1. FDA Regulation of In Vitro Diagnostic Tests FDA Regulation of In Vitro Diagnostic Tests George Washington University March 8, 2011 Katherine Serrano Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health/FDA Katherine.serrano@fda.hhs.gov

2. Center for Devices and Radiological Health Center for Drug Evaluation and Research Center for Veterinary Medicine Center for Biologic Evaluation and Research Center for Food Safety and Applied Nutrition Office of Regulatory Affairs FDA Center for Tobacco

3. Legal Basis of Regulation Authority to regulate medical devices Public Health Services Act Federal Food Drug and Cosmetic Act (FFDCA) of 1938 Medical Device Amendments 1976 Other legislation FDA Modernization acts of 1997, 2002 and 2007

4. Medical Devices Artificial Hearts Drug Eluting Stents Hospital Beds Thermometers Tongue depressors Insulin Pumps In Vitro Diagnostic tests (IVDs)

5. In Vitro Diagnostic Tests for: DiagnosisDiagnosis ScreeningScreening PreventionPrevention Risk AssessmentRisk Assessment SurveillanceSurveillance First ResponseFirst Response etc…etc… Not Environmental ScreeningNot Environmental Screening What is an IVD?

6. FDA IVD Regulation Medical Devices (including IVDs) are regulated to an extent that is driven by the risk of their Intended Use (i.e. tongue depressors have a lower regulatory bar than artificial hearts)

7. Intended Use The risk of an IVD is based on the consequences of a false resultThe risk of an IVD is based on the consequences of a false resultExamples: High risk – Lower risk –

8. Intended Use The risk of an IVD is based on the consequences of a false resultThe risk of an IVD is based on the consequences of a false resultExamples: High risk – HIV, tuberculosis Lower risk –

9. Intended Use The risk of an IVD is based on the consequences of a false resultThe risk of an IVD is based on the consequences of a false resultExamples: High risk – HIV, tuberculosis Lower risk – Calcium, pregnancy

10. Risk-Based Classification The risk of an IVD is based on the consequences of a false resultThe risk of an IVD is based on the consequences of a false result 3 Classification levels3 Classification levels Class I:Class I: common, low risk devices Class II:Class II: more complex, moderate risk Class III:Class III: most complex, high risk and novel intended uses

11. Class II IVDs “Moderate risk” devices, tend to be more complex Examples: Blood glucose meters Troponin General Controls Usually require premarket review in the form of a premarket notification [510(k)] submission Special Controls

12. Premarket Notification: 510(k) 510(k) submission required of most class II devices Submission has 90 day review clock FDA clearance based on “substantial equivalence” to legally marketed device (predicate device) What substantial equivalence to predicate device means: –Similar intended use –Similar performance characteristics What substantial equivalence may not mean –Identical technology Submissions may require clinical data Summary of FDA’s review and basis for decision is posted on the FDA website

13. Class III IVDs Represent highest risk intended uses –Sometimes includes devices with new intended uses, technologies/methodologies, scientific questions –Examples: Hepatitis B and C, HPV tests Total PSA for prostate cancer screening Continuous Glucose Monitoring Devices Premarket Application [PMA] Submissions often include clinical data

14. Premarket Application (PMA) 180 day review clock Demonstration of safety and effectiveness Does not use predicates Submissions often include clinical data Pre-approval inspection performed FDA may seek may require advisory panel decision prior to approval Summary of Safety and Effectiveness Data (SSED) posted publicly on web

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

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

17. Other Performance: Software/Instrumentation FDA regulates all software/instrumentation used in diagnostic test systems –Database integrity –Cyber-security Engineering Considerations related to Instrumentation –Design Robustness Cleaning/disinfection Handling –Environmental Factors Temperature Humidity Altitude

18. Direct to Consumer IVDs for consumer use (OTC) have additional requirements:IVDs for consumer use (OTC) have additional requirements: Data submitted to demonstrate that the tests are accurate in the hands of lay users (including sample collection)Data submitted to demonstrate that the tests are accurate in the hands of lay users (including sample collection) Studies are performed to evaluate how well lay users can understand the instructions without prompting, perform a self- test (or collect a sample), and obtain an accurate resultStudies are performed to evaluate how well lay users can understand the instructions without prompting, perform a self- test (or collect a sample), and obtain an accurate result Lay users’ ability to understand the results of the test are also evaluatedLay users’ ability to understand the results of the test are also evaluated Human factors are also considered in the review, where applicableHuman factors are also considered in the review, where applicable

19. Post Market

20. Medical Device Reports (MDRs) Reports to FDA by user facility/manufacturer when a device: Caused or contributed, or may have caused or may have contributed to a death Caused or contributed, or may have caused or may have contributed to a serious injury Malfunctioned or failed to meet specifications (manufacturer only) Recurrence could result in death or serious injury Required timeframe for reporting 5-30 days, depending on severity Follow-ups when needed FDA assesses reports and decides if action is needed

