Postapproval Changes to Combination Products: Marketing Submission Requirements (DRAFT)
This guidance provides recommendations for determining the type of marketing submission required for postapproval changes to combination products approved under a single marketing application (BLA, NDA, or PMA). It covers changes to drug, device, and biological product constituent parts while maintaining their regulatory identity.
This is a draft guidance. Not for implementation.
Recommended Actions
- Identify the type of original marketing application used for the combination product approval
- Determine what type of submission would be required if the changed constituent part was a standalone product
- Use the guidance tables to identify the appropriate submission type based on the original application and type of change
- Consider developing comparability protocols for anticipated future changes
- Request meetings with FDA intercenter review team for complex changes or alternative approaches
- Submit changes requiring the highest level of review when multiple changes are made simultaneously
- Ensure documentation addresses impact on all constituent parts and the combination product as a whole
- Maintain compliance with other requirements specific to the application type used for approval
Key Considerations
Clinical testing
- New clinical data required for changes that result in new indications, clinical effects, or modified patient populations
- Limited confirmatory clinical data may be needed for certain design changes
- Clinical data requirements depend on the type of change and constituent part being modified
Non-clinical testing
- New preclinical testing may be required for design modifications, chemical formulation changes, or hardware/software changes
- The extent of preclinical testing depends on the type and significance of the change
Software
- Software modifications to device constituent parts require appropriate submission based on risk and validation requirements
Labelling
- Significant labeling changes require prior approval supplements
- Minor labeling changes may be submitted as Changes Being Effected supplements
- Labeling changes must align with the type of marketing application
Safety
- Changes that could affect safety and effectiveness require prior approval
- Manufacturing changes that impact product quality require prior approval
- Changes in controlled release or particle size require prior approval
Other considerations
- Multiple constituent part changes should use the submission type for the most significant change
- Early discussion with FDA recommended for complex changes
- Comparability protocols can help establish modification methodologies
- Changes should not affect the primary mode of action or lead center assignment
Relevant Guidances
- Current Good Manufacturing Practice Requirements for Combination Products
- Premarket Review Pathways for Combination Products
- Postmarketing Safety Reporting Requirements for Combination Products
- Human Factors Studies and Related Analyses for Combination Products
- Early Development Considerations for Combination Products
- Obtaining FDA Feedback for Combination Products: Best Practices and Meeting Procedures
- Compliance Policy for Combination Product Postmarketing Safety Reporting Requirements
Related references and norms
- 21 CFR 3.2(e): Definition of combination products
- 21 CFR 314.70: Changes to an approved NDA
- 21 CFR 601.12: Changes to an approved BLA
- 21 CFR 814.39: Changes to an approved PMA
Original guidance
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