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BiomarkersinDrugDevelopment

ShashiAmur,Ph.D.

ScientificLeadBiomarkerQualificationProgramOfficeofTranslationalSciences

CenterforDrugEvaluationandResearchFoodandDrugAdministration

Myotonic Dystrophy Patient‐Centered Therapy DevelopmentSeptember17,2015

Overview

• Introduction

• BiomarkerQualification(BQ)

• BiomarkerSurvey

• Effortstowardsdevelopingevidentiarystandards

• Takehomepoints

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BiomarkersinDrugDevelopment

Molecularpathwaysunderpinningdisease Mechanismofactionoftherapeutics

Preclinicalsafetyassessment Clinicaltrials

• SafetyAssessment• Doseselection• Stratification• Patientselection/enrichment• SurrogateendPoint

CompanionDiagnostic• Selectionofrightpatientsforincreasedefficacy/safety 3

PrototypeDesign orDiscovery

Clinical DevelopmentBasic Research

FDA Filing/Approval &Launch

PreclinicalDevelopment Phase I Phase II Phase III

Amuretal,Clin.Pharm.Ther.98(1)34‐46,201511

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BiomarkerQualification(BQ)Definition:Aconclusionthatwithinacarefullyandspecificallystated“contextofuse”thebiomarkerhasbeendemonstratedtoreliablysupportaspecifiedmannerofinterpretationandapplicationindrugdevelopment

Contextofuse:“Contextofuse”isacomprehensivestatementthatfullyandclearlydescribesthemannerandpurposeofuseforthebiomarkerindrugdevelopment.

• UseStatement:Name,identityandpurposeofuseofthebiomarkerindrugdevelopment

• Conditionsforqualifieduse:Comprehensivedescriptionofconditionsandboundariesforthebiomarkertobeusedinthequalifiedsetting

BiomarkerQualificationConcept

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Average time for biomarker qualification process (Expanded Context of Use): 2 – 3 Years

Clearance and Publication of Guidance and FR Notice

Drafting the Biomarker Guidance

2‐4months

Clearance of guidance and

FR notice

2‐4months

Public Commentand Finalizationof Miniguidance

~4months

Initiation Consultation & Advice

Review

LOI Consideration

2‐ 4months

Briefing Document Evaluation

2– 4monthsperiteration

Full Qualification Package Evaluation

9‐ 12months

BiomarkerQualificationProcess‐ Timeline

Note: Thetimelineisbasedonourexperiencetodateandmayvary.Thistimelinedoesnotcapturethetimeneededbysubmitterstogeneratethedataandsubmitthenecessarydocuments(LOI,Briefingdocument,andFinalQualificationPackage)orrequestedadditionalinformation.

8http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ucm284076.htm

ListofFDA‐QualifiedBiomarkers

Submitters: Can beIndividuals or groups; e.g., Academia,Consortia, Disease foundations, Patient advocacy groups

ConsiderationsforBiomarkerQualification• TypeandCOUofthebiomarkerforuseindrugdevelopment

• Biologicalrationaleforuseofthebiomarker(ifavailable)

• Characterizationsofthevariousrelationshipsamongthebiomarker,theclinicaloutcomes,andthetreatment(whereapplicable)requiredfortheproposedCOU.

• Assayconsiderations(analyticallyvalidatedmethodandunderstandingofpotentialsourcesofvariabilityinthemeasurement).

• Typeofdataavailabletoassessthestrengthofassociationofthebiomarkerwithitsproposedclinicaloutcome:retrospectiveorprospective,registrydata,and/orrandomizedcontrolledtrial(RCT)data.

• Reproducibilityofdata(needfortestdatasetandconfirmatorydataset).

• Useofappropriate,pre‐specifiedstatisticalmethodstodemonstratethehypothesizedrelationshipsfortheCOU.

• Strengthofevidence:thelevelofevidencedependsonthetypeofbiomarkeranditsCOU. 9

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FRNotice‐ Survey

• Goal:IdentifyingPotentialBiomarkersforQualificationandDescribingContextsofUsetoAddressAreasImportanttoDrugDevelopment

• Logistics:PublishedonFebruary13,2015withadeadlineofApril14,2015.ExtendedtoMay15,2015

• Twooptionsgivenforprovidingresponses‐ Docket(35responsesreceived)‐ SurveyMonkey(38responsesreceived)

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Traumatic Brain InjuryPancreaticInfectiousMetabolic

Protein MisfoldingCardiovascular

RenalPulmonary

MiscellaneousMusculoskeletal

HepaticAutoimmune

OncologyNeurology

222334445668

1222 SurveyResults

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ucm459144.htmhttp://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/UCM459168.pdf

Disease BiomarkersDuchenne’sMuscularDystrophy(DMD) Dystrophin

SkeletalMRI Theassessmentofupperextremityfunctionbasedon

theconceptof3‐dimensionalreachableworkspaceDuchennemusculardystrophy(DMD),Facioscapulohumeralmusculardystrophy(FSHD),Beckermusculardystrophy(BMD),andAmyotrophicLateralSclerosis(ALS).

