FDA Requests for Designation: How PMOA Reasoning Determines the Lead Center for Combination Products

How FDA's Office of Combination Products resolves Requests for Designation: the PMOA framework and published lead-center precedents

Key takeaways

• FDA assigns a combination product to a lead center based on its primary mode of action (PMOA), defined as the single mode of action expected to make the greatest contribution to the product's overall intended therapeutic effects ¹⁸⁹¹⁹⁰.
• When PMOA cannot be determined with reasonable certainty, FDA applies a two-step assignment algorithm: first consistency with other combination products raising similar safety and effectiveness questions, then the center with the most expertise on the product's most significant safety and effectiveness questions ¹⁹¹.
• A Request for Designation (RFD) is capped at 15 pages, must include the sponsor's own PMOA-based center recommendation, and is resolved by a letter of designation within 60 days of filing. If FDA misses that deadline, the sponsor's recommendation becomes the designation ^13271330178.
• Where published precedents state their reasoning, it usually comes down to one question: which constituent part actually produces the intended therapeutic or diagnostic effect? Drug-eluting stents and drug-coated or drug-eluting balloons lead to CDRH even when they carry a drug ^748745725. Delivery systems, activating light sources and dispensers lead to CDER because the drug does the therapeutic work ^1250729972. Fibrin sealants on device carriers lead to CBER ^11031074. Several published records state only the lead center without the PMOA rationale, and when PMOA is uncertain the 21 CFR 3.4(b) assignment algorithm controls instead.

The legal framework in 21 CFR Part 3

What counts as a combination product

21 CFR 3.2(e) recognizes four types of combination product ^{1282128312841285}:

1. Single-entity products, where two or more regulated components are physically, chemically or otherwise combined and produced as one entity.
2. Co-packaged products, where drug, device and/or biological products are packaged together as a unit.
3. Separately packaged products intended for use only with an individually specified approved product, where both are required and approval would require a labeling change to the approved product.
4. Separately packaged investigational products labeled for use only with another individually specified investigational product.

Mode of action and PMOA

Part 3 defines mode of action as the means by which a product achieves an intended therapeutic effect or action, including effects to diagnose, cure, mitigate, treat or prevent disease or to affect the structure or function of the body ¹⁸⁴. Each constituent part is characterized by its mode of action:

• Biological product mode of action: acts by means of a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product ¹⁸⁵.
• Device mode of action: meets the device definition, has no biological product mode of action, and does not achieve its primary intended purposes through chemical action within or on the body or by being metabolized ¹⁸⁶¹⁸⁷.
• Drug mode of action: meets the drug definition and has neither a biological product nor a device mode of action ¹⁸⁸.

The PMOA is the single mode of action expected to make the greatest contribution to overall intended therapeutic effects. Primary jurisdiction goes to the center that reviews that type of product ¹⁸⁹¹⁹⁰.

The assignment algorithm when PMOA is uncertain

If FDA cannot determine with reasonable certainty which mode of action contributes most, it assigns the product to the center that regulates other combination products raising similar safety and effectiveness questions for the product as a whole. If there are no such products, the assignment goes to the center with the most expertise on the product's most significant safety and effectiveness questions ¹⁹¹. FDA guidance gives a vision-correcting contact lens containing a glaucoma drug as an example: its distinct therapeutic effects can leave the PMOA uncertain, so the algorithm applies instead of a direct PMOA determination ²⁶².

The drug/device threshold: "chemical action"

Many jurisdiction disputes turn first on whether a component is a drug or a device at all. FDA interprets "chemical action" as a molecular-level interaction with bodily components (such as cells or tissues), or with a foreign entity such as an organism, that mediates a bodily response or changes the entity's interaction with the body. FDA treats this as equivalent to pharmacological action. Merely transferring electromagnetic or thermal energy is not chemical action ¹³²¹³³. The action must achieve the primary intended purpose and occur within or on the body. A hip implant's incidental foreign-body response or an absorbable suture's resorption does not prevent device classification ¹³⁷. FDA contrasts a vaginal lubricant that reduces friction (device) with the same product intended to alter pH, control odor or prevent infection through chemical action (drug) ¹³⁹.

