18interested.
SoIthinkperhapsafterlunch.
19DR.
KRAMER:Dr.
Pickar20DR.
PICKAR:Yes.
AsIrecall--andhelp21me;Igetoldersometimes--itwasasmall22AMatterofRecord(301)890-4188208percentagewhowereIVdrugusersinthissample.
1DoIrecallthatcorrectly2DR.
SKEETE:Yes,andthatwasactuallyin3thesponsor'sslideset,butyes.
4DR.
PICKAR:That'sright.
Oneofthe5questionsthatwe'regoingtobeaskedtotalk6aboutiswhatisthepopulationwhowouldbenefit7andsoforth.
8DR.
SKEETE:Absolutely.
9DR.
PICKAR:Now,Idon'trecallwhether10thatsubgroupwhoareIVdruguserswaslarge11enoughtoanalyzeseparately.
Andifitwas,do12youhaveanyhintofitBecausethatisvery13pertinentbecauseit'sreally--themajorityof14thesefolksareoralopioid--ahugeproblem,no15question,mostofthetimeatleastIVdrugusers.
16Gotit.
17Butwhentheagency'shereaskingusto18considercarefullywhoisthepopulationandan19indication,dowehave--andI'mjustputtingit20outthere.
Dowehaveenoughinformationfor21broadlyonoralopioiduse,orshouldwebetalking22AMatterofRecord(301)890-4188209aboutoraldependencyThey'reaskingmethat1questionthere,andthat'swhatwentthroughmy2mind.
DowehaveanydataDowehaveanythingin3thestats,Dr.
TravisAnythingtherethatcan4helpusthere5DR.
SKEETE:Sowehave--6DR.
TRAVIS:I'mjustgoingtosay,Ididn't7evaluateanythinglikethat,so--8DR.
PICKAR:Youdidn'tlookat--you9didn'tcoveracovariantlikeweusedtodointhe10covariantdays,covariantforIVversusoral11Sorry.
Becausethat'sahuge,hugethinginthe12useofthisproduct.
13DR.
HERTZ:Soperhapsagainwecanlookto14seewhatanalysestheremaybe.
We'llcheckours.
15Thesponsorwillchecktheirsandgetbacktothat16afterlunch.
17DR.
PICKAR:Soundsgreat.
18DR.
KRAMER:Dr.
Campopiano,canyouquickly19askyours20DR.
CAMPOPIANO:Ithinkitmightbea21yes/noquestion.
Istheredataavailableaboutthe22AMatterofRecord(301)890-4188210alcoholornon-opioidsubstanceuseofthese1participantseitherpriortoorduringenrollment2inthestudy3DR.
SKEETE:Therearedata.
Unfortunately,4Idon'thavethatasabackupslide.
Idon'tknow5ifthesponsorhascompiledforthissubstancethe6psychosocialhistorydata.
Idon'tknowif7you--youallhaveitSotheyapparentlyhaveit8asIguessabackupslide,whichwecandisplaynow9orduringthediscussion.
10DR.
KRAMER:Ifthesponsorcouldgetthat11readysothattheycouldshowusthatwhenwecome12back--westillhaveacouplepeoplewhohave13questionsforclarificationfromthesponsor.
And14we'regoingtoadjournnowforlunch.
We'regoing15tocomebackat12:45.
Wedoneedtohavetheopen16publichearingasspecifiedontheschedule,a17requirement.
Andassoonasthat'sover,we'll18returntothosefewquestionsforthesponsorand19seethatslide.
20Thankyou.
Remember,nodiscussingofthe21topicatlunchamongmembers.
22AMatterofRecord(301)890-4188211(Whereupon,at12:00p.
m.
,alunchrecess1wastaken.
)2345678910111213141516171819202122AMatterofRecord(301)890-4188212AFTERNOONSESSION1(12:30p.
m.
)2OpenPublicHearing3DR.
KRAMER:Okay.
Ifeveryonecouldtake4theirseat.
Beforethefirstpersonspeaksinthe5openpublicsession,Ihaveafewcommentsto6addresstoeveryone.
7BoththeFoodandDrugAdministrationand8thepublicbelieveinatransparentprocessfor9information-gatheringanddecision-making.
To10ensuresuchtransparencyattheopenpublichearing11sessionoftheadvisorycommittee,theFDAbelieves12thatitisimportanttounderstandthecontextof13anindividual'spresentation.
14Forthisreason,theFDAencouragesyou,the15openpublichearingspeaker,atthebeginningof16yourwrittenororalstatementtoadvisethe17committeeofanyfinancialrelationshipthatyou18mayhavewiththesponsor,itsproduct,andif19known,itsdirectcompetitors.
Forexample,this20financialinformationmayincludethesponsor's21paymentofyourtravel,lodging,orotherexpenses22AMatterofRecord(301)890-4188213inconnectionwithyourattendanceatthemeeting.
1Likewise,FDAencouragesyouatthe2beginningofyourstatementtoadvisethecommittee3ifyoudonothaveanysuchfinancial4relationships.
Ifyouchoosenottoaddressthis5issueoffinancialrelationshipsatthebeginning6ofyourstatement,itwillnotprecludeyoufrom7speaking.
8TheFDAandthiscommitteeplacegreat9importanceintheopenpublichearingprocess.
The10insightsandcommentsprovidedcanhelptheagency11andthiscommitteeintheirconsiderationofthe12issuesbeforethem.
Thatsaid,inmanyinstances13andformanytopics,therewillbeavarietyof14opinions.
Oneofourgoalstodayisforthisopen15publichearingtobeconductedinafairandopen16way,whereeveryparticipantislistenedto17carefullyandtreatedwithdignity,courtesy,and18respect.
Therefore,pleasespeakonlywhen19recognizedbythechairperson,andthankyoufor20yourcooperation.
21Willspeakernumber1stepuptothepodium22AMatterofRecord(301)890-4188214andintroduceyourselfPleasestateyournameand1anyorganizationyouarerepresentingforthe2record.
3MS.
WILSON:MynameisSarahWilson.
I'm4notbeingcompensatedformytimeheretospeak5today,butthesponsorhascoveredmytravel6expensestoattendthismeeting.
Ibroughtmymom7heretodayformoralsupportasIsharemy8experiencewithyou.
9Probuphinesavedmylife.
Iwashitbya10drunkdriverandhadsevereinjuries.
Atthat11point,IlostmyinsurancewhenIwasnolonger12abletowork.
TheonlytreatmentIcouldafford13outofpocketweredoctorvisitsandprescription14painkillers.
15BythetimeIwasabletoacknowledgemy16addiction,myhusbandandIhadlostourhomeand17everythinginit.
IwasstealingfromthosethatI18loved.
Iwantedhelp,butwasscaredofsuffering19anymorepainthanIalreadywasin.
Iwas20embarrassed.
Addictionisprevalentinmyfamily.
21Ispent15yearsinlawenforcementworkingwith22AMatterofRecord(301)890-4188215thedrugtaskforce.
Iknewwhattoavoid.
But1thereIwas,addictedtopainkillerswithwhatI2feltwasnowayout.
3Myhusbandfoundanadinourlocalmagazine4foraresearchstudyforthetreatmentofopioid5addiction.
Icalledandmadeanappointmentthat6day.
Thepositivechangesinmylifewere7immediateandvisible.
Allofmyyearsof8additionalsufferingwereeased,andIsuccessfully9completedthatfirststudy.
10IagreedtotheimplantstudybecauseIknow11therearerisksassociatedwithsublingual12medication.
Ihavefourchildren.
Ikeepmy13medicationinalockedsafefortheirprotection.
14Ihavetomakesurethepharmacykeepsmy15medicationinstock,andifIwanttotravel,16packingmymedicationisthefirstthingthatI17havetodo.
Theimplanttakesawaythepotential18riskstomychildrenbeingexposedtomy19medication.
Italleviatestheworryofamissed20appointment,ofthepharmacybeingout,or21forgettingmymedicationwhenItravel.
22AMatterofRecord(301)890-4188216Irealizetherearenoperfectanswersfor1opiatetreatment.
Therearevariables,andevery2situationisdifferent.
ButIbelievethat3approvingthisimplantwillprovideamethodof4treatmentdeliverythateliminatesmanyofthe5secondaryrisks.
Thankyou.
6DR.
KRAMER:Thankyou.
Willspeakernumber72stepuptothepodiumandintroduceyourself8Pleasestateyournameandyourorganizationthat9you'rerepresentingfortherecord.
10MJRDEAN:Goodafternoon.
IamMajor11GeneralArthurT.
Dean,andIserveasthechairman12andCEOofCommunityAnti-DrugCoalitionsof13America.
AndCADCAdoesnothaveanyfinancial14relationshipwiththeorganizationindiscussion.
15CADCAisanon-profitorganization,which16representsover5,000communitycoalitionsand17theiraffiliates.
CADCAisastrongadvocatefor18drugabuseprevention,firstandforemost.
The19OfficeofNationalDrugControlPolicydirector,20MichaelBotticelli,hassaidthatprevention21remainsthebestandmostcost-effectiveapproach22AMatterofRecord(301)890-4188217tocurvingournation'spublichealthcrisisof1drugdependenceandoverdose.
CADCAcouldn'tagree2morewiththedirector'sstatement.
3Atthesametime,CADCAandourcoalitions4supportacomprehensiveapproachthatincludes5increasedresearch,expandingoptionsforeffective6treatment,andstrengtheningandsupportforallof7thoseinrecovery.
CADCAandourmembershavea8strongemphasisonpreventingthemisuseandabuse9ofmedicines.
WehostonanannualbasisNational10MedicineAwarenessMontheachOctoberandprovide11numerousresourcesviaourwebsite,whichiscalled12preventrxabuse.
org.
13In2015,CADCAco-convenedtheCollaborative14forEffectivePrescriptionOpioidPolicies.
We15callitCEPOP.
WevisitandpartnershipwithMary16BonoinTrustforAmerica'sHealth.
Because17coalitionsareuniquelypositionedwithintheir18communities.
CADCAmemberswerefirsttorecognize19andbeconcernedaboutthegruelingopioidcrisis,20andthiscametoourattentiongoingbacksome1521yearsago.
22AMatterofRecord(301)890-4188218Today,asyouknow,overdosetakesmore1livesthancarcrises.
Webelievethatincreased2leadershipatthefederallevelcanhelpexpand3researchandhealthcarecoverageforanarrayof4effectivemedicatedassistedtreatmentoptions.
5CADCAdoesnotendorseanysingletreatment6approachormodality.
However,weknowthat7medicationassistedtreatmentcanbeeffective.
It8canhelpmanypatientsreturntocaringfortheir9familyandtheirfamilymembers;maintainin10gainingemployment;andcontributingtoour11society.
12Ofparticularinterestofourmembersisthe13advancementoftechnologiesthatcaneffectively14treatopioidaddictionwhilereducingtheabuse15potentialofthesemedicines.
Abusedeterrent16formulationsarecriticallyimportanttousandour17members,andtheoptionofprovidingmaintenance18treatmentofopioiddependenceviasubdermal19implantisapromisingapproach.
20CADCAapplaudstheFDAandthiscommittee21forfocusingonexpandingeffectivemedicinesfor22AMatterofRecord(301)890-4188219thetreatmentofopioiddependence.
Thankyouvery1much.
2DR.
KRAMER:Thankyou.
Willspeakernumber33pleasestepuptothepodium,introduceyourself,4andstateyournameandorganizationforthe5record.
6MS.
KNADE:Hi.
MynameisSusanKnade.
7I'mthemotherofanopioidaddict.
Iamnotbeing8compensatedformytimetoday,andIamhereto9readaletteronbehalfofDavidSheff,journalist10andauthorofClean:OvercomingAddictionand11EndingAmerica'sGreatestTragedyandBeautiful12Boy:AFather'sJourneyThroughHisSon's13Addiction.
14"Addictionisoneofthebiggestpublic15healthchallengesofourtime,onethat'skilling16moreAmericansthananyothernon-naturalcause.
17Today,theconversationaroundaddictionisriddled18withblame,stigma,andmisinformation.
This19conversationneedstochange.
20"Contrarytopopularbelief,addictionis21notamoralfailingorapersonalchoice.
Itisa22AMatterofRecord(301)890-4188220chronic,progressivebraindiseasethatisboth1preventableandtreatable.
MyfamilyandIhave2witnessedandbattledfirsthandthestrugglethat3addictsundergoeachandeveryday.
4"MysonNickfoughtaddictionforovera5decade.
Hisbattleincludedrehabcenters,6residentialtreatmentprograms,andoutpatient7programs,numeroustripstotheER,andmany8relapses.
There'snotadaythatgoesbywhenI9don'thearfrompeoplewhohavesimilarstories,10includingmanythathaveamuchlesspositive11outcomethanours.
Theywritelong,heartbreaking12lettersabouttheirchildrenwhodidn'tmakeit.
13"It'salarmingandinexcusablethatasmany14as90percentofpatientswhoenteraddiction15treatmentprogramsintheU.
S.
don'treceive16evidence-basedtreatments,whichincludesoneof17themostsuccessfultreatmentswehaveinour18arsenal;medicationsproventotreataddiction,19particularly,addictiontoopioids,including20heroinandprescriptionmedicationslikeOxyContin.
21It'snosurprisethatthepatientsleavingsuch22AMatterofRecord(301)890-4188221programsoftenrelapse,andtheynevergotthehelp1thattheyneeded.
2"AccordingtoareportinTime,studiesshow3thatpeopleaddictedtoopioidsmorethanhalve4theirriskofdyingduetotheirhabitiftheystay5onmaintenancemedication.
Thereareother6benefitstoaddictionmedicines,butthereare7challenges.
Amajoroneiscompliance,whichis8whyIbelieveProbuphinewillbealife-saving9treatmentformanyofthepeoplesufferingfrom10addiction.
11"Mysonisalivetodaybecauseofmedication12hewasfinallyprescribedafteralmostadecadeof13failedtreatments.
Hetakesbuprenorphinein14combinationwithbehavioraltherapyandhasbeen15soberforsixyears.
However,therearemany16peopletakingbuprenorphinetodaywhostill17strugglewithrelapse.
Wakingupeveryday,they18arefacedwithachoice:takemybuprenorphineor19gogethigh.
20"Thesepeopleareoftenblamedfortheir21relapse,butblaminganaddictforrelapsingis22AMatterofRecord(301)890-4188222blaminghimforbeingill.
Relapseisasymptomof1thisdisease.
Thisiswhymedicationsthatcan2preventrelapsearecritical.
Probuphinewould3takeawaythedailychoicebetweentakingtheir4dailydoseofSuboxoneorreturningtoheroinor5anotherdrug.
6"MysonwouldhavebenefitedfromProbuphine7aswellaswouldcountlesschildren,husbands,8wives,partners,andotherlovedones.
Mysonand9ourentirefamilysufferedforadecadelargely10becauseinnovativeevidence-basedtreatmentslike11Probuphineweren'tavailable.
It'sencouragingto12seeprogressinthisarea,andindeedIsee13Probuphineasabreakthroughstepforward.
Ihope14it'sthefirstofmanynewoptionsforpatients.
15"Iurgeyoutomaketherightchoiceand16approvethismedicationthathasthepotentialto17helpalleviatethesufferingofsomanypatients18andtheirfamilies,andthepotentialtosaveso19manylives.
Thankyouforyourtimeand20consideration.
Sincerely,DavidSheff.
"21DR.
KRAMER:Thankyou.
Willspeakernumber22AMatterofRecord(301)890-41882234steptothepodium1MR.
JERNIGAN:Goodafternoon.
Mynameis2ScottJernigan,andI'mnotbeingcompensatedfor3mytimetospeakheretoday.
However,Braeburn4Pharmaceuticalshasexpensedmyflightandtravel5expenses,alongwithmywife's,tocomeuphere.
6I'mquitesurethatmywife,whenwegot7married,knewthatopioidaddictionwasgoingtobe8apartofourvows.
She'sgonethroughsomuch9withme,andIcouldneverhavegottentothepoint10thatIamnowwithouthere.
Weallheretodayhave11onethingincommon.
Weareproductivemembersof12society.
Iwasnotthatwayforalongtime.
In13fact,IwasinthedepthsofdespairsobadthatI14neverthoughtIwouldgetout.
15Whilemydaughterwasgettingher16undergraduatedegreeandhermaster's,whilemy17wifewastravelingtheworldforhercompany,Iwas18tryingtogethigh.
Iwastryingtostopthepain19ofwithdrawal.
Iwaslosingacompany.
Iwas20everythingthatadirtyjunkieis,exceptIdidn't21thinkofmyselfthatway.
Ithoughtofmyselfas22AMatterofRecord(301)890-4188224white-collarbusinessmanthatdoestheright1things,butIwasn't.
2However,thisdrughassavedmylife,and3theimplantandhowitoperatesisgreatforalot4ofdifferentfactorsthatIknowwe'veallgone5overandyou'veseen.
AsIsaidbefore,we're6productivemembersofsociety.
Andwiththis7deliverymethod,allIhavetofocusonnowismy8newnormal.
Idon'thavetoberemindedeveryday9thatI'majunkie,everymorning.
Idon'thaveto10beremindedeverydayoreverymonthwhenIlook11intoapharmacist'seyes,andthey'relike,"Oh.
12It'soneofyouagain.
"13I'vestartedmyowncompany.
I'mpresident14ofmyowncompanyagain.
I'mnotadirtyjunkie,15butIdoneedhelp.
Andthisdrugandwiththis16implantisgoingtoallowthattohappen,Ihope.
17Ibelieveweasaddictshavehurtour18familiesenough.
AndwhenIcameupheretoday,I19hadtoremindmywifeonceagainthatIwasan20addict.
Aswecametotheairport,Ihadtolook21overtomywifeandsay,"Man,IhopeIpackedmy22AMatterofRecord(301)890-4188225medicine,"andbringthatup,andwhatitbringsto1thetablealloveragain.
Withtheimplant,we2won'thavetodothat.
Itwillbeonelesshurdle3forusasaddictstogetover.
AndIhopeyoulook4seriouslyatthatdeliverymethod.
Thankyouvery5much.
6DR.
KRAMER:Thankyou.
Wouldspeaker57steptothepodiumandintroduceyourself8MS.
KULKARNI:Goodafternoon.
Mynameis9ShrutiKulkarni.
I'mapolicyadvisorforthe10not-for-profitCenterforLawfulAccessandAbuse11Deterrence,CLAAD.
Thesponsorisamemberofthe12CLAADcoalition.
13Asyouknow,opioidabuseisapublichealth14epidemicintheUnitedStates.
In2013,over1524,000Americansdiedfromopioidrelated16overdoses.
Over16,000deathsinvolved17prescriptionopioidmedicationsandover8,00018deathsinvolvedheroin.
CLAADworkstoreduce19prescriptiondrugfraud,diversion,misuse,and20abusewhileadvancingconsumeraccessto21high-qualityhealthcare.
22AMatterofRecord(301)890-4188226Thankyoufortheopportunitytoprovide1CLAAD'sinputontheproposedbuprenorphine2subdermalimplantforthemaintenancetreatmentof3opioiddependence.
Thismedicationadvancestwo4nationalgoalssetforthinCLAAD'snational5strategyandtheWhiteHouse's2013NationalDrug6Control:increasedaccesstohigh-qualitycare,7includingmedicationassistedtreatmentfor8patientswithsubstanceusedisorders,and9reductionindiversion,misuse,abuseof,and10pediatricexposuretocontrolledprescription11medications.
12CLAADsupportsandthankstheNational13InstituteofDrugAbuse,theOfficeofNational14DrugControlPolicy,andtheFoodandDrug15Administrationfortheirsupportforthe16developmentofnoveltherapiesforthesubstance17usedisordersandmedicationsdesignedtoreduce18thelikelihoodofdiversion,misuse,abuse,and19pediatricexposure.
20Themedicationyouareconsideringtodayis21aresultofpublic-privatecollaborationtosupport22AMatterofRecord(301)890-4188227thenationalprioritiestoadvancehigh-quality1treatmentsforsubstanceuseandtodevelop2medicationsthatposelowerriskstopatients,3families,communities,andtraditional4formulations.
Today,Iwillspeaktotheissuesof5thepopulationthatwilllikelybenefitfromthe6implantablebuprenorphinemedicationandthe7likelihoodthattheimplantablemedicationcould8reducediversion,misuse,abuse,andpediatric9exposure.
10Apatientpopulationthatcould11significantlybenefitfromtheuseof6-month12buprenorphineimplantconsistsofindividualsin13themaintenancephaseofrecoverywhocannot14routinelyvisitopioidtreatmentprograms,15addictiontreatmentproviders,orpharmaciesfor16geographicorotherpracticalreasons.
17Acomprehensivemedication-assisted18treatmentprogramincludesbothmedicationsto19treatsubstanceusedisorderandbehavioral20therapy.
Theimplantmedicationofferspatients21themaintenancephaseandopportunitytoaccess22AMatterofRecord(301)890-4188228necessarytreatmentwithoutadditionalburdenso1thattheymayfocusonthepsychosocialandother2vitalaspectoftheirlong-termrecovery.
3Additionally,buprenorphineimplant'snovel4deliverysystemoffersseveralbenefitstopatients5andaddressesanimportantpublichealthneed.
6First,theimplantsupportmedicationcompliance7overa6-monthtreatmentperiod,providing8clinicianstheconfidencethattheprimarydoseis9administeredaccordingtothetreatmentplan.
10Second,giventhatthebuprenorphineimplant11wouldnotbedispensedtopatientsforself-12administration,itprovidesanotheravenuetohelp13reduceprescriptiondrugdiversion,misuse,abuse,14andpediatricexposure.
15Finally,whilepatientstreatedwithany16formofbuprenorphinemayneedoccasional17supplementaldoses,accesstotreatmentwitha18buprenorphineimplantmeansultimatelytherewould19belessoralbuprenorphineavailableinthehome20fordiversion,misuse,abuse,orpediatric21exposure.
22AMatterofRecord(301)890-4188229Inconclusion,thebuprenorphineimplantis1aproductofandstandstofurtheradvancetwo2nationalpriorities:accesstohigh-quality3medication-assistedtreatmentanddeliverysystems4thatposelowerrisksofdiversion,misuse,abuse,5andpediatricexposure.
Thankyouagainforthe6opportunity.
IfCLAADcanbeofanyfurther7assistance,pleasecontactus.
8DR.
KRAMER:Thankyou.
Speakernumber6,9wouldyousteptothepodium,please,andintroduce10yourself11(Noresponse.
)12DR.
KRAMER:Okay.
We'llmoveontospeaker13number7.
14DR.
GINNAN:Goodafternoon.
I'm15Dr.
ShannonGinnan,andIamthedirectorof16medicalaffairsforthenot-for-profitAlliancefor17theAdoptionofInnovationsinMedicine,Aimed18Alliance.
Ourorganizationworkstoimprovehealth19careintheUnitedStatesbysupportingdevelopment20anduseofnovelevidence-basedtreatments.
Ihave21nofinancialrelationshipstodeclare.
Thankyou22AMatterofRecord(301)890-4188230fortheopportunitytoofferthesecommentson1behalfofAimedAlliance.
2Compliancewithatreatmentregimeniskey3tosuccessofanymedicaltherapy.
Foracute4conditionssuchasaninfectionorrash,compliance5isrelativelyhighbecausethereissignificant6rewardtothepatientinrelievingthesufferingof7thatcondition.
Ofcourse,"fairlyhigh"isa8relativeterm,ascompliancedropstoonly950percentnearlybecausesymptomssubside,which10isoftenwellbeforetheendoftheprescribed11term.
12Evenconvenienceplaysalargepartin13compliance.
Withadherencetomedicationregimens14fallingby20percentormoresimplywhen15increasingdosagefromonetimeperdayto3or4.
16Now,asdiscussed,complianceforachronic17conditionsuchashypertension,diabetes,high18cholesterol,andmostrelevanttotoday's19discussion,substanceusedisorders.
Complianceon20oraltherapiesintheseconditionsfallaslowas2150percentinsomestudies,50percentcompliance22AMatterofRecord(301)890-4188231fortreatmentsthatpatientsarewellawarewill1decreasetheriskoflife-threateningconsequences.
2Thepatientwithasubstanceusedisorder3mayhaveeverydesiretogetbettergiventhe4statisticsofmedicationcompliance.
inthebest5ofcircumstances.
However,howcanwepossibly6feelthatwe'regivingthesepatientsthebest7chanceofrecoverybyusingstandarddispensing8practicesifJoeSmithandSusieJonescan'teven9remembertotaketheirantibioticwhenthere's10nothingintheirbrainfightingthem11Howsuccessfulwouldtheybeiftheirbrain12werescreaming,"No.
Don'ttakethatantibiotic.
13Thisragingbacterialsinusinfectionfeelsso14good.
"That'swhatourpatientswithsubstanceuse15disordersareupagainst.
Andasphysiciansand16regulators,itisourdutytoofferthemevery17possibletooltowinthatfight.
18Buprenorphineworks.
Whenthemedicationis19takenasprescribed,itworks.
Ithasaproven20trackrecord,butcomplianceiskey.
A2012study21intheAmericanJournalonAddictionsfoundthat22AMatterofRecord(301)890-4188232addictionpatientswhowerenon-compliantwith1theirbuprenorphinemedicationregimenswere102timesmorelikelytorelapsetoopioidusethan3thosewhowerecompliant.
4Thebuprenorphineimplantsolvesthis5problem.
Itcanbeadministeredquicklyand6efficientlyinasinglevisit,releaseasteady7controlledamountofaneffectivemedicationfor8sixmonths.
Simplybyadoptingthisnewdelivery9method,wecanbypassallthecomplianceissues:I10forgottotakemymedication.
Ileftitathome.
11Idon'twanttotakeit.
Idon'tneedtotakeit.
12Icangetbywithoutit.
I'drathersellitfor13money.
14Itavoidsissuesofchildrengettinginto15theirparents'drugcabinetandfindingthe16buprenorphine.
Itmakesrecoverymorefeasiblefor17thosewhomayhaveconsiderablesocioeconomicor18geographicchallengesthatgetinthewayof19frequentphysicianvisits.
Itpreventsgreedy20physiciansfromtakingadvantageofthesystemand21makingmoneyaspillmills.
Itcanbeareliable22AMatterofRecord(301)890-4188233cornerstonetoplacingourpatientsdownthepath1ofsustainablerecovery.
2Theriskassociatedwithinsertionand3removalofimplantablemedicationscurrentlyonthe4marketareproperlymanagedtotheextentthat5implantablemedicationshavebecomethestandardof6care.
Forinstance,theAmericanAcademyof7Pediatricsrecommendssubdermalimplantsasthe8preferredcontraceptivemethodforadolescentsthat9arenotabstinent.
Yet,unlikeotherimplantson10themarket,thebuprenorphineimplantcontainsa11controlledsubstance.
Andexpelledbuprenorphine12implantcouldresultinpediatricexposure,13diversion,misuse,orabuse.
14AimedAlliancesupportstheuseofREMSto15managetherisksassociatedwithmedications.
An16appropriateREMScouldaddresstherisksof17complicationsassociatedwiththeinsertionand18removalprocedurestoreducethelikelihoodof19pediatricexposure,diversion,misuse,andabuse.
20AimedAlliancehasreviewedthesummaryof21theREMSincludedintoday'sbriefingmaterialsand22AMatterofRecord(301)890-4188234considerstheprogramadequatetoaddressthe1anticipatedriskofbuprenorphinesubdermal2implant.
Theavailabilityofa6-month3buprenorphineimplantwiththeproposedREMScould4providetremendousbenefittoanindividual's5overallwellbeingaswellastofamilies,6communities,andthepublic.
Thankyou.
7DR.
KRAMER:Thankyou.
Speakernumber8,8andIbelievewehavesomeonewho'sgoingtoread9that.
10MR.
GINNAN:Andthatwouldbemeaswell.
11DR.
KRAMER:Okay.
12MR.
GINNAN:I'mreadingthisonbehalfof13AmandaWilson,M.
D.
I'mnotawareofanyfinancial14relationshipsforher.
15"I'mthefounder,CEO,andpresidentof16CleanSlateCenters.
IfoundedCleanSlatein200917toprovidehigh-qualitymedicalcareandimproved18accesstotheunderservedpopulationofpatients19seekingaddictiontreatment.
Wecurrentlytreat20nearly6,000patientsonamonthlybasiswith21buprenorphineinmultiplestates.
22AMatterofRecord(301)890-4188235"Asapracticingphysician,mylife's1missionistohelppeoplestrugglingwiththe2opioidaddictionsothattheycanleadhealthier3morefulfillinglives,sotheirfamiliesandloved4onesmayalsoexperiencesomereleasefromthe5collateralandoftentragicburdenofthischronic6braindisease.
7"IwantedmythoughtsheardtodaybecauseI8knowfirsthandhowdesperatetheneedistoexpand9therangeofmedicationtreatmentoptionsfor10opioidaddiction,andbecauseIknowthatthis11communityiscurrentlyevaluatingpotentialnew12therapythatIbelieveeffectivelyaddresses13significantunmetneeds.
