510(k) for Combination Products: Drug-Device, Biologic-Device, and More

A combination product is any product composed of two or more regulated components — drug and device, biologic and device, drug and biologic, or all three — that are physically, chemically, or otherwise combined or mixed and produced as a single entity, or packaged together in a single package, or separately packaged but labeled for use exclusively with an approved or cleared counterpart.

Common examples: drug-eluting stents, prefilled syringes, antibiotic-coated catheters, insulin delivery pens, and increasingly, digital therapeutics paired with pharmaceutical treatment protocols.

Primary mode of action

The regulatory pathway for a combination product is determined by its primary mode of action (PMOA) — the single mode of action that provides the most important therapeutic action. FDA assigns the combination product to the center (CDER, CDRH, or CBER) whose regulations cover the PMOA constituent part.

• If the primary therapeutic effect comes from the drug component → CDER leads, drug regulations apply, NDA/ANDA or IND pathway
• If the primary therapeutic effect comes from the device component → CDRH leads, device regulations apply, 510(k) or PMA pathway
• If the primary therapeutic effect comes from the biological component → CBER leads, biologics regulations apply, BLA pathway

For a drug-eluting stent: the stent physically opens the artery (device action) and the drug prevents restenosis (drug action). FDA has determined that the device component provides the primary therapeutic benefit — so CDRH leads, and a PMA (not 510(k)) is typically required given the Class III risk level.

Requesting a PMOA determination

If you're uncertain which center should lead, request a formal PMOA determination from FDA's Office of Combination Products (OCP) using a Request for Designation (RFD). FDA has 60 days to respond with a written designation.

The RFD is non-binding on your submission strategy — you can disagree with the designation and appeal — but FDA's determination is highly predictive of how your product will be regulated. Get it early, before investing heavily in any particular pathway.

When a 510(k) applies to a combination product

510(k) applies to combination products when CDRH leads (device PMOA) and the device component is Class II with a valid predicate. In practice, this covers a narrower range of combination products than pure device submissions — many device-led combination products are Class III due to the complexity introduced by the drug or biologic component.

For a 510(k)-eligible combination product, the predicate must also be a combination product with the same constituent parts. A predicate that's a standalone device without the drug component is not a valid predicate for the drug-device combination — the drug component creates technological characteristics that the standalone device predicate doesn't address.

Cross-center review under intercenter agreements

Even when CDRH leads review of a combination product, CDER or CBER typically participates as a consulting center under intercenter agreements. This means your submission may be evaluated by reviewers from multiple FDA centers — each applying their own center's standards to the relevant constituent part.

For drug-device combinations where CDRH leads: expect CDER to review the drug component under drug standards (manufacturing, stability, safety pharmacology) even though CDRH controls the overall review timeline and decision. Your submission package must satisfy both centers.

Predicate research for combination products

Predicate research for combination products is more constrained than for standalone devices because you need a predicate that matches both the device component and the combination nature of the product. Search strategies:

• Start with the product code for the device component type — this narrows to the right device category
• Filter for applicants that are pharmaceutical or combination product companies — pure device companies are less likely to have submitted combination product 510(k)s
• Look for clearances where the device name includes drug names, concentrations, or formulation descriptors
• Check clearance type — combination product 510(k)s are more likely to be Traditional (not Abbreviated) given their complexity

Manufacturing considerations

Combination products subject CDRH-led submissions to additional manufacturing requirements because the drug or biologic component must be manufactured under applicable FDA manufacturing standards (cGMP for drugs, cGTP for biologics) in addition to device Quality System Regulation requirements.

If you're manufacturing a drug-device combination, your facility must satisfy both 21 CFR Part 820 (device QSR) and 21 CFR Parts 210/211 (drug cGMP). Plan your manufacturing quality system to address both sets of requirements before submission — FDA will ask.