How an RFD is filed and resolved

Required content

Under 21 CFR 3.7, an RFD may not exceed 15 pages including attachments ¹³²⁷. It must identify the sponsor and describe the product in detail. That description covers composition, the status of any component, developmental and animal testing, manufacturing, proposed use, known modes of action, the mode providing the most important therapeutic action and the basis for that conclusion, schedule and duration of use, dose and route, and related products ^13281329. The sponsor must recommend a lead center based on the mode of action that provides the most important therapeutic action. If the sponsor cannot determine that with reasonable certainty, the recommendation must apply the § 3.4(b) assignment algorithm and assess the assignments of other combination products the sponsor wants FDA to consider ¹³³⁰.

FDA's RFD guidance, How to Write a Request for Designation (RFD) (final, April 2011) ¹²⁵¹, tells sponsors to identify the most important therapeutic action, substantiate the PMOA with evidence, address the assignment algorithm, and explain why the proposed center should lead ^227222223.

Timelines and default designation

OCP checks an RFD for completeness within 5 business days of receipt ²³¹. The product jurisdiction officer must issue a letter of designation within 60 days of the filing date. If no letter issues in that time, the sponsor's recommended center becomes the designated center ¹⁷⁸²³¹.

Reconsideration and later changes

A sponsor that disagrees with the designation may file a written request for reconsideration of no more than five pages within 15 days of receiving the letter. The request may not include new information, and FDA must respond in writing within 15 days ¹⁷⁹.

After designation, FDA may change the assigned center with the sponsor's written consent. Without consent, it may do so only to protect public health or for other compelling reasons. A nonconsensual change requires 30 days' written notice, an opportunity for written objections and a meeting, a reasoned written determination, and concurrence of the Principal Associate Commissioner ^13141315. FDA guidance describes the designation letter as a binding determination that applies only to the product as described, including its proposed uses. A new determination may be appropriate if the product or indication changes, or if new information shows the product works differently from what the RFD described ^{1323132413251326}.

Pre-RFD and other feedback routes

The Pre-RFD is an informal, nonbinding alternative ^219220221169. FDA revised its Pre-RFD guidance in November 2025, replacing the February 2018 version ^12521253. Under the 2025 guidance, OCP aims to assess adequacy within 10 business days and to give written feedback within 60 calendar days of acknowledging acceptance ²³²²³³. The 2018 guidance had made a sponsor's own PMOA analysis optional in a Pre-RFD, noting that FDA would run the same analysis either way ²²⁸.

Once the lead center is settled, sponsors use that center's processes (device pre-submissions, drug and biologic formal meetings). Combination Product Agreement Meetings (CPAMs) are available only after any PMOA question has been resolved ^172173174. These routes are described in Requesting FDA Feedback on Combination Products (December 2020) ¹²⁶⁰.

What the lead-center assignment controls

The application type generally follows PMOA. Device-led products use a PMA, De Novo or 510(k). Drug-led products use an NDA or ANDA. Biologic-led products use a BLA ⁶⁸. FDA generally considers a single application appropriate, but that application must permit an evaluation substantially similar to reviewing each constituent part separately. In limited cases, FDA has used an application type associated with the non-lead constituent part ⁶⁸⁶⁹. The lead center consults other centers and OCP as needed, and sponsors should route all interactions through the lead center ⁶⁷⁷⁰⁷¹.

Published precedents: outcomes and stated PMOA reasoning

The table below collects jurisdiction outcomes and PMOA statements found in publicly released FDA review and decision documents (Drugs@FDA, CBER biologics, PMA and De Novo records). Some entries record a formal RFD or Product Jurisdiction Officer decision. Others record only the PMOA rationale the reviewing center stated in its decision documents. The table notes which is which.

Patterns in the PMOA reasoning

Physical or mechanical therapeutic action leads to CDRH

For drug-eluting stents and drug-coated or drug-eluting balloons, FDA's decision documents describe the mechanical function (lumen support, vessel expansion, lesion dilation) as the PMOA. The drug's antiproliferative effect is described as secondary ^748725745. The same logic appears in wound care. For Silvion, FDA attributed the PMOA to the device's moisturizing action, not to the ionic silver antimicrobial ⁷⁵⁷. For the NIMBUS gauze with pDADMAC, OCP designated the product a device for CDRH review ¹⁴⁵¹⁴⁷. Magtrace is another example: FDA found a device PMOA because the iron oxide particles work through physical filtration in lymph nodes and magnetic detection, not pharmacology ⁷⁴⁰⁷⁴¹.

