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This is a draft guidance. Not for implementation.
What You Need to Know? 👇
What type of submission is required when modifying a device component of a combination product approved under an NDA?
For device component changes in NDA-approved combination products, use Table 1 to correlate the device submission type with the appropriate NDA submission. For example, a change requiring a PMA 180-day supplement would need an NDA Prior Approval Supplement.
How do I determine the appropriate postmarket submission for combination product modifications?
Follow the four-step process: identify the original application type (NDA/BLA/PMA), determine what submission the constituent part would need as a stand-alone product, check if application types match, and if not, use the correlation tables provided in the guidance.
Can I submit multiple constituent part changes in a single postmarket submission?
Yes, when making changes to multiple constituent parts, submit using the most significant change type. For example, if one change requires a prior approval supplement and another requires changes being effected, submit the prior approval supplement for both changes.
What happens if my combination product change affects the primary mode of action?
This guidance does not address changes affecting the primary mode of action, lead center assignment, or underlying marketing application type. Such changes may require different regulatory pathways and should be discussed with FDA through an intercenter review team meeting.
How can I discuss complex postmarket changes with FDA before submission?
Request a meeting with the intercenter review team by contacting the lead center that approved your original application. Include a cover letter requesting consulting center representatives and provide background material supporting your proposed approach. OCP may also attend.
Are there specific timelines for combination product postmarket submissions?
The timelines follow those of the original application type used for approval. NDA/BLA submissions follow drug/biologic timelines, while PMA submissions follow device timelines, regardless of which constituent part is being modified.
What You Need to Do 👇
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