1. 1 Testing in the Open Market Testing in the Open Market AAAS Colloquium on Personalized Medicine: Planning for the Future June 2, 2009 Courtney C. Harper, Ph.D. Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health/FDA courtney.harper@fda.hhs.gov

2. 2 Choose the Right Drug, in the Right Dose, for the Right Person. Goal = Translation of Basic Science Discoveries to Clinical Use Personalized Medicine is of interest to both FDA, Academia, and Industry (part FDAs Critical Path Initiative) Personalized Medicine

3. 3 FDA is concerned that molecular diagnostic tests be reliable and FDA is concerned that molecular diagnostic tests be reliable and that patients and health care professionals understand both the Value and the Limitations of such testing Personalized Medicine

4. 4 FDA Premarket Review All IVDs must establish adequate: Analytical performance How accurately does the test measure the analyte? How accurately does the test measure the analyte? How reliably? How reliably? Clinical performance How reliably does the test measure the clinical condition? How reliably does the test measure the clinical condition? Labeling (21 CFR 809.10) Adequate instructions for use Adequate instructions for use Intended use, directions for use, warnings, limitations, interpretation of results, performance summary Intended use, directions for use, warnings, limitations, interpretation of results, performance summary

5. 5 Analytical Performance Repeatability/Reproducibility Repeatability/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 sample? Will I get the same result as someone else testing the same sample? Accuracy Accuracy 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, predicate device, etc… Truth – may be a reference method, clinical endpoint, predicate device, etc… Limit of Detection Limit of Detection Potential Interferences/ Cross-Reactivity Potential Interferences/ Cross-Reactivity Cross-contamination / Carry-over Cross-contamination / Carry-over etc… etc…

6. 6 Test developers must establish the clinical validity of their tests Test developers must establish the clinical validity of their tests Challenges: Challenges: Biomarker associations should be discovered and validated in separate, independent data sets Biomarker associations should be discovered and validated in separate, independent data sets (i.e., GWAS is a great exploratory method, findings should be validated) Validation testing should be done in the intended use population Validation testing should be done in the intended use population The right study can be challenging The right study can be challenging Clinical Performance

7. 7 New clinical studies? New clinical studies? Should represent Intended Use population Should represent Intended Use population Prospectively collected (ideal) Prospectively collected (ideal) Clearly defined inclusion/ exclusion criteria Clearly defined inclusion/ exclusion criteria Sample size/trial design statistically appropriate Sample size/trial design statistically appropriate Retrospective studies OK? Yes – IF: Retrospective studies OK? Yes – IF: The study supports the intended use of the test Samples were collected and stored appropriately No sampling bias Clinical Performance

8. 8 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

9. 9 Lab Developed Tests: Tests developed (i.e., designed, manufactured, assembled, and validated) by a single lab for use only in that lab Different regulatory threshold than FDA reviewed tests – non-parity Different regulatory threshold than FDA reviewed tests – non-parity No premarket review No premarket review No independent research phase No independent research phase No requirement for clinical validity No requirement for clinical validity Varying quality in test development and validation Varying quality in test development and validation Genentech petition: States that FDA should regulate all LDTs, especially those intended for personalized medicine Genentech petition: States that FDA should regulate all LDTs, especially those intended for personalized medicine Laboratory Developed Tests

10. 10 Laboratory Developed Tests FDA has authority over medical devices FDA has authority over medical devices An LDT is a medical device An LDT is a medical device If a laboratory makes an LDT, then they are a medical device manufacturer If a laboratory makes an LDT, then they are a medical device manufacturer FDA has applied enforcement discretion over most LDTs FDA has applied enforcement discretion over most LDTs Just because you have a CLIA certificate, doesnt mean that you are not a medical device manufacturer and everything you do is under FDA enforcement discretion Just because you have a CLIA certificate, doesnt mean that you are not a medical device manufacturer and everything you do is under FDA enforcement discretion

11. 11 Laboratory Developed Tests This policy has not changed, but it could. This policy has not changed, but it could. In the meantime, FDA will take actions if patients are being put at risk In the meantime, FDA will take actions if patients are being put at risk Significant public health and policy decisions need to be made, but Significant public health and policy decisions need to be made, but Should be done in an open transparent manner with stakeholder input Should be done in an open transparent manner with stakeholder input Should not be a surprise Should not be a surprise

12. 12 Laboratory Developed Tests LDTs do not include: LDTs do not include: Distribution of tests between sites within an organization Distribution of tests between sites within an organization (e.g., within a corporate entity or coalition of labs) Contract manufactured tests Contract manufactured tests Custom manufactured devices Custom manufactured devices Tests obtained through agreements, purchase, from others Tests obtained through agreements, purchase, from others Non-laboratory services (software analysis, web tools, etc.) Non-laboratory services (software analysis, web tools, etc.)

13. 13 Laboratory Developed Tests Tests required for drug use (companion diagnostics) require FDA approval even in LDTs Tests required for drug use (companion diagnostics) require FDA approval even in LDTs FDA doesnt go looking for trouble, but some actions easily catch our attention

14. 14 Challenges What level of clinical evidence for new tests would assure FDA approval, adoption by clinicians, and payor reimbursement? What level of clinical evidence for new tests would assure FDA approval, adoption by clinicians, and payor reimbursement? We are able to test, but should we test? We are able to test, but should we test? How to balance innovation and patient protection? How to balance innovation and patient protection?

15. 15 Summary: Bad News For cutting edge new technology Multiplex Multiplex Bioinformatics Bioinformatics Nanotechnology Nanotechnology Few material or method standards Few material or method standards Biological and clinical nuances Biological and clinical nuances Financial uncertainties Financial uncertainties

16. 16 Summary: Good News Regulatory trail is well lit Regulatory trail is well lit Literature, Standards, Guidances, Precedents Literature, Standards, Guidances, Precedents Broad menu of regulatory tools Broad menu of regulatory tools Pre-IDE Pre-IDE Expedited reviews Expedited reviews Real time reviews Real time reviews De novo classification De novo classification Mandate to be least burdensome Mandate to be least burdensome New scientific resources -- MDUFA New scientific resources -- MDUFA New regulatory programs -- OIVD data template, Critical Path New regulatory programs -- OIVD data template, Critical Path

17. 17 courtney.harper@fda.hhs.gov courtney.harper@fda.hhs.gov Thank you!