Postmarketing Safety Reporting Requirements for Combination Products
This guidance addresses postmarketing safety reporting (PMSR) requirements for combination products that have received FDA marketing authorization. It clarifies reporting obligations for Combination Product Applicants and Constituent Part Applicants, including what reports are required, timelines, content, and submission processes.
What You Need to Know? 👇
What is a combination product and how does FDA regulate it?
A combination product is composed of any combination of a drug, device, and biological product. FDA assigns each combination product to a lead Center based on the primary mode of action (PMOA) - whichever constituent part provides the greatest contribution to the overall therapeutic effects.
Who must comply with the combination product PMSR final rule?
The rule applies to two types of applicants: Combination Product Applicants (who hold the only application or all applications for a combination product) and Constituent Part Applicants (who hold applications for constituent parts when other parts are marketed by different applicants).
What are the key reporting requirements for combination product applicants?
Combination Product Applicants must meet both application type-based requirements (based on their marketing authorization type) and constituent part-based requirements (based on the types of constituent parts in their product), including ICSRs, FARs, BPDRs, and correction/removal reports as applicable.
Can multiple reporting requirements be satisfied with a single submission?
Yes, streamlined reporting is allowed when reports can be submitted in the same manner and the combined report satisfies all applicable requirements and submission timelines. This includes combining multiple ICSR types or including correction/removal information in ICSRs.
What information sharing is required between constituent part applicants?
Constituent Part Applicants must share initial information about deaths, serious injuries, or adverse experiences associated with the combination product with other Constituent Part Applicants within 5 calendar days of receipt, regardless of which constituent part may be implicated.
What are the recordkeeping requirements for combination products?
Combination Product Applicants must retain PMSR records for the longest time period required under all applicable PMSR requirements for their product. Constituent Part Applicants must retain reporting records per their constituent part requirements and information-sharing records for specified periods.
What You Need to Do 👇
Recommended Actions
- Determine if you are a Combination Product Applicant or Constituent Part Applicant
- Identify all applicable reporting requirements based on:
- Application type (NDA, BLA, Device Application)
- Constituent parts (drug, device, biologic)
- Establish processes to:
- Monitor and assess safety events
- Submit required reports within specified timelines
- Share information between Constituent Part Applicants
- Maintain required records
- Implement systems to:
- Track reporting obligations and deadlines
- Ensure complete reporting of required information
- Submit reports through appropriate FDA systems
- Document compliance with requirements
- Train relevant personnel on:
- Reporting requirements and processes
- Assessment of reportable events
- Report preparation and submission
- Record keeping requirements
- Review and update procedures periodically to ensure continued compliance
- Contact FDA’s Office of Combination Products when guidance is needed on specific situations
Key Considerations
Labelling
- Labeling must be considered when determining if an adverse event is “unexpected” for reporting purposes
- Whether an event is “expected” is based on whether it is listed in any current labeling accompanying the combination product
Safety
- Must submit 15-day reports for serious and unexpected adverse experiences
- Must submit 5-day reports for events requiring remedial action to prevent substantial harm
- Must submit malfunction reports for device issues likely to cause death/serious injury if recurrent
- Must submit Field Alert Reports for distributed products with drug constituent parts
- Must submit Biological Product Deviation Reports for products with biological constituent parts
- Must submit correction and removal reports for actions to reduce health risks
- Must maintain records for specified time periods
Other considerations
- Must identify the product as a combination product in reports
- Must include information about all constituent parts in reports
- Must share certain safety information between Constituent Part Applicants
- Can streamline reporting by combining multiple report types when appropriate
- Must submit periodic safety reports for NDA/ANDA/BLA combination products
- Must follow specific timelines for different report types
- Must submit reports through appropriate FDA systems based on application type
Relevant Guidances đź”—
- Compliance Policy for Combination Product Postmarketing Safety Reporting Requirements
- Current Good Manufacturing Practice Requirements for Combination Products
- Premarket Review Pathways for Combination Products
- User Fees for Combination Products and Associated Waivers
- Early Development Considerations for Combination Products
- Obtaining FDA Feedback for Combination Products: Best Practices and Meeting Procedures
Related references and norms đź“‚
- 21 CFR Part 4: Regulation of Combination Products
- 21 CFR Part 314: Applications for FDA Approval to Market a New Drug
- 21 CFR Part 600: Biological Products
- 21 CFR Part 803: Medical Device Reporting
- 21 CFR Part 806: Medical Devices; Reports of Corrections and Removals