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  1. 1. New Draft Guidance for Multiplex Tests Elizabeth Mansfield and Michele Schoonmaker Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) CDRH/FDA
  2. 2. <ul><li>Notice of Availability was posted in the Federal Register on April 21, 2003. </li></ul><ul><li>Draft guidance can be found at: </li></ul><ul><li> </li></ul><ul><li>Draft comment period is 90 days </li></ul><ul><li>Draft will be withdrawn and amended </li></ul>Draft Multiplex Guidance
  3. 3. <ul><li>Recommendations are non-binding </li></ul><ul><li>OIVD has little experience reviewing multiplex tests </li></ul><ul><li>OIVD hopes that industry will step forward with meaningful ideas for good guidance </li></ul>Major Points
  4. 4. <ul><li>As with other devices, regulatory path will be determined using a risk-based approach (not technology-based) </li></ul><ul><li>FDA does not consider multiplex tests as ASRs </li></ul><ul><li>Genomics and genetics have been combined in a single draft </li></ul>Major Points
  5. 5. Technical Issues in Multiplex Test Validation
  6. 6. Intended Use <ul><li>FDA requires that a device have an intended use, which usually encompasses the indications for use. </li></ul><ul><li>Intended use specifies what the test measures, why, and in what population it should be used. </li></ul><ul><li>FDA generally does not recommend multiple intended uses in a single submission. </li></ul>
  7. 7. Platform Design and Manufacturing <ul><li>Should conform with applicable parts of the Quality System Regulation </li></ul><ul><li>Recommend characterization of design, components, instruments/software, methods/conditions, layout and stability, etc. </li></ul><ul><li>Controls and calibrators: identity and physical location (if applicable), value assignment, span decision points (if applicable), etc. </li></ul>
  8. 8. Test Design: Pre-analytical <ul><li>Describe collection, storage, handling processing of sample (identity, acceptance criteria, etc.) </li></ul><ul><li>Validate purification and/or amplification methods </li></ul><ul><li>Describe acceptance criteria for material used in assay (e.g., 260/280, conc., etc.) </li></ul>
  9. 9. Specific performance characteristics <ul><li>Analytical studies on clinical samples (where appropriate) </li></ul><ul><li>Sensitivity </li></ul><ul><li>Reproducibility/precision </li></ul><ul><li>Cut-off, ref. range, decision point </li></ul><ul><li>Assay range </li></ul><ul><li>Effect of excess/limiting sample </li></ul><ul><li>Specificity and interfering substances </li></ul>
  10. 10. Array and data processing <ul><li>Optimization of multiple simultaneous target detection </li></ul><ul><li>Sample carry-over/signal bleeding </li></ul><ul><li>Computational methods </li></ul><ul><li>Limiting factors, e.g., saturation level of hybridization </li></ul>
  11. 11. Instrumentation <ul><li>Instrumentation can be general purpose or part of a system </li></ul><ul><li>If general purpose, should be characterized and have specifications </li></ul><ul><li>If part of a system, will be reviewed </li></ul><ul><li>Describe calibration of and uncertainties introduced by instrument </li></ul>
  12. 12. Regulatory Strategies
  13. 13. 510(k): Class II devices <ul><li>Compare to: </li></ul><ul><li>A commercially available predicate device (percent agreement) </li></ul><ul><li>A reference method or “gold standard” </li></ul><ul><li>(Sensitivity/specificity) </li></ul><ul><li>Standard is substantial equivalence </li></ul>
  14. 14. PMA: Class III devices <ul><li>Comparison to clinical diagnosis </li></ul><ul><li>Define “clinical truth” first </li></ul><ul><li>Sample adequate specimens/populations </li></ul><ul><li>Determine ref. ranges if appropriate </li></ul><ul><li>May verify with second detection system (e.g. RT-PCR, other appropriate system) </li></ul><ul><li>Standard is “safe and effective” </li></ul>
  15. 15. De novo 510(k) <ul><li>A clearance process for certain moderate-risk novel devices that have no predicate </li></ul><ul><li>Compare to reference method or clinical diagnosis </li></ul><ul><li>Standard is “safe and effective” </li></ul>
  16. 16. Pre-IDE (protocol review) <ul><li>IDE not required </li></ul><ul><li>Sponsor describes proposed intended use and supporting studies </li></ul><ul><li>Interactive process to provide feedback prior to initiating studies. </li></ul><ul><li>Non-binding on either party </li></ul><ul><li>Recommended for novel devices or uses </li></ul>
  17. 17. Clinical Effectiveness <ul><li>New markers, mutations, patterns should meet FDA standard for effectiveness for clinical use (see 21 CFR 860.7) </li></ul><ul><li>Established markers may refer to clinical literature to support the effectiveness of the marker for clinical use. </li></ul>
  18. 18. Use of Literature <ul><li>For some markers, mutations or patterns, a sufficient literature base may exist to support clinical validity. </li></ul><ul><li>Provide summary of available information pertinent to device. </li></ul><ul><li>Should use same technology as “new” test and similar patient population. </li></ul>
  19. 19. Problem areas
  20. 20. Study Design <ul><li>How to establish appropriate sample numbers, identities, etc., esp. when available samples are rare </li></ul><ul><li>Archived vs. prospective sampling? </li></ul><ul><li>Multiple intended uses for a single test? </li></ul>
  21. 21. Statistical Methods <ul><li>Depending on type of test, statistical methods may be straight-forward, complex and/or novel. FDA is uncertain what types of methods may be presented. </li></ul><ul><li>Describe statistical methods used for calculations, including measures of precision, confidence intervals </li></ul>
  22. 22. Quality Control <ul><li>What will be the measure of quality control? </li></ul><ul><li>Will there be universal standards/controls for arrays? </li></ul><ul><li>Importance of controls in inter- and intra-assay reproducibility at manufacturer and user level </li></ul>
  23. 23. Regulatory Environment <ul><li>Least Burdensome </li></ul><ul><li>TPLC principles </li></ul><ul><li>Transparency (truth in labeling) </li></ul>
  24. 24. Your role <ul><li>Review draft guidance carefully </li></ul><ul><li>Make comments to the docket </li></ul><ul><ul><li>On the guidance </li></ul></ul><ul><ul><li>On related issues </li></ul></ul><ul><ul><ul><li>Unvalidated features on clinical diagnostic </li></ul></ul></ul><ul><ul><ul><li>General vs. specific claims </li></ul></ul></ul><ul><ul><ul><li>Combination devices (CDRH and CDER or CBER) </li></ul></ul></ul><ul><li>Understand QSR (formerly GMP) </li></ul>
  25. 25. Future Directions <ul><li>Specific guidance is probably needed for QSR/GMP for microarray and multiplex devices—input from interested parties would be valuable </li></ul>
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