With the promise of simplified and improved treatments, the $118 billion combination-product market is projected to increase at a compound annual growth rate (CAGR) of 8.8%. Working to bring these valuable new therapies to patients, sponsors engaged in strategic development often approach Premier Consulting for regulatory clarification: “Is this actually a combination product? What do we need to do if it is?” They realize that proceeding down the wrong development pathway risks precious time and money, so it’s crucial to identify what kind of combination products they have, from the start.

This blog post aims to bring clarity to this confusing subject for sponsors.

Determining if you have a combination product

The high-level definition of combination product seems straightforward: a product with at least two constituent parts, such as:

• Drug/biologic (e.g., therapeutic drug/monoclonal antibody)
• Drug/device (e.g., insulin injector pen)

• Multiple drugs/device (e.g., metered-dose inhaler)

However, the four-part definition in 21 CFR 3.2(e) reveals more detail — and gray areas:

• Two or more regulated components, in one package (e.g., typical drug device, biologic device)
• Two or more separate components, co-packaged (e.g., prefilled syringe)
• A drug used with a specified device in clinical trials — but that may be used with other devices once marketed (e.g., a post-approval label change that will allow other devices to be used for administration)

• A drug that, even when marketed, must be used with a specific device, and must be labeled as such — even if the device is sold separately and/or from a different manufacturer

Note that two drugs co-administered as a multi-active pharmaceutical ingredient (API) drug do NOT constitute a combination product.

Approaching a particularly confusing case

In certain circumstances, it’s necessary to scrutinize the FDA drug vs. device product classification guidance to identify whether a product meets both criteria. (Also see the FDA’s FAQs on this topic.)

Consider a drug formulated with a polymer that modifies release. The drug product is packaged and shipped as a solid powder. When water is added, the polymer forms a gel that allows for direction application to the affected area. The release rate is controlled through physical means and is not impacted by physiological conditions. Is this a drug product or drug-device combination product?

The above-referenced FDA guidance offers insight. Sections B(ii-iii) in the drug vs. device product classification section state that for a medical product to be a device, it must not achieve its intended purpose through chemical action within or on the body and must not depend upon metabolization.

In the case above, the polymer is used to control release through physical deposition and does not interact with the patient directly. Excipients that modify the release of an API are not typically considered devices. However, because it forms a polymeric gel that physically controls release, the component would meet the definition of a device, and the described product would be classified as a combination product. (Note: This product may fall within a regulatory “gray” area and require further considerations during development.)

Consulting the FDA very early via RFD to learn how to proceed

As the example described above illustrates, identifying combination products can be a challenge. An additional key means of addressing ambiguity is to consult the FDA for clarity very early via a Request for Designation (RFD) meeting and pre-RFD emails to determine:

• Is it a combination product?
• What type — drug-led or device-led?

The FDA response to these inquiries provides essential guidance on how you will proceed:

Differences in regulatory process between drug-led and device-led combination products

	Drug-led	Device-led
Review focus	Review Focus: efficacy, potency, safety — typical drug studies	Review Focus: device action, compliance with ISO and other applicable standards
Reviewing division	Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER)	Center for Devices and Radiological Health (CDRH)
Application type	New Drug Application (NDA) or Biologics License Application (BLA)	Premarket Approval (PMA) or 510(k) premarket submission

 

Understanding the device classification allows for streamlined development and provides foundational considerations for a pre-IND meeting.

Gaining further insight through a pre-IND

After product designation, a pre-IND meeting should be the next step to establish what level of work needs to be done to satisfy regulatory requirements. While this meeting is optional, it often yields time-saving information. By allowing the agency to review the development plan in advance, you can learn whether regulators view it as sufficient, identify missing components, and understand the FDA’s thinking regarding your product. In this way, you’ll identify missing development steps early, while it’s still practical to obtain the necessary data.

The good news is that for combination products, there is a sliding scale of development considerations and regulatory requirements for varying device classifications. For example, a drug prefilled into an IV bag is a combination product, per 21 CFR. However, the regulatory steps for a container/closure system such as the IV bag are relatively minor. In contrast, a device that doses the product, such as a prefilled syringe, requires more elaborate testing.

Key Takeaway

Identifying combination products and defining the level of development needed for each component separately and in combination can be confusing. To facilitate approval efficiency and speed products to market, the FDA encourages constant communication to identify each combination product’s proper regulatory pathway. Sponsors are well-advised to follow the FDA’s suggestion in this regard.

Premier Consulting supports combination product development, from concept through commercialization. We help sponsors determine whether they have a combination product and identify key aspects of their development program. We also provide additional support during development to ensure all requirements are met and all challenges are overcome, from IND to NDA to post-approval changes. Connect with our experts for more detailed insight specific to your program.

Author:

Ryan Key, PhD
Manager, RA CMC