What is a Combination Product? 2025 FDA Guide
- Beng Ee Lim
- 3 days ago
- 10 min read
Most medical device startups discover they're developing a combination product at the worst possible time - after months of development under the wrong regulatory assumptions. This classification confusion can add years to approval timelines and hundreds of thousands in unexpected costs.
Quick Answer: A combination product combines a medical device with a drug, biologic, or both into a single therapeutic or diagnostic product. FDA classification depends on the Primary Mode of Action (PMOA) - whichever component provides the most therapeutic benefit determines which FDA center reviews your product and which regulations apply.
This guide explains combination product basics, classification rules, and the strategic decisions that determine your regulatory pathway.
What Is a Combination Product?
A combination product is a therapeutic or diagnostic product that combines two or more FDA-regulated components: medical devices, drugs, and/or biological products.
According to FDA regulations (21 CFR 3.2(e)), combination products include:
Single Entity Combination Products
Components physically, chemically, or otherwise combined into one product
Examples: Drug-eluting stents, transdermal patches, prefilled syringes
Co-packaged Combination Products
Separate products packaged together as a unit
Examples: Surgical trays with devices and antimicrobial solutions
Cross-labeled Combination Products
Separate products specifically labeled for use together
Both components required to achieve intended therapeutic effect
Investigational Combinations
Products under development that require both components for testing
What's NOT a Combination Product
Device + Device Combinations
Multiple medical devices used together don't qualify as combination products. A surgical kit containing only different devices remains purely device-regulated.
Drug + Drug Combinations
Multiple drugs in one pill are considered combination therapies in clinical medicine, but not regulatory combination products.
Simple Primary Packaging
A vial + stopper (container-closure system) for a drug is not a device; the product remains a drug. But if the drug is in a delivery device (e.g., prefilled syringe, inhaler, transdermal system), the product is a combination product.
Why Combination Product Classification Matters
This call sets your entire playbook. Whether FDA treats your product as a device, drug, biologic, or a combination product determines your review center, pathway, evidence burden, user fees, timelines, and even the quality system you must stand up.
The High-Stakes Classification Decision
Different FDA Centers, Different Rules
CDRH (Devices): 510(k) (substantial equivalence; 90 FDA-day goal), De Novo (novel Class I/II), or PMA (Class III; safety/effectiveness).
CDER (Drugs): NDA with substantial evidence; PDUFA goals: 10 months (standard) or 6 months (priority).
CBER (Biologics): BLA with extensive clinical/CMC; follows PDUFA timelines.
The $500K+ Mistake If FDA disagrees with your primary mode of action determination, it can have disastrous consequences for your regulatory submission, wasting lots of time and money. Wrong classification forces pathway changes, additional studies, and complete regulatory restart.
Strategic Advantages of Proper Classification
Early Development Planning
Correct regulatory pathway from day one
Appropriate clinical study design
Proper quality system implementation
Accurate funding and timeline projections
Competitive Market Intelligence
Understanding how similar products gained approval
Benchmarking against appropriate regulatory standards
Positioning for optimal market entry strategy
Common Combination Product Examples
Medical Device + Drug Combinations
Drug-Eluting Stents (DES) — Scaffold devices coated with drugs to prevent restenosis. The stent (device) provides mechanical support while the drug limits neointimal growth. Device-led combination product (mechanical PMOA; CDRH lead, typically PMA).
Transdermal Patches — Patches delivering drugs through the skin. The patch (device) controls release; the drug provides the primary therapeutic effect. Drug-led combination product (single-entity; CDER lead).
Bone Cement with Antibiotics — Orthopedic PMMA cement containing antibiotics to reduce infection risk. The cement gives structural fixation; the antibiotic provides antimicrobial activity. In the U.S., antibiotic-loaded PMMA bone cement is generally a Class II device under 21 CFR 888.3027 (product code MBB); confirm intended use to verify PMOA.
