10. Hanes Updated final IMMPACT Meeting FDA IBS Presentation.pdfStauffer JW, von Stein T, White RE,...
Transcript of 10. Hanes Updated final IMMPACT Meeting FDA IBS Presentation.pdfStauffer JW, von Stein T, White RE,...
SelectChallengesinIBSClinicalTrials:
RegulatoryPerspective
LesleyS.Hanes,MDMScMedicalOfficer
DivisionofGastroenterologyandInbornErrorsofMedicine (DGIEP)FoodandDrugAdministration(FDA)
July2017
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Disclosures
• Ihavenofinancialintereststodisclose
• TheviewsexpressedinthistalkrepresentmyopinionsanddonotnecessarilyrepresentanyofficialpoliciesoftheFDAorDGIEP
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Overview
• BasicRegulationsforDrugApproval
• SelectchallengesinIBStrialsintendedtosupportdrugapproval
• FDAGuidanceforIndustry:IrritableBowelSyndrome(IBS)
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StatutoryRequirementsforNewDrugApproval
Anapproveddrugmust meeteachofthefollowingstatutoryrequirements:
• Fortheproposedpatientpopulation,thebenefitsofthedrugoutweighitspotentialrisks
• Manufacturingthatensuresproductidentity,strength,andquality
• Evidence-baseddruglabelingthatadequatelyguidesprovidersandpatientstousethedrugsafelyandeffectively
AmendmentstotheFood,Drug,andCosmeticAct,19624
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1962DrugAmendmentstotheFood,Drug&CosmeticAct:
• Requirestheestablishmentofdrugeffectivenessasaprerequisiteformarketingapproval
• Effectivenessisdemonstratedby“substantialevidence”
RegulatoryRequirements:DemonstratingEfficacy
21CFR314.50and21CFR314.126
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BenefitofTherapy
• Afavorableeffectonameaningfulaspectofhowapatientfeels,functions,orsurvives asaresultoftreatment*
• Clinicallymeaningful,measurable,andinterpretable
• Labelingclaim(s)usingwordsthatrepresentthemeasuredconcept
*Patient-ReportedOutcomeMeasures:UseinMedicalProductDevelopmenttoSupportLabelingClaims;FDAPROGuidance
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IBS:“FunctionalGastrointestinalDisorder”
• DescribesaspectrumofchronicGIconditions– Chronictimecourseandunpredictablesymptomexacerbations
• Therearenoknownanatomical,structural,orbiochemicalabnormalities
• Signsandsymptomsarebelievedtoberelatedtoabnormalintestinalmotility,abnormalintestinalperception,and/orabnormalbrain-gutcommunication
• Diagnosis:signsandsymptomsascertainedfromthepatient– TheRomeDiagnosticCriteria
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RomeIVDiagnosticCriteria
IBSisdefinedasrecurrentabdominalpain,onaverage,atleast1dayperweekinthelast3months- associatedwith2ormoreofthefollowingcriteria:• Relatedtodefecation• Associatedwithachangeinstoolfrequency• Associatedwithachangeinstoolform
ImagefromLacyBE,Mearin F,ChangL,etal.Boweldisorders.Gastroenterology2016;150:1393
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CollaboratinginIBSDrugDevelopment
• Weworkwithmultiplestakeholders,includingpatients,pharmaceuticalcompanies,academia,andprofessionalsocieties
• Thepatientperspectiveiskey
• PublicmeetingonFunctionalGIDisordersPatient-FocusedDrugDevelopment
pre-IND INDPhases
IND NDA/BLA
Discovery&chemicalsynthesis
Non-Clinical:ResearchLab&Animals
ClinicalPhase1:Safety/TolerabilityandPharmacologicalStudies
ClinicalPhase2(proof-of-concept):EarlyEfficacyTesting&DoseDetermination
ClinicalPhase3:SafetyandefficacyStudies
DrugDevelopmentProcessforIBS
Post-m
arketin
g
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SelectChallenges
inIBSDrugDevelopment
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TheImportanceofPatient-ReportedOutcomes
• Patient-reportedoutcomes(PROs)canrepresentdirectmeasuresoftreatmentbenefitregardinghowapatientfeelsorfunctions
• Patientinputisessentialtocaptureimportantandclinically-relevantdiseasesignsandsymptoms
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DifferentiatingAbdominal PainandRelatedSymptoms
• Areabdominalpain andabdominaldiscomfort describingthesamesymptom?
• Abdominaldistension orbloating– Aretheyredundantwithpainordiscomfort?