14"In2012,CleanSlatewasthefirst15recipientoftheSAMHSAScienceandServiceAward16forOffice-BasedOpioidTreatment.
Ourtreatment17modelatCleanSlateappliesaholisticapproach18thatintegratesbehavioralcounselingwithsafeand19effectiveprescriptionmedicines.
Wearedeeply20aware,basedonreal-lifeexperience,that21medication-assistedtreatmentwithbuprenorphine22AMatterofRecord(301)890-4188236canmakeasignificantdifferenceinhelping1patientsattainrecovery,yetwearealso2profoundlyawarethatanopioid3addiction-sustainingrecoveryisnotdefinedbythe4conceptofcure.
Itisalifelongstruggle5typicallymarkedbyoccasionalrelapse,interim6neurologicalcravings,andthechallengesof7adherencetobothmedicationtherapyand8counseling.
9"Giventhesechallenges,weneedtoexpand10therangeoftreatmentoptionssothatmorepeople11andfamiliescanbehelped.
Whilethere'snocure12forthischronicdisease,thesubjectoftoday's13meetingillustratesthatthereareimmediate14opportunitiestomaketangible,life-changing15progressinthishorrificstruggle.
16"Medication-assistedtherapyhasbeen17enormouslybeneficialtopatients,andtheadvent18ofoffice-basedtreatmentwithoraldaily19buprenorphinewasatremendousstepforward.
Itis20ourcollectiveandcontinuingresponsibilityto21addressanylimitationswithcurrenttreatment22AMatterofRecord(301)890-4188237optionsthatmayposechallengestorecoveryor1correctableriskstohouseholdandfamilysafety.
2"Adherencetodailymedicationtherapy,3includingoralformsofbuprenorphine,isan4ongoingchallengetorecoveryformanypatients.
5Firstandforemost,animplantthatdelivers66monthsofcontinuousbuprenorphinetreatmentcan7eliminatethisvariableforpatientschallengedby8adherence.
9"Wearealsoawarethatopioidaddiction10presentsextendeddangerstofamilyhouseholdsand11societyatlarge.
Tragically,someofthese12potentialdangersareinadvertentlyposedbythe13treatmentsthemselves.
Medicationsthatmustbe14storedinpatients'homesarevulnerabletothe15potentialforaccidentalingestionbychildren,16recreationalexperimentationbytheirfamily17members,ordiversiontoillicitcommerceonthe18street.
TheProbuphineimplantpresentsnosuch19risksordangers.
20"BasedontheProbuphineclinicaltrial21results,Iandmanyofmymedicalcolleaguesare22AMatterofRecord(301)890-4188238excitedandoptimisticaboutthepotentialofthe1proposedbuprenorphine6-monthimplantto2effectivelyaddressthesepatientadherence,3householdandsafety,anddiversionchallenges.
4"Thecurrentinnovationgapthatexistsin5thetreatmentofopioidaddictionisunacceptable.
6AccordingtothePharmaceuticalResearchand7ManufacturersofAmerica,rightnow,therearemore8than1200medicationsindifferentstagesof9developmentfordiabetes,cancer,andheart10disease.
11"Opioiddependenceisnotevenrecognizedat12thiscategory,inwhichtheorganizationis13trackingnewmedicationsanddevelopment.
Given14thestigmaandshamesurroundingaddiction,it's15sadlynotsurprisingthattheresearchand16developmentaroundthiscomplicated,17life-threateningdiseasepalesincomparisonto18otherseriousdiseases.
Thishastochange.
19"Weurgentlyneedtoseesociety--new20opioidaddictionasequallydeservingofnew21treatmentadvancesandunderstanding.
Yet,despite22AMatterofRecord(301)890-4188239itsbroadeninginepidemicscale,opioidaddiction1continuestobemisunderstoodasachoiceormoral2failinginsteadofachronicdiseasewhosebasisis3inbrainchemistry.
Sufferersandtheirfamilies4toooftensecretlybeartheburdenofshameand5stigma,whichfurtherdiscouragesrecovery.
6"Thankyoufortheopportunitytosharemy7perspectiveattoday'simportantmeeting.
"8DR.
KRAMER:Thankyouverymuch.
Speaker9910MR.
MENDELL:Goodafternoon.
Mynameis11GaryMendell.
Thankyoufortheopportunitytobe12heretoday,andIhavenofinancialinterest.
I'm13herespeakingfirstandforemostasafather,a14fatherwhohasexperiencedsomethingthatnoparent15shouldeverhavetoexperience.
16MysonBriandiedattheageof25dueto17addictionofopiates.
Butevenmoretragic,his18deathwaspreventable.
Myson,afterbeing19addictedformanyyears,wasprescribed20buprenorphineinhistreatmentprogram.
Andthen21hewassenttoahalfwayhouse,andtherethe22AMatterofRecord(301)890-4188240doctorintheoutpatientprogramdidn'tbelievein1buprenorphine,andhetriedtotitratehimdown,of2whichIobjected.
3Whilemysonwasonit,itwasthebesthe4hadeverdoneinyears.
Hewashappy.
Hewas5working.
Hewasdoinggreat.
Andseveralmonths6later,hedied.
Ifoundout,afterhediedwhenI7sawhispapers,thattheyweretitratingdown.
And8therewereabunchofemailsbetweenmysonandthe9doctor,mysoncomplaining,"Stoptitratingmedown10orI'mgoingtotellmyparents.
"11Aweekaftermysondied,hissponsorcalled12meupcryinghysterically.
Hesaid,"Gary,I'mso13sorry.
I'msosorry,Mr.
Mendell.
IlovedBrian.
14Itriedtogethimoffthatdamnbuprenorphine,but15hewasnotgoingtobeabletoreachhishigher16power.
Itriedsohardtogethimoffit.
"17ThemonthstofollowBrian'sdeath,I18learnedthatforeverymajordiseaseinthis19country,thereisonewellfundednational20organization,pioneeringresearch;advocatingfor21changesinpublicpolicies;gettinginformationand22AMatterofRecord(301)890-4188241researchthat'sproventowork;implementedinour1communitiesandourhealthcaresystem;reducing2stigmaassociatedwiththeirdisease;andproviding3information,support,andhopeforsomany4families.
Andfromthat,avisionemergedof5unitingmillionsofAmericanstocombataddiction6andempoweringthemtohelpothers.
Andfromthat,7anorganization,thisorganization,Shatterproof,8wasformed.
9I'mproudtobeheretodayrepresenting10Shatterproof,anorganizationthatIfoundedand11themillionsofAmericansacrossthiscountrywho12havejoinedwithusonthisvisiontocombat13addictionandthestigmaassociatedwithit.
14Wemustchoosetotreataddictionasa15disease,adiseasejustlikecancerordiabetes,16andtreatthisdiseaseaccordingly.
Arecentstudy17intheJournalofAmericanMedicalAssociation18foundoutthat80percentofthosewiththese19diseasearenottreatedwithevidence-based20protocols,80percent.
Imeetfamilieseveryday21acrossthiscountrywhohavelovedonesstruggling22AMatterofRecord(301)890-4188242withaddiction,andstrugglingwithopioid1addiction,whoaredesperatefortreatment,2anythingthatwillhelptheirlovedonerecover3withabetterchanceofsuccess.
4Youallheretodayhaveanopportunityto5changethis.
ApprovingProbuphinewillincrease6thetreatmentchoicesphysicianshavetotreatthis7disease,achronic,life-threateningdisease.
If8weasasocietycanchangethewaywethinkabout9addiction,thewaywethinkaboutotherdiseases,10thenmoreofourlovedoneswillfeellovedand11connected.
Morewillseektreatment.
Fewerwill12die,andfewerfamilieswillbeshatteredbeyond13repair.
14Ithankyou.
Ithankyouasafather,asto15mysonBrian,IoweallthatIamandallthatI16havetoendthisdisease.
Notjustaddiction,but17attitudes.
Notjustasickness,butthisstigma18thattookhislife.
Thankyou.
19DR.
KRAMER:Thankyou.
Speakernumber10.
20MR.
CAMPBELL:Hi.
MynameisWayne21Campbell.
I'mthepresidentofTyler'sLight.
I'm22AMatterofRecord(301)890-4188243notbeingcompensatedformytimeheretoday,but1thesponsorhascoveredmytravelexpensesto2attendthismeeting,whichisBraeburn3Pharmaceuticals.
4Goodafternoonandthankyouforletting5myselfandthepublicspeak.
Eachday,nearly706Americansdiefromopioidoverdose.
Tome,this7isn'tjustastatistic.
ThisishowIlostmyson8also.
MynameisWayneCampbell,andIfoundedan9organizationcalledTyler'sLight.
We'rea10non-profit,basedinColumbus,Ohio,aimedat11equippingourcommunitieswithinformationand12resourcestohelpchooseadrug-freelifeand13battleaddiction.
14IbeganTyler'sLighttwoweeksaftermyson15Tylerpassedawayfromanaccidentalheroin16overdose.
Asinthecaseofmanyaddicts,Tyler17paththroughaddictionstartedveryinnocently.
As18aDivision1footballplayer,Tylerwasintroduced19toopioidsafterafootballinjury.
Hisdoctor20prescribedPercocettomanagehispainafter21surgery.
Fromthere,PercocetledtoOxyContin,22AMatterofRecord(301)890-4188244andthenOxyContinledtoheroin.
1Thistrendweareseeingmoreandmore2frequentlyamongathletesofbothhighschooland3collegelevel.
Moreoftenthannot,athletes4experienceinjuriesthatrequirepainmanagementor5evensurgery.
Whendoctorsprescribepainkillers6tomanagethepain,athletesandtheirparentsare7notadequatelywarnedorevencautionedatall,in8manycases,abouttherisksinvolvedintaking9opioids,includingthepotentialforaddiction.
10Collegestudentsareparticularly11susceptibletodevelopopioidaddictionsasit's12incrediblyeasytoaccesspainkillers,whichare13typicallyjustacalloradormroomaway.
With14footballplayersandathletes,theseaddictive15pillsarediscretelyexchangedinlockerrooms16becausethey'reexpectedtoplaythroughpain.
As17theseplayerscontinuetotakepainkillers18throughouttherecoveryprocess,theiraddiction19canescalate,andeventuallytheymaybecomemore20andmoredependentonstrongerandcheaperdrugs21suchasheroin.
22AMatterofRecord(301)890-4188245MywifeChristyandIneverthoughtthatour1loving,energetic,football-fanaticsonwouldfall2victimtoaddiction.
Itwasdevastating.
We3witnessedTylergofromacompetitiveathletewho4liveforfootballtoakidwhowasfocusedonlyon5wherehewasgoingtogethisnextfix.
Ourlives6becameconsumedwithhelpingTylergetcleanand7backontherighttrack.
8Wetookhimtocounseling,supportedhim9whenhetookabreakfromschooltotrytoget10healthy.
Weenrolledhiminsix-weekprograms,11helpedhimthroughatotalofsixdifferent12rehabilitationattempts.
Herelapsedaftereach13stint,somethingthatisaverycommonoccurrence.
14Intheend,itwasn'tenoughtosavehim.
Tyler15diedwithin12hoursofa30-dayinpatientstay.
16Afteroursonpassed,mywifeandImadeit17ourmissiontolearnasmuchaboutopioidaddiction18aspossibletotryandpreventotherfamiliesfrom19experiencingthesamepain.
Oneofthethingswe20realizedwashowfewresourcesexisttohelp21educatepeopleaboutthewaystopreventopioid22AMatterofRecord(301)890-4188246addictions,itswarningsigns,effective1interventions,andtreatmentoptionsavailable.
2Tyler'sLightbeentosevenstates,2003schools,andspokento100,000studentssofarina4matteroffouryears.
Therealityofthisopioid5addictionisabraindiseasethatdoesn't6discriminatebasedonage,race,economics,or7education.
Thediseaseisrunningrampantinour8veryowncommunities,yetpeopleturnablindeye9toit,ignoringitthatitmightgoaway.
Wecan't10waitforourkidstodie.
Wehavetointervene11earlyanddeliberately.
Takeitfromme.
12Deathduetoaddictioncanbeprevented.
13Lookingback,IwishIwouldhavehadaccessto14effectivemedicationstohelppreventhisrelapses15aftercompletingaddictiontreatmentprograms.
16Noneofthesixaddictiontreatmentprogramsthat17Tylerattendedemphasizedprescriptionmedication18asacentralpartofmaintenanceaftertheprogram.
19Whilebehavioraltherapycanbeagreatway20tohelppatientsrecoverfromaddictionformost,21it'sjustonepieceofthepuzzle.
Addiction22AMatterofRecord(301)890-4188247impactseverypartofaperson,anditdoesn'tstop1there.
Thewholefamily'simpacted.
2Asabraindisease,addictionisnota3choiceorasignofweakness.
Ithasemotional,4psychological,chemicalrepercussions.
Assuch,it5needstobetackledfromallangles,including6biologicallywithmedication.
Giventheoption,we7definitelywouldhaveencouragedtohimtoadhere8toamedicationaftercompletingrehab,asthereis9irrefutableevidencethatlong-termuseis10effectiveintreatmentopioiddependence.
11Today,we'reheretodiscussProbuphine,a12drugthathasthepotentialtochangetheoutcome13ofmillionssufferingfromopioidaddictionand14theirfamilies.
Thislong-actingimplantmayhave15beentheantidotethatsonneeded.
Asyou16deliberate,Iurgeyoutoconsiderhowtreatment17optionslikeProbuphinecanhelpmovetheneedleon18reducingopioidaddictioninthiscountry,given19thosesufferingafightingchanceofrecovery.
20Theopiateepidemicisconsuminga21generationinourcountry.
Thereisnooneanswer,22AMatterofRecord(301)890-4188248nomagicbullettosolvethisproblem.
Shortof1banningtheproductionofprescriptionopioids--2DR.
KRAMER:Mr.
Campbell,I'msorry.
The3light'son.
Couldyoutrytowrapupquickly4MR.
CAMPBELL:It'sonesentence.
5Shortofbanningtheproductionof6prescriptionopioid,it'sincumbentuponallofus7toprovideeverytoolwecantotrytosavelives8inopioidaddiction.
Probuphinecanbe,andshould9be,oneofthosetools.
Thankyouforyourtime10andconsideration.
11DR.
KRAMER:Thankyou.
Speakernumber11.
12DR.
RUPP:Thankyoufortheopportunityto13speaktoday.
MynameisDr.
TracyRupp.
Iwas14previouslyaclinicalpharmacistatDukeUniversity15MedicalCenter,andI'mnowthedirectorofpublic16healthpolicyinitiativesattheNationalCenter17forHealthResearch.
Ourresearchcenteranalyzes18scientificandmedicaldataandprovidesobjective19healthinformationtopatients,providers,and20policymakers.
Wedonotacceptfundingfromthe21drugormedicaldeviceindustry,andIhaveno22AMatterofRecord(301)890-4188249conflictsofinterest.
1Westronglysupportaccesstosafeand2effectivetreatmentsforopioiddependence.
In32014,moreAmericansdiedofopioidoverdosethan4anyotheryearonrecord,soweneedsafeand5effectivetreatmentoptions.
Currentlyavailable6medicationsforopioiddependenceareeffectivebut7couldbeimprovedtomakethemmoredifficultto8divertandabuseandlesslikelytobeaccidentally9ingestedbysmallchildren.
Along-acting10medicationcouldhelpimproveadherencewith11therapy,potentiallyimprovingtreatmentsuccess.
12However,inseekingtosolvetheseproblems,we13mustbecertainwearenotcreatingnewproblems.
14First,wedonothavesubstantialevidence15ofProbuphine'sefficacyasrequiredbystatute.
16Infact,theevidenceforefficacycomesfroma17singlecontrolledtrialwithmultipledesignflaws.
18Forexample,patientsrequiringasignificant19amountofsupplementalsublingualbuprenorphine,20afterthefirstmonth,shouldbeconsidered21treatmentnon-respondersduetothenon-titratable22AMatterofRecord(301)890-4188250natureoftheimplant.
However,thestudy's1sponsordidnotconsiderthesepatientsasnon-2responders.
3Patientswhoreceivedstudydrugbut4discontinuedthestudywithoutprovidingany5efficacydatawerenotincludedinthesponsor's6intention-to-treatanalysis.
Appropriate7statisticalanalysisrequiresthatthesepatients8areincludedintheintention-to-treatpopulation.
9Somemissingurinetoxicologytestswerecountedas10negativetests.
However,itiswellknownthat11opioid-dependentpatientsoftenskipurineteststo12avoidapositivetest.
Missingtestsshouldbe13countedaspositive.
14Second,wealsodonothavesubstantial15evidenceofProbuphine'ssafetyasrequiredby16statute.
Thelackofinformationregardinghowto17safelytransitionpatientsfromoralbuprenorphine18totheimplantincreasestheriskthatpatients19willsufferadangerousrelapseduringthis20criticalwindow.
Therisksofapoorlymanaged21transitioncannotbeoverstatedsincearelapsefor22AMatterofRecord(301)890-4188251patientswhowerepreviouslystablewouldbe1particularlydevastating.
2Thestudyprotocolinstructedpatientsto3stoptheiroralbuprenorphine12to24hoursbefore4placementoftheimplant.
However,the5pharmacokineticsoftheProbuphineimplantindicate6thatittakes3to4weeksfordruglevelstoreach7steady-stateconcentrations.
Therefore,toensure8patientsareadequatelytreatedanddecreasethe9riskofrelapse,continuationoforalbuprenorphine10forthefirstfewweeksoftherapywouldseemtobe11necessarytomaintaindruglevels.
12Becausethetransitionwasnotproperly13managedorstudied,wedon'thavetheinformation14neededtoinstructprovidersandpatientsonhowto15managethetransition,period,todecreasetherisk16ofrelapse.
Thisisanunacceptableriskfor17stablepatients.
18Lastly,84percentofthepatientsstudied19werewhiteandveryfewwerestudiedbeyondsix20months.
Thisisnottherealworldofopioid21addiction.
Manyofthesepatientswillrequire22AMatterofRecord(301)890-4188252treatmentforyears.
Weneedlong-termsafetydata1fromdiversepopulations.
Patientswillrequirea2newincisionevery6months,creatinganongoing3riskofharmduetobleedingandinfectious4complications.
TheProbuphineimplanthasahigher5riskforbleedingandcomplicatedremovaland6infectioncomparedtocontraceptiveimplants,sowe7needabetterunderstandingofitslong-termsafety8profile.
9Inconclusion,basedonthedatapresented10anddiscussedtoday,I'mdisappointedtoconclude11thattherisk-benefitprofileofProbuphinedoes12notsupportitsapprovalforthepopulation13studied.
Thankyoufortheopportunitytocomment14todayandforconsiderationofourviews.
15DR.
KRAMER:Thankyou.
Speakernumber12.
16MR.
HARROLD:Goodafternoon.
I'mMark17Harrold.
Iserveaslawenforcementliaisonand18legalconsultantfortheCenterforLawfulAccess19andAbuseDeterrents,orCLAAD.
I'manattorney,20formerfederalprosecutor,andformerCityof21Atlantapoliceofficer.
IshouldnotethatI22AMatterofRecord(301)890-4188253appeartodayinmypersonalcapacity,andIhaveno1financialrelationshipwiththesponsor.
2Wheneverthiscommitteeseekstomake3crucialrecommendationsrelatedtonewdrug4applications,itisimportanttoconsiderthe5mannerinwhichthenewtreatmentcanassistlaw6enforcementinexercisingdiscretiontowards7individualsstrugglingwithaddictionandthose8involvedindrugpossessionasopposedto9traffickingandviolence.
10Specificallytotheconsiderationhere11today,anyeffectivetreatmentaimedatopioid12addictionisadvantageousfromalawenforcement13perspectivebecauseithelpsremoveindividuals14fromthecycleofpossession,sales,trafficking,15andrelatedcriminalactivity.
16Morespecificallytothetypeofimplantable17treatment,Inotethreeprimaryadvantagesthat18willassistlawenforcement.
First,ifan19individualgoestojailorrehabduringthetime20theimplantisworking,therewon'tbean21interruptioninmedicationaccessorriskof22AMatterofRecord(301)890-4188254withdrawal,whichcreateschaosfortheindividual1aswellasthosearoundhimorher.
2Thetreatmentcannotbereadilystolen,3sold,ortradedillicitly,whichisespecially4importantgiventhatoralmedicationsarecommon5contrabandwithincorrectionalinstitutions.
Fewer6oralmedicationsinthehandsofpatientsmeans7fewerdrugsavailableforthediversionofthe8blackmarket.
9Itisofcoursemucheasiertorememberto10renewmedicationeverysixmonths,forexample,11thantogotoamethadoneclinicortakeanoral12drugeveryday.
Bettermedicationadherencecan13reducerelapse,riskand,recidivism,anditcan14allowindividualstofocusonthepsychosocial15supportsnecessarytoliveahealthy,productive16lifeoutsideofthecriminaljusticesystem17Thankyouverymuchforlettingmesharemy18thoughtswithyoutodayonthisveryimportant19issues.
Thankyou.
20DR.
KRAMER:Thankyou.
Speakernumber13.
21DR.
MALIK:Thankyouverymuch.
I'm22AMatterofRecord(301)890-4188255Dr.
AzfarMalik.
I'mapsychiatrist,addiction1specialist,andIamachiefmedicalofficerand2CEOatCenterpointHospital.
I'lltalkaboutthe3hospitalalittlelater,butfirstIwantto4clarifythatI'mnotbeingpaid,compensated,to5speakoverhere.
Ofcourse,thesponsorshave6coveredmytravelexpensestobehere.
7Itisbecauseofmypassiontotreat8patientswithaddictionandpsychiatrythatbrings9mehere,andIfeelit'sanhonortopresentthis10tomycolleaguesandtothiscommunityregarding11thisveryimportantsubject.
12Ithasbeenonourmind.
Myinterestand13passionhasbeenpsychiatry.
Igraduatedfrommy14residencyabout30yearsago,andpsychiatrywas15exactlywhereaddictionpsychiatryistoday.
There16werenotenoughmedications.
Wehadverysimilar17primarymedicationsthatweuseinfrequently,and18patientandoutcomeandtreatmentswerenotas19good.
Iseeaddictionpsychiatryexactlywherewe20were30-35yearsago.
Therearenotenough21significanttreatment,efficacy,andwetalkabout22AMatterofRecord(301)890-4188256comparativeanalysisofwhatpsychiatrydidand1whereweare.
2Firstofall,alotofourpatients,at3leastwhoweadmit,about60to70percentofthese4psychiatrypatientshavecomorbidsubstanceuse5disorder,andtheyblendtogether.
Justtogoto6somestatistics,about16,000patients--people,I7wouldusetheworld--diedintheU.
S.
in20138usingopioidpainmedications.
That'sabout49timeshigherthan1999.
10Prescriptionshaveincreasedover11300percentsince1999,andthathas12resulted--thereisaverycomparableproportion13today,increaseinaddiction,too,atthepresent14time.
CDCreportedthatin2012,mostofthe15medicalpractitionerswroteabout259millionpain16prescriptions.
Thatcertainlyleadstowhatwe17see.
Wehaveheardourspeakersnumber1,18number4,andsoonandsoforth.
19AtCenterpointHospital,ourgoalisto20treatthewholehealthproblems,including21psychiatryandaddiction.
Weseeabout30to22AMatterofRecord(301)890-418825740percentofpatientscomingintoourhospital1systemswhohaveaddiction.
Wedodetox.
Wedo2rehab.
WiththeIC,wehavefouraddiction3psychiatristsinoursystem.
Wetreatabout500to4600patientswithbuprenorphine.
Buttheproblem5isthere'sarestriction,andwecertainlycannot6providemoretreatment,andwewouldloveto.
7I'vebeenpracticingpsychiatryforover308years.
Atbest,ourtreatmentforaddictionat9thistimeismediocreIwouldsay.
Peopledon't10seektreatmentbecausethereislesseffective11treatment.
Myexperiencehasbeenwithtrials,and12wehavedonetheProbuphinetrialimplant.
13Iconsiderthisverysimilartohowwehad14Risperdalpillsoratypicalantipsychotics,leading15tolong-termLAIs,whicharelong-acting16injectables,whichlastforamonth.
Now,wehave17LAIs,whicharelastingfor3months,whichis18InvegaSustenna;Idon'tknowifyoumayknowabout19it.
Iconsiderthisasverysimilar.
Wetreat20patientswhoaretakingSuboxoneorvarious21products.
Thereisaproblemgettingthem22AMatterofRecord(301)890-4188258refilled,gettingthemchecked.
Idofeellong-1termmaintenancetreatmentissomethingweshould2consider,seriously.
3Wewereapartofthe814study.
Mostofmy4patientswhowereinthestudylovedit.
They5wouldwanttocontinuewiththat,butcertainlyI6havenooptionsatthistime.
Iwillcertainly7considermoredrugsandmorenewtechnologiestobe8broughtin.
Thankyouverymuchforgivingmethe9opportunity.
10DR.
KRAMER:Thankyouverymuch.
11Speaker14.
12MS.
TUOHY:Goodafternoon.
Thankyoufor13thisopportunitytospeakbeforeyou.
Mynameis14CynthiaMorenoTuohy.
I'mtheexecutivedirector15forNAADAC,theassociationforaddiction16professionals.
Ihavenofinancialinterests.
17NAADACrepresentsover85,00018addiction-focusedcounselors,directors,managers,19educators,andresearchersacrossthiscountryand20abroad.
I'manadministrator,aclinician,a21treatmentprogramdeveloper,anaddiction22AMatterofRecord(301)890-4188259curriculumwriter,atrainer,aneducator,andI1havethehonorofdoingthatalloverthisworld,2andthatdoesn'tmatter.
3Ihavebeenintheaddictionsandsocial4workprofessionforover40yearsnow,andevery5timeIhearstories,aswehaveheardtoday,of6someoneoverdosingbecausetheyhaveanaddictive7disease,orafamilymemberindeepsorrowoverthe8lossoftheirfamilymembertoanoverdose,orthe9fearofaparentwhowillloseormaylosetheir10childtoanoverdose,itremindsmewhyIdowhatI11do,andwhyI'vedoneitsolong.
12Itremindsmewhythishearingisso13important.
AnditremindsmewhyIrepresent14counselorsacrosstheUnitedStatesandabroadwho15workwithaddictivediseasesinordertotryto16makeadifference,totrytoassistpeople'slives,17eitherthepersonwhoisaddictedortheirfamily18member.
19Soyousee,whenyouworkinthis20profession,itreallydoesn'tmatterhowmanyyears21youdothisworkbecausetherearestorieslike22AMatterofRecord(301)890-4188260thisthatweheareveryday,andmoresonowthata1personintheUnitedStates,now,isoverdosingand2dyingfromopioidsevery2minutesofeveryday.
3Oftentimes,wedon'thavethemedications4availableforlong-termrecovery.
Yes,wehearthe5storiesfromthepeopleweservewithanopioid6addiction.
"Oh,Istartedmytreatment.
I'mdoing7well.
Andmybrainstartstocravemyaddiction,8mydrug,andthenIwanttouseagain.
AndthenI9gooutandIfindawaytouse.
"10Withoutthemedicationsthatwillservethe11addictedbrainandinamethodthatworksfora12varietyofpersonswhoareaddictedtoopioids,13thereisahigherpercentageofrelapseanda14higherchanceofdeath.
NAADACstronglysupports15theconceptthatmedicationisatoolthatcan16suspendthecravingordesiretouseandgaintime17andperspectiveforthepersonwithanaddictive18disordertomakeadifferentchoice,tomakea19choicenottouseagain.
20Inthispresentation,youmayhearmesay21thisword"medication"versusadrug.
Inthe22AMatterofRecord(301)890-4188261addictiontreatmentandrecoveryworld,wedon't1usethatterm"drug"becauseitreferstoastreet2drug.
Wedon'twantthebraintogothere,sowe3refertothisasamedication.
Andanmedication4isatoolthatwillassistapersonintheir5treatmentandrecoveryprocess,thenweunderstand6thatit'shelpful.
Weunderstandthatthis7drug--no,thismedication--isasafeand8effectivemedication.
Weunderstandthatit's9helpfulforopioiddependence.
Weunderstandthat10ithasaplaceinthetreatmentworld.
11Thisworkismypersonalaswellasmy12professionalmission.
Ilostmymother--sorry.
13Ilostmymothertoadrugoverdose.
Wouldithave14madeadifferenceinherjourneyhadshehadthe15opportunitytobeonamedicationthatcouldchange16thewayherbrainreacted.
Ihearit.
17(Chimesound.
)18MS.
TUOHY:Doyouknowthatmywishisthat19everyaddictioncounselor,everyfamilymember,has20theopportunitytogiveamedication--I'mso21sorry--thatcouldchangethebrainSoIurge22AMatterofRecord(301)890-4188262youtoconsiderthismedication,andIthankyou.
1DR.
KRAMER:Thankyouverymuch.
Speaker2number15.
3(Noresponse.
)4DR.
KRAMER:Speakernumber16.
5MR.
EMSWILER:MynameisDavidEmswiler.
