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FDA Overview of Molecular Diagnostics and the Critical Path Initiative
Steven Gutman, MD, MBADirector, Office of In Vitro
Diagnostics
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Medical Device Amendments of 1976
General controlsRegistration and listingGood manufacturing practicesPost market reporting
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Premarket Review
510(k)sPMAAdministrative differencesCommon scientific base
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Analytical Performance
AccuracyPrecisionAnalytical specificityAnalytical sensitivity
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Clinical Performance
Signals can be turned in to clinical actionDiagnostic sensitivityDiagnostic specificityPredictive value or positive or negative results
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Labeling -- 809.10(b)
Intended usePerformance characteristicsLimitations
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Life Cycle
Analytical performanceFeasibility *Clinical performance FDA approval – market access---------------------Real world use
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The Real World of Regulation
FDA CMS (CLIA)CMS and others (third party pay)
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Critical Path Initiative
Biomarkers appear in two contextsDiagnosisDrug discoveryConcept of personalized medicine grounded in genomic map but not bounded by this
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Critical Path Initiative
InfrastructureOpportunities listPilot programs
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Bad News
Cutting edge new technology --multiplex, bioinformatics, nanotechnologyPaucity of material or method standardsBiological and clinical nuancesFinancial uncertainties
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Bad News
Scientific limitations are clear Spectrum biasVerification biasImpact of missing data pointsDiscrepancy
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Good News
Regulatory trail is well litLiteratureStandardsGuidances
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Principle Road Maps
STARD InitiativeReMARK Initiative
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Growing Literature on Co-Development
Simon and Wang, 2006Pennello and Vishnuvajjala, 2005Sargent et al, 2005Pustzai and Hess, 2004
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Growing FDA Guidance
Voluntary Genomic Data Submissions guidanceConcept paper on co-developmentStatistical guidance on IVD labelingGuidance on pharmacogenetic and heritable genetic testsBayesian statistics
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Good News
Broad menu of regulatory toolsMandate to be least burdensomeNew scientific resources -- MDUFMANew regulatory programs -- FDA data template, critical path
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Flexible Regulatory Tools
Pre-IDEExpedited reviewsReal time reviewsDe novo classification
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Review Successes
Cystic Fibrosis test – 109 daysAvian flu – 14 daysUGT1A1 – 9 days
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Co-Development
If predictive diagnostic determines drug choiceSafety and effectiveness of drug becomes hostage to diagnosticNeed to understand system as a whole
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Predictive Marker
Identify patients by biomarker status; randomize therapy across all patientsIdentify patients by biomarker status; randomize therapy in subsetsRandomize by treatment; look back at biomarkers
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Predictive Marker
H (non-response)
G (response)
F (non-response)
E(response)
Placebo
D (non-response)
C(response)
B (non-response)
A (response)
Therapy
Neg testNeg testPositive test
Positive test
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Predictive Marker
F (non-response)
E(response)
Placebo
B (non-response)
A (response)
Therapy
Positive test
Positive test
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FDA Mission
Promote public healthProtect public healthTension in objectives
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Good Science