SelectChallengesinIBSClinicalTrials:

RegulatoryPerspective

LesleyS.Hanes,MDMScMedicalOfficer

DivisionofGastroenterologyandInbornErrorsofMedicine (DGIEP)FoodandDrugAdministration(FDA)

July2017

2

Disclosures

• Ihavenofinancialintereststodisclose

• TheviewsexpressedinthistalkrepresentmyopinionsanddonotnecessarilyrepresentanyofficialpoliciesoftheFDAorDGIEP

3

Overview

• BasicRegulationsforDrugApproval

• SelectchallengesinIBStrialsintendedtosupportdrugapproval

• FDAGuidanceforIndustry:IrritableBowelSyndrome(IBS)

4

StatutoryRequirementsforNewDrugApproval

Anapproveddrugmust meeteachofthefollowingstatutoryrequirements:

• Fortheproposedpatientpopulation,thebenefitsofthedrugoutweighitspotentialrisks

• Manufacturingthatensuresproductidentity,strength,andquality

• Evidence-baseddruglabelingthatadequatelyguidesprovidersandpatientstousethedrugsafelyandeffectively

AmendmentstotheFood,Drug,andCosmeticAct,19624

5

1962DrugAmendmentstotheFood,Drug&CosmeticAct:

• Requirestheestablishmentofdrugeffectivenessasaprerequisiteformarketingapproval

• Effectivenessisdemonstratedby“substantialevidence”

RegulatoryRequirements:DemonstratingEfficacy

21CFR314.50and21CFR314.126

6

BenefitofTherapy

• Afavorableeffectonameaningfulaspectofhowapatientfeels,functions,orsurvives asaresultoftreatment*

• Clinicallymeaningful,measurable,andinterpretable

• Labelingclaim(s)usingwordsthatrepresentthemeasuredconcept

*Patient-ReportedOutcomeMeasures:UseinMedicalProductDevelopmenttoSupportLabelingClaims;FDAPROGuidance

7

IBS:“FunctionalGastrointestinalDisorder”

• DescribesaspectrumofchronicGIconditions– Chronictimecourseandunpredictablesymptomexacerbations

• Therearenoknownanatomical,structural,orbiochemicalabnormalities

• Signsandsymptomsarebelievedtoberelatedtoabnormalintestinalmotility,abnormalintestinalperception,and/orabnormalbrain-gutcommunication

• Diagnosis:signsandsymptomsascertainedfromthepatient– TheRomeDiagnosticCriteria

7

8

RomeIVDiagnosticCriteria

IBSisdefinedasrecurrentabdominalpain,onaverage,atleast1dayperweekinthelast3months- associatedwith2ormoreofthefollowingcriteria:• Relatedtodefecation• Associatedwithachangeinstoolfrequency• Associatedwithachangeinstoolform

ImagefromLacyBE,Mearin F,ChangL,etal.Boweldisorders.Gastroenterology2016;150:1393

9

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

10

11

SelectChallenges

inIBSDrugDevelopment

12

TheImportanceofPatient-ReportedOutcomes

• Patient-reportedoutcomes(PROs)canrepresentdirectmeasuresoftreatmentbenefitregardinghowapatientfeelsorfunctions

• Patientinputisessentialtocaptureimportantandclinically-relevantdiseasesignsandsymptoms

13

DifferentiatingAbdominal PainandRelatedSymptoms

• Areabdominalpain andabdominaldiscomfort describingthesamesymptom?

• Abdominaldistension orbloating– Aretheyredundantwithpainordiscomfort?

14

AdditionalIBSSymptomsandSigns

IBS-C

• AbdominalDiscomfort

• Straining

• AbdominalDistentionorBloating

IBS-D

• AbdominalDiscomfort

• Urgency

• Incontinence

• Flatulence

• AbdominalDistentionorBloating

15

AdditionalSelectChallenges

• Benefitvs.RiskofTherapy

• Exploredosesandefficacyendpoint(s)

• Assesswithin patientchangesand

responderdefinitions

• Trialdesignandplaceboresponserate

• Trialdurationandtreatmentdurability

16

17

IBSGuidanceRecommendedPrimaryEndpointsComponents

AbdominalPainIntensity

- and-

AbnormalDefecation

IBS-C:stoolfrequencyIBS-D:stoolconsistency

18

AbdominalPainIntensity:ResponderDefinition

• AnAbdominalPainIntensityResponderisdefinedasapatientwhoexperiencesadecreaseintheworstabdominalpainofatleast30%comparedwithbaseline(inthepast24hours)

• Overallresponder:patientachievesthepre-specifiedimprovementinweeklyordailyresponseforatleasthalfoftheweeksordaysoftreatment

19

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

20

FinalThoughts• ManychallengesintheclinicaldevelopmentofIBStherapies

• Encourageearlycollaboration

• Considerleveragingphase2trialstooptimizeprogramsuccessby:– DefineEndpoints– Defineclinicallymeaningfuleffectsize– Identifyappropriatedosesforphase3trials– ConsidertheplaceboresponserateinIBStrials

21

ThankyouandAcknowledgements

• TaraAltepeter,MDMedicalTeamLeader,DGIEP• KerryJoLee,MDMedicalOfficer,DGIEP• DonnaGriebel,MDDivisionDirector,DGIEP• JulieBeitz,MDOfficeofDrugEvaluationIIIDirector

21

23

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

24

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.