6I'mnotbeingcompensatedformytimetospeakhere7today,thoughthesponsorhascoveredmytraveland8lodgingexpensestoattendthemeeting.
Ialso9broughtmywifeCindyheretodayformoralsupport10asIsharemyexperiencewithyou.
11Thankyouforthisopportunitytospeak.
It12hasbeensaidthatI'minremission.
The13dictionarydefinesremissionasaperiodinthe14courseofadiseasewhensymptomsbecomeless15severe,atemporaryrecovery.
Addictionisthe16disease,anditcancomeback.
I'vebeencleanfor17fouryearsthismonth,andonlyIcancontrolifI18remaininremission.
19Irememberalltoowellthesicknessof20withdrawalfromopioids,andIdon'twanttofeel21thatwayagain.
It'soneofthefactorsthat22AMatterofRecord(301)890-4188263drivesmetomakemyremissionpermanent.
Oneof1theotherfactorsismywifewho'sherewithme2today,andtheotheronecallsmeGrampy.
3Opioidstookovermylife,andIamoneof4thefortunateoneswhodecideIneededhelpbefore5itwastoolate.
I'vebeenafirefighterformore6than20years.
I'mtheposterchildforitcan7happentoanybody.
I'veseenaddictionfromboth8sidesasapatientandasaprovider.
9MyaddictioncostmemoremoneythanIcare10toknow.
Ihatemoney.
Iliedtogetmoney.
It11affectedmylifeathomeandtookatollonmywife12andkidsandmyparents,thoughnoneofthemknew13untilItoldthem,andIdecidedtogethelp.
14Thankfully,theyallstoodbyme,andIdidnot15havetosufferthroughwhatwouldhavebeenmy16greatestloss.
Iamblessedtohaveawonderful17supportsystemathomeaswellasintheclinical18setting.
19Afterstartingmymedication,Ifeltnormal20forthefirsttimeinyears.
Iwasn'thigh.
I21wasn'twithdrawing.
Myheadwasfinallyclear,and22AMatterofRecord(301)890-4188264Icouldfunctiononaday-to-daybasis.
1MedicationslikebuprenorphineandProbuphineallow2thatstateofnormalcy,Probuphineonaneven3higherlevelbecauseIdon'thavetoworryabouta4pilleverydaythattakencorrectlytakes455minutes.
AndIdon'thavetoleavethatpillthat6couldkilltheloveofmylife,mygranddaughter,7ifshefounditandtookit.
8I'dalsoliketoaddthatneitherSuboxone9orProbuphinealonewillworkwithouttheproper10supportsystemconsistingoftheappropriate11prescriberswhounderstandhowthemedications12work,aswellassomeformofcounseling.
Ichose13one-on-onecounselingalongwithvisitstoaclean14siteeverytwoweeks.
Othersmaychooseoneofthe1512-stepprogramsorcounselingwiththeir16prescriber.
Whichevermethodischosen,itis17imperativethateveryoneinvolvedworkstogether18withthecommongoalofconstantremissionand19recovery.
20I'lldealwiththisfortherestofmylife.
21Rightnow,mymedicationisasafetynetforme,22AMatterofRecord(301)890-4188265andthethoughtofnothavingthatnetscaresme.
1It'sacomforttoknowthatIhavetreatment2availabletomeandthereispotentialfor3Probuphinetobeapproved.
Oneday,Imayhaveto4stopusingmedicationformyrecovery,andIwill5crossthatbridgewhenIcometoit.
Butuntil6thattime,treatmentslikeSuboxoneandProbuphine7areliterallysavingliveseveryday,includingmy8own.
Thankyouforyourtime.
9DR.
KRAMER:Thankyou.
Speakernumber17.
10DR.
MALIK:Thankyouagain.
I'mhere11presentingforDr.
AmitVijapura.
He'soneofthe12otherinvestigatorswhoIknow,buthecouldn't13makeit.
Hewasaprincipalinvestigatorin14multipletrials,5trials,805,807,809,811,and15814.
I'lljustreadhisstatement.
Heclaims:16"I'vebeenworkingwiththecompoundforthe17pastfiveyearsin3differentdouble-blindstudies18and2open-labelstudies.
I'veseensignificant19improvementintheleveloffunctioningforeach20individualparticipantsintheclinicaltrial.
21Eachparticipantintheopen-labelphaseshoweda22AMatterofRecord(301)890-4188266significantimprovementandsteadymaintenanceof1theirsymptoms,withoutanycravingorwithdrawal2symptoms.
3"Insertingandremovingoftheimplantisa4simpleprocedurethatcanbedonebyanyqualified5physicianinanoutpatientsetting.
Asaclinician6treatingopioiddependenceinmyclinicalpractice,7I'veseenmanyofmypatientsstrugglingtostay8compliantwiththecurrentavailablebuprenorphine9products.
Itismybeliefthathavingthe10Probuphineimplantavailabletothosepatients11couldbealife-changingexperience.
12"Ihavesurveyedmanyofmypatientsinmy13practicetoaskthemiftheywouldbeinterestedin14a6-monthimplantasatreatmentoption,andmost15ofthemsaidtheywouldconsiderthistreatment16optionwhenhopefullyapprovedbyFDAforthe17maintenancetreatmentofopioiddependency.
I've18askedsimilarquestionstophysicianswhoare19treatingopioid-dependentpatients,andI'vefound20thesamelevelofinterestfrommycolleaguesas21well.
22AMatterofRecord(301)890-4188267"Thankyouforyourtimeandconsideration.
1AmitVijapura,boardcertifiedpsychiatry,2addiction,medicine.
"Thanks.
3DR.
KRAMER:Thankyou.
Speakernumber18.
4DR.
GAY:Thankyou.
MynameisJoeGay.
5BraeburnPharmaceuticalshaspaidformytravel6expensesandlodging,butI'mnototherwise7compensatedformytestimony.
Iamaclinical8psychologistbytrainingandtheexecutivedirector9ofHealthRecoveryServices,Incorporated,which10I'llrefertoasHRS,basedinAthens,Ohio.
HRS11isaprivate,non-profitbehavioralhealthcare12agencyspecializedinaddictiontreatmentand13prevention.
14Thecommitteeisundoubtedlyawareofthe15dramaticincreaseinproblemsrelatedtoopioid16use.
Ohiofeelsasifitisinthecenterofthe17storm.
OpioidrelateddeathsinOhiohave18increasedtenfold,from198intheyear2000,to191988intheyear2014.
In2014,Ohiorecordedthe20secondhighestnumberofoverdosedeathsofany21stateintheU.
S.
,anddependingonthemethodof22AMatterofRecord(301)890-4188268calculation,thethirdorfifthhighestdeathrate.
1HRSisanareaofthestatethathasbeen2highlyimpactedbytheincreaseinopioiduse.
3Duringtheyear2000,onlyseven-tenthsof41percentofouradmissionswereopioidrelated,5whereasnow,theycompriseabout50percentofour6admissions.
7Forseveralyears,westruggledtotreatthe8risingnumberofopioid-dependentindividuals9withouttheuseofmedication-assistedtreatment,10alsoknowasMAT.
Withouttheuseofmedication,11onlyabout15percentofopioid-dependentclients12evensuccessfullycompletedacourseoftreatment.
13In2000,webeganutilizing14medication-assistedtreatment.
Sincethattime,we15haveprovidedMATtocloseto900individuals16utilizingprimarilybuprenorphine-basedmedication.
17Ouroverallratesoftreatment,retention,or18successfulcompletionhaveincreasedtoroughly1940percent.
Weareconvincedoftheefficacyof20opioidagonisttreatmentsolongasitisdelivered21appropriately.
However,significantproblemshave22AMatterofRecord(301)890-4188269ariseninthedeliveryofsuchmedication.
1Probuphinehasthepotentialforaddressingsomeof2thekeychallenges.
3Thediversionofbuprenorphine-based4medicationhasemergedasasignificantissue.
5Individualstypicallyusedivertedmedicationto6avoidwithdrawalandtoreducedrugcraving,7obviouslyusesforwhichthemedicationwas8intended.
However,oftenthemedicationisused9onlytemporarilywiththeintentofresumingthe10misuseofopioids.
11Buprenorphine,whichhasthepotentialfor12beingamajoradjuncttotreatmentandrecovery,13thusbecauseacomponentoftheaddictivepattern14ofuse.
Theindividualforwhomthebuprenorphine15isprescribedremainsengagedinaddictiverelated16behaviors,includingdrugtrafficking,andimmersed17inthedrugsubculture.
Thecustomerreceives18prescriptionmedicationwithnomedicaloversight.
19Diversionhasalsoseriouslyunderminedthe20credibilityofopioidagonisttreatmentand21renderedtheuseofbuprenorphineinitscurrent22AMatterofRecord(301)890-4188270formulationunacceptabletoimportantreferral1sources,particularlyinthecriminaljustice2system.
3Asaresultofthecircumstancesdescribed4above,wewouldwelcometheavailabilityofa5productsuchasProbuphine,primarilybecauseit6reduces,ifnotcompletelyeliminates,the7potentialformedicationdiversion.
Italso8reducescertainbarrierstotreatment,including9thetransportationchallengesfacedbythose10receivingmedicationandthedifficultiesin11accessingphysiciantimetoprescribemedication.
12Thankyoufortheopportunitytotestify.
13DR.
KRAMER:Thankyouverymuch.
14Speaker19.
15MR.
MENDELL:Hi.
MynameisGaryMendell,16andI'mfounderandCEOofShatterproof.
AndI'm17here--I'mreadingaletterwrittenbyPatrick18Kennedy,formerU.
S.
Representative,Democratfrom19RhodeIsland,founderoftheKennedyForumand20co-founderOneMind.
21"I'mhumbledandhonoredtowriteinsupport22AMatterofRecord(301)890-4188271ofsomethingthatisabsolutelycriticaltothe1futureofthiscountry,expandingaccessto2addictiontreatmentforopioiddependency.
Ayou3knowfromrecentnews,opioidoverdosesareat4epidemiclevelsinmanypartsofthenation.
5Peoplearedyingeveryday,andthepublichealth6andcriminaljusticesystemsarestretchedtotheir7limits.
Andthisisn'thappeninginavacuum.
8"ArecentpublicopinionpolloutofNew9Hampshirecitesheroinoverdosesasthenumberone10concernofvotersinthatstate,notthenumberone11healthconcernnorthenumberonecrimeissue,the12numberoneissueoverall.
Weneedsolutionsnow.
13WhyAddictionisadiseasethatdoesnot14discriminatebasedonrace,gender,economic15status,orgeography,yetsolutionstothis16epidemicaresparse,orworse,non-existentfor17millionsofAmericanswhoneedthem.
Addictionis18aprogressivediseasewithatrajectorymarkedby19deathanddisabilityifuntreated.
Thatmust20change.
21"Iwritetothispanelnotonlyasaformer22AMatterofRecord(301)890-4188272memberofCongressandauthoroftheMentalHealth1ParityandAddictionEquityAct,butassomeonewho2haslivedtheexperienceofopioidaddiction.
My3addictionbeganasaresultoftreatmentforback4pain.
Justlikemanyotherswhooriginallysought5reliefforaninjuryorchronicpain,asmy6symptomssubsided,theywerereplacedbyaddiction.
7"Ihavebeenopenedaboutmystrugglewith8prescriptionpainkillersandmentalhealthissues,9whichoftenco-occur,inthehopesthatIwillset10othersfreefromlivingwiththisall-consuming11diseaseandsilence.
Thestigmaofseeking12treatmentisaburdennooneshouldhavetobear.
13"Today,millionsofpeoplearelivingwith14theverysamescenario,theonethatIhave15dedicatedmylifetounderstanding,fighting,and16advocatingtosolve,whetherasaprivatecitizen17orthroughthepassageoftheparodylaw.
18"Now,wehavenewtreatmentoptionsatour19disposalwhichareworthconsiderationforthis20panel.
Tothatend,theabundanceofclinical21researchshowsthatmedicationisacriticalpart22AMatterofRecord(301)890-4188273oftherecoveryprocess.
Buprenorphinein1particularishighlysuccessfulinhelpingpeople2likemyselfwhohavestruggledwithopioid3addiction.
Itallowedmetolivetothepoint4whereIlivenow,instablerecoverywithout5medication-assistedtreatment.
6"Thatsaid,thereweremanypointsinmy7earlyrecoverwhereIreliedonmedication-assisted8treatmentinordertofunctionfreeofthe9debilitatingeffectsofmyfull-flownaddiction.
10ThatiswhyIamexcitedtolearnaboutthe11long-termtreatments,likea6-monthimplant,as12wellasweeklyandmonthlyinjectables.
Stricter13adherencetoacourseoftherapymeansagreater14chanceofachievingalong-termrecovery,agoal15thatisessentialtothesemedicaladvancesandwhy16thispanelshouldapproveanynewformofthis17treatment.
18"Ifeelstronglythatinjectablesandother19similarmedicalinterventionsarecriticaland20noteworthyinterventionsofanexistingmedication.
21Myexpandingcurrentlyavailableoptionsfor22AMatterofRecord(301)890-4188274treatingthisillness,you'llbeofferingthesame1personalizedmedicineforaddictionaswehavecome2toexpectfortreatmentofotherdiseases.
In3otherwords,wewillbetreatingthediseaseof4addictioninanequitablewaybackedby5complementarymedicalpractices,whichisthe6cornerstoneoftheMentalHealthParityand7AddictionEquityAct.
It'sgoodmedicine,andit's8partofthelaw.
Thankyou.
9DR.
KRAMER:Thankyouverymuch.
Is10speaker20here11(Noresponse.
)12DR.
KRAMER:Ifnot,speaker21.
13MR.
CAMPBELL:MynameisWayneCampbell,14andI'mgoingtoreadaletterfromTimothyLepak.
15AndneitherTimothynorhisorganizationshave16receivedanyfinancialsupportfromTitan17Pharmaceuticalsoritsaffiliates.
18"TimothyrepresentstheNationalAllianceof19AdvocatesforBuprenorphineTreatment,NAABT,which20isa501(c)(3)non-profitorganizationformedin212005toeducateandhelpconnectpatientstomodern22AMatterofRecord(301)890-4188275evidence-basedaddictiontreatment.
Ourmembership1includesover4,000buprenorphineprescribing2physicians,andoutpatientphysician-matching3servicehasbeenusedbymorethan93,000patients4seekingevidence-basedaddictiontreatment.
Iam5instrongsupportoftheFDAapprovalof6Probuphine.
7"Sincebuprenorphinewasapprovedforthe8treatmentofopioidaddictionin2002,ithas9becomethestandardofcare.
Wenowhaveovera10decadeofclinicalexperiencewithmillionsof11patients,whichhasshownbuprenorphinetobesafe12andeffectivewhencomparedtoalternative13treatmentoruntreatedaddiction.
14"Over76,000peoplehavediedfromopioid15overdosesincetheFDArejectedProbuphinein2013.
16Wecan'tknowhowmanyliveswouldhavebeensaved17byProbuphine,butwecanbevirtuallycertainit18outnumbersanylivessavedfromwithholdingit.
19Theneedsoenormouslyoutweighstherisks.
It's20bafflingthatthistoolhasnotbeenrushedinthe21handsofdoctorsalready.
22AMatterofRecord(301)890-4188276"Probuphineisuniqueamongbuprenorphine1medicationsasithasmanyattributescurrently2unavailableinthecurrentofferings.
Itprovides36monthsofstable-statemedication,which4virtuallyguarantees6monthsofcompliance.
It's5difficulttodivert,eliminatesaxonalpediatric6exposure,dosingerrors,misseddose,andlost7medication.
8"Althoughitlastsfor6months,itcontains9aboutone-sixthtoone-thirdofthemedication10requiredfortakingtabletsorfilmduringthesame11timeperiod,thusfurtherreducingtheriskfrom12diversion.
Iteliminatestheriskortheritualof13takingapharmaceuticaldaily,whichcanbea14triggerforpeopleaddictedtoprescription15opioids.
16"Clinicaltrialswithbuprenorphinetitrated17theinitialdoseupoverthecourseofseveral18days.
Thismethodwasinitiallyadoptedby19clinicians,butitledtopatientsdroppingoutof20treatmentbeforestabilizing,withsomerelapsing21anddying.
Ittookclinicalexperienceto22AMatterofRecord(301)890-4188277recognizethatpatientscouldberetainedifthey1weredosedtoaffectonthefirstday,thus2suppressingcravingsandwithdrawalasquicklyas3possible.
4"ThesoonerProbuphinegetstoclinicians,5thesooneritsparticularbestpracticescanbe6determined,somethingthatcannotbeascertained7andlimitedpreapprovalclinicaltrials.
With878opioidoverdoseddeathsaday,weneedthis9uniquetoolinthehandsofphysiciansassoonas10possible.
Pleaserecommendtheapprovalof11Probuphine.
Thankyouverymuch.
"12ClarifyingQuestions(continued)13DR.
KRAMER:Thankyou.
Thatconcludesthe14speakers.
15Theopenpublichearingportionofthis16meetingisnowconcluded,andwewillnolonger17takecommentsfromtheaudience.
Thecommittee18willnowturnitsattentiontoaddressthetaskat19hand,thecarefulconsiderationofthedatabefore20thecommitteeaswellasthepubliccomments.
21Beforewegoanyfurther,wearegoingto22AMatterofRecord(301)890-4188278givethesponsorachancetoanswerthequestions1thathavebeenposedtothem.
Andwhentheyare2finished,wewillgotothethreepeoplewhohavea3questionforclarificationforthesponsorearlier.
4Thenwe'lltakeabreak.
5MS.
SHELDON:We'llstartwiththe6discussiononrouteofadministration.
7Seventy-fivepercentofpatientsinPRO814hada8historyofprescriptionopioidversus25to930percentonheroine.
Andwe'vetakenthatdata10andlookedatbothkindsofdrugabusebymethodof11administration.
12IfyoucouldputslideRR-5uppleaseBoth13forheroinandforprescription,peopleinjectand14inhale.
Inthe--slideup--inthe15heroin--it'snotup.
Okay,herewego.
Fifteen16outof22heroinpatientsonsublingualwere17injecting;12outofthe15Probuphineheroin18patientswereinjecting.
Youcanseethe19inhalationnumbers.
Iwassortofsurprised.
20Actually,10percentoftheprescriptionabusewas21alsoviaIVinjection.
22AMatterofRecord(301)890-4188279Intermsofresponserate--wehavethe1slidemadeIfwedon't,I'lljusttellyouwhat2thoseare.
Sixteenoutofthe21sublingualIV3users,or76percent,wereresponders,and17out4of18ProbuphineIVhistory--5DR.
KRAMER:Youlosttheslide6MS.
SHELDON:Yes,becausethatslide--I7havegoneontotheresponserates,sorry,for8whichapparently,aslideisnotmadeyet.
But994percentofthepatientsintheProbuphinegroup,10whowereintheirhistoryusingtheireither11prescriptionopioidorheroinbyanIVroute,were12respondersversus76percentofthoseinthe13sublingualgroup.
14WedohavesomedataonbothIVuseof15heroin,IVuseofprescriptionopioidpills,as16wellasinhalation.
Itdoesnotappearthat,17overall,there'sadifferenceinresponseto18Probuphineortothesublingualgroupdependingon19priorhistoryofuse.
20Therewasalsoaquestionaboutlengthof21stability,Ithink,betweenthe6monthsandthe22AMatterofRecord(301)890-41882803months.
Justtoclarifythatwhilewewanted1peopletohavebeeninbuprenorphinetreatmentfor26monthspriortoentryintothestudy,the3stabilitycriteriawasonlyfor90days.
4That90-daystabilitycriteriainvolvedno5evidenceofillicitopioidusebyurinetoxicology6orself-report,aswellasthephysician7attestationthattheywereclinicallystable,as8wellasbeingonadoseof8milligramsorlessfor9that3-monthperiodoftime.
10Wehadaquestionalsoonpredictorsof11supplementaluse.
Weactually,attherequestof12theagencypreviously,didamultivariateanalysis13toseeiftherewereanypredictors.
Andwelooked14atallthetypicalthings--ageandsex,and15historyofabuse,dailydosepriortoentryinto16thestudy--andwedidnotseeanypredictorsof17response.
Therewerenovariablesthatseemtobe18abletopredictwhowas--I'msorry,not19predictorsofresponse,butpredictorsof20supplementaluse.
Theredonotappeartobeany21variablesthatwouldleadyoutobeabletopicka22AMatterofRecord(301)890-4188281prioritywhowasgoingtobecomeasupplemental1user.
2DR.
KRAMER:Couldyouclarify3MS.
SHELDON:Sure.
4DR.
KRAMER:Didyoujustlookatprior5dose,ordidyoulookatdosageformwiththis6questionofwhethertheformulationhada7different--8MS.
SHELDON:Thereweredefinitelypatients9inourtrialthatcameonfilm,ontablets,andon10different--onthenewproductsaswell,Bunavail11and--again,thatwasalsoarequestedanalysis12thatwedidfortheagency,andtherewereno13differencesdependingonwhatpriormedication14patientsweretaking.
15Wesawearliertheslidethatthepriordose16alsodidnotpredictresponsebetweenthetwoarms,17althoughingeneral,thepatientswhoweretaking18lowerdosesbeforetheycameindidalittlebit19better.
Ithinkthosearedifficulttodetermine20fromastatisticalstandpoint.
21IthinkIhave--yes,Ihaveonemore22AMatterofRecord(301)890-4188282deliverabletoyouguys.
Youaskedabouthistory1ofotherillicitdruguses.
Wedidnotactually2collectalcohol,orcigarettes,ornicotinebutwe3did--slideup--lookatentrycriteriaat4screeningatothertypesofillicitdruguse.
5Ingeneral,theywerebelow10percentof6thevariousillicitdrugsthatyoucanseeonthe7screenwiththehighest,asagainmaybeexpected,8beingcannabisatabout16.
2percentacrossthe9entirestudypopulation.
10Lastone,thequestionof--again,for11clarificationandforyourdeliberations,the12questionofwhathappensaftertwoyearshascome13up.
Previously,aspartoftheprevious14submission,wehadmadecommitmenttodoinga15same-sitestudy.
16Assoonaswewouldhaveapproval,wewould17immediatelystartaPKstudytoshowthatyoucan18insertintothesame--intoapreviouslyinserted19sitesothat,asiscommonwiththecontraceptive20implants,you'dbeabletogobackin.
Certainly,21wellbeforethetwo-yearmarkisreached,wewould22AMatterofRecord(301)890-4188283beabletoprovidethatPKdata.
1Alternatively,othersiteshavebeen2consideredandrecommendedbysomeofourexpert3clinicians,soit'spossibletoinsertintoother4partsliketheabdomenorthelowerback.
5DR.
KRAMER:Justtoclarifythat.
You6wouldsaythattheoverallstrategythatthe7companyhasistoprovideamaintenancetreatment8thatwouldbelongterm,sincethesepeople,by9yourownsurvey,havebeenonitforyearsandsome10ofthepeopleupto10years11You'renottalkingaboutwithdrawalpeople.
12Andallofthedata,subsequenttowhatwehave13now,istoconduct--allthestudyofthatisto14beconductedinthefutureafterapproval;isthat15whatyou'resaying16MS.
SHELDON:Theonlystudythatwewould17doafterapprovalwouldbetoshowthatyoucan18insertintothesamesite,sothatyoucango19beyondtwoyearsbyinsertingintothesamesite.
20However,othersitesarealsopossiblefor21insertionbeyondjustthearmashasbeendonewith22AMatterofRecord(301)890-4188284otherproductsandoccasionally,eveninour1studieswhereit'sbeenmoreacceptableforthe2patients.
Theabdomenandtheupperbackareother3possiblesitesforinsertionoftheimplants.
4We'veaskedclinicianshowlongtheyexpect5tokeeppatientsonProbuphine,and4percentsaid6once.
Thevastmajoritysaidaslongasthe7patientneedsit,andthenthereweresometimesin8between.
Itseems,basedonwhateveryonehasbeen9saying,thatbuprenorphineisaproductthat,of10course,shouldbeusedforthelongterm.
Wehave11dataforuptooneyearandapossibilitytogoto12twoyearswiththesitesthatareavailableinthe13arms.
14DR.
KRAMER:Okay.
Wehavequestionsfrom15Dr.
Bradyfirst.
16DR.
BRADY:Yes.
Iwasjustcuriousabout17theREMS,thetrainingplan.
Itlookslikeithas18kindoftwocomponents:onewhichisjustforthe19prescriber,whichlookslikeitcouldbedone20online,butthentheotherpartofthetraining21that'sforthepersondoingtheprocedure,itlooks22AMatterofRecord(301)890-4188285likethat'sprettyintensivehands-ontraining.
1HaveIgotthatright2MS.
SHELDON:Sothe4-hourcompetency3trainingisactuallyrequiredforeveryone,whether4you'reaprescriberorwhetheryoujustintendto5implantoryouhaveadualrole.
6Thedifferencewillbethattheprescribers7whodon'tintendtoimplant,they'llstillgo8throughthepracticesotheyunderstandthe9procedure.
Theyjustwon'thavetotakethe10competencyassessmenttest.
11Slideup.
Justtoreiterate,intermsof12theabilityforthetrainingprogramtofully13preparepeoplefordifficultremovals,inthehuman14factorstudyandinthetrainingprograms,aswe've15donethemevenforpreparingtheinvestigators,we16actuallymadeitprettydifficult.
17Therewasonlyonethatwaspre-inserted18properlyforthetraineestoremove.
Onewas19fractured.
Onewassuperglued,asDr.
Chavoustie20explained.
Andonewasintentionallyinsertedway21toodeepsothattheintentionwasthattheywould22AMatterofRecord(301)890-4188286notbeabletoremoveit.
Andthentheappropriate1thingatthatpointwouldbetosay,Ican'tfind2it;Ineedtosendthisforimaging.
3Obviously,allthose4thingswillnot4happeninthesameperson,butwewantedtomake5surethatpeoplearefullypreparedfordifficult6removals.
7DR.
BRADY:What'sthegeneralplaninterms8oframpingupthattrainingtomakeit--willit9bedonebyBraeburn--tomakeitaccessibleand10frequentenoughtoaccommodatetheneedsofthe11prescribers12MS.
SHELDON:Wehave20mastertrainersas13ofthistime,andwehavea5to1ratio,sowecan14trainahundredateachsession.
Weplantoruna15coupleofsessionsaday.
Actually,wecandosome16prettyintensivetraining,andplanto,if17approved,beabletotrain1500peopleinthefirst186weeksorsoandhavealreadyassessedwherethe19locationswouldbe,kindofmirroringwherethe20currentuseofbuprenorphineandbuprenorphine21prescribersare.
22AMatterofRecord(301)890-4188287DR.
BRADY:Thankyou.
1DR.
KRAMER:Dr.
Kotz,didyoustillhavea2question3LCDRSHEPHERD:Itwasfromthismorning.
4DR.
KRAMER:Forthesponsor.
5DR.
KOTZ:Idon'tknowwhetherthisis6appropriatenowfordiscussion,butI'mwondering7iftheimplantobviouslyisgoingtocountunder8theregulationthatwehavenowofahundredcap9perphysician.
Theimplantwould10be--conceivably,onephysiciancouldhavea11hundredpeopleonimplants.
12MS.
SHELDON:We'vebeendiscussingthe13potentialforthe--obviously,whenDATA-2000was14initiallyputout,therewasnocontemplationofan15implant.
It'llbeyettobedeterminedexactlyhow16theimplantwillbetreated.
17Oneinterestingfindingsofaristhatmany18oftheclinicianswhoareinterestedinProbuphine19actuallylikebuprenorphinebutdon'tlikesomeof20thediversionaspects.
Sotheyactuallyhappento21bepeoplewhoarebelowtheircap,sothisactually22AMatterofRecord(301)890-4188288willresultinanexpansionofaccessforpatients1becausethesephysiciansarenottakingmore2patients.
Butexactlyhowthecapwillapplyto3Probuphineisamatterwe'restilldiscussing.
4DR.
KOTZ:Butcurrently,thelawis,right,5thatProbuphinecountsasa--6MS.
SHELDON:Yes,basedonthecurrentlaw,7thatwouldbethecase.
Obviously,we'reall8eagerlyawaitingsomenewHHSannouncementsof9potentialchangestoincreaseaccess.
10DR.
KOTZ:Thankyou.
11DR.
KRAMER:AdamGordon12DR.
GORDON:Goodafternoon.
Ihavea13questionabouttheurinetestresultsforPRO814.
14Inoticedthatinthequantitativeanalysisofyour15urinedrugtestresults,you'renotmeasuring16buprenorphineatall.
I'mwonderingwhetheryou17specificallyassessedintheself-reportdata18whetherpatientsweretakingillicitlydiverted19buprenorphineproducts.
20MS.
SHELDON:Theself-reportforillicit21drugswaslimitedtonon-buprenorphineproducts.
22AMatterofRecord(301)890-4188289DR.
GORDON:SothenIcouldsurmisethatwe1wouldnothaveanyresultsthatindicatethat2patientsmaybetakingsupplementalbuprenorphine3offthestreetsinthedatapresentedinthe4results5MS.
SHELDON:Obviously,notfromthe6resultsthatwehave.
