FDA Evaluation of Prescription Genetic Tests

1. Molecular and Clinical Genetics Panel for Direct-to-Consumer (DTC) Genetic Tests FDA Evaluation of Prescription Genetic Tests Reena Philip, Ph.D. OIVD/CDRH/FDA March 9, 2011

2. IVD Device Regulation Safety • Are there reasonable assurances, based on valid scientific evidencethat the probable benefits to health from use of the device outweigh any probable risks? [21 CFR 860.7(d)(1)] Effectiveness • Is there reasonable assurance based on valid scientific evidencethat the use of the device in the target population will provide clinically significant results? [21 CFR 860.7(e)(1)]

3. Genetic Tests: Categories • Single analyte tests • Genotyping • Multiple analyte genetic tests • Multiplex

4. FDA Cleared Prescription Genetic Tests: Examples • Single analyte genetic tests • Factor II / Factor V / MTHFR (aid in diagnosis claim) • Multiple analyte genetic tests • CFTR (carrier testing, newborn screening, and confirmatory diagnosis claim) • CYP2D6 genotyping (drug metabolism claim)

5. What Does FDA Review for Prescription Genetic Tests? • Intended use/indications for use • Device description (platform, software) • Pre-analytical • Analytical validation • Clinical validation • Instrumentation, software validation (if applicable) • Labeling (package insert)

6. What Does FDA Review for Prescription Genetic Tests? • Intended use/indications for use • Device description (platform, software) • Pre-analytical • Analytical validation • Clinical validation • Instrumentation, software validation (if applicable) • Labeling (package insert)

7. Intended Use/Indications for Use • Intended use specifies • What the test measures • Why (the clinical indication for use) • In what population it is intended to be used • Setting in which the device is meant to be used

8. Example: Intended Use • The –---- Cystic Fibrosis Kit is a device used to simultaneously detect and identify a panel of mutations and variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in human blood specimens. The panel includes mutations and variants currently recommended by the American College of Medical Genetics and American College of Obstetricians and Gynecologists (ACMG/ACOG), plus some of the worlds most common and North American-prevalent mutations. The ----- Cystic Fibrosis Kit is a qualitative genotyping test which provides information intended to be used for carrier testing in adults of reproductive age, as an aid in newborn screening, and in confirmatory diagnostic testing in newborns and children.  • The kit is not indicated for use in fetal diagnostic or pre-implantation testing. This kit is also not indicated for stand-alone diagnostic purposes. • For Prescription use only.

9. Intended Use/Indications for Use • Device needs to have a clinical indication • The types of validation studies that are needed depend on the claims that are made in the intended use

10. What Does FDA Review for Prescription Genetic Tests? • Intended use/indications for use • Device description (platform, software) • Pre-analytical • Analytical validation • Clinical validation • Instrumentation, software validation (if applicable) • Labeling (package insert)

11. Pre-analytical • Sample collection/transport/storage • Sample preparation/conditions • Nucleic acid isolation • Stability of the analyte in the patient specimen

12. Analytical Performance • Does my test measure the analyte I think it does? • Correctly? • Reliably?

13. Analytical Performance • Accuracy • Precision (repeatability, reproducibility) • Performance around the cut-off • Limit of Detection • Interference, cross-reactivity • Sample type/matrix • Potential for carryover, cross-hybridization • Effect of excess/limiting sample

14. Analytical Performance: Accuracy • Closeness of the agreement between the result of a test and result of reference method.

15. Analytical Performance: Accuracy • Compare to ………. • Comparison to a reference method • e.g., bi-directional DNA sequencing • Comparison to a clinical truth • Real clinical samples • Multiple clinical samples per allele • Cover every claimed allele/result, genotypes, subtypes/classes

16. Analytical Performance: Accuracy(Continued) An example of why we ask accuracy data of every individual allele the test claims to detect:

17. Analytical Performance: Precision • Studies should demonstrate that the intended users can get reliable results • All sources of variability should be identified and assessed for its impact on assay precision • Should use clinical samples where possible • Adequate coverage of all genotypes/tumor types • In limited cases (i.e., very rare alleles) may use contrived samples • Samples should mimic the molecular composition and concentration of real clinical samples • All analytical steps of the assay should be included

18. Test Performance: Evaluation • Analytical performance - does my test measure the analyte I think it does? Correctly? How reliably? • Clinical performance- does my test result correlate with target condition of interest in a clinically significant way?

19. Clinical Performance: Genetic Tests • When there is sufficient information that establishes well-known association between genetic variants and medical condition – • For each claimed allele: • Peer-reviewed articles • Genotype – Phenotype

20. Clinical Performance: Genetic Tests (Continued) • When there is not enough information that establishes well-known association between genetic variants and medical condition – • May require clinical studies

21. Clinical Performance: Examples • CFTR mutation panel • ACOG/ACMG recommendation • Published literature • Mutations in a novel gene to predict risk of developing cancer • Most likely needs clinical studies

22. Clinical Effectiveness Established Markers (Medical literature) • New Markers • (Should meet FDA standard for effectiveness) • (based on valid scientific evidence that the use of the device in the target population will provide clinically significant results[21 CFR 860.7(e)(1)])

23. What Does FDA Review for Prescription Genetic Tests? • Intended use/indications for use • Device description (platform, software) • Pre-analytical • Analytical validation • Clinical validation • Instrumentation, software validation (if applicable) • Labeling (package insert)

