Q.01

What is a combination product?

A combination product is a US FDA category for a product that combines two or more of a drug, a device and a biological product. It is defined in 21 CFR 3.2(e), and that definition covers four types:

  1. Single-entity: "two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity."
  2. Co-packaged: "Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products."
  3. Cross-labeled: a drug, device or biological product "packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect." It also has to be the case that, once the new product is approved, the labeling of the approved product "would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose."
  4. Investigational cross-labeled: any investigational drug, device or biological product "packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect."

Two related definitions in the same section matter in practice:

  • Mode of action (§ 3.2(k)): "the means by which a product achieves an intended therapeutic effect or action," which can be biological, device or drug.
  • Primary mode of action (§ 3.2(m)): "the single mode of action of a combination product that provides the most important therapeutic action of the combination product." Part 3 is the FDA's product-jurisdiction rule, and this definition is what it uses to work out how a combination product is regulated.

I couldn't retrieve the EU MDR (Regulation (EU) 2017/745) Article 1 text this time, so this answer covers only the US definition. That article is where the EU deals with devices that incorporate or deliver a medicinal product.

Approach: I quoted the definitions from the GovInfo edition of 21 CFR 3.2 (the 2024 annual CFR); the current eCFR page and FDA's combination-product guidance pages wouldn't open. None of the datasets I can search hold 21 CFR Part 3.

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Q.02

How does the FDA regulate drug-device combination products?

The FDA regulates a drug-device combination product according to its primary mode of action (PMOA). The FDA identifies the part of the product that makes the greatest contribution to its therapeutic effect, and the center that reviews that kind of product leads the whole review: the drug center if the PMOA is a drug, the device center if it is a device. The legal basis is FD&C Act §503(g) (21 U.S.C. 353(g)), with the details in 21 CFR Part 3 (which center has jurisdiction) and Part 4 (manufacturing and postmarket safety reporting).

1. Statute: 21 U.S.C. 353(g)

  • Lead center: FDA "shall... assign a primary agency center" (§353(g)(1)(A)). It "shall determine the primary mode of action" (§353(g)(1)(D)).
    • PMOA is defined as "the single mode of action... expected to make the greatest contribution to the overall intended therapeutic effects" (§353(g)(1)(C)).
    • A drug PMOA goes to the drug center, a device PMOA to the device center, and a biologic PMOA to the biologics center (§353(g)(1)(D)(i)-(iii)).
  • Chemical action limit: FDA "shall not determine that the primary mode of action is that of a drug or biological product solely because the combination product has any chemical action within or on the human body" (§353(g)(1)(E)).
  • If a sponsor disagrees with the PMOA call (§353(g)(1)(F)):
    • The sponsor can ask for, and FDA "shall provide," a substantive scientific rationale.
    • The sponsor may propose studies, and the two sides "shall collaborate" to agree on their design within no more than 90 calendar days.
    • The original determination stays in effect until FDA reevaluates it.
  • One application or two:
    • FDA "shall conduct the premarket review... under a single application, whenever appropriate" (§353(g)(1)(B)).
    • Sponsors are not barred from separate applications for each part "unless the Secretary determines that a single application is necessary" (§353(g)(6)).
  • Previously approved parts: where a constituent part is already approved or cleared, FDA may require only the data "necessary to meet the standard," including "any incremental risks and benefits," using a risk-based approach (§353(g)(3)-(4)).
    • If a device application (PMA, 510(k) or De Novo) relies on someone else's approved drug, it must include the patent certification and notice that a section 505(b)(2) application would. It is also treated as a 505(b)(2) application for patent infringement purposes (§353(g)(5)).
  • Combination-product meetings: on a written request, FDA "shall, not later than 75 calendar days after receiving such request, meet with the sponsor." Where a PMOA determination is needed, the sponsor can request the meeting only after it is made.
    • The meeting can cover approval standards, postmarket modifications and GMPs.
    • Any agreement must be in writing and stays binding except in limited cases (§353(g)(2)).
  • Office of Combination Products (OCP): it assigns the lead center, coordinates reviews involving more than one center, and makes the lead center the sponsor's main point of contact (§353(g)(8)).
    • It keeps postmarket regulation consistent and takes disputes about review timeliness (§353(g)(8)(B)-(E)).
    • Sponsors "shall identify the product as a combination product" when seeking agency action (§353(g)(8)(C)(v)).

2. Jurisdiction procedures: 21 CFR Part 3

  • §3.4: assignment follows the PMOA. If the PMOA "cannot be determined with reasonable certainty," FDA assigns the product to the center that regulates similar combination products. If there are none, it goes to the center with the most expertise on the most significant safety and effectiveness questions.
  • §3.6: OCP acts as the product jurisdiction officer.
  • §3.7 (Request for Designation): the request covers the product description, modes of action, manufacturing and proposed use, plus the sponsor's own recommendation, in no more than 15 pages.
  • §3.8: FDA issues a letter of designation within 60 days of filing. If it does not, the center the sponsor recommended becomes the designated center.
  • §3.9: a designation can be changed only with written consent, or to protect public health.
  • §3.10: any jurisdiction review stops the review clock while it runs.

3. Manufacturing (CGMP): 21 CFR Part 4, Subpart A

  • §4.3: each constituent part is subject to its own CGMPs: Parts 210/211 for drugs and Part 820 for devices.
  • §4.4: for single-entity and co-packaged products, a manufacturer can either comply with every applicable set of rules in full, or use the "streamlined" option. The streamlined option has two versions:
    • Drug-CGMP-based system: add the device provisions §820.20 (management responsibility), §820.30 (design controls), §820.50 (purchasing), §820.100 (CAPA), §820.170 (installation) and §820.200 (servicing).
    • Device-quality-system-based system: add the drug provisions §§211.84, 211.103, 211.132, 211.137, 211.165, 211.166, 211.167 and 211.170 (component testing, yield, tamper-evident packaging, expiry dating, release testing, stability, special testing, reserve samples).
    • The streamlined option can start only once the constituent parts are at the same facility; until then, each site must meet the full requirements for its own part (§4.4(c)-(d)).
    • Where the rules conflict, the regulation most specifically applicable to the constituent part prevails (§4.4(e)).
  • Recent change: the device rule, Part 820, became the Quality Management System Regulation (QMSR) on February 2, 2026. FDA says it made "conforming edits to part 4... These edits do not impact the CGMP requirements for combination products."
    • The §820 section numbers above come from the 2024 CFR edition, which predates those edits. I couldn't open the current text of §4.4(b)(1) to see how it now refers to device requirements.

4. Postmarket safety reporting: 21 CFR Part 4, Subpart B (§§4.100-4.105)

  • Scope: applies to marketed combination products, not investigational ones.
  • What the combination product applicant reports (§4.102):
    • for the device part: 5-day, malfunction, and correction/removal reports;
    • for the drug part: field alert and fifteen-day reports;
    • for a biologic part: deviation and fifteen-day reports;
    • the 2024 text also has a 30-day timing variant when the product was authorized under a device application.
  • Sharing between applicants (§4.103): where parts are held by different applicants, death, serious injury and adverse event information must go to the other constituent part applicants within 5 calendar days, with records kept.
  • How to submit (§4.104): through the route that matches the marketing application type.
  • Record keeping (§4.105): records are kept for the longest retention period that applies.

Approach: The FDA and US Code datasets I can search didn't respond this time, so I worked from the official statute (US Code, current through October 7, 2026) and the 2024 CFR on GovInfo. I couldn't open the current eCFR, the Federal Register QMSR rule page, or FDA's guidance "Requesting FDA Feedback on Combination Products."

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Q.03