1 testing in the open market testing in the open market aaas colloquium on personalized medicine:...
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Testing in the Testing in the Open MarketOpen Market
AAAS Colloquium on Personalized Medicine: AAAS Colloquium on Personalized Medicine: Planning for the FuturePlanning for the Future
June 2, 2009June 2, 2009
Courtney C. Harper, Ph.D.Courtney C. Harper, Ph.D.Office of In Vitro Diagnostic Device Evaluation and SafetyOffice of In Vitro Diagnostic Device Evaluation and Safety
Center for Devices and Radiological Health/FDACenter for Devices and Radiological Health/[email protected]@fda.hhs.gov
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Choose the Choose the Right Drug, Right Drug, in the in the Right Dose, Right Dose, for the for the Right Person.Right Person.
Goal = Translation of Basic Science Goal = Translation of Basic Science Discoveries to Clinical UseDiscoveries to Clinical Use
Personalized Medicine is of interest to both Personalized Medicine is of interest to both FDA, Academia, and IndustryFDA, Academia, and Industry
(part FDA’s Critical Path Initiative)(part FDA’s Critical Path Initiative)
Personalized MedicinePersonalized Medicine
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FDA is concerned that molecular diagnostic FDA is concerned that molecular diagnostic tests be reliable and tests be reliable and
that patients and health care professionals that patients and health care professionals understand both the understand both the
VValue and the alue and the LLimitationsimitations of such testingof such testing
Personalized MedicinePersonalized Medicine
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FDA Premarket ReviewFDA Premarket Review
All IVDs must establish adequate:All IVDs must establish adequate:
Analytical performanceAnalytical performance• How accurately does the test measure the analyte?How accurately does the test measure the analyte?• How reliably?How reliably?
Clinical performanceClinical performance• How reliably does the test measure the clinical How reliably does the test measure the clinical
condition?condition?
Labeling Labeling (21 CFR 809.10)(21 CFR 809.10)
• Adequate instructions for use Adequate instructions for use • Intended use, directions for use, warnings, limitations, Intended use, directions for use, warnings, limitations,
interpretation of results, performance summaryinterpretation of results, performance summary
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Analytical PerformanceAnalytical Performance• Repeatability/ReproducibilityRepeatability/Reproducibility
• Will I get the same result in repeated tests over time?Will I get the same result in repeated tests over time?• Will I get the same result as someone else testing the same Will I get the same result as someone else testing the same
sample?sample?
• AccuracyAccuracy Will I get results that are the same as “Truth”?Will I get results that are the same as “Truth”? ““Truth” – may be a reference method, clinical endpoint, Truth” – may be a reference method, clinical endpoint,
predicate device, etc…predicate device, etc…
• Limit of DetectionLimit of Detection• Potential Interferences/ Cross-ReactivityPotential Interferences/ Cross-Reactivity• Cross-contamination / Carry-overCross-contamination / Carry-over• etc…etc…
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Test developers must establish the Test developers must establish the clinical validity of their testsclinical validity of their tests
Challenges:Challenges:• Biomarker associations should be discovered Biomarker associations should be discovered
and validated in separate, independent data sets and validated in separate, independent data sets (i.e., GWAS is a great (i.e., GWAS is a great exploratoryexploratory method, findings method, findings
should be validated)should be validated)• Validation testing should be done in the Validation testing should be done in the
intended use populationintended use population• The right study can be challengingThe right study can be challenging
Clinical PerformanceClinical Performance
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New clinical studies?New clinical studies? Should represent Intended Use populationShould represent Intended Use population Prospectively collected (ideal)Prospectively collected (ideal) Clearly defined inclusion/ exclusion criteriaClearly defined inclusion/ exclusion criteria
Sample size/trial design statistically Sample size/trial design statistically appropriateappropriate
Retrospective studies OK? Yes – Retrospective studies OK? Yes – IFIF::The study supports the intended use of the testThe study supports the intended use of the testSamples were collected and stored Samples were collected and stored
appropriatelyappropriatelyNo sampling biasNo sampling bias
Clinical PerformanceClinical Performance
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IVDs – Unequal Regulation IVDs – Unequal Regulation
Longstanding FDA policy results in a non-level playing field for IVD
manufacturers.
