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.
What You Need to Know? 👇
What are combination products and how does FDA determine which center has primary jurisdiction?
Combination products are medical products comprised of two or more different types (drug, device, and/or biological product). FDA assigns them to a lead center based on the primary mode of action (PMOA) - the constituent part expected to make the greatest contribution to overall therapeutic effects.
Can I submit separate applications for different constituent parts of my combination product?
Generally, FDA prefers a single application for combination products to streamline regulatory interactions. However, separate applications are permissible for cross-labeled combination products. You should coordinate with both centers and may request OCP assistance for efficient review.
What premarket pathways are available for device-led combination products?
Device-led combination products can use PMA, De Novo classification, or 510(k) pathways depending on the device classification and risk profile. The pathway must enable evaluation substantially similar to what would occur if constituent parts were reviewed separately.
When is a 510(k) pathway appropriate for device-led combination products?
A 510(k) is appropriate when the combination product has the same intended use and technological characteristics as a predicate, or different characteristics that don’t raise different safety/effectiveness questions. Adding drug/biologic constituents typically creates new intended uses requiring PMA or De Novo.
What data is required for drug constituent parts in device-led combination products?
Device applications for combination products must include data typically required for drug evaluation: nonclinical pharmacology/toxicology, clinical pharmacology (including pharmacokinetics), and chemistry, manufacturing, and controls (CMC) information to demonstrate safety and effectiveness of the drug constituent.
How does the Cures Act affect combination product regulation?
The Cures Act enhanced clarity and consistency for combination products by requiring coordinated premarket reviews, ensuring single points of contact, mandating identification of combination products in submissions, and clarifying data requirements when incorporating previously approved constituent parts.
What You Need to Do 👇
Recommended Actions
- Determine the primary mode of action (PMOA) of the combination product
- Identify the appropriate lead FDA center based on PMOA
- 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)
- 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
- Consider early interaction with FDA through pre-submission meetings
- Identify any special controls or additional requirements based on product type
- Develop post-market surveillance plan if required
- Ensure manufacturing facilities meet applicable requirements
- Maintain documentation of compliance with all applicable regulations
- 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
- Single application generally preferred over multiple applications
- Application type should align with primary mode of action (PMOA)
- Special controls may be needed for device-led combination products
- Bridging studies may be needed when changing constituent parts
- Manufacturing facility compliance requirements apply
Relevant Guidances 🔗
- Current Good Manufacturing Practice Requirements for Combination Products
- Compliance Policy for Combination Product Postmarketing Safety Reporting Requirements
- User Fees for Combination Products and Associated Waivers
- Postmarketing Safety Reporting Requirements for Combination Products
- Obtaining FDA Feedback for Combination Products: Best Practices and Meeting Procedures
- Early Development Considerations for Combination Products
- Postapproval Changes to Combination Products: Marketing Submission Requirements (Draft)
Related references and norms 📂
- 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