Combination Product: What to Consider for both Medical Device and Drug Constituents

What are the required actions when a product includes both a medical device constituent and a drug constituent?

What is a combination product?

A combination product is defined in the regulatory world as a product that consists of two or more regulated components (device, drug or biologic) that are combined in a way to produce a single entity. For example, if the product consists of a device+drug combination or a biologic+drug combination or a biologic+device combination then it is considered to be a combination product. A few everyday examples are dental floss with fluoride, inhalers, nasal-spray pumps and first aid kits.

A product is not considered to be a combination product if it only incorporates two products from the same category. For example, a drug+drug combination is not considered a combination product, even though it may be considered combination therapy in the clinical world.

The FDA determines the appropriate category that a combination product belongs to by using regulatory pathways. One category is for medical devices (CDRH), one is for drugs (CDER) and one is for biologics (CBER). However, combination products don’t fit perfectly into just one of these categories. In regulatory science, the appropriate category to which a combination product belongs is determined by a concept called the primary mode of action, or PMOA. The category that the combination product belongs to is determined by deciding the most important way that the product accomplishes what it’s intended for. This category or application type also determines what requirements apply to the product.

Combination product regulatory background

In this scenario, the combination product was reviewed by the Center for Devices and Radiological Health (CDRH) and cleared under a 510(k). The combo product is identified with both a NDC/NHRIC identifier and a UDI identifier on the label. Additionally, the combo product is listed as a ‘medical device’ on the FDA/NLM DailyMed and reported as a medical device on the FDA/CDRH/NLM AccessGUDID database.

Because combination products are being developed and produced rapidly, this part of the industry is only expanding for medical device makers. Roughly one-third of all medical products that are currently being developed are combination products. Medical device makers can seize the opportunity to grow their offering while being on the frontlines of correct labeling.

Key compliance considerations for combination products

• Controls – If the Combination Product was cleared under a 510(k), it only needs to comply with medical device regulations pending the details in the FDA product clearance letter. Always revisit the details of the FDA clearance to check for any additional ‘drug-related’ controls.
• DailyMed listing – The medical device Combo Product does not need to be listed in NLM DailyMed. However, note that the drug constituent does need to be independently listed in DailyMed. Medical devices may be voluntarily included in drug kits, but such inclusion is not encouraged.
• DailyMed actions – The FDA may ask the manufacturer to delist the Combo Product from the NLM DailyMed by submitting an SPL update with a Market End Date. Optionally, the FDA may manually remove the Combo Product from the DailyMed without an SPL update.
• NDC/NHRIC identifiers – FDA CDRH is rescinding NDC/NHRIC identifiers from medical devices. The medical device UDI regulation defines end dates for placing legacy NDC/NHRIC identifiers on medical device labels based on UDI Compliance Dates.
• Supporting material – To further support the position that the Combination Product is considered/regulated as a medical device, consider providing links to a few representative product records currently published on the NLM AccessGUDID website. This CDRH related database includes medical device identifiers and attributes and demonstrates reporting of this product as a medical device.

• UDI & combination products — The medical device constituent does not need to have a separate UDI if the Combo Product assembly has a UDI (the medical device constituent is covered by the Combo Product assembly UDI). Medical Device Constituent ID in Combo Product

• Discontinuation of legacy FDA identification numbers assigned to devices §801.57 – On the date your device is required to carry a unique device identifier (UDI) on its label, any National Health-Related Item Code (NHRIC) or National Drug Code (NDC) number assigned to that device is rescinded, and you may no longer provide an NHRIC or NDC number on the label of your device or on any device package. eCFR Section 801.57

Since the UDI regulation was released in 2013, FDA issued Guidance in 2016 that defines enforcement discretion of the prohibition of NDC/NHRIC identifiers on medical device labels until Sep 24, 2021.

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Sources

Combination Product Definition and Combination Product Types — 21 CFR 3.2(e)

Guidance document: Enforcement Policy on National Health Related Item Code and National Drug Code Numbers Assigned to Devices

Discontinuation of legacy FDA identification numbers assigned to devices §801.57 — eCFR Section 801.57

Combo Product ID Device Component / Combo Product Device Component — 801.18(a)  801.30(a)(11)

General exceptions from the requirement for the label of a device to bear a unique device identifier — 801.30(b)

Abbreviations

• CDRH — Center for Devices and Radiological Health/FDA
• FDA — Food & Drug Administration
• NDC — National Drug Code Directory/FDA
• NHRIC — National Health Related Items Code
• NLM — National Library of Medicine/FDA
• DailyMed — NIH/National Library of Medicine/FDA