However,basedonpersonal7experiencewiththesepatients,Ithink8Dr.
Torringtoncouldaddlittlesomethingtothis9conversation.
10DR.
TORRINGTON:Hi.
MattTorrington.
We11didn'treallythinkitwasveryrealisticthat12patientswouldbetakingillicitbuprenorphinewhen13theycouldgetitfreefromtheirstudyprovider14justbyaskingforit.
Itispossible,butitwas15notsomethingthatwethoughtwasverylikely.
16DR.
KRAMER:Dr.
McNicholas17DR.
McNICHOLAS:Thankyou.
Ijusthavea18follow-upontheissueofthe3-monthstability19versusthe6-monthbecausesomethingoccurredtome20overlunch,frankly.
21Weresubjects,inordertoberecruitedinto22AMatterofRecord(301)890-4188290thestudy,didtheyalreadyhavetobein1buprenorphineorcouldtheyberecruited,2maintainedfor3monthsor4monthsor5months,3andthenputontothebuprenorphine4MS.
SHELDON:Theyhadtoalreadybeinon5buprenorphinefor6months,buttheyhadtoonly6havedemonstratedthestabilitycriteriabythe790dayscleanandphysicianattestation.
Slideup.
8DR.
McNICHOLAS:Myotherquestionis,do9youknowiftherewereanyincentivestokeepthe10dosebelow8milligramsotherthanclinical11judgment12Iknowsomeinsurancecompaniesandstuff13kindofrecommendalowerdosethansometimesthe14clinicianwouldlike,andIdon'tknowifyouknow15iftherewereanyincentivesinplayatyour16varioussitesthatmighthaveresultedinalower17thanoptimumdoseforthepatientotherthan18clinicaljudgmentthatthiswasinfacttheoptimum19dose.
20MS.
SHELDON:Wearenotawareofthis21particulareffecthavingbeeninourstudy.
22AMatterofRecord(301)890-4188291Dr.
Lofwal1DR.
LOFWAL:Icanjustaddasoneofthe2studysitesandknowingseveraloftheotherstudy3sites,thatmostofthevolunteerswhoenrolled4wereactuallyourcurrentclinicpatients.
5Thevastmajorityofthepatientsatmysite6werepreviouspatientsandhadbeenforyears.
7Also,Ijusthaveaninterestinpoliciesandwhat8statesaredoing.
I'venotseenanythingwith9insurancecompanieswherethey'rerequiringpeople10togobelow16.
11Wedoinourstatehavethisattestation12thatwehavetohaveevery6months,iftheyareat1316orhigher,whytheyareonthatandwhywe're14notdecreasingthatdose,butIhavenotanystate15orpolicybelowthat.
16DR.
KRAMER:Dr.
CampopianoDidI17pronounceitright18DR.
CAMPOPIANO:It'sCampopiano.
Ihavea19follow-upquestiontothedatathatyoujust20presentedaboutothersubstanceuse.
Thenumbers21thatyoupresented,wasthatwhatwasreported22AMatterofRecord(301)890-4188292priortoenrollmentorwasthatalsowhatyoufound1duringenrollment2That'skindofthefirstquestion.
Go3ahead.
Ijustwanttogiveyouaheadsup,andI4haveafollow-upquestion.
5MS.
SHELDON:Thosearethedataat6screening.
Wecanshowkindofonebyone,ifyou7wouldlike,thedataasthestudyprogressed.
8Generally,othersubstancesofabusedidnot9change.
Butifwe--sorry,canyougobacktothe10otheroneIwasjustlookingattheamphetamine11onesasanexample.
12Slideup.
Thankyou.
Thisisjustthe13exampleforamphetamine,andthepercentagesmore14orlessstayedaboutthesame.
15DR.
CAMPOPIANO:Wasthereareasonyou16didn'ttestforcocaine17MS.
SHELDON:Wedid.
18DR.
CAMPOPIANO:Oh,Ididn'tseeit.
19MS.
SHELDON:It'sjustwehavetogo20back--wedidtestforcocaineaswell.
21DR.
CAMPOPIANO:Youdid.
AndthenI22AMatterofRecord(301)890-4188293noticedthatpeopleweretestingpositivefor1benzos.
Didyoudistinguishwhetherthiswas2prescribedorillicitbenzodiazepineuse3MS.
SHELDON:Weallowedprescribedbenzos4aspartofthestudy.
Anyoftheresultsthatyou5sawwereatscreeningandtheywereillicituse.
6DR.
CAMPOPIANO:IguessI'mforcedto7concludethatpeoplewhowereusingillicitbenzos8andmarijuanawereconsideredclinicallystableby9the--10MS.
SHELDON:Fortheiropioiddependence.
11Thecriteriarequiredthatanyonewhometa12substanceusedisorderforothersubstancesbe13excluded.
Butiftheywereusingbuttheywerenot14assessedtoactuallyhavethatsubstanceastheir15primarysubstanceusedisorder,thentheywere16allowedinthestudy.
17DR.
CAMPOPIANO:Okay.
Beforeyoupresented18thesubstanceusedata,yousaidthatyoudidnot19findacorrelationbetweenanyofthepatient20variablesandwhetherornottheyrequired21supplementaluse,andthenyouwentontopresent22AMatterofRecord(301)890-4188294thesubstanceusedata.
Didyoucheckforany1correlationbetweenthesubstanceusedataand2any--didyoucheckforcorrelationbetweenthat3andsupplementaluse4MS.
SHELDON:Thatwasnotaparameterthat5wechecked,no.
6DR.
CAMPOPIANO:Okay.
Thankyou.
7DR.
KRAMER:We'vehadafewpeoplethat8havesomequestions,theoneswehavefrombefore.
9We'lltakeDr.
Preston,Dr.
Conley,andthenwe're10goingto--Ihadaquestionaswell.
I'llbe11last,andthenwe'lltakeourbreak.
12DR.
PRESTON:I'vereadthat,occasionally,13oneoftheimplantscameoutjustafterbeing14implanted,andIcouldimaginethiscouldhappenif15itwentonthemarket.
Istherearecommendation16forthatIfthatweretohappen,wouldyou17recommendthatitbereplacedorsupplementedwith18someotherreplacementbuprenorphine19MS.
SHELDON:Intheclinicaltrial,when20onecasedidoccurwheretheimplantwas--all421wereremoved,andtheywerereinsertedinthe22AMatterofRecord(301)890-4188295contralateralarm.
Intherealworld,itmaybe1possibletojustreinsertone.
2DR.
KRAMER:Dr.
Conley3DR.
CONLEY:Yes,thanks.
RobConley.
This4wasbasedonthenewpresentationofyourdata.
5Youimpliedthatintrainingontheinsertionand6removaltechniques,whenyoumentionedthethatwas7insertedtoodeep,thattherewassortofaright8answerthatyou'resupposedtoaskforimaging.
9MS.
SHELDON:Intraining,yes.
10DR.
CONLEY:WhatIdidn'treallyseein11trainingistwothings.
Oneisduringthe12insertiontechnique.
Sothefirstquestionis,do13youassesshowwellpeopledothat,andisthat14partofthecompetency15Secondly,ontheremoval,likeforexample,16thebrokenone,obviously,theU-shapedtechnique17didn'tworkorwouldn'twork.
Iassumethere's18someothertechniqueyoutrainedduringthattime19MS.
SHELDON:Yes,soslideup,andI'm20goingtohaveDr.
Chavoustiecomeupanddiscussin21abitmoredetail.
Butthe21insertioncritical22AMatterofRecord(301)890-4188296tasksdoincludetheproperanglewhichisa120-degreeangle,andthat'sintendedtopreventthe2too-deepinsertion.
3DR.
CHAVOUSTIE:TheCompetencyBased4Trainingprogram,whenwedothedeepinsertion,5thecorrectresponsethatwe'reanticipatingfrom6thetraineeistostopandsayIcannotpalpate7thatimplantorIcannotfindthatimplant.
I'm8goingtosutureuptheincision,andI'mgoingto9schedulethepatientin3weeksforanultrasound,10andthenbringthepatientback.
Thatisthe11correctwaytohandleit.
12TheU-technique,thesecondpartofthe13questionwiththeU-technique,whenan14implant--fibrosisandfractures,andmostofthe15fracturesareiatrogenic.
16Whenyougraspaholdoftheimplantwith17theactualatraumaticclamp,ifyou'realittlebit18toooverzealous,whichsomebodylikemecouldbe19withmybiceps,ifyoupulltoohard,youcould20fracturetheimplant.
21However,afractureisinthesameplane,22AMatterofRecord(301)890-4188297almostlikeacocoon,likethecaterpillarina1cocoon.
It'sinthesameplane,sothenyouwould2reachinwith--bytheway,youhavetwoofthese3clampsonthefield,soifyoufractureone,you4grabitandtakethatoneout,andthentakethe5otherone.
TheU-techniqueworksperfectlyinthat6situation.
7DR.
KRAMER:Okay.
Ijusthaveone8question.
Itgetsbacktotheissueofstudy9quality.
Andit'saquestionspecificallyonthe10safety,PRO814andtheinformation,Ithinkitwas11presentedinyourAppendixAofyouroriginal12packet.
Ididn'tseeitpresentedtoday.
13Iwasalittleconfusedbecausedespite14reportingthat93--let'ssee--93percentofthe15Probuphineand94percentofbuprenorphinepatients16completedthestudy,italsostatedthatthe17proportionofpatientswhoreceivedstudytreatment18foratleast24weekswas68.
5percentand1965.
5percentinthetwoarms.
MaybeI'mmissing20something.
Butiftheycompletedthestudy,why21didtheyonlyget68percentofthetreatment22AMatterofRecord(301)890-4188298MS.
SHELDON:Eachstudyassessmentperiod1hada7-daywindow,soitwaspossibleforafew2patientstocomealittlebitearlier.
Inthe3database,ifitwasn't24weeks,itgotcapturedas4lessthan24weeks.
Ifitwas23andahalfweeks5becausetheycameearlyortheycameearlyon2or63oftheirvisits,andtherefore,their7end-of-treatmentvisitwasatweek22,thatended8upnotcountingas24weeks.
9DR.
KRAMER:Thankyou.
10Okay.
We'regoingtotakea10-minute11break.
Justtoprepareyou,numberone,wecan't12talkoutsideduringthebreak;youknowthat.
But13whenwecomeback,it'sgoingtobequitea14challengebecauseifyou'relookedahead,wehavea15lotofdiscussionquestions.
TheFDAreally--we16onlyhaveonevotingquestionbutwehaveatotal17ofninequestions.
18Theyreallywanttohearfromthemembersof19thecommittee,soI'mgoingtoaskforyour20patienceandcooperation.
Wearedefinitelygoing21togototheend,Ithink,ofthetime.
Thankyou.
22AMatterofRecord(301)890-4188299Promptlyat2:35.
1(Whereupon,at2:23p.
m.
,arecesswas2taken.
)3DR.
KRAMER:Pleasetakeyourseats.
We're4abouttorestart.
Thepromptpeoplewillgetto5speakfirst.
Dr.
Hertzisgoingtogiveacharge6tothecommittee.
7ChargetotheCommittee–SharonHertz8DR.
HERTZ:Hi,all.
Thankyoutoeveryone9heretoday.
IjustwanttosaythatIappreciate10thetimeittakesforourcommitteememberstocome11andparticipateandhelpusattheseadvisory12committees.
Wereallyvalueyourefforts.
13Wehavethefirstimplantablebuprenorphine14productthathaspotentialbenefitsstemmingfroma15formthatcannotbeaseasilydivertedorresultin16accidentalexposuresinthehomecomparedto17existingformulations.
Weheardaboutsomeother18possiblebenefitsduringtheopenpublichearing.
19However,therearealsosomenovelrisks,20andtheycenteraroundthesurgicalimplantation21andremoval.
Plus,wehaveheardthat22AMatterofRecord(301)890-4188300buprenorphinecomesinonestrength,anditcannot1betitrated.
2You'veheardpresentationsaboutthe3objectivesandresultsofanovelstudydesign.
4Andascanhappenwithanovelstudydesignsuchas5this,wedidnotfullyanticipateallofthe6factorsthatcouldinfluencetheoutcome.
Andas7canhappen,notalloftheinvestigatorsinstudy8sitescompletelycarriedouttheprotocolas9expectedwithregardtosomeofthecriteria.
10You'veheardthesponsorsandour11interpretationsoftheresultsandhowtheydiffer,12particularlywhywedisagreedwithanyclaimof13superiorityandwiththeoverallresponderrates.
14Thequestionswehaveforyourdiscussion15andvotebeginwithdefiningtheappropriate16patientpopulationfortreatmentandhowtodefine17successfultreatment,particularlywithrespectto18theuseofsublingualbuprenorphineandtheresults19ofurinetoxicology.
20Definingtheintendedpopulation,andnot21justwhetheritworksordoesnotwork,butalso22AMatterofRecord(301)890-4188301whattheresponderrateis,theseareimportantso1thatclinicianshavetheinformationtheyneedwhen2decidingwhethertousebuprenorphineforagiven3patient.
4Ifyouthinkthissponsorhassucceededin5demonstratingthatbuprenorphineiseffectivefora6particulargroupofpatients,helpusunderstand7howtoidentifythosepatients,howclinicians8shouldbeguidedtoproviderescueusewhenneeded,9andhowtotellwhenapatientisnotbenefiting10fromProbuphine.
Ifyouthinkthestudyhasmissed11themark,thenletusknowthat,too,andifyou12thinkthatadditionalworkisneeded.
13While,wedon'tthinkthatProbuphine14presentsanygreatersystemicriskthansublingual15buprenorphine,wedohavesomeconcernsaboutthe16potentialadverseeventsassociatedwithinsertion17andremovalandforwhatmightbecomeofProbuphine18rodsthatcomeout,wheretheymayposeariskof19misuseinaccidentalexposure.
20TheproposedREMSisintendedtominimize21theserisks,andwewouldlikeyourthoughtson22AMatterofRecord(301)890-4188302thatapproachaswell,theapproachtorisk1management.
2Werecognizethepublichealthvalueof3havinganimplantablebuprenorphineproductasa4partofmedication-assistedtreatmentoptions,and5weneedyourassistanceindeterminingwhetherthis6productwillprovidetheanticipatedbenefits.
7We'llgotothequestionsnow.
Thankyou.
8QuestionstoCommitteeandDiscussion9DR.
KRAMER:Giventhenumberofquestions10wehaveandgiventheurgencytogettothevoting11questionwithallofyoupresent--andifpeople12startleaving,itreallydefeatsthewholepurpose13ofwhywe'reheretoday--wewanteachofyouto14haveachancetoweighintothefinalvote--we15reallyneedtotrytokeepthediscussiononeach16oneofthesetoabout10minutes,atthemost1517minutes.
18Sothewaywe'regoingtogoaboutthisis19I'llreadthequestion,andIthinkitwouldbe20bestforthosepeoplewhofeelmotivatedtoaddress21aparticularquestiontohavetheopportunity22AMatterofRecord(301)890-4188303voluntarilyasopposedtoforcingaroundthetable1kindofdiscussion.
Ithinkitbecomesmore2meaningful.
3ThenI'llmakesureattheendofthat4discussion,inaparticularquestionifthereis5anyonewhohasanurgentcommentthattheywantto6make,thentheycanmakeit.
7It'sveryimportant,Ithink,tounderstand8theFDAisasinterested,notjustinyourvote,9butisasinterestedinyourthoughtsoneachof10thesequestionsthey'vecarefullydevelopedto11exploreyourinterpretations.
12We'vegotabackgroundbuzzonthe13microphones.
14Pleasedocomment.
Don'tfeelthattheonly15thingthatcountsisavote.
Okay16Thefirstquestion,buprenorphineis17non-titratableproductthatprovidesafixedplasma18levelofbuprenorphine.
Theoriginalstudiesraise19concernsabouttheappropriatenessofthedosefor20abroadpopulation.
21Theapplicanthasnowspecifieda22AMatterofRecord(301)890-4188304population,namelystablepatientsonarelatively1lowdoseofsublingualbuprenorphineforwhomthey2believethedoseprovidedbybuprenorphineis3adequate.
4ThediscussionisaroundA)whetherthereis5apopulationthatwouldbenefitfromtheuseof6buprenorphineandhowtodefinethispopulation;7B)ifthereisapopulationthatwouldbenefitfrom8buprenorphine,ifthereisone;discusswhetherthe9studyentrycriteriathatthesponsorused10adequatelydefinedthispatientpopulation,and11discusswhetherthepopulationstudiedactually12reflectedthepopulationtheydefined.
13I'llopenitup,andlet'scontinuetohave14youputyournametagsverticalandgetyour15Jennifer'seyes,sowecankeepalistofanyone16whowantstocomment.
17Dr.
Carroll,onthephone,I'mtoldhasa18question.
Dr.
Carroll,yournametaghasbeen19properlyplaceduprightbyDr.
Gordon.
20Areyouthere21DR.
CARROLL:Hello22AMatterofRecord(301)890-4188305DR.
KRAMER:Dr.
Carroll,we'rereadyfor1yourquestion.
2DR.
CARROLL:HelloCanyouhearme3DR.
KRAMER:Now,wecanhearyou.
Go4ahead.
5DR.
CARROLL:Okay.
Iwas6wonderingif--thesponsor,Inote,hadprovided7somesortofestimateastothepopulationof8buprenorphinepatientsthatactuallymightbe9appropriateforbuprenorphinebecauseitstrikesme10asitwouldberelativelysmall,whichcouldaffect11theimpactandmightmakeuslookattheriska12littlebitdifferently.
13Ifwehaveanarrayof--largesampleof14individualsonbuprenorphine,butinclinical15practice,it'ssomethinglike60to70percentof16themdropoutwithinthefirst6months.
Andof17those,alotofthemaren'tstable.
Itseemstome18wemaybedealingwithaverysmall,very19specializedsampleofindividualswhoare20appropriate.
21Thenifwethinkabouthowthestudywas22AMatterofRecord(301)890-4188306doneandmakesomecommentsaround,maybethosewho1aren'tusingalotofbenzosandcocaineare2appropriateforthis,itmightbeavery,very3smallnumber.
SoI'mjustwonderingifwehad4consideredsortofthesizeofthepopulationfor5this.
6DR.
KRAMER:Okay.
Dr.
Carroll,becausewe7actuallydidn'tgiveyouachancetoaskyour8clarifyingquestionearlier,we'regoingtoallow9thesponsortoaddress,answeryourquestionbefore10wegoontofurtherthediscussionandpressyouon11whetheryouthinkthere'sapopulationthatwould12benefit.
13Sponsor,ifyoucouldaddressthesizeof14thepopulationthatyouhaveestimatedwouldbe15appropriateforthisproduct.
16MS.
SHELDON:Sure.
We'velookedatita17coupleofdifferentways.
There'snoeasywayto18figurethisout,obviously.
AndDr.
Walshasked19thesamequestion,sowefiguredshecouldnowgive20theansweraswe'veinvestigatedit.
21Slideup,please.
22AMatterofRecord(301)890-4188307DR.
WALSH:Thankyou.
Hello,Dr.
Carroll.
1Therereallyisnoeasywaytoanswerthis.
2There'snoonesingledatasetthatcaptures3everything.
Ofcourse,wealsoknowthatthereare4manypracticesthatarecache-basedthatarenot5goingtobecapturedinanydatasetprobably.
6Whatyou'relookingatherearedatathat7areproprietarydatafromSymphonyHealth8Solutions,andtheywereaskedtoassessthenumber9ofpatientswhoarereceivingdosesof8milligrams10orlessasthepotentialstartingpointfor11definingthepopulationthatwouldbeappropriate12forProbuphine.
13Youcanseeinthefigureontheleft-hand14side,fromapatientchartstudy,thatwasjusta15randomselectionofpatientchartsfromsomeofthe16largerinsurancecompaniesthatcontain652,the17estimatethereisabout47percentofpatients18acrossdosesareondosesof8milligramsorless.
19Butwhenlookingatalargerclaimsdatabase20ofover72,000individuals,theestimatethereis21about24percent.
Baseduponotherdata,we22AMatterofRecord(301)890-4188308believethatprobablyabout25percentorsois1abouttherightnumberofpatientswhoarebeing2maintainedon8milligramsorless.
3IthinkintheFDAslidesthismorning,they4mentionedthatin2014,that1.
3millionpersons,5uniquepersons,receivedbuprenorphineforthe6treatmentofopioiddependence.
7DR.
KRAMER:Thankyouverymuch.
Okay.
8Dr.
Carroll,didyouwanttocommentonthefirst9discussionquestion,whetheryouthinkthere'sa10populationthatwouldbenefitfromtheuseandhow11youwoulddefineit12DR.
CARROLL:Inlightof--13DR.
KRAMER:I'velostyouagain.
14Dr.
Carroll15DR.
CARROLL:I'msorry.
16DR.
KRAMER:Wedidn'thearanything.
17DR.
CARROLL:Itseemstomewemightwant18todiscusscarefullywhatclinicallystable19actuallymeans.
Imightdefineitabitmore20narrowlythatthat'sdoneinthisparticularstudy,21specificallyaround--withthisdruguse,the22AMatterofRecord(301)890-4188309cleardemonstrationofstabilitygiventhe1potentialriskshere,especiallyforotherdrug2use.
3DR.
KRAMER:Couldyoutelluswhatyou4thinkthepopulationwouldbe5DR.
CARROLL:Ithinkthestablefor66monthsisprobablysmallerthanestimated,butI7wouldalsolookforsortofademonstrationthrough8urinalysisofnootheruseofillicitdrugsthat9arecontraindicatedforbuprenorphine.
Thebenzo10useisabitofaconcerntome.
11DR.
KRAMER:Okay.
Thankyouverymuch.
12Dr.
Grieger13DR.
GRIEGER:Ithinkthecriteria,asthe14sponsorhaslaidout,arereasonableasguidelines15forpatientselection.
Asyoulooktheirdata,not16everypatientmeteveryoneoftheircriteria,but17itsetsthegroundworkforwhoyouwouldstartto18thinkofasaclinician.
19Iwouldn'tprescribeanexactsetof20criteriaorproscribeanothersetofcriteria,but21rathertoleavetheseasbeingguidelinesbecause22AMatterofRecord(301)890-4188310thisisadirtypopulationintermsofcomorbid1substanceuse,comorbidpsychiatricdisorders.
2You'renevergoingtohaveacleanpopulationof3peoplethataren'tabusingotherthings,andyet4youdon'twanttodeprivethemofapotentially5beneficiallong-actingagent.
6Ithinkthecompanyactuallylaidout,with7theirphysicianorprescriberscertificationform,8reasonableguidelinesforwhoyouwouldthinkofto9usethismedicationwith.
10DR.
KRAMER:You'rereferringtoclinical11stabilitychecklist12DR.
GRIEGER:Yes.
13DR.
KRAMER:Okay.
Dr.
Ionescu14DR.
IONESCU:I'mgoingtoagreewith15Dr.
Grieger,too,becauseI'mjustthinkingabout16otherchronicconditionsthatweasphysiciansface17allthetime,likediabetes,hypertension.
18Certainly,ourpatientsdon'tcomeinwithblood19pressuresthatareperfecteverysingletimeor20bloodsugarsthatareperfecteverysingletime.
21Similarly,thisisachronicconditionthat22AMatterofRecord(301)890-4188311I'mtryingtoequatetoit,andIthinkthe1guidelinesoutlinedbythesponsorseemreasonable2fromaclinicalperspective.
It'snotperfection,3butasweallknow,clinicalworkcertainlyisn't4perfection.
5DR.
KRAMER:Dr.
McNicholas6DR.
McNICHOLAS:Thankyou.
I'mgoingto7havetodisagreealittlebit.
Idefinitelythink8thereisapopulationforwhomthismedication9wouldbeagodsend,butI'mnotsureif3to106monthsofstability,andparticularlywith11positiveforotherdrugsofabuse,isreallythe12criteriathatweshouldbegoingby.
13Havingalotofexperiencewiththis14population,there'sahoneymoonphase,andthatcan15lastagood3to6months,andthenit's,"Oh,16well,letmeseewhatIcando.
"SoIthinkI17wouldliketoseethemstablealittlebitlonger.
18Theotherthingis,inmyclinical19experience,mostpatientsearlyintreatmentare20notat8milligrams.
They'reat12to2116milligrams.
Andthenastheystabilizeandas22AMatterofRecord(301)890-4188312theygetintoregulartherapyandtheircognitive1behavioraltherapyandtheirsupportivetherapies2andstuff,thentheystartbackingdownonthe3dose.
4Ithinkthe6monthsisprobablyalittle5bitlightformy--ingeneral,forthepatient6thatIwouldthinkwouldbegoodforthis7medicationbecausethey'rereallycomplex,anda8lotofthemhavemajorissueswhentheycomein,9andyou'vegottogetthatundercontrolbeforeyou10givethem,accordingtothem,alotofthem,11permissionnottocomeinforalloftheir12counselingtherapies.
13DR.
KRAMER:Onthethirdpartofthe14question,discusswhetherthepopulationstudied15reflectedthepopulationyou'redescribing,whatis16yourassessmentofthat17DR.
McNICHOLAS:Ithinkthatwouldhaveto18bequestionabletoano.
19DR.
KRAMER:Okay.
Dr.
Campopiano20DR.
CAMPOPIANO:Focusingonthequestion21thewayFDAhasphrasedit,whichisthisproduct,22AMatterofRecord(301)890-4188313whichisnon-titratableandatarelativelylow1dose,myassessmentofthepopulationthatwouldbe2idealforwouldbeonethatisbehaviorallystable.
3Withtheunderstandingthatthe4pharmaceuticalproductthatwe'relookingatis5onlytreatingtheopioidusedisorder,rarelydo6youseethatbyitself.
Apersonwhois7self-medicatingorhasnotgainedtheinsightinto8theirbehaviorenoughtoabstainfromother9substancesisgoingtobeinadvertentlyinducing10symptomsofwithdrawalinthemselvesorsimilarto11withdrawal,makingthemselvesemotionallyunstable,12psychiatricallyunstable.
13Itwouldbeverydifficulttoexpecta14personwhoisstillstrugglingwithpoly-substance15usetobeabletofunctionwellonsomething16roughlyequivalentto8milligramsorlessof17buprenorphine.
18Abehaviorallystablepopulation19where--again,you'regoingtohavepeoplewho20becomeunstablewhilethey'reonit,andthat'snot21faultoftheproduct.
ButIthinkmaybethat'sthe22AMatterofRecord(301)890-4188314elementoftheconsiderationforenrollmentor1treatmentwiththisproduct,shoulditbeonthe2market,thatmaybeneededtobetweakedabit.
3DR.
KRAMER:Didyoufeelthatthatwasnot4verifiedinthestudy5DR.
CAMPOPIANO:Ican'tsay--itcouldbe6verifiableifthere'sadditionaldatathatcouldbe7lookedatforcorrelationsbetweensubstanceuse,8othersubstanceuse,andcompletionorneedfor9supplementaldosing.
Wecertainlycouldinform10clinicaluseoftheproductifthatdataas11analyzedandprovesuseful.
12DR.
KRAMER:Thankyou.
Dr.
Dodd13DR.
DODD:Asafollow-uptothat,it'svery14hardformetoaddressthisquestionwithoutreally15lookingintothemissingdatamore.
Itreally16concernsme.
AndI'dliketoseesomeanalysisof17predictorsofmissingnessinconjunctionwiththe18analysisthatyouweretalkingabouttoreallyadd19toabetterunderstandingofwhatthepotential20populationitmightbenefitwouldbe.
21DR.
PICKAR:Boy,that'satoughone.
I'm22AMatterofRecord(301)890-4188315enjoyinghearingtheconversation.
Thisisatough1patientpopulation.
Mygoodness.
You're2addressingprobablyaquarterofthepopulationout3there.
Thatfeelsreasonabletome.
4Sincethestudywasdonewiththese5guidelinesandyoustartmovingoutsidethat,you6sortoftakingawayalittlebitfromthestudy.
7Thestudy,Ithoughteverybodyagrees,showed8comparability--what'sthecorrectterm9Noninferiority.
Ithoughtitshowedthat,10non-superiority.
11Now,Idon'tknowwhatthatdoesthattothe12studyifyoustartchangingthepatientpopulation13towardsanindication.
Idon'thaveananswerto14that.
Thesearetoughstudiestodo.
Imean,15who'sdoingthemEverybodywhodealswiththis16patientpopulation17Sohavingsaidthat,I'mrightwithyou,but18Idon'twanttomissachancetosavesomepeople's19lives.
Idon'tknowhowrealisticitistogo20aroundandchangingthestudypopulationposthoc,21andthenmakingassumptionfromthedata.
It'sa22AMatterofRecord(301)890-4188316toughie,andyou'redealingwithalife-threatening1condition.
2Ibothagree,andthenI'mwondering3whether,allthingsbeing,youknow,whatever,that4wegoaheadasTomsuggestedofgoingwiththeway5theylaiditout.
It'showtheydidthestudy.
If6wechangeit,Idon'tknowwhathappensthen.
7DR.