Distributed “Test kits” must undergo FDA review prior to marketing while lab developed tests enter the market
without review
CLIA
“test kit” manufacturer lab
FDA “enforcement discretion”
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Lab Developed Tests:Lab Developed Tests:Tests Tests developeddeveloped (i.e., designed, manufactured, assembled, and (i.e., designed, manufactured, assembled, and
validated)validated) by a single lab for use only in that lab by a single lab for use only in that lab
Different regulatory threshold than FDA reviewed Different regulatory threshold than FDA reviewed tests – non-paritytests – non-parity• No premarket reviewNo premarket review• No independent research phaseNo independent research phase• No requirement for clinical validityNo requirement for clinical validity
Varying quality in test development and validationVarying quality in test development and validation Genentech petition: States that FDA should regulate Genentech petition: States that FDA should regulate
all LDTs, especially those intended for personalized all LDTs, especially those intended for personalized medicinemedicine
Laboratory Developed Laboratory Developed TestsTests
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Laboratory Developed Laboratory Developed TestsTests
FDA has authority over medical devices FDA has authority over medical devices An LDT is a medical deviceAn LDT is a medical device If a laboratory makes an LDT, then they are If a laboratory makes an LDT, then they are
a medical device manufacturera medical device manufacturer FDA has applied enforcement discretion FDA has applied enforcement discretion
over most LDTsover most LDTs Just because you have a CLIA certificate, Just because you have a CLIA certificate,
doesn’t mean that you are not a medical doesn’t mean that you are not a medical device manufacturer and everything you do device manufacturer and everything you do is under FDA enforcement discretionis under FDA enforcement discretion
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Laboratory Developed Laboratory Developed TestsTests
This policy has not changed, but it could. This policy has not changed, but it could.
In the meantime, FDA will take actions if In the meantime, FDA will take actions if patients are being put at riskpatients are being put at risk
Significant public health and policy Significant public health and policy decisions need to be made, but decisions need to be made, but • Should be done in an open transparent Should be done in an open transparent
manner with stakeholder inputmanner with stakeholder input• Should not be a surprise Should not be a surprise
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Laboratory Developed Laboratory Developed TestsTests LDTs do not include:LDTs do not include:
• Distribution of tests between sites within an Distribution of tests between sites within an organization organization (e.g., within a corporate entity or coalition of labs)(e.g., within a corporate entity or coalition of labs)
• Contract manufactured testsContract manufactured tests• Custom manufactured devicesCustom manufactured devices• Tests obtained through agreements, purchase, Tests obtained through agreements, purchase,
from othersfrom others• Non-laboratory services Non-laboratory services (software analysis, web (software analysis, web
tools, etc.)tools, etc.)
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Laboratory Developed Laboratory Developed TestsTests Tests required for drug use (companion Tests required for drug use (companion
diagnostics) require FDA approval even in diagnostics) require FDA approval even in LDTsLDTs
FDA doesn’t go looking for FDA doesn’t go looking for trouble, but some actions trouble, but some actions easily catch our attentioneasily catch our attention
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ChallengesChallenges
What level of clinical evidence for What level of clinical evidence for new tests would assure FDA new tests would assure FDA approval, adoption by clinicians, and approval, adoption by clinicians, and payor reimbursementpayor reimbursement??
We are able to test, but should we We are able to test, but should we test?test?
How to balance innovation and How to balance innovation and patient protection?patient protection?
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Summary: Bad NewsSummary: Bad News
For cutting edge new technologyFor cutting edge new technology• MultiplexMultiplex• BioinformaticsBioinformatics• NanotechnologyNanotechnology
Few material or method standardsFew material or method standards Biological and clinical nuancesBiological and clinical nuances Financial uncertaintiesFinancial uncertainties
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Summary: Good NewsSummary: Good News Regulatory trail is well litRegulatory trail is well lit
• Literature, Standards, Guidances, PrecedentsLiterature, Standards, Guidances, Precedents Broad menu of regulatory toolsBroad menu of regulatory tools
• Pre-IDEPre-IDE• Expedited reviewsExpedited reviews• Real time reviewsReal time reviews• De novo classificationDe novo classification
Mandate to be least burdensomeMandate to be least burdensome New scientific resourcesNew scientific resources -- MDUFA -- MDUFA New regulatory programsNew regulatory programs -- OIVD data -- OIVD data
template, Critical Pathtemplate, Critical Path