Diagnostic systems built around an instrument lead to CDRH, even with a drug reagent

Both early ¹³C-urea breath test systems went to CDRH. In the Oridion case, the RFD 98-03 letter states the combination's PMOA "is that of a device" ¹⁰¹. For the LARA system, the Product Jurisdiction Officer made CDRH primary while the ¹³C-urea component was still reviewed under the new drug provisions ⁸³¹⁸³². These precedents predate the 2005-era PMOA definition now in Part 3, and the released documents give little detail on the reasoning.

Delivery, activation and dispensing devices lead to CDER

Where the device's role is to deliver, dose or activate a drug that produces the therapeutic effect, FDA has consistently assigned CDER. Examples are the iontophoretic system in IONSYS ¹²⁵⁰, the hepatic perfusion system in Melblez ¹⁰⁴⁴, the enteral pump and tubing in Duopa ⁹³⁸, and the photoactivating light sources for Levulan and Visudyne ⁷²⁹⁷³². FDA guidance generalizes this to prefilled syringes, pen and jet injectors, and emergency-use injectors: CDER leads if the drug provides the PMOA, CBER if the biologic does ^255256257. The MYDCOMBI correspondence shows FDA applying this at the level of a product category. Products combining an ophthalmic drug with an eye cup, dropper or dispenser are regulated as drug-led combination products ⁹⁷².

XENOVIEW is a useful edge case. It is a diagnostic imaging product in which the hyperpolarized gas is the drug constituent, and FDA attributed the PMOA to the gas, not to the polarizing hardware. That determination survived a request for reconsideration ⁸²⁴. The contrast with the breath test precedents is instructive: in XENOVIEW, the drug itself generates the imaging signal, whereas the breath test instruments do the measuring and computing ⁸²⁴⁹⁹.

Biologic constituents on device carriers lead to CBER

For both fibrin sealant precedents, FDA located the PMOA in the human fibrinogen and thrombin, not the collagen carrier or applicator. CBER leads, and CDRH consults on the device constituent ^110310741076. MACI (autologous chondrocytes on a porcine collagen membrane) was handled under a CBER BLA with CDRH consults on the membrane and on quality systems. The released documents do not state a formal PMOA determination ^11741177.

Consistency with prior products as a tiebreaker

FDA's reviews show the agency anchoring new classifications to earlier ones, consistent with the first step of the assignment algorithm ¹⁹¹. In the XARACOLL bupivacaine-collagen implant review, FDA explained that treating the product as a combination product was consistent with other drug-delivery implants. It cited the drug-eluting disc example in the 2005 PMOA final rule ^11411142.

Practical implications for sponsors

• Lead with therapeutic contribution, not composition. The regulatory test asks which mode of action contributes most to the intended effect ¹⁸⁹. RFDs that tie the claimed PMOA to the product's mechanism and proposed indication follow the structure FDA asks for ^1329227.
• Watch the indication. The same physical construct can shift jurisdiction if the claims change. FDA's lubricant example (friction reduction versus pH or anti-infective claims) shows how ¹³⁹. A changed indication can also justify a new determination ¹³²⁶.
• Address the algorithm when PMOA is close. If the PMOA is arguable, the sponsor's recommendation must apply the § 3.4(b) algorithm and point to analogous products ¹³³⁰. Precedent class assignments, such as drug-led ophthalmic dispensers and device-led drug-coated vascular devices, are the strongest available anchors ^972748745.
• Use the 60-day clock and reconsideration carefully. The default-designation rule rewards a complete, well-argued recommendation ¹⁷⁸. Reconsideration is short (five pages, 15 days, no new information) ¹⁷⁹, so the evidence has to be in the original RFD.
• Expect intercenter consults regardless of outcome. The lead center routinely consults the other center on non-lead constituents. Examples include CDRH consults on fibrin sealant applicators, prefilled syringes and hepatic delivery systems ^10769021045.

Limits of the public record

FDA's published review documents usually record the jurisdictional outcome but not the full OCP analysis. In several precedents above (the LARA breath test, NIMBUS, Duopa, the fulvestrant prefilled syringe), the released record states the lead center without stating the PMOA reasoning ^832141938872. For PMA-approved drug-device products such as drug-eluting stents and balloons, the PMOA language comes from the sponsor-facing summary of safety and effectiveness, not from a published RFD letter ^748725745. Readers who need the reasoning behind a specific product class (for example, antimicrobial dressings, tissue-based scaffolds or digital drug-device systems such as ABILIFY MYCITE, where CDER led with a CDRH consult ^12131215) should look further into center-specific review memos and OCP's product-class jurisdiction statements.