KRAMER:Doyouthinkthatthesponsor8diddefinetheirpopulationadequatelyandenrolled9thepopulationtheydefined10DR.
PICKAR:Itwouldseemthatthesponsor11defineditinawaythatwasprettyclear,andI12thinkthattheyprobablygotwhattheywerelooking13for,andit'sprobablyagood,soliddatathat14representsabout25percentoftheseriously15addictedpopulation,whichIthinkthatwouldbe16thecase.
17You'resorightabouttheearlyphase,and18it'sbehavioral;allthat'strue.
Justtell19me--Ihatetobesowhatever--exceptthatwe're20dealingwithaspecificquestioninadrug21approval.
22AMatterofRecord(301)890-4188317Idon'tknowwhatyou'ddoifyouchangethe1gameintermsofthepatientpopulationwiththe2data,althoughI'mopentofudgealsotothings,if3youwant,butitjustseemsalittleoddtome.
4That'sall.
5DR.
KRAMER:Dr.
Kotz6DR.
KOTZ:Myconcernisthatthisisn'ta7stablepopulationbecausetherearemanypatients8whodidusesupplementalbuprenorphineafterthey9enteredthestudy.
Infact,someusedit10throughoutthestudy,andtherewasawidevariety:11someusedalittle,someusedalot.
12Leavingoutthebehavioralpart,justfroma13medicationperspective,Idon'tseethisasa14stablepopulation.
Iftheyhadbeenonfor1590days,stableon8milligramsofbuprenorphine,16thenwhathappenedWhatchanged17Weretheyusingillicitlyatthestreet18duringthattimeofthe3monthsor--butIdon't19understandhowtheycangofromstablyusing208milligrams,andthenstartusingsupplemental21Suboxoneafterthat.
22AMatterofRecord(301)890-4188318DR.
KRAMER:IthinkDr.
McNicholashada1follow-uptoDr.
Pickar's.
2DR.
McNICHOLAS:Yes.
Ijustwantedtosay3Ithinkthattheydefinedtheirstudypopulation.
4I'mnotsureitwasthecorrectpopulation.
That's5whereI'mstrugglingherebecauseIthinkthatthey6mayhaveputittonottakingitoutfarenoughin7termsofstabilityofthepatient.
8DR.
PICKAR:Right.
That'salittlebitof9whatDr.
Kotzissayingaswell,isaquestion10aboutthatstudypopulation.
Now,you'regetting11totheheartofthestudyandwasthestudyvalid12inthewaythatyouwantedittobetotell13us--directusproperly.
14Sonow,you'retalkingaboutthestudy;15that'swhatwe'retalkingabout;yourquestion16whetherthestudygroupwasappropriateandafair17grouptostudyforthispurpose.
18DR.
KRAMER:Dr.
Narendran19DR.
NARENDRAN:Iwouldkindofhavesimilar20concernsthatthestudypopulationasdefined,less21than8milligrams,theywereprobablygettingonce-22AMatterofRecord(301)890-4188319a-monthurinesorwhatever.
Buteasily,youcould1haveusedheroinandgoneundetectedbefore,and2youcouldhaveuseditlaterandgoneundetectedas3well.
4Ithinkifweweretosaythattheydefined5thestudypopulation,ithastobenarroweddown6becausetheseweremostlyprescriptionopioid7users,primarilypeoplewhohavebeendiagnosedfor8onlyfiveyears,notreallysevereaddicts,because9myfearwouldbeweknowthatthisdrugat108milligramsdoesn'toccupyalotofreceptorsas1116.
It'sprobablymediumoccupancy,sothere'sa12lotofrangetocontinuetousedrugs.
13Iwouldsuggestthatmostlikely,itshould14benarrowlydefinedofwhoshouldgoonthis15therapeuticbecauseifyouputalotofserious16heroinaddictsonthis,they'reprobablynotgoing17togetenough,andthenthey'regoingtocontinue18touseandrequiremoreandmoresublingualdosing.
19DR.
KRAMER:Howareyouproposingto20narrowlydefineit21DR.
NARENDRAN:Mostlystrictlytrytofit22AMatterofRecord(301)890-4188320intheboxthattheyproposeorwhatthey1recruited,whichispeoplewhohavebeenextremely,26months.
ButIwouldhavelikedtohaveseensome3hairanalysisorsomethingthatcanconfirmthat4theydidn'treallyusebefore.
Idohavesuspicion5ofwhydidtheyusesomuchsublinguallaterthan6iftheywerestable.
SoIthinktherearesome7issues.
8DR.
KRAMER:Okay.
Dr.
Gordon9DR.
GORDON:I'lljustkeepitbrief.
I10thinkwhateverwedecide,IthinktheFDAneedsto11beveryclearonthisindicationaboutwhatthey12believestabilityis.
Isaythatbecausethere'sa13lotofdefinitionsoutthere,evenamongthisroom.
14Ifit'sleftuptothepractitionerabout15whatisastablepatientornot,we'regoingto16havealotofsupplementalbuprenorphineprobably17ontopoftheProbuphineinpractice,andthatmay18defeatthepurposeofhavingthatmedicationinthe19firstplace.
20Theoneindication,Ithink,that'sreally21importantandit'sthisideaofbeingbelow22AMatterofRecord(301)890-41883218milligramsor8milligramsforalongperiodof1time.
Actually,Ithink3monthsisalittlebit2short.
Iwouldprobablygooutto6monthsoreven3ayear,butweneeddataonthat.
Inclinical4practice,thatpopulationwho'sbeenstableonthe58milligramsforalongperiodoftimeisthe6indicationthatIwoulduseforthismedication.
7DR.
KRAMER:Dr.
Bickel8DR.
BICKEL:I'dliketojustsuggestthat9welookatthisintermsoftherealityoftreating10opioid-dependentindividuals.
Howmanypeopleon11buprenorphine,whentheygetonbuprenorphine,12continuetoaskforadditionalmedicationHow13manyabuseothersubstancesIthinkalarge14proportion.
15AsIlookatthenumberofsupplemental16patientswhouse2ormoretimes,thisisCE-56on17page28,Icount10--orIcount8,I'msorry--818whouseditmorethantwotimes.
That'soutof8419participants.
That's10percent.
20Tellmewhatmedicationwe'vegotthat's21reallyworkingwell,thatexceedsa10-percent22AMatterofRecord(301)890-4188322challengeofsomeofthepatientsnotdoingwell1Isaywehavetothink,balancethisagainstour2epidemicandthechallengesthatwe'rereally3facingintherealworldandthinkaboutwhere4we'regoingtodothemostbenefit.
Iwouldaskus5tocalibrateourcommentsintermsofthereal6worldofopioiddependence.
7DR.
KRAMER:Dr.
Troendle8DR.
TROENDLE:Iwasjustbasicallyagreeing9withDr.
Pickarinthatweonlyhaveonestudy,so10I'mnotreallysureIunderstandtheFDA'squestion11tousbecauseit'sjustcompletelyspeculationas12towhatothergroupswoulddo.
13Thesecondpointisalotofthe14supplementaluse,Isuspect,wouldbelargelythe15factthatyou'veenteredthesepeopleinaclinical16trialandmadeitreallyeasyforthemtoget17supplementaldrug;one-fifthofthem.
Lessthan18one-fifthgotsupplementaldrug.
Isuspectthat's19prettymuch--20Intermsofwhetherthey'reverystableor21not,Idon'tknowexactly,buttheyseemlike22AMatterofRecord(301)890-4188323that'sprettystable.
Itcouldbeprettystable,1butitcouldbetheeffectofjustbeingenrolled2inaclinicaltrialwheretheymadeitveryeasyto3getthedrug.
4DR.
KRAMER:IhaveJennifertimingushere,5soIthinkwe'vegottenagoodsenseonthis6question.
Let'sgoontotheotherquestions.
A7coupleofpeoplehad--I'mgivingpeoplewhohave8atleastnotaddressedthequestionachanceto9speak.
I'mnotgivingpeopletwotimesunlessit's10afollow-upclarificationandtrytoseeifwecan11getthroughthis.
12Thesecondquestion,ingeneral,occasional13doseadjustmentsforpatientsonsublingual14buprenorphinecanbeexpectedovertime.
The15sponsorchosenottoincluderescuemedicationas16anelementoftheresponderdefinitionbecause17therewasanexpectationthatpatientswould18requirelittletonorescuemedication.
However,19thatwasnotthecase,asarescuemedicationswas20usedbyanumberofpatients,somethroughoutthe216-monthtreatmentperiod.
22AMatterofRecord(301)890-4188324Discusswhethertheuseofrescueshouldbe1consideredindefiningaresponderfora2long-actingformulationofbuprenorphinesuchas3Probuphine,wherethedosecannotbeadjustedover4time.
Ifrescueshouldbepartoftheresponder5definition,shouldtheuseofrescuebuprenorphine6bedifferentiatedbasedonthepatternorthe7frequencyofrescueuseovera6-monthperiod.
8Considerthefollowingpatternsofuse,the9firstbeingusedprimarilyafterinitiating10buprenorphine;thesecond,usethroughoutthe116-monthperiod;andthird,useonlyattheendof12the6-monthtreatmentperiod.
13Dr.
Conley14DR.
CONLEY:Thanks.
RobConley.
Acouple15ofthings.
Oneisfirst,fortheoverall16definitionofaresponderversusanon-responder17andthenconflatingitwiththerescuemedication18wasaproblemformebecause,aswasmentionedhere19before,therearealotofthingsthatleadto20non-responseandopioidaddiction.
Certainly,21rescuemedicationisaconcern;there'snodoubt22AMatterofRecord(301)890-4188325aboutthat.
Butthat'snotthesameasfailingand1non-response.
2Irealizethere'sonlysomanythingsyou3candoinastudywhenyou'relookingatit4statisticallyandyou'retryingtoseewhetheror5notyouhaveequivalence.
SoIgetwhyyou're6doingit,butIthinkyoumaybetakingittoofar7toactuallysay,moreorless,anyrescue8medicationisafailure.
9Specificallynow,speakingmoreasa10clinicianthansortofafairbalanceonthe11industryside,I'vebothtreatedopioidaddiction12assoonasuseDepomedications,ofcourse,notfor13this,whichisnotindicated,butinpsychosis.
14Andthere,theuseofrescuemedicationisreal.
15AndIthinkusingrescuemedicationafterfirst16initiationwouldberelativelycommonforlotsof17conditions.
18IwouldbegintobeconcernedifIcontinue19tohavetouseitallthetime.
Irealizethat20reallywasn'tpartofthestudy,soit'shardto21addressitfromthecontextoftheoverallstudy.
22AMatterofRecord(301)890-4188326Yousaid,Dave,thestudyisasitis.
It's1hardtochangeitallaround.
Butrightnow,just2incountingupthenumberofcases,theydidn't3seemlargetome.
Itwouldseemtomethat,again,4thinkingaboutwhatyoumightdoinpostmarketing5surveillanceistounderstandwhetherornotpeople6comeoff,ormaybeitislabeling.
Ithinkthisis7alabelingissueofhowmuchrescueshouldbe8allowedbeforetheclinicianconsidersit.
Butto9me,itfeltasifitmightbeaquestionthatcould10beansweredinthatway.
11DR.
KRAMER:Dr.
Grieger12DR.
GRIEGER:Idealwiththechronically13mentallyillpopulationonaday-to-daybasis,and14Ihavealotofpatientsondecanoateinjections15becausethey'renoncompliantwhenthey're16dischargedfromthehospital.
Someofthose17patients,Ialsodischargeonoral.
18Now,thestateguidelinesareyoushouldn't19havesomebodyonoralanddecanoateatthesame20time.
Therationaleisthateveniftheygooff21theoral,theirtimetodecompensationwillbemuch22AMatterofRecord(301)890-4188327sloweriftheyareonthedecanoateaswell,and1that'stherationalefordoingitwhenIdictate2thedischargenarrative.
3Idon'tevenliketheterm"rescue4medication.
"Icallit"augmentationmedication"5becausethat'swhatitis.
You'vegotsomeon6boardthat'slonglasting,andit'snotquite7enoughatvariouspointsandtreatment,andyou8augmenttreatmenteitherwiththesameagentor9anotheragent.
10DR.
KRAMER:Dr.
Troendle11DR.
TROENDLE:Myanswerisno.
Idon't12likeincorporatingthesupplementalmedicationinto13theoutcome,butIdothinkit'sagoodargument14forwhyyoushouldconsidersmallerNImargins.
I15feltweweregoingtobeaskedaboutthat,butI16seeit'snotoneofourdiscussionquestionsabout17thesizeoftheNImargin.
18ButIthinkitdoesraiseof--ifthere'sa19reallotofuseofthemedication,itwouldmake20onewanttoseeasmallerNImarginbecauseitdoes21tendtobringthegroupstogetherandmakeit22AMatterofRecord(301)890-4188328easiertoshowNI.
1DR.
KRAMER:AnysuggestionontheNI2margins3DR.
TROENDLE:It'sveryarbitrary.
Ithink420percentisextremelylarge,though.
You5wouldn'tconsideraproportionof0.
8equaltoa6proportionof0.
6.
It'sahugedifference.
It's7anabsolutedifferenceof20percent,rightIt's8notarelativedifference,Ibelieve.
Ithinkit's9verybig,butIthink,regardless,mostofthe10analysesshowit'squiteabit.
It'snotvery11closeto20percent.
It'sactuallyquiteabit12betterthanthat,itlookslike.
13DR.
KRAMER:Okay.
Dr.
McNicholas14DR.
McNICHOLAS:ThisisnotwhatIwoulddo15inclinicalpractice,butlookingatthestudy16itself,Idothinkthattheuseofrescueor17augmentation--Ilikeyourtermbetter--should18beconsideredincaseB,throughoutthestudy.
19Ithinkifittakes2to3weeksforthe20bloodlevelstocomeupandpatientsneedsomething21initially,youdon'tcountthatasanon-response.
22AMatterofRecord(301)890-4188329Butsomebodywhoneedsitfortheentire6months1they'reon,that'saproblemforme.
SoIthink2thatisanon-responder.
3DR.
KRAMER:Okay.
Thankyou.
Dr.
Kotz4DR.
KOTZ:Thisisjustalittlebitofa5differentaspectonit,andIlikethewaythatyou6calleditaugmentation.
Butthedifferenceforme7betweenotherinjectableantipsychoticdrugsor8medsisthey'renotcontrolledsubstances,and9they'renothavingproblemswithdiversion.
10Soformethatmakesitverydifferent,and11it'slikecomparingittoinsulinandblood12pressuremedication;again,they'renotdiverted.
13Andoneofthereasonsthisstudyisbeingdone14becauseitwillhopefullydecreasediversion15becauseit'simplanted.
16Soifsomebody,asLorisaid,is17using--again,Idon'tknowwhattheaveragewas,18I'dhavetogobackandlookatagraph--somany19additionalSuboxonepillsorfilmduringtheentire206-monthperiod,myquestionis,intheclinical21realworld,okay,ifwegivesomebodyextra22AMatterofRecord(301)890-4188330buprenorphineorfilm,weaskthemtobringinthe1wrapperssothatwecanseewhetherornotthey2usedthemorwhetherornottheydivertedthem,or3gavethemaway,orlentthemtotheirbuddy.
4Idon'tknow--again,withpillsalotof5cliniciansintherealworlddopillcounts.
They6wanttoknowiftheyprescribedextrabuprenorphine7inordertoadjustthedosethattheirpatient8actuallytookitandnotsomebodyelse.
9SoIthinkinthestudytherewassomething10likeoverathousandextrasupplementaldoses11given.
Idon'tknowhowmanymilligramsthatturns12outto.
Andeventhoughitwasarelativefraction13ofthetotalnumberofbuprenorphinethatwasgiven14withouttheimplant,forme,ifoneofthepurposes15ofthestudyistofigureouthowtodecrease16diversion,thenthatwouldbeaconsiderationof17mine.
18DR.
KRAMER:Dr.
Campopiano19DR.
CAMPOPIANO:You'regettingreallygood20atpronouncingmyname.
I'mgenerallyinfavorof21howanon-responderwasdefinedbytheFDA22AMatterofRecord(301)890-4188331analysis.
I'mconcernedaboutincludinganyuseof1supplementalbuprenorphineasanon-responder2becauseIthinkit'sreasonabletoexpectinthat3firstmonth,whenbloodlevelsarestabilizing,4thatpeoplemayneedthat.
5Idon'twanttocreateanexpectationfor6Dr.
Joeoutthereintheworldsomewherethatany7supplementaluseisabadthing.
ButIalsowant8tobecautiousbecausethestudyisnotdesignedto9demonstratewhetherthisreducesdiversion,yet10thatclaimisbeingmadebyavarietyof11stakeholders.
12Sowehavetobesensitivetothat.
And13nobody'stryingtosaythatwe'rehopingthatthis14increasesaccessandreduces,ordoesnotaugment15diversion,butwedon'thaveanyevidencetobase16thaton.
SoIjustwouldliketoseeacautious17pathbetweensayinganysupplementaluseequals18non-responder--allowingsomeclinicaljudgment19andencouragingthecliniciantohaveacautious20andsupportiveattitudeintransitioningthat21personfromstablesublingualortransmucosaluse22AMatterofRecord(301)890-4188332tostableimplantuse.
1Wedon'twanttocauserelapse.
Wedon't2wanttocausepeopletothinkthatIcan'tgive3thispersonanybuprenorphineorthey'rea4non-responder.
5DR.
KRAMER:Soyou'retouchingontwo6thingsthere.
Andonthesecond,acommunication7ofwhatthedatawehavereallyshow,werethisto8beapprovedonthemarket,isgoingtobesomething9Ihopewe'lldiscussthroughouttheremaining10discussionquestions.
11Onthefirstpartwhereyouwerecommenting12onnotwishingtohaveanyusebeanon-responder,13IpersonallyreadtheanalysistheFDAdidassort14ofawhat-ifscenario,wheretheyweretryingto15saytheworstcasewouldbetoconsiderit,and16woulditstillbenon-inferior.
17SoIpersonallydidn'ttakeitliterally,so18maybetheFDAcouldcorrectusifI'vetakenit19wrongandyouwerebeing--butthat'sjustoneway20tolookatit.
Anycomment21DR.
WINCHELL:Someoftheanalyseswedid,22AMatterofRecord(301)890-4188333yes,wereexactlyasyousay,awhat-ifanalysisto1considertheworstcasescenario.
Thefinal2analysisthatDr.
Skeeteexplained,inwhichwesaw3thatpatientswhoneededsupplementaldosingmore4thantwiceiftheywereintheProbuphinearm,were5notbeingadequatelytreatedwithProbuphine.
That6wastheanalysisthatwethoughtwasthemost7persuasive,orthemostappropriate,capturedthe8storythebest.
9DR.
KRAMER:Sothequestionyouposedtous10ofwhetherit'sdose,2timesusingit,versus11pattern,itlookslikeyouchosedose,butIheard12aroundthetablemanypeoplesayingpatternmakes13moresenseearlyonafterinitiation.
14DR.
WINCHELL:Right,itwastwooccasions.
15DR.
KRAMER:Yes,butwedidnotspecify--16DR.
WINCHELL:--butwedidnot17differentiatewhethertheywereinthebeginningor18theend.
Theycouldhavebeeninthemiddle,and19that'sanotheranalysiswecoulddo.
20DR.
KRAMER:SoIjustwantto--21DR.
WINCHELL:We'dbehappytothatone.
22AMatterofRecord(301)890-4188334DR.
KRAMER:--reflectingthecommittee's1comments,thepeoplewhohavecommented,Ithink2I'veheardmorepeoplesaytheywereconcerned3aboutthroughoutthetreatmentperiod,andthey4mightexpectsomeuseshortlyafterinitiation.
5DR.
WINCHELL:Right.
Great.
We'vegot6that.
We'lldothatonenext.
7DR.
KRAMER:Allright.
Anyoneelse8(Noresponse.
)9DR.
KRAMER:Okay.
Nextquestion.
10I'mbeingtoldthatthespeakersshould11remembertospeakdirectlyintothemicsowecan12recorditcorrectly.
13Number3,customarilyinopioidaddiction14treatmenttrials,therearemanymissingurine15samplesduetorelapseanddropoutfromtreatment.
16Becauserelapseisthemostcommonreasonfor17dropout,missingurinesamplesareassumedtobe18positive.
19However,inthisstudy,thepatientswere20stablyabstinentfromillicitdrugs,andtheywere21askedtoprovideonly10samplesover6months.
22AMatterofRecord(301)890-4188335Therefore,itwasexpectedthattherewouldbefew1missingsamples,andthatthesecouldbemissing2forreasonsotherthanrelapse.
Therefore,the3strategyforimputationofmissingdatadidnot4assumethatallmissingsampleswerepositive.
5However,somesituationsaroseinwhichitmightbe6appropriatetoassumethatmissedsamplesare7indicatorsofillicituse.
8Discusshowmissingorincompleteurine9toxicologyresultsshouldbeconsideredwhen10definingaresponder.
Considerthefollowing:11patientswhowerecompletelylosttofollow-up12immediatelyafterreceivingtheProbuphineimplant;13samplesthatwerenotcollecteddueto1)amissed14scheduledvisit,2)amissedrandomsamplevisit,15and3)refusedbythepatient.
AndC)samplesthat16werecollectedonschedulebutwerenotanalyzedin17atimelyfashion,outofthestabilitywindowfor18thetest.
Dr.
Troendle19DR.
TROENDLE:Sothisisonethat'shardto20differentiatebetweentheactualoutcomeor21question4.
They'rerelated.
Onethingisthat22AMatterofRecord(301)890-4188336youcanstartoutbymakinganarbitraryassumption1aboutrespondersbeing2times2monthsormore2havingsomekindofevidenceofopioiduse.
3Ithinkanotherwaytodoitwouldbeto4takeyouractualoutcomethatyoureallyhave,5whichisopioiduseateachindividualtimepoint,6andthatmakesthingsprobablyeasiertoworkwith,7whichavoidskindofanarbitrarydefinitionto8beginwith.
9Youstillhavemissingdata,ofcourse,10issueswiththatoutcome,butIthinkitwouldbe11easierwiththatoutcomealso.
Itsimplifiesthe12modeling,whichapparentlywasnotdone,tofind13outwhatpredictsmissingnessanduseimputation14modelstodothis.
15Itcouldeitherbeyouwouldhavearepeated16measuresregression,couldeitherimplicitlydo17this,oryoucouldhavealsostilluseimputation18modelsseparatelytoimputeformissingvalues.
It19wouldn'taddresstheseissueshereonthisquestion20ofpartB,thedifferenttypesofmissing.
21IthinktheFDAactuallydidaprettygood22AMatterofRecord(301)890-4188337job.
Thatbeingsaid,I'mwonderingwhymorewas1notdoneaboutdevelopingmissingdatamodelsfor2thisdata.
Butgiventhewaytheanalysiswas3defined,theFDAdidaprettythoroughjobof4investigating,Ithink,thedifferentworstcase5scenariosprettymuch,soit'sprettywell--6Theimputationmodelswouldn'taddressthe7differenttypesofmissingness.
Theywouldn'tbe8abletotakethatintoaccountanyway.
Sothatis9one--andthewaytheFDAdiditwasbasicallyto10enforcedifferentrulesbasedonthetypeof11missingness,Ithink.
12Sothereissomethingtodoingitbothways13Isuppose,eventhewaytheFDAdid,butIwould14alsoliketoseeimputationmodelsbecausethey're15alotmoreinformativeingeneralandwouldreduce16theimpactonmissingness.
17DR.
KRAMER:Thankyou.
Dr.
KotzNo18Dr.
Bickel19DR.
BICKEL:Sothere'sanotherwayin20addictionsciencethatpeoplehaveanalyzedurine21samples,whichisdocumentedabstinence.
And22AMatterofRecord(301)890-4188338that'sthenumberofurinesamplesthatdon't1containthesubstancethatyouhaveinyourhand,2andthatwayyou'renotmakinganyinferencesabout3whatthemissingdataare.
Ithinkthat'sbeen4usedinothertrialsandiscertainlyan5appropriateonetoconsiderhere.
6DR.
KRAMER:Dr.
Dodd7DR.
HERTZ:I'msorry.
ThisisSharon8Hertz,overhere,FDA.
I'mnotsureIcompletely9caughtyourpoint,Dr.
Bickel.
10DR.
BICKEL:Soamongtheurinesamplesthat11wereactuallycollected,whatisthedocumented12abstinenceamongthosesamples13DR.
DODD:SoIwanttocommentonpointA14becauseIfeelit'sveryproblematictothrowout15those3patientswhowereimmediatelylostafter16theywererandomizedtogettheProbuphine.
We17justwouldn'tdothat.
18We'dcallitamodifiedintent-to-treat19analysis,butImeantherewasareasonweused20intent-to-treatanalysisastheprimaryanalysis.
21AndIfeelquitestronglythatwedon'tknowwhat22AMatterofRecord(301)890-4188339happenedtothosepatients,anditcouldhavevery1well--itcouldhavebeenthatjustgettingthe2Probuphinesentthemoff,andthat'swhytheywere3losttofollow-up.
SoIfeelquitestronglythat4the87denominatoristhecorrectdenominatorin5that.
6Theotherthing,inreferencetothe7questionaboutanalyzingwhatyouhaveinhand,the8problemisgettingitinhandisinitself9informative.
Sowhenwehavemissingsamples,10that'sgoingtobemorelikelycorrelatedwitha11positivesample.
12Idon'tknowhowtoreallyhandlethat.
I13agreethatsomeimputationapproacheswouldbe14usefultosee.
Ididfindtheotheranalysisthat15youdid,andIthinkthatoneoftheproblemsyou16havetostrugglewithnowis--Imean,it's17clearlynotsuperiorbasedonmyinterpretationof18thedata,butwheredoyoudrawthatlineIthink19somepeoplecouldevenmakeanargumentthatit's20notnon-inferioraswell.
21Sothere'sabiggrayzonehere,whichis22AMatterofRecord(301)890-4188340obviouslywhywe'rehere.
ButIwouldliketosee1moreanalysisofthemissingdataandwhatare2predictorsofmissingness,andifthere'sany3patternstherethatwouldfurtherinformusabout4howtohandlethedataandhowyouwillwritethe5label.
6DR.
KRAMER:Dr.
Pickar7DR.
PICKAR:Thisdoesoverlaptonumber4,8whichwe'llgettoinasecond.
ButpersonallyI9agreewiththewayyoutooktheconservative10approachandthewayyoure-analyzedthedata.
I11thoughtitgottotheheartthatthedrugwasnot12inferior,andtocallitsuperiorjustwouldn't13fly.
Therewasjusttoomuchmissingstuffwithout14consideringitasyoudid.
15SoIthoughtyoudidtherightthingonthat16score.
NotthatIwouldeverdoubttheFDA,butin17thiscaseIthoughtyoudidtherightthing.
AndI18thoughtittoldthestorythatwe'reheretolook19at,whetherthiswasanon-inferiorstudy,a20noninferioritystudy.
21DR.
KRAMER:We'llgoontoquestion4.
The22AMatterofRecord(301)890-4188341protocolspecifiedresponderdefinitiondidnot1takerescueuseintoaccountandemployedan2optimisticimputationstrategyformissingurine3toxicologyresults,yieldingaresponderrateof496percentversus88percentforProbuphineand5sublingualbuprenorphine,respectively.
6Asyouhaveseen,therearemanydifferent7possibleresponderratesoncethesefactorsare8takenintoaccount.
Discusswhichofthevarious9approachestoexpressingaresponderrateyouthink10ismostappropriate.
11Sowe'veheardfromDr.
Dodd.
NoYes,12Dr.
Dodd,thatshedoesnotthinkthatweshould13throwoutthe3patientswhogotthedrugand14disappeared.
Sogoingfromthere,otherpeople15wanttocomment16DR.
PICKAR:WhentheFDAdidtheanalysis,17youdidn'tthrowoutthosefolks.
18DR.
KRAMER:No.
19DR.
PICKAR:Youconsideredthem20non-responders.
IsthatcorrectYes.
21DR.
KRAMER:Dr.
Troendle22AMatterofRecord(301)890-4188342DR.
TROENDLE:Well,it'ssimilartowhatI1saidabout3isverysimilar.
Thisisrelated.
So2Ithinkreallyhavingadefinitionofresponse3that'sateachdifferentmonth--whichisreally4whatyouhaveanyway.
It'snotcomingupwith5anythingnew.
Butusingthatinanactualmodel6wouldbepreferablewithusingimputation.
7Allofthosemissingness,likeLorisays,8certainlythosewouldbeinthisanalysisaswell.
9Theywouldbeallmissing,butyouwouldbe10imputingforthosevaluesifyouhadanimputation,11iftheydevelopedanimputationmodel.
12TheotherthingIdidn'tmentionbefore,13whichthiswouldsimplifyorcouldgetmore14information,isinthecaseswheretheyhadsome15labsavailableandsomenot.
SoIthinkthatwas16oneoftheissuestheFDAlookedatdifferentways17ofdealingwiththat.
Butanimputationmodel18actuallycouldtakethatintoaccountinthecases19whereyoudidhavesomelabsavailable,butyou20weren'tabletodeterminetoxicityonthebasisof21whatwasavailable.
