Combination Products

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FDA-Regulated Combination Products

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What is a Combination Product

A combination product is a product composed of two or more different types of medical products (i.e., a combination of a drug, device, and/or biological product with one another). The drugs, devices, and biological products included in combination products are referred to as “constituent parts” of the combination product.

The constituent parts of a combination product retain their regulatory status (as a drug or device, for example) after they are combined. The final rule clarifies that the Current Good Manufacturing Practice (CGMP) requirements that apply to each of the constituent parts apply to the combination product they constitute.

As technological advances continue to merge product types and blur the historical lines of separation between medical products, the Federal Food and Drug Administration (FDA) expects to receive large numbers of combination products for review

Based on primary mode of action (PMOA), a combination product is assigned to a “lead-center” that has primary jurisdiction for its regulation. PMOA is defined as “the single mode of action of combination product that provides the most important therapeutic action of the combination product”. For example, if the PMOA of device-biological combination product is attributable to the biological product, the Agency component responsible for premarket review of that biological product would have primary jurisdiction for the combination product.

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Combination Product Definition

The term combination product includes:

1.  A product comprised of 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.  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.  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 and where upon approval of the proposed product 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; or

4.  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.

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Combination Product Types

A package that contains only devices is not a combination product. Additionally, a product that is a combination of only drugs is not a combination product. The following are 9 different types of combination products identified.

Type 1: Convenience Kit or Co-Package: Drug and device are provided as individual constituent parts within the same package. Drug or biological product vials packaged with device(s) or accessory kits (empty syringes, auto-injectors, transfer sets), first aid or surgical kits containing devices and drugs

Type 2: Prefilled Drug Delivery Device/ System: Drug is filled into or otherwise combined with the device AND the sole purpose of the device is to deliver drug. Prefilled drug syringe, auto-injectors, metered-dose inhalers, dry powder inhalers, nasal-spray, pumps, transdermal systems, prefilled iontophoresis system or microneedle “patch”

Type 3: Prefilled Biologic Delivery Device/ System: Biological product is filled into or otherwise combined with the device AND the sole purpose of the device is to deliver biological product. Vaccine or other biological product in a prefilled syringe, auto injector, nasal spray, transdermal systems or microneedle patch pre-loaded with biological product

Type 4: Device Coated/ Impregnated/ Otherwise Combined with Drug: Device has an additional function in addition to delivering the drug. Drug pills embedded with sensors, contact lens coated with a drug, drug-eluting stents, drug-eluting leads, condoms with spermicide, dental floss with fluoride, antimicrobial coated catheters/sutures, bone cements with antibiotics

Type 5: Device Coated or Otherwise Combined with Biologic: Device has an additional function in addition to delivering the drug. Live cells seeded on or in a device scaffold, extracorporeal column with column-bound protein

Type 6: Drug/Biologic Combination: Antibody-drug conjugates, progenitor cells combined with a drug to promote homing

Type 7: Separate Products Requiring Cross Labeling: Light-activated drugs or biological products not co-packaged but labeled for use with a specific light source device

Type 8: Possible Combination Based on Cross Labeling of Separate Products: Drug/biological product under development utilizes a device, but   unclear whether the final product will require that the two be cross-labeled

Type 9: Other Type of Part 3 Combination Product (e.g., Drug/Device/ Biological Product)/Combination product not otherwise described: All 3 articles are combined in a single product (e.g., a prefilled syringe containing an antibody-drug conjugate), device to manufacture a biologic also includes a drug or biologic in the kit, or the product contains two different combination product types (e.g., Type 1 and Type 2 are provided together

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What are some examples of medical product types that are commonly mistaken as combination products?

Some FDA regulated products are intended to be used together to achieve their therapeutic or diagnostic effect but do not meet the regulatory definition of a combination product. This can be the case for medical products intended to be used together, for example, syringes marketed for general delivery of unspecified drugs or two or more of the same type of medical product (e.g., a drug and drug, or device and device) that are packaged or labeled for use with one another (e.g., fixed dose combination drugs). Similarly, combinations of a medical product with a non-­medical product, for example a drug with a dietary supplement, cosmetic, or food, are not combination products.

What types of marketing applications are required for a combination product?

Combination products are typically marketed under a marketing authorization type associated with the constituent part that provides the primary mode of action (PMOA) for the combination product (i.e., a new drug application (NDA) or abbreviated new drug application (ANDA) if it has a drug PMOA, a biologic license application (BLA) if it has a biologic PMOA, or a premarket approval application (PMA), de novo classification, or premarket notification (“510(k)”) if it has a device PMOA). A single marketing application is generally sufficient for combination product. In some cases, however, a sponsor may wish to submit separate marketing applications for different constituent parts of a combination product, and FDA may consider this permissible.

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