8.5: Combination Products

Combination Products are therapeutic and diagnostic products that combine drugs, devices, and/or biological products.

One of the more challenging regulated products is combination products. Combination products are therapeutic and diagnostic products that combine drugs, devices, and biological products. Although each has clearly defined regulatory guidance's in place, a combination of one or more of these create a new product with a unique regulatory pathway. An asthma inhaler is an example of a combination device; it includes both the asthma drug and the device to get the drug to the lungs.

FDA expects to receive large numbers of combination products for review as technological advances continue to merge product types and blur the historical lines of separation between FDA’s medical product centers, which are made up of the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Devices and Radiological Health (CDRH). Because combination products involve components that would normally be regulated under different types of regulatory authorities, and frequently by different FDA Centers, they raise challenging regulatory, policy, and review management challenges.

Differences in regulatory pathways for each component can impact the regulatory processes for all aspects of product development and management, including preclinical testing, clinical investigation, marketing applications, manufacturing and quality control, adverse event reporting, promotion and advertising, and post-approval modifications. www.fda.gov/combination-products/aboutcombination-products

Types of Combination Products

Combination products are defined in 21 CFR 3.2(e). 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 whereupon 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.

The table below has been created to identify and describe the nine different types for a combination product. 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.

Type	Description
1	Convenience Kit or Co-Package. Drug and device are provided as individual constituent parts within the same package
2	Prefilled Drug Delivery Device/ System. The drug is filled into or otherwise combined with the device, AND the sole purpose of the device is to deliver drug
3	Prefilled Biologic Delivery Device/ System. Biological product is filled into or otherwise combined with the device, and sole purpose of the device is to deliver biological product
4	Device Coated/ Impregnated/ Otherwise Combined with Drug. Device has an additional function in addition to delivering the drug
5	Device Coated or Otherwise Combined with Biologic. Device has an additional function in addition to delivering the drug
6	Drug/Biologic Combination.
7	Separate Products Requiring Cross Labeling.
8	Possible Combination Based on Cross Labeling of Separate Products.
9	Other Type of Part 3 Combination Product.

Regulatory History

Combination product regulations were first provided in 1990 by the Safe Medical Device Act (SMDA). A provision was added (Section 503(g)) of the FD&C Act, requiring "combination products be assigned to a lead agency based on its Primary Mode of Action (PMOA)." In Title 21 of the Code of Federal Regulation (CFR) part, 3 established a Request for Designation (RFD) process, which allows the FDA to provide guidance on which Center to be assigned to a product without a clear (or disputed) pathway. In 2002, the FDA (through the Medical Device User Fee and Modernization Act (MDUFMA)), amended Section 503(g) mandated the FDA to establish an Office of Combination Products (OCP). The OCP was set up to work with FDA centers to develop guidelines and regulations to clarify combination product regulatory pathway.

Office of Combination Products (OCP)

The OCP is responsible for combination product assignment, coordinating premarket review with the Centers involved, and ensure consistent post-market regulation. Also, they examine and revise Guidance’s and practices unique to combination products. The bottom line – they serve as a facilitator of clearing combination product issues – but do not review the products themselves.

What is a Combination Product? - 21 CFR 3.2(e)

A combination product is defined in 21 CFR 3.2(e) as two or more regulated products; chemically or physically combined (21 CFR 3.2(e) (1)), or co-packaged (21 CFR 3.2(e)(2)), or cross-labeled but separately packaged (21 CFR 3.2(e)(3)).

Explore!

Explore at the FDA website for combination products examples of each of these products:

1. Physically or chemically combined:
2. Co-packaged:
3. Cross-labeled: