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Premarket Review Pathways for Combination Products

This guidance outlines FDA's current thinking on premarket review pathways for combination products, which are products comprised of two or more different types of medical products (drug, device, and/or biological product). It provides information on determining appropriate premarket submission types and requirements based on the primary mode of action (PMOA) of the combination product.

  1. Determine the primary mode of action (PMOA) of the combination product
  2. Identify the appropriate lead FDA center based on PMOA
  3. Select appropriate premarket submission pathway aligned with PMOA:
    • Device-led: PMA, De Novo, or 510(k)
    • Drug-led: NDA or ANDA
    • Biologic-led: BLA under 351(a) or 351(k)
  4. Prepare comprehensive submission including:
    • Data demonstrating safety and effectiveness of complete combination product
    • Information on constituent parts and their interaction
    • Manufacturing and quality control documentation
    • Proposed labeling
  5. Consider early interaction with FDA through pre-submission meetings
  6. Identify any special controls or additional requirements based on product type
  7. Develop post-market surveillance plan if required
  8. Ensure manufacturing facilities meet applicable requirements
  9. Maintain documentation of compliance with all applicable regulations
  10. Plan for lifecycle management considering impact of changes on both constituent parts

Key Considerations

Clinical testing

  • Clinical data must demonstrate safety and effectiveness of the combination product as a whole
  • Clinical studies may be needed to demonstrate lack of unreasonable risk under anticipated conditions of use
  • Clinical data requirements depend on the specific combination product type and pathway

Non-clinical testing

  • Animal studies may be required to demonstrate safety and performance
  • Non-clinical bench testing needed to evaluate technical specifications and performance characteristics
  • Chemistry, manufacturing and controls (CMC) information required for drug/biologic constituent parts

Labelling

  • Must identify product as a combination product in submissions
  • Must include information on patient population, testing summaries, adverse events
  • Must include detailed summaries of clinical and non-clinical testing

Biocompatibility

  • Biocompatibility evaluation required for device constituent parts
  • Must demonstrate compatibility between constituent parts

Safety

  • Safety assessment needed for the combination product as a whole
  • Post-market surveillance may be required
  • Risk mitigation measures must be implemented through controls

Other considerations

  • 21 CFR Part 3: Product Jurisdiction
  • 21 CFR Part 4: Current Good Manufacturing Practice Requirements for Combination Products
  • 21 CFR Part 314: Applications for FDA Approval to Market a New Drug
  • 21 CFR Part 601: Licensing
  • 21 CFR Part 807: Establishment Registration and Device Listing
  • 21 CFR Part 814: Premarket Approval of Medical Devices

Original guidance

  • Premarket Review Pathways for Combination Products
  • HTML / PDF
  • Issue date: 2022-01-26
  • Last changed date: 2022-01-28
  • Status: FINAL
  • Official FDA topics: Medical Devices, Combination Products, Drugs, Biologics
  • ReguVirta summary file ID: 9f6fb2620668c9d7d8ebae3e56d28a40
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