22AMatterofRecord(301)890-4188343Sothatcouldstillinformyouinthese1modelstodetermineabetterprobabilityfor2whetheryouwerepositiveatthatmonth.
3DR.
DODD:DoestheFDAstatisticalgroup4wanttocommentforthecommitteetowhat5Dr.
Troendle'sproposing,orjusttakethatinto6consideration7MR.
PETULLO:We'lltakeyouradviceand8yourcomment,andwe'llexplorethedatafurtherin9ourreview.
10DR.
HERTZ:Hi,thisisSharonHertz.
I'm11seeingapaucityofverticalcards,andIwould12liketojust--anyadditionalcommentsthat13haven'tbeencapturedbyindividualcommentsfor14theearlierquestionsintermsofansweringthis15specificone,whichisreallyjustourattemptat16puttingitalltogetherintermsofifyouhaveany17additionalthoughtsonhowtodefinearesponder.
18It'susefulnow,butbecausethiswasa19noveldesign,andbecausewemayseemore--the20sponsormentionedtheyhaveaproductunder21developmentaswellthat'saDepo,sothismaycome22AMatterofRecord(301)890-4188344upmoreandmore.
Soifyouhaveanyother1commentsonhowyouwouldrecommenddefining2prospectivelytheresponder,wewouldliketohear3that.
4DR.
KRAMER:SoI'llactuallytakeastabat5this.
I'mnotastatistician.
I'mnotgoingto6attempttosaywhattheanalysisshouldbe.
What7I'vebeenstrugglingwithhereasI'vereadallthe8materialsandlistenedtotheopenpublichearing9isthatwehavethisterribleprobleminour10societyofaddiction,andallofuswanta11solution.
12Yet,Ithinkthatwedoneedtohaveclarity13andrigorinthestudiesthatwedo.
AndIwas14verydisturbedaboutcallingsomething15intenttotreatthatwasnotintenttotreat,and16representing--Ifeltthatinsubmittingan17applicationtotheFDA,whichclearlyisthe18organizationthat'sgoingtobemostskeptical19abouttheanalysis,thesponsorwasoverly20optimisticabouttheresultsintermsofclaiming21themostrosypictureintermsofresponserateand22AMatterofRecord(301)890-4188345superiority.
1SoIjustwanttosaythatIthinkthat,2mostly--becauseasyoulookforward,wehaveto3distinguishbetweenthepromiseofasubcutaneous4therapythatcouldreducediversionandreduce5pediatricoverdoseversuswhatweactuallyhave6hereintermsofdata.
Andwehavesomething7that--there'safairamountofadditionaluse,8andsomeofthewholepurposeofthisisn'treally9clearinthelongterm.
10Youknow,whatarewetryingtodoArewe11talkingabouttwoyearsifothersites--if12implantationattheoriginalsitecan'tbe13repeatedArewetalkingaboutashorterterm14thingthatafterbeingonProbuphineforacouple15ofyearsyou'regoingtohavetogobackon16sublingualIdon'tthinkastrategywasput17forward,anditwasn'tcleartomewhenIstarted18readingthiswhattheoverallstrategywas.
19SoIwouldjustencouragesomerigorsothat20wehaveaprecedentuponwhichwe'recomfortable21withthedecisionswemake,andthatwehave22AMatterofRecord(301)890-4188346somethingtofollowonwhenothercompaniesand1otherproductscomealongforconsideration.
I2knowthat'skindofgeneral,butspecificallythis3wholeissueaboutthrowingoutthe3patientsI4feltverystronglyabout.
5DR.
WINCHELL:Well,tofollowonthat,6thesearen'treallynecessarilystatistical7questions.
Someofthesearequestionswereally8lovetheinputoftheaddictionmedicineclinicians9heretotelluswhatassumptionsyouthinkwouldbe10clinicallyappropriatetomakeaboutapatient,for11example,whoreceivesanimplantofastudydrug12andisneverheardfromagain,thisbeingapatient13who'salreadybeenintreatmentforatleast146months,wellknowntosomebodywhoreferredhim15anddisappears,orwhethersomeonebeing16incarcerated.
17Inouranalysis,wethought,well,these18aren'tgoodoutcomes,andwedescribedthose19patientsasnon-responders.
We'dliketoknowfrom20yourclinicaljudgmentifyouthinkthatwasthe21rightwaytogo.
Andsimilarly,wethoughtifa22AMatterofRecord(301)890-4188347patientwasn'tabletocometotheclinictogivea1requestedrandomsamplethatthatkindofboded2ill,orevenascheduledvisit.
Wediscussedthat3internally,whetherscheduledvisitsandrandom4visitswouldbedifferent.
5Ontheotherhand,iftheywereableand6willingtogiveasample,thatcouldnotbe7completelyanalyzedduetosamplehandlingissues8atthesiteorsomethinghappenedinthelab,would9itbefairtosaythatthatcouldbeconstruedasa10negativesample.
11Sothesearetheassumptionsthatwemadein12ourdoingouranalysesthatwerebasedonour13hunchesand--sorry,wehavesevenaddiction14medicinespecialistshere.
Wewouldreallyloveto15hearifwewenttherightdirectionwiththose16assumptions.
17DR.
KRAMER:Dr.
Grieger18DR.
GRIEGER:Icompletelyagreewiththe19intent-to-treatapproach,thatifyoustarted20somebodyinaprotocol,theygetcountedinthe21protocol.
Ihavenoproblemwiththat.
22AMatterofRecord(301)890-4188348I'dgobacktotheuseofrescuemedication,1supplementaldoses,whatever.
Imeanit'sa2noninferioritystudy,right,soyou'reputtinghalf3thepeopleinessentiallystandardcare,andyou're4puttingtheotherhalfinanothertypeofcare.
5Whywouldyousayit'sokaytogiveadditionaloral6tothepeoplethatareintheoralcategorybutnot7inthepeoplethatareintheothercategory,if8whatyou'relookingatishowthetwodotogether9Itdoesn'tseemlogicaltomethatyouwould10allowitonearmbutnotintheother.
I'venever11seenthat.
Iunderstandthetheorythatyou12shouldn'tneedanythingbecauseyou'vegotalong-13actingDepo,butinthenoninferioritything,both14sidesaregettingadditionaldoses,sowhytreat15themdifferentlystatistically.
16DR.
KRAMER:Dr.
Ionescu17DR.
IONESCU:Ithinkasfarastoanswer18yourquestionfromtheFDAaboutfromaclinical19perspectivehowdoweliketothinkaboutthis,I20definitelythink,yes,ofcoursewehavetoinclude21those3patientswithoutadoubtinanew22AMatterofRecord(301)890-4188349medicationthat'snot--sorry,anewindication1foramedication,certainlyanewdosingroute.
2JustonethingI'vebeenkindofthinking3aboutaswe'retalkingaboutthesepatients,4especiallythethreethatwerejustlostto5follow-up,Ispendabout90percentofmytime6seeingpatientsinclinicalresearch,andonething7thatwe'vedoneforstudiesthathashelpediswe8havetheseexternalratersthattalktothestudy9patientsbeforeweenrollthemintothestudy.
And10theydoSCIDquestions,doublechecktomakesure11theymeetcriteriafordepression.
12Maybemovingforward--andIknowofcourse13wecan'tgobackintimetodothis.
Butmaybe14movingforward,havingpatientsalsointerviewedby15anexternalraterthattheynevermeet,wecan16mayberuleoutsomepatientsthatmightbelostto17follow-up.
Ithinkcertainlyinthistypeofstudy18wehavetoassumethemostrigorouscase,andwe19havetosaythatthemedicationdidn'tworkorthat20theywerenon-respondersorsomethinglikethat.
21ButIknowasaclinicalresearcherthat's22AMatterofRecord(301)890-4188350notalwaysthecase.
Sometimespeoplearelostto1follow-upnotbecauseofthatreason.
Andbyusing2theseexternalraters,wecaneliminatesomeof3thatsothequalityofthestudyisbetter.
Iknow4thesethingsarerelativelynew,butIdon'twant5toseemedicationthatcouldpotentiallyworknot6beapprovedbecauseofmaybepatientselection.
7DR.
KRAMER:Dr.
Conley8DR.
CONLEY:Yes,thanksagain.
RobConley.
9Toaddresswhatyouweresayingbefore,Dr.
Hertz,10aboutotherstudiesthatyou'retalkingaboutas11opposedtothisone,forthisone,Icertainlyalso12thinkthattheITTdesignmakessense,andthat's13whatyoushoulddo.
Butagain,goingbacktoother14Depomedications,wecertainlyhavedefinedinthe15fieldnon-respondercriteriainadvance.
16Tome,Ithinkyou'reright.
Therearesome17thingsherethatyouworryabout,likethemissed18urinesamples.
Inmanysituations,inmanyliving19situations,thatwouldgetsomeonekickedoutof20theirhousingorsomeotherproblem.
Itcould21actuallyleadtorealsequelabesidestheobvious22AMatterofRecord(301)890-4188351sequelaofabusing.
1Ithinkthatmakessomesense,butIdo2thinkyouhavetobeverycarefulwiththatbecause3therearesometimeswhenlabslosesamplesordo4testswrong.
Sothat'sonewhereIdothink5that--whatIwassurprisedhere,andagainIcame6intothiskindoflatereadingit,isthatthere7wasn'talotofpre-specificationaboutstufflike8that.
9Iunderstandtherewasanassumptionthat10thiswasn'tgoingtohappenverymuch.
Igetthat.
11Butitseemstomelikeifthere'salearningfor12thenexttime,itreallyiskindoflikein13advance,whatdowereallythinkresponseisgoing14tobe.
BecauseonelastthingI'llsayisIfeel15likesomethinginthisstudythatsurprisedme,and16Idon'tknowifitsurprisedyouallornot,was17thatthecompletionratewasreally,reallyhigh,18butforbothgroups.
19Sotherewassomethingaboutthecare20situationthatwasleadingtoahighcompletion21rate.
That'sagoodthing,butatthesametime22AMatterofRecord(301)890-4188352thenitraisesalltheotherquestionsofhowelse1dowedefinestuff.
Becausetheonlythingyou2couldhaveeasily--whatIwouldhaveexpectedin3astudylikethisisyouwerehearingthere'sso4muchchurninbuprenorphineuseintheregular5clinicisthatthepeopleonoralbuprenorphine6weren'tgoingtomakeittotheendofthis,and7theydid.
8Sothatwastheotherkindofunusual,I9don'tknowifyouwanttocallitagoodthing,but10somethinginterestingaboutthisstudylikethe11highcompletionrate.
AndI'dliketogivean12agentcreditforthatifitdeservesthecredit13becausetoadegreewhateverthecaresituationwas14hereinthisstudy,itmusthavebeenprettygood15togetthathighcompletionrate.
Andthentobe16abletokindoffigureoutwhatitmeansunderneath17that,Ithinktheurinesareimportant.
18DR.
KRAMER:Dr.
Campopiano19DR.
CAMPOPIANO:Ihadmynamesignsitting20up,andthenIthought,ohI'mgoingtobe21repeatingmyself,soIputitbackdown.
SoI'll22AMatterofRecord(301)890-4188353keepmymouthshutforawhilelonger.
1DR.
KRAMER:Okay.
2DR.
CAMPOPIANO:Thankyou.
3DR.
KRAMER:Dr.
Narendran4DR.
NARENDRAN:No.
5DR.
KRAMER:Samething.
Dr.
Carroll6Dr.
Carrollonthephone.
7DR.
CARROLL:Canyouhearmenow8DR.
KRAMER:Yes.
9DR.
CARROLL:Oh,good.
Yes.
Idothink10thecriteriaforaresponderwasfartoolooseand11hadsomeconcernsaboutitbeingacceptedhere12becauseit's[inaudible].
13DR.
KRAMER:Dr.
Carroll,we'renothearing14you.
15DR.
CARROLL:Itseemslike[inaudible].
16DR.
KRAMER:We'renothearingyou.
17DR.
CARROLL:Okay.
Yes,I'lljusttryto18doitbyemail.
19DR.
KRAMER:Okay,andthenwe'llreadit.
20Thankyou.
21Dr.
McNicholas,whilewe'rewaiting.
Okay.
22AMatterofRecord(301)890-4188354DR.
McNICHOLAS:Firstofall,I'mnotgoing1tobeatadeadhorseintenttotreatis2intenttotreat.
Youdon'tgettosaywe'renot3goingtocountitbecausewedon'tlikeit.
4Ithinkthoughwhenyou'redefining5responder,youdohavetolookatanumberof6things.
Iwouldnotnecessarilythinkthatinitial7supplementationwithbuprenorphineisaproblem.
8Ikindofdisagreealittlebit,9Dr.
Grieger,onthedifferencebetweenthetwoarms10becauseifIhaveapatientthatI'mtreatingand11theycomeinandtheysayXYZisn'tgoingwell,I'm12feelinginthisway,I'mgoingtochangetheir13dose,whicheffectivelyiswhathappenedwithsome14ofthesepatientsinthesublingualarm,is15effectivelytheychangedtheirdose,theyincreased16theirdose.
Idoitallthetime.
Mypatientsgo17upanddowndependingonwhat'sgoingon.
That's18calledtreatment.
19Butifyou'redoingastudy,youhavelimits20overwhichyoucan'tgo.
Andit'snotfair21sometimestothepatients,andsometimesItell22AMatterofRecord(301)890-4188355patientstowithdrawfromthestudybecauseIneed1totreatthemappropriately.
Andmaybethatshould2havehappenedwithsomeofthesepatients,thatyou3don'tjustkeepsupplementingandsaythatthey're4aresponderwheninfacttheyshouldhavebeen5withdrawnasanon-responderandtreated6appropriately.
Andthere'swhereIthinksomeof7thequestionaboutwhatisaresponderversusa8non-responderdoesneedtobelookedat.
9Intermsoftheurines,frankly,Ican'tsee10whyascheduledurinewouldbemissed.
Any11addictedpersonworthhisorhersaltcanfigure12outtonotusefor3days.
Arandomtestbeing13missedwouldbeaflagforme.
Arefusaltogive14wouldbeamajorflagforme.
Ifmypeopledidn't15senditoutduringtheappropriatetimeframe,16that'snotonpatients,soIdon'tthinkthat17shouldbechargedagainstthepatientatall.
But18Idon'tthinkthatarandomsampleorarefusal19shouldbetolerated.
Thatdoesn'tevenrequire20imputationonmypart.
That'sanassumedpositive.
21ButIdothinkthatthewholequestionof22AMatterofRecord(301)890-4188356responderversusnon-respondermaybeneedstobe1lookedatandthedatareanalyzed,seeifwecan2getabetterpictureofwhat'sactuallygoingon3here.
4DR.
KRAMER:Dr.
Gordon5DR.
GORDON:Soputtingonmyhealthservice6researchhat,IthinkIwasprettyimpressedhow7theFDAwentthroughandlookedatthedifferent8responsenon-responders,andIjustwanttogive9kudos.
Ithinktheydidagoodjob.
10I'mveryconcernedaboutthestabilityof11thesepatientswhoweresupposedlyverystable,and12allofsuddenthedosesaregoingeverywhereor13supplementalthingsaregoing,and3peopledropped14outprettyquicklyafterrandomization,which15doesn'tindicatestability.
16Soasaclinician,I'malittlebitworried17aboutthat,butIjustwanttogivekudostothe18FDA.
Ithinktheydidagoodjob.
Fora19noninferioritytrial,modelthatweuse,andusing20aconservativeestimatetheFDAdid,stillshowed21noninferiority,whichistheintent.
22AMatterofRecord(301)890-4188357Now,wecouldtalkaboutthelimits,andI1totallyagreewiththecommentearlierthata220percentnoninferioritystudyiskindofodd.
So3ifyouwanttobereallycritical,Iwould4potentiallyconsiderreducingthat20percentdown5to10percentor5percent.
Thanks.
6DR.
KRAMER:Dr.
Brady7DR.
BRADY:Yes.
IjustwanttoechothatI8thoughttheanalysisdonebytheFDAwasreally9thorough.
Andgenerally,whenwelookatdatalike10this,asDr.
McNicholassaid,wetakeavery11conservativeapproach.
Andamissedscheduled12visit,missedrandomsample,orarefuseby13patient,itwouldallbeconsideredpositive.
And14aswasjustpointedout,evendoingtheanalysisin15thatmostconservativeway,thattherewasstill16noninferiority,soIthinkthatsaysalot.
17Mymainquestionintermsofresponder18definitionforherereallydoeshavetodowiththe19supplementaldosage.
Ifoneofthelarge--oneof20thebiggerrationalesisthatthisisgoingto21preventhavingmedicationsaroundfordiversion,22AMatterofRecord(301)890-4188358andit'sclearthatfor--itwasn'tawholelotof1them,butitwasforthat8or10,this2dose--wellmaybenoteven8or10,butthefew3thatrequireddosingalmosteveryday,thisdose4wasnotsufficient,sotheywerenon-responders.
5SoIthinkthatIwouldhopethatina6futurestudy,andmaybeeveninlookingbackat7thisdata,Ithinksomethresholdaround8supplementaldosingshouldbeconsideredinthe9definitionofaresponder,thattherewouldbesome10thresholdbeyondwhichyoucan'tgoandstillbe11calledaresponder.
Ithinkoneortwodoses12shouldbefine.
13DR.
KRAMER:Dr.
Preston14DR.
PRESTON:Yes.
Iwantedtothinkabout15thisasadouble-blindstudy,andpresumablyitwas16trulyblind.
Ithinkwearemakinganassumption17aboutstablepatientsandthattheydidnotmiss18urinecollectionspriortobeinginthestudy.
I19don'tknowhowgoodthatassumptionis,oreven20thattheytrulydidnotgetanyextrabuprenorphine21priortojoiningthestudy.
Andasapersonwho's22AMatterofRecord(301)890-4188359donethesekindsofstudyformorethan20years,1itdoesn'tsurprisemethatafewparticipantsdrop2ourimmediatelyafterenrollment.
3Itdoesn'tsurprisemethatpeopledon't4comeinwhenthey'resupposedto.
AndIassume5whenmydentistcallsmethedaybefore,that6everybodymissesthesekindsofvisits,notjust7ourpatients.
SoIwasreallyconvincedbythe8thoroughandvariouswaysthattheFDAreanalyzed9thingsandtrieddifferentresponderevaluations.
10SoIfoundthatveryconvincing.
11DR.
KRAMER:Thankyou.
Dr.
Dodd12DR.
DODD:Yeah,Ijustwanttocomebackto13thiscommentaboutthenoninferioritymarginand14thefactthatweseemtobesatisfiedthatallthe15analysispointtononinferiority.
Becauseinmy16view,alotofthenoninferiority,thesensitivity17analyses,actuallymakethetwogroupslookmore18similarthanmoredifferent.
19Sowe'remakingassumptionsthat--Imean20ifeverybodyhadmissingdataandweimputedall21thevaluesasfailuresorasresponders,they'dbe22AMatterofRecord(301)890-4188360identical,andwe'dhitthenoninferiority1boundary.
Sowehavetokeepthatinmind.
2Thisisaverydifferentbeast.
3Noninferioritytrialsarenotsuperioritytrials.
4SoIalwaysgetconfused.
Wehavetoask5ourselves,whatisthenullhypothesishereThe6nullhypothesishereisthatthisisaninferior7drug,right,andthatmeanswe'reinadifferent8realm.
It'sverydifferenttothinkaboutthese9trials.
10SoIthinkaswegothroughthis,andthis11willbeprecedentsetting.
Igetthefeelingthat12thisideaofusinganoninferioritydesignisnew13tothisspecificfield.
14Anda20percentmargin,Itellyou15everybody'sgoingtoreportthat,ohtheydidit16witha20percentmargin,andthatwillbecomethe17standard.
18SoIjustencourageyou--andIstruggle19withthis.
Mymainareaistuberculosis,andI20strugglewiththisbecausepeoplewanttodothese21widemargins,anditdrivesmecrazy.
SoIwould22AMatterofRecord(301)890-4188361lovetohearyouropinionsaboutwhat'sa1reasonablemarginherebecauseasthisfieldmoves2forward,you'regoingtohearthisquestionagain3andagain.
4DR.
KRAMER:Dr.
Bickel5DR.
BICKEL:SoIjustwantedtoecho6Dr.
Brady'scommentandsaythatthefrequencyby7whichthereissupplementalbuprenorphineshouldbe8consideredaspartofthefailure.
Butacouple9times,regardlessofwhereit'slocated,early,10middleorlate,isprobablynotthatbigadeal11becausethesepeople'slivessometimescanbevery12chaotic.
Andsometimesabriefmodificationof13doseisanecessarywaytodealwiththeirstresses14andchallenges.
15DR.
KRAMER:Dr.
Grieger,youhadasecond16DR.
GRIEGER:Justaquickclarification.
I17wouldn'tconsiderthepeoplethatneeded18supplementalbuprenorphinewhoareontheimplant19asresponders.
ButIalsowouldn'tconsiderthe20peoplewhoneedsupplementalbuprenorphineonthe21oralorbuccalformulationtoberesponderseither.
22AMatterofRecord(301)890-4188362Ithinktheyshouldjustbetreatedthesame.
I1don'tknowifIwasclearaboutthatbefore.
2DR.
KRAMER:SoIjustseems--I'mprobably3oneofthefewwho'sanon-addictionspecialist,4butbacktoDr.
Dodd'scomment,we'refacingbotha5verydifficultpatientpopulationtostudy,and6we'refacingthewholeissueofnoninferiority7studieswherethesloppieryouare,thebetter8chanceyouhaveofbeingsuccessful.
Andfrankly,9Ineedsomeadvicefrompeoplewhocanputthose10twotogether.
11Wehavetwomorepeoplewiththeirhandsup.
12Dr.
Narendran13DR.
NARENDRAN:Idowantto--becauseyou14askedaboutfuturestudies,Ithinksomethingto15keepinmindis,likethenoninferioritymargin16Dr.
Doddmentioned,youalsowanttomakesurethat17it'snotlikeaninferiordoseisbeingshownina18noninferioritymargin,whichissomethinglikewhen19yougivethismuchsublingualbuprenorphineto20augmentbotharms,itreallyraisesthequestionof21didtheyjustpickaninferiordosetoshowa22AMatterofRecord(301)890-4188363noninferioritymargin,whichwasprettylarge,and1that'swhyithappened.
SoIthinkthat's2somethingtobemore,becauseit'saprecedent3settingstudy,tothinkaboutforyouguysgoing4forward.
5DR.
KRAMER:We'regoingtomoveon.
6Questionnumber5,patientsmanagedwith7buprenorphinemayrequiredoseadjustmentover8time.
However,inclinicalpractice,unlike9patientsonsublingualbuprenorphine,Probuphine10treatedpatientswouldnotnecessarilybeseenfor11regularvisitswithbuprenorphinedoseadjustments.
12Discusshowtheneedforoccasional13supplementaldoseswilltranslateintoclinical14practiceforpatientstreatedwithProbuphine.
If15patientsneedtohavesublingualbuprenorphineon16handinadditiontoProbuphine,discusshowthese17prescriptionswillimpacttheproduct'sabilityto18mitigatemisuse,abuse,andaccidentalpediatric19exposure.
20SomepatientsonProbuphinerequired21supplementalsublingualbuprenorphineonlybriefly22AMatterofRecord(301)890-4188364afterinsertion,whileothersrequireditonlyat1theendofthedosingperiodwhenplasmalevels2couldhavebeenfalling.
Incontrast,some3patientsrequiredongoingsupplementaldosing4throughoutthe6-monthtreatmentperiod.
5Discusswhetherthepatternofsupplemental6sublingualbuprenorphineshouldbetakeninto7considerationwhendecidingifProbuphineis8effectiveandshouldbecontinuedforagiven9patientinclinicalpractice,andthe"inclinical10practice"isemphasized.
11Discusswhetherthereisapatternof12sublingualbuprenorphineusethatwouldresultin13thediscontinuationofProbuphine.
14Sowe'veobviouslyalreadydiscussedaspects15ofthis,anddoestheFDAfeelwe'vefully16discussed,ordoyouwanttohearsomecomments17fromthecliniciansaboutwhentheywouldconsider18discontinuation,forinstance.
19DR.
HERTZ:Right.
Ithinkreallyatthis20point--Imean,we'veheardalotIthinkalready21aboutthis--ifpeoplewouldcaretodiscussor22AMatterofRecord(301)890-4188365recommendinstructionsforcliniciansaboutwhat1theythinkwouldbeappropriateuseofrescueor2patientdiscontinuation,justkindoffocuson3that.
4DR.
KRAMER:Inthesettingofpatientswho5wouldn'tbeanticipatedtobeseenthatfrequently.
6DR.
HERTZ:Yes.
7DR.
KRAMER:Okay.
Dr.
Bickel,doyou8reallyhaveyourcarduptospeakoristhatfrom9beforeDr.
McNicholas10DR.
McNICHOLAS:I'llgettheballrolling.
11DR.
KRAMER:Okay.
12DR.
McNICHOLAS:IfIhavetosupplement13throughoutthecourseofanimplant,I'mnotgoing14toimplantagain.
Thepatientisclearlynotbeing15maintainedonthedoseintheimplantortheblood16levelsthatheorshecanattainfromthatimplant.
17SoI'mgoingtoputthepatientonanappropriate18doseandgofromthere.
19Unlesstheywantitout,Iwouldprobably20simplyputthembackonaregularlyscheduled21clinicvisit,andtheywouldget2weeks,ora22AMatterofRecord(301)890-4188366month,orwhateverwasappropriatefortheirlevel1ofstabilityintermsofongoingcarewhilethe2implantisin.
ButwouldIputanotherimplantin3Inallprobability,not.
Idon'tseeanyreasonto4putinoneandthensupplementwith4or8more5milligramsaday.
6Ifyoudoneedalot,Ithinkthatitreally7begsthequestionofarewedoinganythingto8decreasepotentialdiversion.
Andsomeofmy9patients--andIthinkanybodyaroundthistable10whotreatsthesepatientsknowsthatoneofthe11thingswedealwithonaday-to-daybasisismy12partnerneededsome.
Isoldhalfofit.
IfIgot13a24milligramadaydose,theyknowtheycanget14byon12.
15SodoIwanttoputoutanymorethanIhave16toNo,Idon't.
Sothat'soneofthereasonsI17don'tthinktheycanbecalledrespondersinthis18thing.
19Buttheotherthingis,iftheyneed20medication,theyneedtobeseen.
Iforoneamnot21goingtogivepatientsabottlefullof22AMatterofRecord(301)890-4188367buprenorphineandsaytakeitwhenyouneedit.
1Thattomeisnotgoodclinicalcare,andit'snot2somethingyoudoevenwithastablepatientwhohas3anaddictionissuebecausethat'showtheytreat4upsanddownsintheirlives.
5Iftheirlivesaregoingupanddown,then6theyneedmorecounseling.
Theyneedtobeseen7morefrequently.
Sotheywouldnothaveasupply8tostickinthecloset.
Andifyouthinkyouneed9it,goaheadandtakeit.
No,theywouldneedto10beseenandgetanappropriateprescriptionforthe11periodoftimethatwasneeded.
12DR.
KRAMER:Dr.
Gordon13DR.
GORDON:Speakingasaclinician,I14thinkI'mkindofreflectingwhatIdowithmy15chronic,stablepatientsonbuprenorphine.
16Currently,I'mseeingthemonamonthlybasis.
17Maybemystaffareseeingthemonamonthlybasis,18andIseethemeveryothermonth.
Butthemost19part,Iwanttomakesurethatthey'reattentiveto20alltheiraddictionrelatedneeds,whetherthatbe21pharmacotherapy,butalsonon-pharmacological22AMatterofRecord(301)890-4188368approachestotreatment.
1I'mkindofreflectingandtryingtothink2out,how,ifIhadbuprenorphineinmyclinical3practice,wouldIchangethatatall.
ButIstill4wanttoseethemonamonthlybasis,andIthinkI5would.
6SoIthinkthatdosageadjustmentscan7occur,evenwiththismedicationorwithoutitin8currentpractice.
AndIalsothinkthataddiction9isnotsomethinglikewegiveamedicationfor104monthsor6monthsandsaygoodbye.
It'sjust11notthattypeofmodalityofadisease.
12SoIthinkoneofthethingsthatwemay13wanttoconsiderifthisisapprovedandan14indicationgoesout,thattherearespecial15attentiontoregularvisitsorregularattentionto16addictionrelatedneeds,Ithinksomethingthat17mightbeintheinstructionsforproviderstomake18surethatthoseregularneedsaretakencareof.
19Thanks.
20DR.
KRAMER:Dr.
Campopiano21DR.
CAMPOPIANO:Ihaven'theardanything22AMatterofRecord(301)890-4188369todaythatmakesmethinkthatthisstatementin1question5,Probuphinetreatedpatientswouldnot2necessarilybeseenforregularvisitswith3buprenorphinedoseadjustmentstobeatrue4statement.
Iwouldwanttoseethisperson5regularly,andIwouldnotwanttocreatethe6expectationyoucanjustimplantthisandsay7bye-bye.