Medical Device + Biologic Combinations
Tissue-Engineered Scaffolds — Scaffolds with cells or growth factors for regeneration. If the biologic drives the therapeutic effect, expect CBER lead; if mechanical support dominates, expect CDRH. PMOA decides.
Cell-Seeded Devices — Pre-loaded devices with therapeutic cells. Both components are essential; PMOA determines the lead center.
Diagnostic Combinations
Companion Diagnostics (CDx) — Tests used to select/monitor therapy for specific drugs. Usually not combination products; FDA typically requires separate drug and IVD submissions coordinated by labeling.
Point-of-Care Testing with Integrated Therapy — If a device diagnoses and administers a drug (or is cross-labeled so both products must be used together with label changes), it can be a combination product. Otherwise, many POC-plus-action systems are device-only.
Software-Based Combinations
SaMD with Drug Protocols — Software that recommends dosing/adjustments. Becomes a cross-labeled combo only if intended for use with a specific drug and label changes are needed for that drug; otherwise it’s typically SaMD (device) supporting drug use.
AI-Powered Drug Discovery Tools — Platforms that identify candidates or optimize delivery are R&D tools, not combination products. They may inform submissions, but they aren’t marketable therapeutic/diagnostic products by themselves.
Primary Mode of Action (PMOA) Determination
PMOA decides your lane. The Primary Mode of Action sets your lead FDA center (CDRH/CDER/CBER) and, with it, the regulations, user fees, evidence strategy, and timelines.
How FDA Determines PMOA
Primary Mode of Action Definition — It’s the single mode of action that provides the most important therapeutic action—the mode expected to make the greatest contribution to the product’s overall intended therapeutic effects.
PMOA Evaluation Criteria
FDA considers:
Your intended use/indications and how the product achieves its effects.
The relative contribution of each constituent (and the duration of that contribution).
Data and literature supporting which mode makes the greatest contribution.
Related products and how FDA handled them.
Strategic PMOA Considerations
Lead with evidence, not preference. A blanket “device-led” stance is risky. Use a Pre-RFD to pressure-test your PMOA and get OCP feedback before you lock studies and budgets. If needed, file a formal RFD (FDA issues a jurisdictional decision within 60 days).
Make a balanced case. Describe all modes of action, quantify relative/time-based contributions, and cite precedents (similar products and their lead centers).
Avoid avoidable pain. Picking the wrong route can trigger RTA (e.g., device ineligible for 510(k)) or RTF for drug/biologic filings—costly resets you can sidestep with early alignment.
PMOA Argument Checklist
□ All MOAs described; PMOA identified with clear rationale.
□ Intended use + how effects are achieved spelled out.
□ Relative & duration contribution of each constituent quantified (with data).
□ Related products/precedents cited; note similarities/differences.
□ If uncertain, Pre-RFD used; RFD plan in place (60-day decision).
FDA Office of Combination Products (OCP)
The Office of Combination Products serves as the central coordination point for all combination product regulatory activities across FDA centers.
OCP Roles and Responsibilities
Classification and Assignment
Classify products as drugs, devices, biologics, or combination products
Assign products to appropriate FDA centers for review
Resolve disputes about product classification
Coordination and Oversight
Ensure timely and effective premarket review
Coordinate reviews involving multiple FDA centers
Monitor intercenter consultation processes
Guidance and Policy Development
Develop regulations and guidance for combination products
Clarify regulatory requirements and expectations
Provide industry education and outreach
When to Contact OCP
Pre-RFD Consultation (Informal) Contact OCP early for informal feedback on product classification. This non-binding guidance helps inform development strategy without formal regulatory commitment.
Request for Designation (RFD) (Formal) Submit formal RFD when product classification is unclear or disputed. FDA provides binding determination of product classification and center assignment.
Jurisdiction/Timing Issues Use OCP to facilitate resolution of jurisdiction and intercenter timing/alignment questions that could slow review. (Formal sponsor disputes follow center-specific dispute-resolution procedures.)