24. Labeling and Reporting Results • 21 CFR part 809 (subpart B) • Tests provide results, limited interpretation required

25. Most Frequent Issues…FDA Evaluation of Genetic Tests • Lack of clinical samples covering all genotypes • Lack of literature to support validity • One or two references may not be sufficient • Genotype and Phenotype not indicated • Pre-analytical issues • Lack of specimens from start to end (e.g., whole blood  assay result) • Sample matrix issues

26. Summary: What Does FDA Review for Prescription Genetic Tests? • Safety and effectiveness generally determined based on: • Satisfactory analytical performance • Clinical performance in the context of use • Labeling that is compliant with the labeling regulations for IVDs (21 CFR 809 Subpart B) • And other factors such as ability to repeatedly manufacture the device to specifications

27. Relevant Guidance Documents • Guidance on Pharmacogenetic Tests and Genetic Tests for Heritable Markershttp://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071075.pdf • Class II Special Controls Guidance Document: CFTR Gene Mutation Detection Systemshttp://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071104.pdf • Class II Special Controls Guidance Document: Drug Metabolizing Enzyme Genotyping System - Guidance for Industry and FDA Staff http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071085.pdf • Class II Special Controls Guidance Document: Instrumentation for Clinical Multiplex Test Systems - Guidance for Industry and FDA Staff http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071061.pdf

28. Performance of FDA Approved/Cleared Genetic Tests are Publicly Available • Decision summaries of 510(k)s http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm • Summary of Safety & Effectiveness of PMAs http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm

29. Thank You! Reena.Philip@fda.hhs.gov

30. Molecular and Clinical Genetics Panel for Direct-to-Consumer (DTC) Genetic Tests Principles of FDA Regulation for In Vitro Diagnostic Tests for Home Use Carol C. Benson OIVD/CDRH/FDA March 9, 2011

31. Overview Examples of home use testBenefitsRisksInterpretation of results Device performanceLabeling Human factors

32. Examples of Home Use Tests FDA Regulates

33. Examples of Home Use Tests FDA Regulates (Continued) And others …but “No” genetic tests

34. What are the Benefits for Home Use Tests? Condition/disease that needs to be monitored at home? Diabetes – home glucose meters monitor the management of diabetes home user under care of a physician Not for diagnosis – no performance

35. What are the Benefits for Home Use Tests? Condition/disease that can be identified to allow for early detection at home? Pregnancy – urine hCG tests users retest, go to HCP

36. What are the Benefits for Home Use Tests? Condition/disease that can be screened for at home? Drug detection – Home DOA urine test Not a definitive test Mitigation - send sample for confirmation testing

37. What are the Risks of Home Use Tests? Is the device robust? Simple to use Works correctly every time Not affected by environmental conditions or different operators Can a home user read instructions and Collect the sample correctly Perform the test Get accurate results and interpret results

38. Interpretation of the Results to Ensure Safe and Effective Use Does the home user know what to do with the results? Test again on another day Collect another sample and retest Contact HCP – seek treatment Not seek treatment Not suspect the test may be wrong

39. What are the Risks of False or Inaccurate Results at Home? Failure to seek treatment Delay in seeking treatment Improper self management/treatment No follow up with health care provider Unnecessary worry False sense of security

40. Do the benefits outweigh the risks? If yes, then…

41. Evaluate Performance of the Test in the Hands of the Intended User: Home User Study • Compare home user results to laboratory method • How well the test should work at home depends upon benefit and mitigation of risks • Likelihood of incorrect results

42. Labeling Does the labeling provide adequate information so home user can perform the test and interpret the results for safe and effective use?

43. How Does FDA Review Labeling for Home Use Tests? Written at 8th grade reading level Simple instructions Pictures and diagrams on how to get sample and perform test Clear instructions on how to interpret the results (what to do with the results – call HCP – retest) Users know when device did not work User know what to do if device does not work Telephone number to call for assistance

44. How Do Human Factors Play a Role in Home Tests? • People have different abilities to follow directions • Home users are not trained users so no “good laboratory practice” standard for them • Fail to get adequate or appropriate sample • Can perform test incorrectly • Can interpret results incorrectly

45. Summary – FDA Principles for Regulation of Home Use Tests • FDA regulates home use tests • Benefits vs. risks • Mitigation of risks • Interpretation of results by home user • Performance of the device by home user • Labeling • Human factors

46. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfIVD/Search.cfmhttp://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfIVD/Search.cfm Website for Database Search for Home Use Tests:

47. Thank You! Carol.Benson@fda.hhs.gov

48. Molecular and Clinical Genetics Panel for Direct-to-Consumer (DTC) Genetic Tests Risk Assessment Tests Marina Kondratovich, Ph.D. OIVD/CDRH/FDA March 9, 2011

49. Overview • Introduction • Basic concepts: risks, relative risks, • likelihood ratios, odds ratios • 3. Description of a typical DTC risk • assessment test • 4. Clinical validation • (discrimination and calibration)

50. 1. Introduction • Susceptibility/Pre-dispositional tests (Risk Assessment tests): • tests that estimate the lifetime risk (relative or • absolute) that an individual will develop a condition. • Examples: test for Alzheimer’s disease, • test for prostate cancer, • test for type 2 diabetes • Possible Intended Use Claim: • “…to estimate the likelihood that an individual will develop <target condition> during the lifetime…”