8Oneofthethingsthathappenspresentlyis9thetendencyofprescriberstomedicatecravings,10whicharecomplexpsychosocialphenomenathatcan't11betreatednecessarilyorcompletelyeliminated12withmedication.
Sotosendsomebodyhomewitha13bottleandsaytitrateyourselftocomfortisbad14clinicalpractice,andnotsomethingthatthis15product--there'sanyreasontothinkwecando16withthisproductasopposedtoasublingual17product.
18Sothere'sariskthatifwecreatethis19expectationthat,oh,onceinawhileyou'regoing20toneedalittlebitmore,andyoumightneedit21moreoftenandduringthebeginning,oryoumight22AMatterofRecord(301)890-4188370needitmoreoften,ormaybeduringthemiddleand1attheend,itjustkindofabsolvestheprescriber2ofresponsibilityforfiguringoutwhat'sgoingon3herewiththispersonandgivesthemlicensetosay4seeyouin6monthswhenyou'rereadyforyournext5implant.
6I'lltimetravelbackto2003when7buprenorphinewasfirstapprovedandhitthe8market,andwehadverylittleofanything,9guidance,onhowtouseitoranythingotherthan10theFDAlabeltogoon.
AndIcankindof11strategizewithmyself,okay,whatwouldIdo12I'dexpectsomebodymightneedadditional13medicationthefirstmonthwhilethey're14stabilizing,whiletheirbloodlevelsarecoming15up,whilethey'retransitioningfromtheiroral16producttotheirnewproduct.
17IfI'mseeingpersistentneedformore18medicationafterthatperiod,I'mprobablygoingto19triggerarestabilizeandtitrate.
I'mgoingto20restabilizeyouonadosethatworksforyouevery21dayontopofyourimplant,andthenwe'regoingto22AMatterofRecord(301)890-4188371talkaboutwhetheritmakessensetotitratedown1tojusttheimplant.
Andifwegetthereand2you'restable,andyou'renotusingother3substances,andit'stimeforanewimplant,then4wemakeadecisionaboutwhetherwecontinuewith5theimplantorwegobacktoasublingual6transmucosalthatgivesustheflexibilityof7titratingbackupifweneedto.
8Idon'tseealotofmedical,legally,9psychosocially,andanyother,ethically,tobe10gainedincreatingapopulationofpeoplethatare11onbothanimplantandreceivingsublingual12transmucosal.
Thatsoundslikemedicallywasteful.
13Itsoundslikearecipefordiversion.
Itsounds14likearecipefordisappointingthepublic15expectationthatsomehowthisisgoingtoboth16increaseaccessandreducediversioninsomemagic17way.
18SoIthinkit'sgoingtobereallyimportant19totakestandardmedicalthinkingandapplyitto20whatyoudowiththispersonnowthatyouhaveto21managetheminthecontextofa6-monthimplantand22AMatterofRecord(301)890-4188372justkindofcompartmentalizeitinto--andgive1specificstrategies.
2DR.
KRAMER:Couldyoucommentonthe3frequencythatyouwouldseeapatientlikethat4DR.
CAMPOPIANO:Iwouldn'tseesomebody5lessthanonceamonthwithoutextenuating6circumstances,orImightsharetheircarewitha7colleague.
Buttheywouldbeseenbysomebody8qualifiedtoevaluatethematleastonceamonth.
9Ihadpeopleonbuprenorphinefor10years,10andIneversawthemforlessthanonceamonth11withoutneedingtochangetheirdose.
Idon'tsee12doinganydifferentlywiththisproduct.
13DR.
KRAMER:Dr.
Winchell14DR.
WINCHELL:I'dliketoaskanyonewho's15familiarwiththepopulation,theruralpopulation,16theotherpopulationsthatwerereferredtointhe17openpublichearingandinothervenues,the18populationforwhomaccessto--comingtomonthly19visitsisalogisticalhurdle,andthismedication20waspositedaspotentiallybeinganoptionfor21patientswhohavealongdistanceorsignificant22AMatterofRecord(301)890-4188373logisticaldifficulties.
1Doyouthinkthisisnotthemedicationfor2thosepatients3DR.
CAMPOPIANO:I'lljustcontinue.
I4thinkthatit'salottoputonthismedicationto5fixthatproblembecauseweneedtouseother6resources,telehealth,aphysicianextender,7so-calledproviderstohelpimproveaccess.
8Tosaythatyoudon'tneedtobeevaluated9furtherbecauseofthisproduct,Ithinkis10shortchangingthatruralperson.
Andbasedonwhat11wassubmitted,theexpectationisthatthe12standardsforbehavioralinterventionsand13professionalbehavioralsupport,counselingandso14on,isunchangedforthispopulation.
Andthe15realityistheydon'thavegoodaccesstothatin16theruralareaseither.
17Sosavingthemaprovidervisitisgreat,18butyoucoulddothatwithtelehealth.
Thisisn't19goingtofixthefactthatwedon'thavetreatment20programsandcounselorsandstuffinruralareas.
21Sowehavetoberealisticaboutwhatweexpect22AMatterofRecord(301)890-4188374thiscanaccomplish.
1DR.
GRIEGER:Iwouldagreeforwhatyou're2sayingwiththis,butIknowinthesystemI've3workedinforawhileandtheVAsystemthatwasin4ruralnortheastMaryland,we'veusedtelehealthand5anumberofotherthings.
6Icouldseeanagentlikethis,adepot7agentbeinguseful,youknowbecauseyoudon'tneed8tohaveapersonphysicallycomeintoseea9physiciannecessarily.
Therecouldbeanothertype10ofacheckthatthepersonwouldhave.
11IagreewithallmycolleaguesthatIhave12neverfeltcomfortableinagrouplikethisseeing13themlessthanonceamonth,andIdon'tthinkthis14isgoingtochangeanything.
ButIwouldsaythis15couldgiveanoptionbecauseitgoesbacktohow16manypills,orhowmuchamIwillingforsomeoneto17leavemyofficewith.
That'softenanissuein18veryruralsubjectswhenitisanissueforthemto19getintogetaphysicalrefillandthiscouldhelp20thatbutnotthecontact.
21Infact,Iworryaboutthisandanydepot,22AMatterofRecord(301)890-4188375isthatsomehowthisopensthewaytoseethe1patientless.
NowIdon'tthinkthatshouldbea2reasonfornotapprovingthisparticularsubstance,3butIthinkit'satensionwejusthavetobeaware4ofinthemedicalsystemthatIwouldhopethis5wouldn'tleadtoalossofsupportforcontinuing6toseepeopleonaroutinebasisbecauseIthink7that'sreallyneeded.
8DR.
KRAMER:Dr.
Brady9DR.
BRADY:Yes.
Ijustwantedtoreiterate10andemphasizesomethingthatLaurasaid,justabout11iftheexpectationisthatmaybeparticularlyearly12oninthetreatment,peoplemayneedsome13supplementaldosageorwhenstressfultimescome14up.
15Ithinkhoweverthough,itshouldbe16emphasized.
AndI'dsayjustaboutanymedication17Igivesubstanceusingpatients,butinparticular18ifit'samedicationwithabusepotential,Iwould19neversayPRN,justtakeitasyouneedit.
20SoIthinktheemphasisshouldbethismay21happenoccasionally,maybeparticularlywhen22AMatterofRecord(301)890-4188376they'retitratedwiththeinitialtitration,if1extrasupplementaldosingisneeded,thepatient2needstobeseenfrequentlyduringthattime.
3Ithinkthatwouldhavetobeemphasized4whenitcomestothesupplementaldosing,thatthat5isanindicatorthatsomethingisgoingonthat6meansthepatientneedstobeseen.
7DR.
KRAMER:Dr.
Narendran8DR.
NARENDRAN:Idowanttosayalthough9patientsprobably--Idoagreetheyhavetobe10seeneverymonth,butthere'salsotheadded11benefitoflike,quiteoften,patientscalltheir12andtheirmedicationwasstolen,andthey're13hustlingtogetin,andtheycan'tgetan14appointment,andtheygouseoutsideandrelapse.
15Soitcouldpreventthatkindof--when16theyfeellikeallofasuddentheydon'thave17theirmedicationandthey'vegottogouse,andif18thisperson'sinruralWestVirginiaorsomething,19it'sapossibilitybythetimetheycangetto20Pittsburgh,atleasttheydon'thavetofreakout21over--sotherearedefinitelysomebenefits,22AMatterofRecord(301)890-4188377althoughitmaynotreducethefrequencyperse.
1DR.
KRAMER:Dr.
Gordon,didyouhave2anothercomment3DR.
GORDON:Yeah,justquick.
I'llagree4witheverythingDr.
ConleyandDr.
Campopianohave5indicatedtotheFDA'squestion.
Iactuallythink6thefearthatIhadwiththismedicationisthat7therewouldbelessfrequentvisitswithproviders.
8AndIdon'tagreewiththeFDAthatthisisa9reasontohelpruralcommunities.
Thereareso10manyotherthingsthatwecouldbedoing.
A11medicationthat'saDepoinjectionisnotthe12answer.
13DR.
KRAMER:Idon'tthinktheFDA--I14didn'tinterpretthemassayingtheythoughtthat,15butweheardthatcommentfromthepublichearing16thatpeoplewerehopingforsomethingthatcould.
17SowehaveacommentfromKathleenCarroll,18firstonquestion--well,shehasoneon19question4.
I'llreadherquestion5response20first,sincewe'reonthat.
21Sheagreesstronglythatongoingmonitoring22AMatterofRecord(301)890-4188378monthlytelehealthandurinechecks,evenwith1droppingoffatalab,isneeded.
2"SotheFDAhasaskedthatwekindof3summarizewhereweareoneachquestion.
SoamI4correctinsayingthatitsoundedtomelike5everyonewhospokewasinfavorofthesepatients6needtobeseen;thatyoucan'tjustputitinand7thinkthatthat'sgoingtomeangoodbye.
Atleast8onceamonthIheard.
9"Iheard,atleastDr.
McNicholassaythat10shewouldnotreimplantsomeonewhowasneeding11thisthroughoutthetreatmentperiod.
Isthata12generalfeelingIdon'twanttoputwordsin13anyone'smouth.
Isthatafairsummaryofwhat14we'veheard"15Okay.
IfIcouldjustgobackandread16Dr.
Carroll'sthoughtfulcommentsonquestion4,17shecommentedthatintenttotreatmeansall18patientsrandomized.
Therespondercriteria,the19currentdefinitionisnotappropriate.
Shewas20particularlyconcernedwiththatchosenbythe21sponsorasitmaybesomesortofprecedentfor22AMatterofRecord(301)890-4188379futurestudies.
1Theoverlyoptimisticcasepresentedbythe2sponsorisofconcern,becauseofthehigh3demand/expectationsasvoicedinthepublic4comments.
TheworstcasescenariodonebyFDAis5closertowhatactualoutcomeslooklike.
I'mnot6clearwhydefinitionsusedinotherlarge7buprenorphinetrialswerenotused.
8Iwouldsuggestsomethinglike,Norescue9dosesafteronemonth;nomissedrandomurines;no10missed/positiveurinesinthelast2months.
This11ismoreinlinewiththatofWeiss,etal.
,in122011.
13Okay.
We'llmoveontoquestion6.
The14sponsorhasprovidedinformationonatrainingand15certificationprogramtoensurethatpractitioners16cansafelyinsertProbuphine.
However,the17procedureofremovingProbuphineafter6monthsof18implantationisnotreadilymodeledforthe19purposesoftrainingbecausethereisdevelopment20offibrotictissuearoundtheimplants.
21Discussthestepsthesponsorshouldtake22AMatterofRecord(301)890-4188380toensurethatremovals,includingcomplicated1removals,areperformedappropriately.
2Dr.
Grieger3DR.
GRIEGER:Thiswasmybiggestconcern4aboutthiswholeproposal,isthatIthinkthat5practicingonaporkloinjustdoesn'tgetitfor6me.
Imeanthat'snotthewayIlearnedtobea7doctor.
Ifyou'regoingtodoprocedures,Ithink8youhavetodothemonhumanswithapreceptor9watchingyoudothem,unlessit'ssomethingso10closetowhatyoualreadydo.
11Butyou'retalkingabouttogettotheouter12rods,you'redoingonedissectionunderneaththe13skinandtryingnottocauseanyproblems.
Idon't14eventhinkmostanesthesiologistsareusedtodoing15that.
ProbablyICUdocsareusedtodoingthat16becausethey'reputtinginmainlinesandstufflike17that.
ButIthinkthat,really,thereneedstobe18somethingmorethanpracticingonapigloin.
It19justdoesn'tmakeit.
20I'mcuriousaboutthe--wehadsomepeople21fromthat,whatisit,DBRUP'sgroup,inhere22AMatterofRecord(301)890-4188381earlier.
WhatdoestheNexplanoncertification1programrequireItriedtogetthatfromthem,2butyouhavetosignupandgotothecourse.
They3won'tjusttellyouoverthephonewhatitisthey4do.
5ButImean,Idon'tknow.
Otherphysicians6inhere,wouldyoufeelcomfortabledoingthat7Wouldyoufeelcomfortablewithhavingitdoneto8youbysomebodythatdoesn'troutinelydothat9DR.
PICKAR:Byyou,Tom,anytime.
10DR.
GRIEGER:No.
Iwouldn'tfeel11comfortabledoingit.
That'smyconcernisthatit12wouldrequiresomedifferenttypeoftraining.
13DR.
KRAMER:SomeonefromFDA'sgoingto14helpusouthere.
15DR.
CHANG:MynameisChristinaChang.
I'm16theclinicalteamleaderinDBRUP,theDivisionof17BoneReproductiveandUrologicProducts.
Soasyou18know,theNorplantwasthefirstiteration.
Andin19thehistoryofcontraceptiveimplants,therehave20beenmany,manyiterationsuntilNexplanon.
21Soourexperiencewiththeseimplantsreally22AMatterofRecord(301)890-4188382haveevolved,andNorplantwasmarketedquickly,1andthelaunchwasverywide.
Thenwithinafew2yearsorso,marketingwasdiscontinued;Ithinkit3wasbackin2002.
4Rightnow,theuseofNexplanon,it'scoming5back,butithasn'tcertainlyreachedthepromise6thatwasheldoutforNorplantbackthen.
At7first,whenNorplantwasapproved,therewasno8certificationprogram.
Sowemayberegretting9thatatthismoment,butthere'snothingwecould10havedone.
11TherewasnoREMSprogrambackthen,andby12thetimeNexplanonwasapproved,wefeltlikethe13OB/GYNexperience,orthecommunity,isexperienced14enoughthatwedidn'tneedacertificationprogram.
15Sothat'sthesentimentthatwehaverightnow16becauseeveryone'sfairlyfamiliarwiththerisks17oftheprocedures.
18DR.
GRIEGER:Well,I'malittleconfused,19becauseifyougoontotheirwebsite,they'vegot20athingtosignuptogetthecertification21training,andthey'vegotthesameREMSthingwhere22AMatterofRecord(301)890-4188383youcanputinyourzipcodeanditwilltellyou1within50miles,100miles,150miles,whois2certifiedtodothat.
Andit'sawidevarietyof3people.
Therearephysician'sassistantswhoare4certified.
Therearenursepractitionerswhoare5certified.
OB/GYNthatarecertified,andsurgeons6thatarecertified.
SoIdon'tthinkittakesa7physiciantodoit,buttheyhavesometypeof8certificationprogramthattheyrequireinorderto9beabletodotheimplants.
10MS.
CHANG:Well,thecertificationprogram11isimplementedvoluntarilybytheapplicantfor12Nexplanon.
13DR.
KRAMER:Dr.
Ionescu14DR.
IONESCU:Ithinkinthegrandschemeof15proceduresfrommanyofoursurgicalcolleagues,16ICUcolleagues,thisisprobablynotabigdeal.
17However,Idothinkthatbecausethisissomething18new,asfarastheremovalsgo,Ithinktherehas19tobeareallystrictprograminplaceifthiswere20togetpassed.
21Forexample,therearesomesuperusersthat22AMatterofRecord(301)890-4188384havedonethismany,manytimeswhoareexperts.
1Maybeiftheyforthefirstfewyearscouldbekind2ofoncallandmaybetheycoulddolikeFacetimeor3somethingwiththephysiciansthathavealready4certifiedandkindofondemand--itmightbe5somethingthattheykindofhavetobeoncalland6canansweratanytimeifsomeoneneedshelp,or7maybehavesuperuserssetupincertainurban8areasasindicatedbyzipcode,wherepatientsand9providers,ifthey'rehavingissues,theyhave10someonethattheycangoto.
11Becauseultimately,attheendoftheday,12proceduresareallaboutvolume,andthemorea13providerdoesit,thebetterthey'regoingtobeat14it.
However,thosefirstfewyearsmightbea15littlebittrickyaspeoplegettheirvolumes.
So16Ithinkit'sdoable;it'sjusthavingsomethingin17place.
18MS.
SHELDON:Ijustwanttoconfirm,both19ofyoursuggestionsareactuallypartofourplan.
20They'renotpartoftherequiredREMS,butwewill21bemakingourmastertrainersavailableatanytime22AMatterofRecord(301)890-4188385inordertoFacetime,orgetanyotherkindof1consultation,andthemapwillbeavailablefor2locationofclinicianswhoarekindofsuperusers3andcentersofexcellence.
4DR.
KRAMER:I'dhatetobethepatient5sittingtherewhenthedoctorpickedupthephone6andtriedtodoFacetimetofindoutwhatthey're7doingwrong.
Sorry.
It'sgettinglate.
8Dr.
Higgins9DR.
HIGGINS:Ijustwantedtoraisethe10pointthattheNorplantexperienceiscompletely11differentwhenwe'retalkingaboutacompletely12differentpopulation.
Iimaginethiswouldbeused13inpeoplewiththinnertissue,lackofmusculature14structuresthatwouldbepresentinayounger15population.
16DR.
KRAMER:Dr.
Narendran17DR.
NARENDRAN:Yes.
Ijustthinkforthe18non-proceduralist,forpsychiatrists,general19practitionerswhodon'treallydoroutinely20surgicalprocedures,it'sprobablygoodtohave21likealivepersonandmaybelikeobservethemfor22AMatterofRecord(301)890-4188386thefirstthreeorfive--likethat'swhattheydo1ifwehavedoarteriallinesinourstudies.
The2anesthesiologistkindofseeshowwedoit,sothey3giveus--likeafterfive,theycredentialus.
4Somaybeforthem,itmustbeadifferent.
5Andprobablyforananesthesiologistdoingitona6porktenderloin,probablynotabigdeal.
I'msure7it'snotnecessary.
8DR.
KRAMER:Dr.
Kotz9DR.
KOTZ:Ijustwantedtoclarify.
My10understandingisthatwhenthepersonthat11implants,theproceduralist,thattheyhavetobe12waivered;isthatrightIsthatwhatoneofthe13slidessaid14Soifthat'stheanswer,thenwhenyoujust15said,Tom,thatwhenyougoonthewebsitethereis16nursepractitionersandotherpeoplebesides17physiciansthatarebeingtrained.
I'mnotsure18whythatis.
19DR.
KRAMER:Okay.
Areyouaskinga20questionofthesponsor,Dr.
Kotz21DR.
KOTZ:Pardonme22AMatterofRecord(301)890-4188387DR.
HERTZ:Ithinkthatwebsitethatwas1referredtobyDr.
GriegerwasforNorplantorfor2thecontraceptive,notforthis.
3DR.
KOTZ:Oh,okay.
Thankyou.
4DR.
KRAMER:Wellifwehaveaquestion,5I'llcallyou.
Dr.
CampopianoOkay.
Allright.
6Sowhat'safairsummaryofthisThereare7somepeoplethatareuncomfortablewiththe8explantationprocedureandthebluntdissection.
A9suggestionofactualobservedimplantationwitha10mentorpriorto--butwedon'thaveany--11DR.
GRIEGER:Unlessyou'reinpracticeand12especiallywhereyoudosomethingverysimilarto13that.
Yes,ifyou'redoingarterialvenous14grafting,you'regoingtoknowhowtodothis.
15DR.
KRAMER:Andwhat'sthemechanism,16thoughAreyouproposingthatthisbe--17DR.
GRIEGER:Idon'tknowwhataclear18mechanismwouldbeotherthanwhat'skindof19traditional,isthatyouwouldgotoacenterthat20routinelydoesabunchoftheseandhangoutfora21morningandwatchfiveofthemgetremoved.
The22AMatterofRecord(301)890-4188388problemiswhenitfirststartsoutandyoudon't1havealotofcenters--2DR.
KRAMER:Andarepeoplegoingtodo3this4DR.
GRIEGER:Who'sgoingtobedoingit5DR.
KRAMER:Dotheyhavethetimetodo6this7DR.
GRIEGER:Right.
ButIthinkifyou8thenwanttodoitthreeyearsfromnow,asa9psychiatrist,Imightbeinterestedindoingit.
10ButIthinkI'dhavetogowatchtwoofthembe11done,andI'dhavetodooneunderdirect12supervisionandmakesureI'mgoingthroughthe13checklist,justliketheydowiththepork14tenderloin,butwithrealskin.
15DR.
KRAMER:Realskin,realperson.
16DR.
GRIEGER:Andrealbleeders,andwhatdo17youdoifyouhitanarteriolethat'spulsingouta18littlebitbloodDoyoujustputpressureonit19andletitoozeandturnintoahematomaOrdo20you--whatdoyoudowithit21DR.
KRAMER:Dr.
McNicholas22AMatterofRecord(301)890-4188389DR.
McNICHOLAS:IagreewithwhatTomhas1said,butIthinkthatthere'salargerproblem2here,andIdon'tknowhowitcanbeaddressedby3thesponsor.
Andthatis,yousendabunchof4practicingpsychiatriststoevenpracticeonapork5tenderloin,halfofthemaren'tgoingtobeableto6doit.
7Howmanypsychiatristsinthisroomhaveput8suturesin,inthepast10yearsIthinkifyou9haveabunchofpsychiatristsandprobablyeven10internistswhodon'tdoitandstufflikethat,you11takethemandyoustarttotrainthem,andthey're12goingtogo,"Thisistoomuchtrouble.
I'mnot13goingtodoit.
"14Idon'tknowhowthatgetsaddressed,butI15thinkthat'samajorconcern,thatyouhavegotto16figureouthowtomakethispalatabletothe17clinicalpopulationthatneedstobeabletouse18it.
19DR.
KRAMER:Ithinkweneedaclarification20fromthesponsor.
Ithoughtthesponsorsaidthat21theyoriginallyconsideredjustusingsurgically22AMatterofRecord(301)890-4188390trainedindividuals,andthenchangedtheirmind,1orsomethinghappened.
Couldyouclarifythat2MS.
SHELDON:Right.
Sotostart,3psychiatristsareclearlyverycriticaltothis4fieldandtotheadoptionofanyproduct,butyou5guysare24percentofthepeoplewhoprescribe6buprenorphinerightnowandthevastmajorityof7otherclinicianswhoprescribebuprenorphinehave8somesortofsurgicalspecialtybackgroundthat9allowsthemtodoso.
10We'veactuallyalsohadanumberof11psychiatristswhosaidthatthisisasecond12specialtyandtheyfeelthattheycanactuallydo13theprocedure.
14Inouroriginalestimation,wesuggested15thatpeoplewithproceduralspecialtyorfolkswho16havedone--they'vejustkindofgottenintodoing17someproceduresandhavedoneoneatleastinthe18lastthreemonths,shouldbetheonesthatare19allowedtotakethetraininginthefirstplace.
20TheDivisionofRiskManagementpointedout21thatrestrictingaccessbyvirtueofsomeone's22AMatterofRecord(301)890-4188391specialtyortrainingmaynotbeappropriate.
And1we,ourselves,didseeinthehumanfactorstudy2thatthiswasn'tsomethingthatwasgeneralizable.
3Thereweresomepsychiatrists,especiallyifthey4wereprettynew,theywereprettyearlyintheir5careerandhadjustbeenoutoftrainingacouple6ofyears,whodidfantasticallywell.
7Soitseemedmorereasonabletoletpeople8self-select,andifpsychiatriststhinkthatthey9canlearntheprocedure,they'rewelcometocometo10trainingandpassthecompetency.
Iftheydon't11passthecompetency,thentheywillnotbe12certifiedtoimplant.
13Ifsomebodyneedstogotoanotherclinic,14atleasttoreferouttoanotherclinician,the15otherclinicianwillneedtobedatawaived.
16DR.
KRAMER:Thankyouforthe17clarification.
Dr.
Pickar18DR.
PICKAR:Yes.
Idon'tthinkthere's19necessarilyadanger.
Theypsychiatristswhowant20totrainwillbeabletodoitjustfine.
The21biggerissueforyoufolksiscanyougetinto22AMatterofRecord(301)890-4188392enoughpeopleIt'sjustsimplythemechanicsof1gettingthisimportantdrugoutandgettingitinto2people,andthat'sastrategy.
Idon'tknowif3that'sforus.
Butboy,that'sgoingtobea4strategyforyoufolks,andI'msureyou're5thinkingaboutitalltheway.
Butthat's6critical,whetherit'sthefamilypracticeguysor7theshrinks.
8Idon'tthinkyou'llgetincompetentguys9doingthat,orgals.
Idon'tthinkthat'swhat10willhappen.
Youjustmightnotfindthatmany11frequentpsychiatristsdoingit.
12DR.
KRAMER:Dr.
Campopiano13DR.
CAMPOPIANO:Ithinkitmakessenseto14trainanybodywho'swillingtocomeandbetrained15andcertifythosewhocanpassthetraining,and16thenperhapshavesomethinginplacelikethe--I17can'tyournamesign,butthedoctorfrom18Pittsburghoverthere--thatifyoudon'thavea19certain--ifyoucan'treportacertainnumberof20proceduresinthelastreasonableperiodoftime,21thenperhapsyouneedtodothis,yourfirstcase,22AMatterofRecord(301)890-4188393undersupervision.
1Thatmaysoundburdensome,butIthinkit2mayactuallypromoteadoption,becausethatperson3who'sjustalittle,like,yes,Ireallywanttodo4thisandIthinkIcandoit,butI'mnevergoing5todothatfirstcase,becauseI'mjustnotquite6comfortableenough--butifsomebody'scomingout7andisgoingtostandovermyshoulder,andtalkme8throughit,orjustbethere,maybethenIwill9adoptthattechnology.
10Soit'safinelinebetweenmakingit11burdensomeversuspromotingadoption.
ButIthink12thatthere'sprobably--maybeitneedstobea13fairlysolidrulethatifyoudon'thaveXnumber14ofproceduresofacertaintypeinyourbackground15inthelastcertainwindowoftime,youwillhave16somebodywatchyoudoyourfirstone,sortofthe17waytheyrequireyourrecordswhenyouwanttoget18procedureprivilegesinthehospitalorsomething,19justtomakeitveryclear.
20DR.
KRAMER:Okay.
Allright.
Goahead.
21DR.
IONESCU:It'skindoflikeECTalittle22AMatterofRecord(301)890-4188394bit.
NopsychiatristeverdoesECTwithoutbeing1trained.
Ithinkthisiskindofequivalentto2that.
3DR.
PICKAR:That'sagoodanalogy.
4DR.
KRAMER:Okay.
Number7.
Thesponsor5hasproposedariskevaluationandmitigation6strategy,whichconsistsofrestricteddistribution7andatraining/certificationprogramforhealthcare8professionalswhowillinsertandremovethe9product.
10DiscusswhethertheREMSisadequateto11addresstheriskofpotentialcomplications12associatedwiththeinsertionandremovaland13abuse,misuse,andaccidentaloverdose.
14Ithinkthediscussionwejusthadis15absolutelyrelevanttothisquestion.
IthinkI16heardasummarythatthereshouldbeactual17hands-ontrainingonpeople,andthatwerealize18thatyouprobablycan'tspecifybyspecialty,but19thetrainingshouldberequired.
AndIthought20Dr.
Campopiano'swayofexpressingthatthat21actuallycouldpromotetheusebecausepeople22AMatterofRecord(301)890-4188395wouldn'thavetofeelthere'ssomethingwrongwith1thembecausetheyareuncomfortable;theymightget2overthat.
3SoisthereanythingelsetheFDAislooking4foronthatquestionNoIsitpossiblethat5we'reontothevotingquestionOkay.
Yes6DR.
McNICHOLAS:Onthatquestion,theyhave7stuffonnotjusttheinsertionandremoval,but8abuse,misuse,andaccidentaloverdose.
DidImiss9partofthatonwhatisincludedintheREMSon10that11DR.
KRAMER:Yes,yes.
Okay,we'llopenit12uptocommentsonthat.
Oh,I'mbeingtoldIhave13toreadthatintotherecord.
IthoughtIdidread14it.
DiscusswhethertheREMSisadequateto15addresstherisksofpotentialcomplications16associatedwiththeinsertionandremoval17procedures,andabuse,misuse,andaccidental18overdose.
19DR.
