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Understanding the Complex Combination Product Pathway

Oct 18, 2022 | Medical Device, Regulatory

Combination products—as the name suggests—represent a mixture of medical products. They comprise any combination of a drug and a device; a biological product and a device; a drug and a biological product; or a drug, device, and a biological product. 

The variety of possible combinations make them a difficult product category to usher through the regulatory process, and device manufacturers can quickly find themselves lost in a complicated and ever-changing undertaking. 

In this post we’ll examine how to make the regulatory route for combination products easier to navigate and cut down on the time and cost required to bring them to market. 

What are examples of combination products?

There are three different types of combination products. Some are single entity, where the components are combined, such as a monoclonal antibody combined with a therapeutic drug, or a device coated or impregnated with a drug or biologic. Prefilled drug delivery systems, like syringes, insulin injector pens and metered dose inhalers, are included in this category of combination product.  

The second group is co-packaged combination products such as a drug or vaccine vial packaged with a delivery device, or first aid kits containing devices (like bandages or gauze) and drugs (such as antibiotic ointments or pain relievers).

Finally, there are cross-labeled combination products, where components are provided separately but specifically labeled to be used together. A photosensitizing drug and an activating light source (i.e., laser) is a good example of this category of combination product. 

Who regulates combination products?

In the United States, the U.S. FDA regulates combination products, but manufacturers need to work with a specific center within the agency, depending on the nature of the product they want to take to market. 

The Office of Combination Products (OCP) is the starting point. OCP is the focal point for combination product issues and medical product classification. It also develops the guidance to clarify the regulation of combination products. 

After OCP, drug and device manufacturers must submit to different FDA centers depending on the type of combination product. The Center for Drug Evaluation and Research (CDER) focuses on drug-related products, the Center for Devices and Radiological Health (CDRH) reviews medical device products, and the Center for Biologics Evaluation and Research (CBER) assesses biological products. Each of these centers have different expectations and requirements, which makes submitting a combination product for review potentially complex. 

Ensuring a successful submission

1. Start Early and Establish Primary Mode of Action 

It is vital that manufacturers start early when submitting a combination device for regulatory review. This means establishing a plan of action well ahead of time to meet deadlines. The first step in the process is to determine a product’s primary mode of action (PMOA). The U.S. FDA defines the PMOA as the single mode of action that provides the most important therapeutic action of the combination product.

The PMOA dictates which of the U.S. FDA centers a manufacturer must approach first. Defining the PMOA in a combination product requires a manufacturer to look closely at how a drug or device interact with each other. 

If the device is the primary mode of action, the manufacturer should submit to the CDRH for initial review. CDER would be the first point of contact for a company with a combination product in which the drug is the PMOA. Device manufacturers of biological products should consult first with CBER. 

If a device has two independent modes of action and neither can be described as subordinate to the other, the U.S. FDA uses an algorithm to determine center assignment

This is arguably the most important step in the process. The correct lab testing partner can navigate the tricky waters of a combination product submission and guide a manufacturer through any unexpected twists and turns.

2. Select an experienced lab testing partner 

Manufacturers also need a lab testing partner with firsthand knowledge of the current regulatory environment, which can evolve or change over time. Regulators’ expectations are both complex and dynamic. An experienced lab partner is continuously engaged with regulators throughout the world, which can help inform and quicken the entire process. 

Finally, lab partners provide the expertise (through their equipment, credentials, and databases) to meet new requirements and expectations, such as complete chemical characterization of medical devices or compound elucidation of drug components. There just isn’t a great substitute for lab partners who understand the regulatory environment and have the capacity and capability to guide a new product toward submission.

3. Request a pre-submission meeting

Manufacturers can save a lot of time and effort if they request a pre-submission meeting with the U.S. FDA. Pre-submission meetings are informal opportunities to receive feedback or answer agency questions while preparing products for submission. They are also invaluable in understanding regulators’ expectations. They really help establish the most efficient route to regulatory success for combination products. Also, lab testing partners can help prepare, and even participate in, such meetings. 

The bottom line

The regulatory route for a combination product can easily become a maze for manufacturers with little experience or assistance. Establishing the right U.S. FDA center to submit to can be challenging, especially given a combination products’ PMOA is sometimes unclear.  

Selecting the right lab testing partner with ample expertise, deep knowledge about regulations, and experience dealing with combination products can make the entire process much more straightforward. 

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