FDA Regulation Combination Products.

Information & Training. | Validation .


Example Combination Product:

The Endeavor Zotarolimus-Eluting Coronary Stent for use in treating patients with narrowed coronary arteries, the blood vessels supplying the heart.

Manufactured by Medtronic, Inc., the device is a tiny metal mesh tube coated with a small amount of a drug, zotarolimus, developed only for use on a stent. It is crimped around a balloon and delivered to the narrowed section of the coronary artery via a long thin catheter during a procedure known as an angioplasty. Once the stent is positioned, the balloon is inflated, expanding into the vessel wall where it will remain in place, acting as a mechanical scaffold to keep the artery open.

The slow release of zotarolimus over time prevents the artery from re-narrowing when new tissue begins to form.

FDA Regulation Combination Products

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Other examples of Combination Products:

Surgical mesh with antibiological coating.

Anti-biotic bone cement.

Equipment and process for photo dynamic therapy.

Prefilled syringes, insulin injector pens, metered dose inhalers, transdermal patches.

Skin substitutes will cellular components.

Surgical tray with surgical instruments, drapes, lidocaine or alcohol swabs.


Determining the Regulatory Approval Process for Combination Products.

The “primary mode of action” determines the regulatory approval process and the FDA regulatory agency which will perform the product compliance reviews.

The primary mode of action (PMOA), as defined by the FDA is the “single mode of action of a combination product that provides the most important therapeutic action of the product.  The most important therapeutic action is the mode of action expected to make the greatest contribution to the overall intended therapeutic effects of the combination product.”

When the PMOA is determined, then the FDA regulatory agency and associated approval process becomes clear:


If the PMOA is as a medical device, then the applicable FDA agency is the Center for Devices and Radiological Health (CDRH)
If the PMOA is as a drug, then the applicable FDA agency is the Center for Drug Evaluation and Research (CDER)
If the PMOA is as a biologic then the applicable FDA agency is the Center for Biologics Evaluation and Research (CBER)

For the majority of products, the PMOA should be clear, however, where the PMOA is not immediately obvious, then there is a process called the “Request for Designation (RFD)” where the FDA’s Office for Combination Products will review a product and make a determination of the appropriate PMOA and lead agency. The FDA Office for Combination Products will make its jurisdictional determination within 60 days of an organization submitting the RFD.


Regulatory Requirements:

There are a range of statutory and regulatory provisions pertaining to the classification and assignment of biological products, drugs, devices, and combination products.

21 CFR Part 3 – the regulations pertaining to the assignment of products to FDA components for review of premarket applications.

21 CFR 3.4 – the regulation regarding how FDA designates the review of combination products.  Designation of lead FDA review center is based on the Primary Mode of Action (PMOA) of a product.  FDA issued a “final rule” for the definition of PMOA.

Statutory provision regarding classification of products and the roles and responsibilities of the Office of Combination Products can be found in section 563 of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 360bbb-2]

The Office of Combination Products was established per SEC. 204 of the Medical Device User Fee and Modernization Act of 2002 (MDUFMA).
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Product and Process Validation.

  • The Validation Master Plan. Performing a Gap Analysis. Validation in the Design Process. Etc..
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  • How to ensure that Validation activity is appropriately documented, reviewed and aligned with requirements.
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Medical Device:

      • Validation. Classification. Regulation. Requirements. Current best practices.
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FDA. Post-marketing Safety Reporting for Combination Products
FDA. Combination Products Guidance Documents