The last three decades have seen vast growth in the development of therapeutic and diagnostic products that are a combination of two or more components. These products, termed combination products, are a distinct category of medical products regulated in light of their constituent parts.

But the question still remains – what is a true combination product?

Classification of Combination Products

A combination product, as defined under Part 3 of Title 21 of the Food, Drug, and Cosmetic Act’s Code of Federal Regulations (21 CFR Part 3), is any combination of drug and biologic; drug and device; biologic and device; or drug, device and biologic.

The components of a combination product can be chemically, physically or otherwise combined as a single entity, or two or more different products can be packaged together or separately.

If packaged separately, the labeling of each component must state they are to be used together.

Products that incorporate two or more components from the same category — for example, drug-drug combinations and device-device combinations — are not considered combination products.

Examples of Combination Products

A classic example of a combination product is the TAXUS Liberté Paclitaxel-Eluting Coronary Stent System, a metal scaffold coated with a drug that prevents the artery into which it is placed from narrowing following surgery.

Another example is DuraLock-C, a venous catheter locking solution contained within a pre-filled syringe. The solution component of this combination product occupies space within a catheter and exerts pressure to prevent blood from backfilling into the catheter and clotting.

These two examples constitute a simplistic view of combination products.

Most products are more complex than this, and thus, their classification is not so clear-cut.

An example of a product that blurs the classification boundaries is Ovile, a drug that must be inserted into a body cavity with a fingertip glove. As the fingertip glove is considered a medical device, Ovile is classed as a combination product rather than a drug.

Another example is Bexxar, a therapeutic regimen that was indicated for the treatment of patients with certain types of non-Hodgkin’s lymphoma. Bexxar comprised an injectable monoclonal antibody (tositumomab) with a radioactive substance (Iodine-131) attached to it.

These two components were packaged separately but had to be used together to destroy cancer cells.

A growing class of borderline combination products is companion diagnostics — diagnostic devices or tests used to determine whether specific drugs or biologics will be efficacious and/or safe for use in certain patients.

One of the best-known examples of companion diagnostics is the HercepTest, a laboratory test that measures the level of HER2 protein produced by cancer cells. If the test reveals overexpression of HER2, the cancer cells are more likely to respond to treatment with a monoclonal antibody called Herceptin. Although the HercepTest is packaged separately from Herceptin, it is considered a combination product as its label indicates it is to be used with the drug.

Obtaining a Formal Classification Determination

If the classification of a product is unclear or in dispute, the Office of Combination Products recommends filing a request for designation (RFD) in accordance with 21 CFR Part 3. This will enable you to obtain a formal classification determination and establish the minimum standards for combination product manufacturing.

You should submit a RFD as soon as you have sufficient information for the Food and Drug Agency to make a classification determination, and before you file any investigational or marketing applications for your product.

Product classification errors can put you at risk for regulatory noncompliance. Determining whether a product truly is a combination product is key to ensuring compliance and avoiding wasted resources.