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 New Draft Guidance for Multiplex Tests Elizabeth Mansfield and Michele Schoonmaker Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) CDRH/FDA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. Notice of Availability was posted in the Federal Register on April 21, 2003. Notice of Availability was posted in the Federal Register on April 21, 2003. Draft guidance can be found at: Draft guidance can be found at: http://www.fda.gov/cdrh/oivd/guidance/1210.pdf Draft comment period is 90 days Draft comment period is 90 days Draft will be withdrawn and amended Draft will be withdrawn and amended Draft Multiplex Guidance

3. Recommendations are non-binding Recommendations are non-binding OIVD has little experience reviewing multiplex tests OIVD has little experience reviewing multiplex tests OIVD hopes that industry will step forward with meaningful ideas for good guidance OIVD hopes that industry will step forward with meaningful ideas for good guidance Major Points

4. As with other devices, regulatory path will be determined using a risk-based approach (not technology-based) As with other devices, regulatory path will be determined using a risk-based approach (not technology-based) FDA does not consider multiplex tests as ASRs FDA does not consider multiplex tests as ASRs Genomics and genetics have been combined in a single draft Genomics and genetics have been combined in a single draft Major Points

5. Technical Issues in Multiplex Test Validation

6. Intended Use FDA requires that a device have an intended use, which usually encompasses the indications for use. FDA requires that a device have an intended use, which usually encompasses the indications for use. Intended use specifies what the test measures, why, and in what population it should be used. Intended use specifies what the test measures, why, and in what population it should be used. FDA generally does not recommend multiple intended uses in a single submission. FDA generally does not recommend multiple intended uses in a single submission.

7. Platform Design and Manufacturing Should conform with applicable parts of the Quality System Regulation Should conform with applicable parts of the Quality System Regulation Recommend characterization of design, components, instruments/software, methods/conditions, layout and stability, etc. Recommend characterization of design, components, instruments/software, methods/conditions, layout and stability, etc. Controls and calibrators: identity and physical location (if applicable), value assignment, span decision points (if applicable), etc. Controls and calibrators: identity and physical location (if applicable), value assignment, span decision points (if applicable), etc.

8. Test Design: Pre-analytical Describe collection, storage, handling processing of sample (identity, acceptance criteria, etc.) Describe collection, storage, handling processing of sample (identity, acceptance criteria, etc.) Validate purification and/or amplification methods Validate purification and/or amplification methods Describe acceptance criteria for material used in assay (e.g., 260/280, conc., etc.) Describe acceptance criteria for material used in assay (e.g., 260/280, conc., etc.)

9. Specific performance characteristics Analytical studies on clinical samples (where appropriate) Sensitivity Sensitivity Reproducibility/precision Reproducibility/precision Cut-off, ref. range, decision point Cut-off, ref. range, decision point Assay range Assay range Effect of excess/limiting sample Effect of excess/limiting sample Specificity and interfering substances Specificity and interfering substances

10. Array and data processing Optimization of multiple simultaneous target detection Optimization of multiple simultaneous target detection Sample carry-over/signal bleeding Sample carry-over/signal bleeding Computational methods Computational methods Limiting factors, e.g., saturation level of hybridization Limiting factors, e.g., saturation level of hybridization

11. Instrumentation Instrumentation can be general purpose or part of a system Instrumentation can be general purpose or part of a system If general purpose, should be characterized and have specifications If general purpose, should be characterized and have specifications If part of a system, will be reviewed If part of a system, will be reviewed Describe calibration of and uncertainties introduced by instrument Describe calibration of and uncertainties introduced by instrument

12. Regulatory Strategies

13. 510(k): Class II devices Compare to: A commercially available predicate device (percent agreement) A commercially available predicate device (percent agreement) A reference method or “gold standard” A reference method or “gold standard” (Sensitivity/specificity) (Sensitivity/specificity) Standard is substantial equivalence Standard is substantial equivalence

14. PMA: Class III devices Comparison to clinical diagnosis Comparison to clinical diagnosis Define “clinical truth” first Define “clinical truth” first Sample adequate specimens/populations Sample adequate specimens/populations Determine ref. ranges if appropriate Determine ref. ranges if appropriate May verify with second detection system (e.g. RT-PCR, other appropriate system) May verify with second detection system (e.g. RT-PCR, other appropriate system) Standard is “safe and effective” Standard is “safe and effective”

15. De novo 510(k) A clearance process for certain moderate-risk novel devices that have no predicate A clearance process for certain moderate-risk novel devices that have no predicate Compare to reference method or clinical diagnosis Compare to reference method or clinical diagnosis Standard is “safe and effective” Standard is “safe and effective”

16. Pre-IDE (protocol review) IDE not required IDE not required Sponsor describes proposed intended use and supporting studies Sponsor describes proposed intended use and supporting studies Interactive process to provide feedback prior to initiating studies. Interactive process to provide feedback prior to initiating studies. Non-binding on either party Non-binding on either party Recommended for novel devices or uses Recommended for novel devices or uses

17. Clinical Effectiveness New markers, mutations, patterns should meet FDA standard for effectiveness for clinical use (see 21 CFR 860.7) New markers, mutations, patterns should meet FDA standard for effectiveness for clinical use (see 21 CFR 860.7) Established markers may refer to clinical literature to support the effectiveness of the marker for clinical use. Established markers may refer to clinical literature to support the effectiveness of the marker for clinical use.

18. Use of Literature For some markers, mutations or patterns, a sufficient literature base may exist to support clinical validity. For some markers, mutations or patterns, a sufficient literature base may exist to support clinical validity. Provide summary of available information pertinent to device. Provide summary of available information pertinent to device. Should use same technology as “new” test and similar patient population. Should use same technology as “new” test and similar patient population.

19. Problem areas

20. Study Design How to establish appropriate sample numbers, identities, etc., esp. when available samples are rare How to establish appropriate sample numbers, identities, etc., esp. when available samples are rare Archived vs. prospective sampling? Archived vs. prospective sampling? Multiple intended uses for a single test? Multiple intended uses for a single test?

21. Statistical Methods 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. 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. Describe statistical methods used for calculations, including measures of precision, confidence intervals Describe statistical methods used for calculations, including measures of precision, confidence intervals

22. Quality Control What will be the measure of quality control? What will be the measure of quality control? Will there be universal standards/controls for arrays? Will there be universal standards/controls for arrays? Importance of controls in inter- and intra- assay reproducibility at manufacturer and user level Importance of controls in inter- and intra- assay reproducibility at manufacturer and user level

23. Regulatory Environment Least Burdensome Least Burdensome TPLC principles TPLC principles Transparency (truth in labeling) Transparency (truth in labeling)

24. Your role Review draft guidance carefully Review draft guidance carefully Make comments to the docket Make comments to the docket –On the guidance –On related issues Unvalidated features on clinical diagnostic Unvalidated features on clinical diagnostic General vs. specific claims General vs. specific claims Combination devices (CDRH and CDER or CBER) Combination devices (CDRH and CDER or CBER) Understand QSR (formerly GMP) Understand QSR (formerly GMP)

25. Future Directions Specific guidance is probably needed for QSR/GMP for microarray and multiplex devices—input from interested parties would be valuable Specific guidance is probably needed for QSR/GMP for microarray and multiplex devices—input from interested parties would be valuable