Biomarkers in Drug Development - Myotonic...Biomarkers can be integrated into drug development...
Transcript of Biomarkers in Drug Development - Myotonic...Biomarkers can be integrated into drug development...
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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?
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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