McNICHOLAS:DoestheREMSaddressthe20lastthree:theabuse,misuse,andaccidental21overdose,becauseIdon'tthinkthatwegotalot22AMatterofRecord(301)890-4188396ofinformationonthat.
1DR.
KRAMER:Oftheimplantorofsublingual2buprenorphine3DR.
PICKAR:It'sjustthewaythe4question'sworded.
5DR.
KRAMER:Yes.
Wouldyoulikemeto6expandonit7DR.
LEHRFELD:Hi.
ThisisKimLehrfeld,8DivisionofRiskManagementattheFDA.
The9accidentaloverdose,misuse,andabuse,it'sreally10relatedtoifthedeviceissomehowexpelledfrom11thepatient.
Therefore,theeducationisjusthow12apatientshouldadequatelyhandleifadevice13startstoprotrudeoractuallyfallsout.
14Soithasmoretodowithwhathappensin15thoserarecasesthatwesaw,butveryimportant16cases.
Soitreallyhastodowithpatient17counseling,themedguide,beingreviewedbythe18inserteraswellastheprescriber,aswellasthe19patientcounselingtoolavailabletoprescriberwho20maynotbetheoneinsertingit,butneedstotalk21aboutifthosecomplicationsoccur.
Andmaking22AMatterofRecord(301)890-4188397suretheenddisposaloftheproductappropriately1whenit'sremoved.
2Also,sincetheprescribermaynotbethe3oneinsertingit,wedowantthemtobeawareif4thatpatienthastobemanaged3monthsafterit's5insertedandthere'sacomplication.
Wewantthem6tobeawaretohowtocounseltheirpatientifit7doesprotrude8DR.
KRAMER:Dr.
Grieger9DR.
GRIEGER:Wegotthegenerallayoutof10thething,whichbasicallyhadabigcircle,and11thepatientwasinonepartandthedispensing12personwasinanotherpartofthecircle.
Iguess13thequestionishavetheyprovidedthedetailsof14exactlyhowthey'regoingtomonitorthatIfthis15eventoccurs,whodoeswhat,what'sthetimeframe16ofgettingthesethingsdone17AREMSprogramiscomplicated.
Likethe18clozapineREMSprogram.
Literallyyou'vegot19designeesthataresendingstuffupandyouhaveto20acceptnewpatientsintoyourthing.
It'savery21systematicwayofdoingtheREMS.
Idon'tknowif22AMatterofRecord(301)890-4188398they'vegiventhatsameamountofdetailatthis1point,andmaybetheydon'thaveto.
Imean2they'velaidoutwhattheyplantodo.
Maybethe3specificscanfollowlater.
4DR.
LEHRFELD:Wehavesomedetails.
Iwill5saybecauseallofthetraininghastobelive,6it'salittleeasierforthemtosetthisup,as7longastheyhavethetrainingsessionsetup.
8That'swhereeveryonewillbeenrolled.
There's9notanonlinecomponenttothiswherethere's10trainingoranyaspectofthat.
Atthispointin11time,everything'sgoingtobelive.
Sothe12prescribersandtheimplanterswillbothhavetogo13tothatsession.
That'swherethey'llbecome14enrolled.
15Sowedohavesomeofthosedetails,andwe16alsohavedetailsofthedistributionprocess.
17But,aswithallREMS,therewillbegrowingpains18whenitfirstgetsapproved.
Wedoeverythingwe19cantogetasmuchdetailaswecansowe20understandtheprocesssothatdoesn'thappen,21but--22AMatterofRecord(301)890-4188399DR.
KRAMER:Okay.
Dr.
McNicholas1DR.
McNICHOLAS:Yes,whenIlookatthis2distributionsystem,thephysicianhastoorderthe3medication.
Isthatgoingtohavetogothrough4DEAformsAndwhenit'sreceived,doesithaveto5beloggedinandloggedoutandetcetera,6etcetera.
Isthisgoingtobeapaperwork7nightmarefortheoffice.
8DR.
LEHRFELD:I'llhonestlysayI'mnotthe9expertinthat.
ThisisaC3asopposedtoaC2.
10C2'shavealotmorecontrols,butthereare11specificoutlinesforhowbuprenorphineismanaged12whenprescribersrightnoworderit.
Sothe13recordingandloggingwouldbethesameforanyone14elsewhokeepsanybuprenorphineintheiroffice15forinitiatingSubutexonpatientsifanyone's16doingthat.
17DR.
KRAMER:AndisthereaDEA--can18anyoneansweritmore19DR.
McNICHOLAS:Imean,mostpeopledon't20keepitintheiroffice,becauseit'sso21burdensome.
There'sadifferencebetweenwritinga22AMatterofRecord(301)890-4188400prescriptionforapatientandorderingfroma1supplier.
2DR.
LEHRFELD:Icompletelyagree,andlike3Isaid,Idon'tknowwhattheCSArequiresof4recordingforpeoplewhoorderbuprenorphinein5theiroffice.
Idon'tknowifanyoneherehasany6experiencewiththat.
7DR.
KRAMER:Itsoundslikethisisan8implicationofadecision,butit'snotthebasis9forourconsiderationsheretoday,butit'savery10goodquestion.
11DR.
LEHRFELD:No,itwouldnotbewithin12theREMS.
Wewouldexpectthattheprescribers13wouldunderstandhowtoorderit.
14DR.
KRAMER:Dr.
Hertz15DR.
HERTZ:Iwouldliketoseeifthe16sponsorwouldcaretoaddresssomeofthemechanics17ofthepracticalitieshere.
18MS.
SHELDON:Probuphinewouldhavetobe19orderedthroughasingledistributor,throughabuy20andbillprocess,andthesamecontrolled21substancesregulationswouldapplyintermsof22AMatterofRecord(301)890-4188401storinginalockedandsecurecabinetand1disposingaspharmaceuticalbiohazardwaste.
2Wehaveprovidedalog-insheet,and3dependingonhowtheofficeisusedtokeeping4records--becausewhilemanycliniciansdon't5currentlykeepbuprenorphineintheiroffices,some6do,andsomeactuallykeepotherkindsof7controlledsubstances.
Sotheymayhavetheirown8systemsforlogginginandloggingout.
9Wehaveareceiptformwhereyouwould10recordreceivingit,andthenafterwards,whenit's11been,ofcourse,disposed,sothateverythingis12properlydocumented.
Thisagainisnotconsidered13partofREMSatthispoint,butasitmaybeof14assistancetopeopleinfollowingwhatisrequired15bytheControlledSubstancesAct,itwillbemade16available.
17DR.
KRAMER:Okay.
Thenextquestionisa18votingquestionandI'mgoingtoreadyou19instructionsaboutthevoting,butfirstI'llread20question8.
Basedonthedatapresentedand21discussedtoday,dotheefficacy,safety,and22AMatterofRecord(301)890-4188402risk-benefitprofileofProbuphinesupportthe1approvalofthisapplicationforapopulationof2patientspreviouslystableonaregimenof3sublingualbuprenorphine,asdefinedduringprior4discussion5Thenindiscussionafterthat,we'regoing6todiscuss,comment,onfurtherdevelopmentsor7explorations,higherdosesthesponsorshould8undertake.
Anyquestions9DR.
DODD:Withregardtothisquestion,we10sayefficacy,whatarewetalkingabout11NoninferiorityArewetalkingaboutsuperiority12Arewetalkingaboutthe20percentmarginArewe13talkingabout--whichanalysisarewereferring14toCouldIgetsomeclarification15DR.
HERTZ:It'salwaysinterestingtofind16howourincrediblyworkedon,thoughtup,discussed17andeditedquestionscancomeoutlessthancrystal18clear.
19SoIthinkthefairestwaytosaythatthe20efficacyquestionwouldbe,withinwhatyou've21heardtoday,doyouthinkthere'sefficacyand22AMatterofRecord(301)890-4188403safetysuchthattheoverallprofilesupports1approval2Ithinkthatopensyouuptodecideonthe3analysisyouconsiderappropriateandthesafety4thatyouconsiderappropriate.
Andthen,perhaps,5whenwegoaroundtoaskfolkstosaytheirvote6fortherecord,ifyou'dliketocommentonany7aspectofwhatyoutookintoaccounttosupport8yourvote,thatmightbeanopportunitytoexplain9alittlemore.
10DR.
KRAMER:Wewillbeusinganelectronic11votingsystemforthemeeting.
Oncewebeginthe12vote,thebuttonswillstartflashingandwill13continuetoflashevenafteryouhaveenteredyour14vote.
Pleasepressthebuttonfirmlythat15correspondstoyourvote.
Ifyouareunsureof16yourvoteoryouwishtochangeyourvote,youmay17pressthecorrespondingbuttonuntilthevoteis18closed.
19Aftereveryonehascompletedtheirvote,the20votewillbelockedin.
Thevotewillthenbe21displayedonthescreen.
TheDFOwillreadthe22AMatterofRecord(301)890-4188404votefromthescreenintotherecord.
Next,we1willgoaroundtheroom,andeachindividualwho2votedwillstatetheirnameandvoteintothe3record.
Youcanalsostatethereasonwhyyou4votedasyoudid,ifyouwant.
Wewillcontinuein5thesamemanneruntilallquestionshavebeen6answeredordiscussed.
7Doesanyonehaveanyquestions,8clarificationsIseveryonereadytovoteOkay.
9(Votetaken.
)10LCDRSHEPHERD:Fortherecord,thevoteis1112yes,5no.
12DR.
KRAMER:Now,thevoteiscomplete,13we'llgoaroundthetableandhaveeveryonewho14voted,statetheirname,vote,andifyouwantto,15youcanstatethereasonwhyyouvotedasyoudid16intotherecord.
Dr.
Campopiano,wouldyoumind17startingofftherecord18DR.
CAMPOPIANO:I'msupposedtosaymy19nameOkay.
MelindaCampopiano.
Myvoteisyes.
20I'msatisfiedthattheproductisnotinferiorand21offersabenefitnotcurrentlyavailableinother22AMatterofRecord(301)890-4188405products.
1My,Iguess,modificationsorstipulations2wouldbethatthepatientsbebehaviorallystable3andthatclearclinicalguidanceaboutwho's4appropriateforthismedication,howtomanage5breakthrough,withdrawal,relapse,polysubstance6use,etcetera,whileonthemedicationbeprovided7andthatsupervisionofthemedicationand8behavioralinterventionsbeonparwithother9formulations.
10DR.
BICKEL:WarrenBickel,Ivotedyes.
11I'llsecondallyoursupplementarymaterial,butI12foundthattheFDA'sveryconservativeanalysis13thatrenderedanoninferiorityanalysiswasvery14importantinmydetermination.
15DR.
DODD:LoriDodd,andIvotedno,16largelybecauseIwasn'tsurewhatIwasvoting17for,soIdidn'twanttovoteyes.
Ithinkit18dependsalotonwhatthenoninferioritymarginis.
19Andfurthermore,itdependsonsomeyettobeseen20analysesofthemissingdata,whichIthinkhave21beendescribedthroughthepanel.
Soifyoucall22AMatterofRecord(301)890-4188406mebackinamonth,Imightchangemyvote.
1DR.
TROENDLE:JamesTroendle.
Ivotedyes.
2AlthoughIthinkthesponsor'sanalysiswaspretty3muchincomplete,IdothinktheFDA'sanalysiswas4prettythoroughandgavewhatIwouldconsiderto5beprettyconservativeassumptionsthatstillbeing6abletopassafairlysmallnoninferioritymargin.
7SoIwasconvincedbythat.
8MR.
YESENKO:MichaelYesenko.
Ivotedno9basedonthewaythequestionwaswritten.
The10sponsorwasabletoprovideananalysis,butI11votedaccordingtothewaythequestionwas12written,ratherthanthewayFDAinterpreteditat13theend.
14DR.
HIGGINS:JenniferHiggins.
Ivotedno.
15DR.
PRESTON:KenziePreston.
Ivotedyes.
16IthinktheFDAdidaverythoroughevaluation.
I17dowanttosaythatIthinkthelabelingneedsto18beveryclearaboutthepatientpopulationonwhom19itwastested,thatpeopleonlowdosesof20buprenorphinewho'vebeenshowntobestable.
21DR.
McNICHOLAS:LauraMcNicholas.
Ivoted22AMatterofRecord(301)890-4188407yes.
IalsoagreewiththeFDA'sanalysisofthe1datamoresothanthesponsor's.
AndIalsosecond2theissueofthewaythatthelabelneedstobe3wordedintermsofbehavioralstability,aswellas4thedoseofbuprenorphine.
Ialsothinkthere5needstobesomethinginthelabelabouthowto6managesupplementaldosesandwhattheimplications7ofsupplementaldosesare.
8DR.
GRIEGER:TomGrieger.
Ivotedyes.
I9thinkthatoverallthedatadidhavesomeproblems10intheanalysis.
AstheFDAputtheirinputinto11it,itwasimproved.
Ithinkclearlytherewasnot12evidenceofsignificantriskusingthisagent,and13thereisevidenceofsignificantbenefitand14hopefullygreatpromiseonceit'sactuallyout15there.
16DR.
PICKAR:Ivotedyes.
IthinktheFDA17didaverynice,fairjobinsortofreanalyzingit18asitwas.
AndIthinktheissueofefficacyin19thiscase,innoninferioritywasdemonstrated.
I20thinkthiswillsavesomefolkslives,andweheard21fromthepubliconhowintenseandawfulthese22AMatterofRecord(301)890-4188408experiencesareforeverybodyinvolved.
1SofromasafetypointofviewIthink2you'reingoodshapeandIthinkit'snoninferior,3andIvotetoapproveit.
4DR.
KRAMER:Couldyoustateyourname,5Dr.
Pickar,intotherecord6DR.
PICKAR:MynameisDavePickar,and7I'llstandbythat.
8(Laughter.
)9DR.
KRAMER:Andyouvotedyes.
10DR.
PICKAR:AndIvotedyes.
11DR.
KRAMER:MynameisDr.
JudithKramer,12andIvotedno,andIwasveryconflictedabout13this.
Itseemedtome,startingwiththereviewof14thematerialsinadvanceandlisteningtothe15discussionstodayintheopenpublichearing,quite16ablurringbetweenthefundamentalproblemwe've17gotoftheepidemic,whichistrulyapublichealth18crisis.
AndIthinkallofus,everyoneinthe19room,thesponsor,thepanel,andallthepeoplein20theopenpublichearingdesperatelywantsomething21tobeavailabletoustouse.
22AMatterofRecord(301)890-4188409Irealizethisisavery--Imostlyfocused1onclinicaltrialsinmycareer,andIrealizethis2isaverychallengingclinicaltrialpopulation.
I3fullyunderstandthat.
ButIwasdismayedbywhat4Ithoughtmetallthecriteriafornotavery5rigorousapproachonthepartofthesponsorin6termsofthingslikedecidingtoleaveout73patientsandthenclaimingthatitisreally8superior,andrepeatedlyusingthatastheline.
9SoIfeltthattherewasalreadyan10inflationgoingon.
AndwhenIstartedtohearthe11statisticianstalkaboutthelackof12conservativenessofthemargin,ofthe13noninferioritymargin,IrealizedI'mvery14concernedabouttheprecedentthissetsaboutwhat15we'regoingtodoforthisepidemic.
16Thebiggerpicture,thewholetimeI'vebeen17thinkingtomyself,thiswaspresentedlikeitwas18a6-monthtreatmentorayeartreatment.
Butwait19aminute,thesepeoplehavebeenonfor10years20Andwe'renotsureaboutthetrainingandwe'renot21sureaboutwhat'sgoingtohappen,butafterit's22AMatterofRecord(301)890-4188410onthemarket,we'lllookintoit1Wedon'thaveastrategy.
Thereweresome2thingsinthematerialthatdidn'tcomeoutinthe3discussiontodayaboutopioidusebeingasurrogate4endpointforlack--we'retalkingabouttreating5opioidaddiction,sowhatisthegoalWhatarewe6actuallydoing7Itdoesn'tappearwe'retryingtowithdraw8peoplebecausethespecialistswhosaythatthese9patientsatthislevel,iftheycomeoff75to1080percentofthemwillbeusing.
11Sowearetalkingaboutlong-termtreatment,12maintenancetreatment,butwehaven'tstudiedthat.
13Andwe'reclaimingit'ssuperiortosomethingthat14weknowhasdonewellandhassavedmanylives.
15Andthebiggestelephantintheroomisthatwe16haveanaccessproblem.
Peoplearen'tgetting17treatmentsthatareavailablebecauseofalawthat18limitsthenumberofpatientsapractitioner,who19wouldbewillingtotreatmore,couldtreat.
20SoIdon'tthinkwithourdesiretodo21something,weshouldbecarelessaboutwhatwe22AMatterofRecord(301)890-4188411address.
Somebodyneedstogetactiveandchange1thelawandgetmorepeopleabletotreatanduse2thedrugsthatareapproved,andweneedtobe3rigorousabouttheprecedenceweset.
AndI'llsee4whatDr.
Doddthinksinafewweeks.
5DR.
IONESCU:DawnIonescu.
Ivotedyes,6primarilythankstotheFDA'sverythorough7analysis,showingthatthisdid,indeed,passthe8noninferioritymarginthatwassetattheoutset.
9Whetherornotthatmarginisright,itwasset,10andthereforebeatthat.
11Justasanaside,Ithinkthatthis12representssomewhatofanexcitingthingbeyondthe13statistics,beyondthenumbers,andthatthisisan14exampleofpsychiatrybreakingthroughthestatus15quothatwecurrentlyhave,thinkingoutsidethe16box,thinkingforfuture,potentialfuture17treatment.
Sothankyouforthat.
18DR.
NARENDRAN:RajNarendran.
Ivotedyes.
19IthoughttheFDA'ssensitivityanalysis,evenwith20alltheconservativeassumptions,seemto21demonstratenoninferiority,andIthinkthere'sa22AMatterofRecord(301)890-4188412need.
Although,Idofeelthatthelabelinghasto1becrystalclearandofferaverynarrow2indication,whichshouldreallymimicthe3populationtheyrecruitedandtheirsample.
I4thinkthat'sveryimportant.
5DR.
BRADY:KathleenBrady.
Ivotedyes,6andIreallydon'tthinkIhaveanythingtoaddto7allthereasonspeoplehavealreadygiven.
8DR.
KRAMER:Dr.
Carroll,wouldyoulikeme9toreadyourresponseintotherecord10DR.
CARROLL:Yes,ifyoucan.
11DR.
KRAMER:Okay.
IfIsayanything12incorrect,pleasespeakup.
Fortherecord,13KathleenCarrollvotedyes,butwithmixedfeelings14andwithmultiplecaveatsandconcerns,including:15aclearerdefinitionofwhatconstitutesastable16patient;clearlanguagewithlabelingcoveringsome17oftheconcernsraisedinthediscussionregarding18regularmonitoring;re-analysisofsponsortrial19datawithcorrectionsasnotedinthediscussion20includingITT,handlingofmissingdata;consider21otherdefinitionsofresponse,clarity,andREMS22AMatterofRecord(301)890-4188413regardingtrainingofphysiciansforimplantation1andremoval.
2Dr.
Gordon3DR.
GORDON:AdamGordon.
Ivotedyes.
I4actuallyhadadifficulttimeonthisonesimply5becauseofseveralcaveatsI'llmentionbriefly.
I6dothinkthattheFDAdidagreatjobin7re-analyzingthedataandbeingveryconservative8intheiranalysis.
AndIthinkthenoninferiority9issuereallyswayedme.
10Certainly,Ithinkthatthere'smorebenefit11thanriskatthispointforthisapproval,and12that'swhatreallyswayedme.
However,Idowant13topointouttwoorthreethingsthatIthought14werereallyconcerning.
15Ithinktheissueofstabilityisnot16well-defined.
Andbasedonthatlackofaclear17definitionofwhatastablepatientis,Ireally18worry,postmarketing,whetherwe'regoingtohavea19lotofaberrantbehaviors,aberrantuseofthis20medicationinthisveryvulnerablepopulation.
21Ithinkingeneral,reflectingonmypatient22AMatterofRecord(301)890-4188414population,Ithinkyou'regoingtohavealotof1peopleonsupplementaldosesofthismedication.
2Andparticularlyifpeople,practitioners,whowe3can'tregulaterightnowwithnormalbuprenorphine4practices,aredoinguntowardthings,Ireally5worrythatwemayinsightaharmwiththis6implantabledevice,implantablemedicationinthis7population.
8Sowiththosecaveats,Iwasalittlebit9concerned,butoverall,basedontheevidence10presentedtoday,nottheimplicationsdownthe11road,buttheevidencepresentedtoday,Ivoted12yes.
13DR.
KOTZ:MargaretKotz.
Andit'swith14mixedfeelingsIvotedno.
Thereasonsformy15votingnowerereallyspelledoutwellbyDr.
Kathy16Carroll.
Andthemainthingswerethesupplemental17medication,andintermsthatdoeshaveincreased18riskfordiversionIfeel.
Andtheotherthing19was,iswhatdoyoudoaftertwoyearsThatstill20isahugequestionforme.
21DR.
KRAMER:Okay.
Sowe'vereadintothe22AMatterofRecord(301)890-4188415recordeveryone'sresponse,andwestillhave1question9,whichistocommentonanysuggestions2regardingfurtherdevelopmentorexplorationsthat3thesponsorshouldundertake.
Forinstance,higher4dosesoranythingelseyouwanttosuggest.
5JenniferHiggins6DR.
HIGGINS:I'dliketoseemore--a7diversepopulationstudiedifpossible.
8DR.
KRAMER:Dr.
Bickel9DR.
BICKEL:I'dliketoseedifferentdoses10explored.
I'dliketoseebettercharacterization11ofwhorespondswelltothistreatment.
I'dlike12toseeexplorationintohowitcouldbeextended13beyondtwoyears.
14DR.
KRAMER:Dr.
McNicholas15DR.
McNICHOLAS:Iwouldliketoseedataon16needforsupplementaldoses.
Ithinkthatneedsto17befollowedasthisdrugisrolledout,asto18whetherornotpatientsrequiresupplementaldoses,19andalsohowoftenthey'rebeingseen;arethey20beingseenonaregularbasisasclinically21appropriate22AMatterofRecord(301)890-4188416DR.
KRAMER:Youmeansurveillanceofthat1orastudy2DR.
McNICHOLAS:Yes.
3DR.
KRAMER:Dr.
Campopiano4DR.
CAMPOPIANO:Iagree,allofthat,plus5Ithinkthere'sauniquepotentialforthistypeof6implantableorDepoproduct,becauseitdoesn'tgo7tozeroimmediately.
SoIthinkthere'sa8potentialforaroleforthistypeoftechnologyin9long-termslowtitrationoffofmedicationfor10peopleforwhomit'sappropriate.
AndIthinkthat11wouldbeworthstudying.
12Thatsaid,futureproductsshouldbe13analyzedmuchmorerigorouslybythesponsorand14muchmoreconservatively,becausedespitethefact15thatpeoplearedying,wehavetheprivilegeof16providingthismedicationthroughanactof17Congress.
Andthatcanbetakenawayfromusifwe18areirresponsiblewiththismedicationorwescrew19itupbecausewe'retooglib.
20Sothat'sjustawordofcaution,becauseI21understandmoreproductsareindevelopment,and22AMatterofRecord(301)890-4188417theyneedtocomeforwardabsolutelycrispand1conservativeintheiranalysis.
2DR.
KRAMER:Dr.
Narendran3DR.
NARENDRAN:Myrecommendationiswe4reallydoaPEToccupancystudy.
Getthe5appropriatedose,80percentoccupancy,andtest6it,becauseIfeellikeanythingelseislike7sub-therapeutic.
It'ssortofaninferiordose.
8There'sagoodliterature.
Ididn'tquote9that,butameta-analysiswason21clinicaltrials10inbuprenorphine,thatshowedthatpatients1116milligramsorhigherhaveahigherretentionin1221clinicaltrials.
Iknowyourtrial,youfelt13veryhighretentionrate.
14Soit'sclearevidencethatwithmethadone15andbuprenorphine,youhavetobeatamuchhigher16dose.
Soan80percentoccupancydosetoshootfor17wouldhavesavedyoualotoftrouble.
18DR.
KRAMER:Dr.
Ionescu19DR.
IONESCU:Asfarasrecruitingpatients,20maybeconsideringoneofthoseexternalreader21strategiestoreallyhaveanice,ascleanaswe22AMatterofRecord(301)890-4188418canget,currentlypopulation.
1DR.
KRAMER:Dr.
Brady2DR.
BRADY:Yes,Ithinkitwouldbegoodto3haveastudythatwouldhelpdeterminewhat'sthe4bestwayforinductionorgettingpeoplestartedon5it,howsupplementaldosesshouldbeusedandhow6manyandforwhatperiodoftime7DR.
KRAMER:Dr.
Pickar8DR.
PICKAR:Ithinkthismightbean9opportunitytoreallyutilizepostmarketingdataof10anynewdrugthatIthinkabout.
I'mjust11fascinatedtoseehowitgoes.
Inmyjudgment,the12risk-rewardwasonthebasisofmovingitalong.
13Butthisisjustaninterestingopportunity,soall14thequestionsarepertainingtothat.
Butwhatwe15havealittlemoreuniquelynowistoseedata16comingin.
Sohoweveryoucankeeptrackofthese17guysandseewhatwesee,Ithinkwillbevery18helpfulfortheirfuturedevelopment.
19Intermsoftheirnotsoconservative20analysis,that'swhytheFDAishere.
Everybody's21gotarole.
22AMatterofRecord(301)890-4188419DR.
KRAMER:Dr.
Dodd1DR.
DODD:Yes,fromadesignperspective,2I'dliketoseealittlemoreexplorationofthe3frequencyoftheurinemeasurementsbecauseIdon't4wantthemessagetobesentthat--becauseinthe5previousstudies,theydidmuchmorefrequent6measurement,wellwecanbackitoffandthenwe7getanon-inferiorresult.
8SoI'dliketoseemoreofthatexplored.
9Maybethat'sapleatothestatisticianstoexplore10this.
11DR.
KRAMER:Actually,onthatpoint,I12rememberreadinginthepacketthatwhentheydid13thesurvey,thattheresponsewasthatevery--I14thinkthatevery2weekswouldhavebeenconsidered15reasonable;2weeksandamonthwasthelongest,16andyetthesponsorchosethemonthinsteadofthe17every2weeks.
Itlookslikeitwouldhavebeen18withintherealmofpracticeforthesepatients19thataremaintained.
20Dr.
Preston21DR.
PRESTON:Soobviouslyhavingdosesthat22AMatterofRecord(301)890-4188420wouldbehigherwouldbeagoodthing.
Italso1occurstomethatoneofthefrequentcausesof2relapseismisseddoses.
Soifwecanpossibly3thinkofthisassortofthebaselinemedication4administrationundersublingualdosing,andthat5thiswould,perhapsifpeoplemissdoses,keepthem6fromhavingarelapse.
Andthatwouldbeatotally7differentparadigmfromwhat'splannednow.
Butit8seemslikeapotentialuseofthisdose9administration.
10DR.
KRAMER:Andittakesawaytheadvantage11ofavoidingdiversionandpediatricoverdose--12DR.
PRESTON:Yes,that'strue.
13DR.
KRAMER:--andthemarketing.
14DR.
McNICHOLAS:Onelastthing,anditjust15occurredtome,becauseIknowcomingfrom16Philadelphia,wehadthisproblemwithsomething17calledanaltrexoneimplant.
Wehavegottokeep18trackofanyERvisits,etcetera,ifpatientstry19andtaketheimplantsoutthemselves.
Thathasgot20tobefollowed,becausethat'sdangerthatweneed21toknowabout.
22AMatterofRecord(301)890-4188421DR.
KRAMER:Doyouknowofwaystodothat1DR.
McNICHOLAS:Actually,theERsinthe2tri-stateareasetupacomputerbasethatthey3couldallplugintoandsaythepatientcameinand4somebodyhaddugitoutofhisorherbackor,and5nowthey'reinwithaninfection,etcetera.
6DR.
KRAMER:Somebodywouldhavetoorganize7that.
There'snosystemthatwouldcurrently8surveilthis.
9DR.
McNICHOLAS:No,thesponsorcansetup10asurveillanceonthat.
11DR.
KRAMER:Isthedevicesgroupinvolved12inlookingatthiswithyouornotBecauseIknow13they'vegottenintosurveillanceof–14DR.
HERTZ:Onlytotheextentthatthey're15evaluatingthetrochar,theimplantationdevice.
16DR.
KRAMER:Couldtheyhelpinsurveillance17ofexplants18DR.
HERTZ:Wewillcertainlyaskthemwhat19theyhaveavailable.
We'lltakethistopicupfor20furtherdiscussionandseewhatresourcesmightbe21availableormightneedtoberequested.
22AMatterofRecord(301)890-4188422DR.
KRAMER:Anyothercomments1(Noresponse).
2Adjournment3DR.
KRAMER:TheFDAgottheirquestions4answeredThankyouallforstayinguntilthe5bitterendandbeingsoforthright.
6DR.
HERTZ:Yes,thankyouall.
Greatly7appreciatealltheinput.
8(Whereupon,at4:55p.
m.
,themeetingwas9adjourned.
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