Classification Pathways and Processes
Request for Designation (RFD) Process
When to Submit RFD
Product classification is unclear or disputed
Novel combination with no clear precedent
Multiple regulatory pathways seem applicable
Early development planning requires classification certainty
RFD Requirements (21 CFR Part 3)
Detailed product description and intended use
Analysis of each component's mode of action
Recommendation for classification with supporting rationale
Relevant predicate devices or drug products
Supporting scientific data and literature
RFD Timeline and Review
FDA has 60 days to review complete RFD submissions
Classification determination is binding on FDA
Provides clear regulatory pathway for development
Pre-RFD Consultation
Informal Feedback Process
Non-binding preliminary guidance on classification
Helps inform RFD strategy and development planning
Lower cost and faster than formal RFD process
Strategic Timing Submit Pre-RFD during early development when classification uncertainty could impact fundamental design decisions or funding strategies.
Regulatory Requirements by Classification
Device-Led Combination Products
Quality Systems
21 CFR Part 820 (Quality System Regulation)
Design controls and risk management
Because it’s a combo: confirm overlays in 21 CFR Part 4.
Premarket Requirements
Drug Component Oversight CDRH coordinates with CDER for drug-related requirements while maintaining lead center authority.
Drug-Led Combination Products
Good Manufacturing Practices
21 CFR Parts 210 and 211 (cGMP for drugs)
Drug quality and manufacturing standards
Validated manufacturing processes
Clinical Requirements
IND application for clinical studies
Phase I, II, III clinical trials
NDA submission for marketing approval
Device Component Review CDER coordinates with CDRH for device-related safety and effectiveness evaluation.
Biologic-Led Combination Products
Biologic Manufacturing
21 CFR Part 600 series regulations
Facility registration and licensing
Lot release and testing requirements
Clinical Development
IND for biological products
Clinical trials specific to biologic safety
BLA submission for approval
Common Classification Mistakes
Mistake 1: Assuming Simple Device Classification
The Problem Companies develop what they think is a simple medical device, only to discover drug or biologic components make it a combination product requiring different regulatory pathway.
Real-World Example A startup developing "smart" contact lenses with drug reservoirs assumed device classification. Late-stage discovery of combination product status required complete regulatory strategy overhaul and additional clinical studies.
Prevention Strategy Evaluate all product components during early design phase. Any drug, biologic, or therapeutic substance integrated with your device creates combination product.
Mistake 2: Inadequate PMOA Analysis
The Problem Superficial primary mode of action analysis leads to incorrect classification and regulatory pathway selection.
The Cost Wrong PMOA determination can force pathway changes that add 18-24 months to approval timeline and $500K+ in additional development costs.
Prevention Strategy Conduct thorough PMOA analysis with quantitative data supporting each component's therapeutic contribution. Document rationale with regulatory precedents.
Mistake 3: Delayed Classification Determination
The Problem Waiting until late development to address classification uncertainty creates expensive pivot points when fundamental changes are needed.
Strategic Timing Address classification questions during concept development, not after significant investment in specific regulatory pathway. Early RFD or Pre-RFD consultation prevents costly mid-development surprises.
Mistake 4: Ignoring Cross-Center Coordination
The Problem Focusing only on lead center requirements while ignoring consulting center input leads to regulatory deficiencies and review delays.
Comprehensive Strategy Plan for requirements from all relevant FDA centers. Device-led combination products still need drug-related data; drug-led products still need device safety information.
International Combination Product Considerations
European Union Approach
Medical Device Regulation (MDR) Integration EU classifies drug-device combinations based on principal mode of action, similar to FDA approach but with different regulatory frameworks.
Integral vs. Co-packaged Products
Integral combinations follow medicinal product regulations if drug action is principal
Co-packaged products require separate conformity assessments for each component
Notified Body Requirements Combination products may require opinions from notified bodies on device component conformity even when classified as medicinal products.
Global Harmonization Trends
IMDRF Initiatives International Medical Device Regulators Forum working toward harmonized combination product guidance across major markets.
