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

  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. What is an IVD? In Vitro Diagnostic Tests for: • Diagnosis • Screening • Prevention • Risk Assessment • Surveillance • First Response • etc… • NotEnvironmental Screening

  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 result Examples: High risk – Lower risk –

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

  9. Intended Use • The risk of an IVD is based on the consequences of a false result Examples: 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 result • 3 Classification levels • Class I: common, low risk devices • Class II: more complex, moderate risk • 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: • 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 result • Lay users’ ability to understand the results of the test are also evaluated • Human 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. 1) Commercially Distributed Test Pathway: FDA approval “test kit” manufactured for distribution to multiple labs “Test kits” distributed to patients, hospital, or clinical lab 2) Lab Developed Test (LDT) Pathway: Patient Patient FDA “enforcement discretion” LDTs (lab developed tests) enter the market without review Test designed, manufactured, and used in a single lab Lab Developed Tests – Unequal Regulation

  24. Enforcement Discretion: • 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)

  25. History: LDTs - Then • 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

  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) • 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 US • 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 tests • CLIA inspects labs to ensure that adequate testing quality is in place

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

  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!