Ascalableandsustainableremotemeasurementplatformforupperextremityfunction.

Myotonicdystrophy(DM) Biomarkersforcardiacandcentralnervoussystem. Predictivegeneticbiomarkers.CELF1protein

(upregulatedinDM1tissues,particularlyinheart).

Numberofresponsesreceivedinthesurvey

EffortsatDevelopingEvidentiaryStandardsAMultiplestakeholdereffort:Workshops

• PhRMA‐FDAworkshopin2007• InstituteofMedicineWorkshoponBiomarkerQualification in2009• FDA‐cosponsored“Biomarkersworkshop”withHHMIin2013• FDA‐cosponsoredBrookingsmeetingon“AdvancingtheUseof

BiomarkersandPharmacogenomics”in2014• FDA‐cosponsoredworkshopwithM‐CERSIandPSTC“Evidentiary

ConsiderationsforIntegrationofBiomarkersinDrugDevelopment“heldtoday(August21,2015)

• NIH‐FDAWorkshopplannedforOctober,2015• FNIH‐FDAWorkshopplannedfor2016

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TakeHomePoints

Biomarkerscanbeintegratedintodrugdevelopmentthrougheitherofthetwopathways:1. Regulatorysubmissionsfordrugapprovalinthe

contextofasingledrugor2. Biomarkerqualification

BiomarkerQualificationisintendedforbiomarkersthatwillbeusedinmultipledrugdevelopmentprograms

BiomarkerQualificationisavoluntaryprocess

EarlyengagementwithFDAonbiomarkerqualificationencouraged 14

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Acknowledgements

JanetWoodcockShaAvhréeBuckman‐GarnerChrisLeptakSuzieMcCuneMarianneNooneSarmisthaSanyal

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Back up slides

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Identifypromisingbiomarkerspotentiallyusefulindrugdevelopment

Availabilityofareliablemethodtomeasurethebiomarker(preferablyanalyticallyvalidatedatthisstage)

ContextofUseofthebiomarker‐ How(mannerandpurposeofuse)canthebiomarker(s)beusedindrugdevelopmentprograms?

Collectavailabledata,evaluategapsinthe knowledge

Usefulnessofavailabledataforqualification(retrospectivedataacceptable);whichstudiestoselectandwhy

Additionalstudiesneeded?Planstudies‐ consultFDAearly

Considerresourcesneeded

ConsiderDesignprinciples,datastandardization,anddatasharingneeded

Prospectivestatisticalanalysisplan

Testing/confirmatorydatasets

InPreparationforBiomarkerQualification

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2008 2009 2010 2011 2012 2013 2014 2015

1st nephrotox BMs Guidance DDT Qualification (draft)

2nd nephrotox BMs

Cardiac toxicity BMs

Histopath Guidance (draft)

Guidance DDT Qualification (final)

Invasive Aspergillosis BM

CDER DDT Qualification 

MAPP

HHMI Level of Evidence Meeting

LOS 

Brookings Meeting

CPIM Guidance 

and MAPP

LOI Harmonization

FR notice ‐BQ survey

Timeline for Salient BQ-related Efforts

CPIM introduced

OND survey

Quarterly EMA‐FDA teleconferences

M‐CERSI Meeting‐Aug 2015

BMQGuidances and MAPPs

FDA-EMA collaboration

CPIM

Meeting/workshop

OND survey

LOS

LOS

FR notice- survey Plasma fibrinogen in COPD

Total Kidney 

Volume in ADPKD

LOS

LOS

LOS

LOS

IOM meeting

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What types of submissions are we seeing for Biomarker Qualification?

30http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ucm409960.htm

August,2015Update

WhereareTheSubmissionsintheBQProcess?

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16/24submittersagreedtoaddtheirSubmissioninformationtotheFDAwebpage

OpportunitiesforCollaboration• Developevidentiarystandardsforcontext‐of‐use‐specificbiomarker

qualification

• Prioritizespecificdiseasesandrespectivebiomarkerswhosedevelopmentandqualificationwouldadvancedrugdevelopmentandsatisfyunmetmedicalneeds

• Expandqualificationbydevelopingandmaintaininganaccessibledatabaseforcollectingbiomarkerdata,andarepositoryforsamples

• Developstandardsforbiomarkermeasurementtools…Reproducibilityinitiatives…

• Encourageandfundbiomedicalresearchthatisnecessaryasthebasisfordevelopmentofnewbiomarkers

• Coordinateexistingpartnershipsandconsortiasothattheyeffectivelydirecttheireffortstowarddevelopmentandqualificationofprioritybiomarkers

• Traininvestigatorsonregulatoryconsiderationsforbiomarkerdevelopment22

SlidefromDr.ShaAvhreeBuckman

Guidances

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http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM230597.pdf

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm332181.pdf

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm285297.pdf