Regulatory Convergence Similar PMOA-based classification approaches emerging across regions, though specific requirements and timelines differ significantly.
Strategic Planning for Combination Products
Early Development Considerations
Design Phase Integration Classification isn’t an afterthought. Tie your intended use and user needs to design inputs and reviews from day one so the regulatory pathway drives testing and evidence—not the other way around.
Technology Selection Choose architectures and materials that satisfy clinical needs and support a defensible PMOA. If your center/pathway hinges on that PMOA, run a Pre-RFD for non-binding feedback and, when needed, seek a binding RFD (FDA decides within 60 days of filing).
Intellectual Property Strategy Expect a multi-track portfolio (device claims + drug/biologic claims + methods of use). Coordinate IP timelines with regulatory milestones to avoid disclosure surprises.
Funding and Timeline Planning
Regulatory Pathway Costs
Investor Education Many investors don't understand combination product complexity. Clear classification and regulatory strategy essential for funding success.
Market Entry Strategy
Competitive Positioning Combination products often create new market categories with unique value propositions and pricing models.
Reimbursement Considerations Combination product reimbursement may require demonstrating value from both device and drug components.
Emerging Trends in Combination Products
Technology-Driven Innovation
Digital Health Integration Software-based medical devices increasingly incorporate drug protocols and therapeutic algorithms, creating new combination product categories.
Personalized Medicine Companion diagnostics and precision therapy combinations becoming standard in oncology and other therapeutic areas.
Nanotechnology Applications Nanoscale drug delivery systems integrated with medical devices creating novel combination products with unclear classification precedents.
Regulatory Evolution
AI and Machine Learning FDA developing guidance for artificial intelligence-enabled combination products that adapt therapy based on patient data.
3D Printing and Customization Custom-manufactured combination products challenge traditional classification frameworks and manufacturing regulations.
Regenerative Medicine Tissue-engineered products combining cells, biomaterials, and growth factors require new regulatory approaches.
About Complizen
Complizen simplifies regulatory compliance for medtech companies using AI, helping life-saving innovations reach patients faster. We guide companies through regulatory pathways, from early-stage startups to established medical device manufacturers. Our mission is to make regulatory expertise accessible so breakthrough medical technologies can improve lives worldwide.
Frequently Asked Questions
How do I know if my product is a combination product?
If your product includes both a medical device and a drug/biologic component that work together to achieve the intended therapeutic effect, it's likely a combination product. When in doubt, contact FDA's Office of Combination Products.
Can I choose which FDA center reviews my combination product?
No - FDA determines center assignment based on Primary Mode of Action (PMOA). However, you can argue for your preferred PMOA determination with supporting data and rationale.
What's the difference between a Pre-RFD and an RFD?
Pre-RFD provides informal, non-binding feedback on classification. RFD provides formal, binding determination of product classification and center assignment.
How long does FDA take to classify combination products?
Pre-RFD typically takes 30-45 days. Formal RFD has 60-day FDA review timeline for complete submissions.
Can combination products use existing predicates for 510(k) submissions?
Yes, if classified as device-led and appropriate predicates exist. However, drug/biologic components may require additional data beyond typical 510(k) requirements.
What happens if FDA disagrees with my PMOA determination?
FDA may reclassify your product to different center, requiring new regulatory strategy. This can add 12-24 months to timeline and significant costs.
Are there special manufacturing requirements for combination products?
Yes - you must comply with regulations for all component types. Device-drug combinations need both QSR (21 CFR 820) and drug cGMP compliance.
Can I appeal FDA's combination product classification?
Classification determinations are generally final, but you can submit new RFD with additional data or request OCP assistance with regulatory disputes.
How do international regulations affect combination products?
Each region has different classification approaches. EU uses similar PMOA concept but different regulatory frameworks. Plan for region-specific requirements.
Should I submit RFD before starting development?
For novel combination products or unclear classifications, early RFD or Pre-RFD consultation prevents costly mid-development regulatory surprises.