21. Recalls Method of removing or correcting products that are in violation of laws Products present a risk of injury or gross deception or are otherwise defective Usually voluntary by manufacturer, but must be reported to FDA FDA Conducts health hazard evaluation (HHE) Classifies recall Posts recall information on website Ensures manufacturer completes recall

22. Laboratory Developed Tests

23. Lab Developed Tests – Unequal Regulation “test kit” manufactured for distribution to multiple labs Test designed, manufactured, and used in a single lab FDA “enforcement discretion” FDA approval LDTs (lab developed tests) enter the market without review Patient “Test kits” distributed to patients, hospital, or clinical lab Patient 1) Commercially Distributed Test Pathway: 2) Lab Developed Test (LDT) Pathway:

24. Definition: When FDA does not enforce some or all applicable laws and regulations on certain categories of products (drugs, devices, biologics, etc.) Key Points: Enforcement discretion not unique to LDTs Enforcement discretion does not change the fact that the law applies Many different reasons for this practice (risk, history, timing, resources, etc.) Practices like this do occur, but may change (often because of changes in risk profile of the products) Enforcement Discretion:

25. Local Mostly non-commercial Tests generally used FDA-approved components Test methods generally well established, accessible Most tests were single signal tests Used simple, well-defined chemical, biological, or immunological principles (IHC, RIA, etc.) Clinician/Pathologist/Patient relationships Simple software – calculations Performed by specialists with advanced training and require expert interpretation (karyotype, IHC) Small test volumes History: LDTs - Then

26. History: LDTs - Now Volume and types of LDTs has grown significantly Often a mechanism for market entry of novel tests Higher proportion in commercial labs and biotechnology companies Often no clinician/pathologist/patient relationship Tests developed for broad, commercial use Tests broadly advertised Often require complex software

27. CLIA What does CLIA stand for? Clinical Laboratory Improvement Amendments (1988)Clinical Laboratory Improvement Amendments (1988) Implemented by the Centers for Medicare and Medicaid Services (CMS)Implemented by the Centers for Medicare and Medicaid Services (CMS) What does CLIA provide for? The regulation of laboratories that perform clinical testing on human samples in the USThe regulation of laboratories that perform clinical testing on human samples in the US Requires adequate personnel training/education, quality system for testing, record keeping, proficiency testing, etc.Requires adequate personnel training/education, quality system for testing, record keeping, proficiency testing, etc. CLIA requires that labs have adequate methods/records of analytical validation of testsCLIA requires that labs have adequate methods/records of analytical validation of tests CLIA inspects labs to ensure that adequate testing quality is in placeCLIA inspects labs to ensure that adequate testing quality is in place

28. Why did FDA apply enforcement discretion to LDTs? Should they? Why or Why not? LDT Enforcement Discretion

29. Greater Oversight for LDTs? Oversight: Concerns –Burden of FDA regulation is too great –Stifle innovation –Decreased patient access to critical tests –Effect of regulation on rare disease testing –Oversight already exists under CLIA

30. Greater Oversight for LDTs? Oversight: Pro –In some cases, there is an FDA cleared/approved alternative –Patient protections needed –Independent evaluation of data and claims needed –Innovation needs to be controlled –Unlevel playing field and regulatory uncertainty

31. Potential Framework Elements Risk-based, phased-in over time to allow for predictability, planning Exemptions for certain categories of LDTs –Rare Diseases –Tests used for forensic (law enforcement) purposes List of who offers what –Coordinate with NIH’s Genetic Test Registry? Implement modifications to current oversight structure where appropriate

32. LDT Example: Her2/neu testing Her2/neu Test Test determines whether a woman with breast cancer will respond to Herceptin treatment 3 FDA approved tests available Many LDTs also available Recent report – 20-50% of Her2 tests inaccurate

33. Example: Her2/neu testing What are the potential reasons for this inaccuracy? What are the potential risks of inaccurate results?

34. Direct to Consumer Genetic Testing

35. DTC Genetic Testing A number of for-profit companies now provide personal genomic testing services directly to patients Companies uniformly claim “laboratory developed test (LDT)” status Wide range of information provided by these services ranges:  Some usually do not meet definition of medical device  Ancestry  Forensics  Non-medical information  Some do meet definition of medical device  Pharmacogenetic profiles  Mendelian disease mutations  Risk prediction for disease/condition  Others

36. Challenges to DTC Oversight  Patients require protection from misleading, false information  Correct measurement, valid clinical claims  Medical device regulation must keep up with science and technology  Assessment of new technology (i.e. multiplexed devices)  How to promote quality and innovation  Healthcare community requires training in how to use new information  Wide variety of genetic information available, spectrum of usefulness

37. DTC What potential benefits to patients are there through this testing? What potential risks may be posed through this type of testing?

38. Summary LDTs and genetic tests have so far avoided regulatory oversight but this is changing FDA tries to minimize stifling new technology while concentrating on areas that pose greatest risk to patients If you find consumer protection in health care important consider working at the FDA!