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AdditionalIBSSymptomsandSigns
IBS-C
• AbdominalDiscomfort
• Straining
• AbdominalDistentionorBloating
IBS-D
• AbdominalDiscomfort
• Urgency
• Incontinence
• Flatulence
• AbdominalDistentionorBloating
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AdditionalSelectChallenges
• Benefitvs.RiskofTherapy
• Exploredosesandefficacyendpoint(s)
• Assesswithin patientchangesand
responderdefinitions
• Trialdesignandplaceboresponserate
• Trialdurationandtreatmentdurability
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IBSGuidanceRecommendedPrimaryEndpointsComponents
AbdominalPainIntensity
- and-
AbnormalDefecation
IBS-C:stoolfrequencyIBS-D:stoolconsistency
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AbdominalPainIntensity:ResponderDefinition
• AnAbdominalPainIntensityResponderisdefinedasapatientwhoexperiencesadecreaseintheworstabdominalpainofatleast30%comparedwithbaseline(inthepast24hours)
• Overallresponder:patientachievesthepre-specifiedimprovementinweeklyordailyresponseforatleasthalfoftheweeksordaysoftreatment
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IBSGuidanceRecommended TrialEntryCriteria
IBS-C(constipation)
• AbdominalPainIntensity:weeklyaverageofworstdaily(inpast24hours)abdominalpainscoreof>3.0ona0to10pointscale
and• StoolFrequency: fewer
than3CSBMs(completespontaneousbowelmovements)perweek
IBS-D(diarrhea)
• AbdominalPainIntensity:weeklyaverageofworstdaily(inpast24hours)abdominalpainscoreof>3.0ona0to10pointscale
and• StoolConsistency: atleast
1stoolwithaconsistencyofType6orType7Bristolstoolscore(BSS)onatleast2daysperweek
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FinalThoughts• ManychallengesintheclinicaldevelopmentofIBStherapies
• Encourageearlycollaboration
• Considerleveragingphase2trialstooptimizeprogramsuccessby:– DefineEndpoints– Defineclinicallymeaningfuleffectsize– Identifyappropriatedosesforphase3trials– ConsidertheplaceboresponserateinIBStrials
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ThankyouandAcknowledgements
• TaraAltepeter,MDMedicalTeamLeader,DGIEP• KerryJoLee,MDMedicalOfficer,DGIEP• DonnaGriebel,MDDivisionDirector,DGIEP• JulieBeitz,MDOfficeofDrugEvaluationIIIDirector
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ReferencesCodeofFederalRegulation• Documentedby“Substantialevidence”(21CFR201.56(a)(3))• Evidencefrom“Adequateandwell-controlledclinicaltrials”(21CFR314.126)• Themethodsofassessmentofsubject’sresponseare“well-definedandreliable” (21
CFR314.126)
FDAGuidanceDocuments• USFoodandDrugAdministration.GuidanceforIndustry:Patient-ReportedOutcome
Measures:UseinMedicalProductDevelopmenttoSupportLabelingClaimsDevelopmentTools.December2009.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf.
• USFoodandDrugAdministration.GuidanceforIndustry:IrritableBowelSyndrome–ClinicalEvaluationofDrugsforTreatment.May2012.https://www.fda.gov/ucm/groups/fdagov-public/documents/document/ucm205269.pdf
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References(continued)• TheVoiceofthePatient:FunctionalGastrointestinalDisorders(5-11-15):
https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM480542.pdf
• IrvineEJ,TackJ,CrowellMD,GweeKA,KeM,Schmulson MJ,WhiteheadWE,SpiegelB. DesignofTreatmentTrialsforFunctionalGastrointestinalDisorders. Gastroenterology.2016May;150(6):1469-1480.e1.doi:10.1053/j.gastro.2016.02.010.
• DworkinRH,TurkDC,Wyrwich KW,BeatonD,Cleeland CS,FarrarJT,HaythornthwaiteJA,JensenMP,KernsRD,Ader DN,BrandenburgN,BurkeLB,Cella D,ChandlerJ,CowanP,Dimitrova R,DionneR,HertzS,Jadad AR,KatzNP,Kehlet H,KramerLD,ManningDC,McCormickC,McDermottMP,McQuay HJ,PatelS,PorterL,Quessy S,RappaportBA,Rauschkolb C,Revicki DA,RothmanM,Schmader KE,StaceyBR,StaufferJW,vonSteinT,WhiteRE,WitterJ,Zavisic S. Interpretingtheclinicalimportanceoftreatmentoutcomesinchronicpainclinicaltrials:IMMPACTrecommendations. JPain.2008Feb;9(2):105-21.Epub 2007Dec11.PubMedPMID:18055266.