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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.

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By ReguVirta
3 min read

What You Need to Know? 👇

What are the key regulatory requirements for highly multiplexed microbiological diagnostic devices?

HMMDs require premarket clearance through 510(k) or de novo classification before marketing. They must conform to general controls of the FD&C Act and demonstrate substantial equivalence to predicate devices through comprehensive analytical and clinical performance studies.

How many targets must a device detect to be considered highly multiplexed under FDA guidance?

A device must be capable of detecting ≥20 different organisms/targets in a single reaction using nucleic acid-based technology to be classified as a highly multiplexed microbiological/medical countermeasure device (HMMD) under this guidance.

FDA recommends a two-part clinical validation: prospective study of minimum 1500 patients with infection symptoms for specificity evaluation, and retrospective archived specimens (minimum 50 positive per organism) for sensitivity evaluation across multiple testing sites.

What are the specific analytical performance characteristics required for HMMD validation?

Key requirements include limit of detection studies, analytical reactivity/inclusivity testing, cross-reactivity evaluation, precision studies across multiple sites, interference testing, and carry-over/cross-contamination studies using representative panels of target organisms at specified concentrations.

How should ancillary reagents be controlled and validated for HMMDs?

Manufacturers must conduct risk assessments for specific ancillary reagents, implement quality controls, provide user labeling, establish material specifications, and demonstrate that quality controls adequately detect performance problems with ancillary reagents.

What are the requirements for adding new targets to an existing cleared HMMD?

Adding new analytes requires a traditional 510(k) submission with focused studies on the new target including LoD, analytical reactivity, cross-reactivity, competitive interference, single-site precision, and limited clinical evaluation while confirming existing analyte performance remains unchanged.

What You Need to Do 👇

  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

  • Post-market monitoring for performance erosion
  • Device modification procedures
  • Stability testing
  • Ancillary reagents control
  • Quality system requirements

Relevant Guidances 🔗

Related references and norms 📂

  • 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 ID: a843e865300db92c84541ed2ca254987
FDA guidance, Final
Medical Devices Laboratory Tests IVDs (In Vitro Diagnostic Devices)
This post is licensed under CC BY 4.0 by the author.