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Highly Multiplexed Microbiological/Medical Countermeasure In Vitro Nucleic Acid Based Diagnostic Devices

This guidance addresses highly multiplexed microbiological/medical countermeasure in vitro nucleic acid based diagnostic devices (HMMDs) capable of detecting ≥20 different organisms/targets in a single reaction. It covers devices using technologies like PCR, RT-PCR, bead-based arrays, microarrays, and re-sequencing approaches to aid in diagnosis of infections from viruses, bacteria, parasites, or fungi and determine drug resistance markers. The guidance does not apply to non-nucleic acid based approaches or devices intended for blood donor screening.

  1. Develop comprehensive validation plan covering analytical and clinical performance requirements
  2. Establish proper controls and quality measures for:
    • Specimen handling
    • Cross-contamination prevention
    • Test performance monitoring
  3. Design and execute clinical studies:
    • Prospective study for specificity
    • Retrospective study for sensitivity
    • Multi-site testing
    • Proper documentation
  4. Implement software validation procedures according to moderate level of concern
  5. Create detailed labeling with all required elements
  6. Establish post-market surveillance system to monitor device performance
  7. Document procedures for device modifications and updates
  8. Implement quality system meeting 21 CFR Part 820 requirements
  9. Maintain proper control of ancillary reagents
  10. Develop comprehensive risk management system

Key Considerations

Clinical testing

  • Clinical validation through a two-part study:
    • Prospective study with minimum 1500 patients for specificity evaluation
    • Retrospective study using archived specimens for sensitivity evaluation
  • Minimum 50 positive specimens per claimed organism
  • Testing at minimum 3 sites (2 in US)
  • Collection of relevant clinical information
  • Proper monitoring and quality control of clinical studies

Non-clinical testing

  • Analytical validation studies required for:
    • Limit of Detection (LoD)
    • Analytical reactivity (inclusivity)
    • Analytical specificity
    • Cross-reactivity
    • Interference studies
    • Precision/reproducibility

Software

  • Software validation required according to moderate level of concern
  • Documentation of software development life cycle
  • Risk analysis and hazard mitigation
  • Validation of proprietary databases if used
  • Software verification and validation testing

Labelling

  • Clear intended use statement specifying:
    • Pathogens detected
    • Specimen types
    • Clinical indications
    • Target populations
    • Qualitative/quantitative nature
    • Limitations

Safety

  • Controls to prevent cross-contamination
  • Quality control measures
  • Proper specimen handling procedures
  • Biosafety considerations

Other considerations

  • CLSI EP05-A2: Evaluation of Precision Performance of Quantitative Measurement Methods
  • CLSI EP07-A2: Interference Testing in Clinical Chemistry
  • CLSI EP12-A2: User Protocol for Evaluation of Qualitative Test Performance
  • CLSI EP24-A2: Assessment of the Diagnostic Accuracy of Laboratory Tests Using ROC Plots
  • ISO 14971-1: Medical devices - Risk management
  • AAMI SW68:2001: Medical device software - Software lifecycle processes
  • ANSI/AAMI/IEC 62304:2006: Medical device software - Software life cycle processes

Original guidance

  • Highly Multiplexed Microbiological/Medical Countermeasure In Vitro Nucleic Acid Based Diagnostic Devices
  • HTML / PDF
  • Issue date: 2014-08-27
  • Last changed date: 2020-03-02
  • Status: FINAL
  • Official FDA topics: Medical Devices, Laboratory Tests, IVDs (In Vitro Diagnostic Devices)
  • ReguVirta summary file ID: a843e865300db92c84541ed2ca254987
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