Guest Column | April 17, 2026

Minding The Gap: Submission Strategies For Combined Use Combination Products

By Lyndsay Sweeney, Splice Regulatory Solutions

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Cross-labeled,1 referenced,2 or “combined use” products are enigmatic entities in the combination product space. However enigmatic, these products are quickly becoming of great interest to companies searching for novel delivery methods for drugs and biologics, specifically within the inhalation route of administration.

Common questions asked by pharmaceutical3,4 and medical device5,6 companies regarding developing and filing marketing authorization for these products are:

  • Does the clearance/approval of either constituent impact the choice of regulatory strategy?
  • What type of submission? How many submissions?
  • How to link the constituent information?
  • How to show the constituent parts work together safely and effectively?

These questions are not always easy to answer, and there is no one-size-fits-all answer for cross-labeled/referenced or combined use products.

Regional Considerations

As with any regulatory strategy, defining the applicable countries and regions is critical to determine the specific regulations and requirements for a combination product. The level of criticality of understanding the potential regional regulatory pathway(s) for cross-labeled combination products cannot be understated. Health authorities in regions and countries, such as Health Canada, do not recognize or regulate these products as combination products,7 while others, such as the FDA, EMA, and EU member states, do.

Does The Clearance/Approval Of Either Constituent Impact The Choice Of Regulatory Strategy?

The answer to this question, as with many questions within regulatory affairs, is “it depends.” Local or regional licensing, approval, or clearance of the device constituent can be beneficial to streamline the regulatory submission strategy. However, this regulatory landscape is nuanced and evolving; various countries or regions do not always recognize the licensing, approval, or clearance of another.

For example, a device that bears a CE (Conformité Européene) mark8 will be beneficial in EU submissions for the combination product but is not advantageous in countries such as the U.S. and Canada, where CE marking is not recognized. To make matters even more complicated, some devices in the U.S. may not be 510(k)9 cleared (or approved via premarket approval application (PMA10)) but may have a device master file (MAF)11 or drug master file (DMF)12 on record with the U.S. FDA, which could also provide opportunities to streamline the submission strategy.

What Type And How Many Submissions?

The answer to this question is also, “it depends.” as already mentioned as a common theme in the world of combination product regulatory affairs. The submission strategy depends on not only the regional regulatory status of the constituent parts and recognition of “combined use” combination products, but on the primary (or principal) mode of action (PMOA)13,14,15 of the final combined product.

Typically, health authorities in countries and regions that recognize cross-labeled, referenced, or combined use combination products prefer a single drug-led application or a single device-led application. However, in situations in which a constituent, for example, a device, is already marketed for general administration of any drug, two stand-alone device and drug submissions may be appropriate.

These details are also determined by the business relationship and joint agreement of strategy of the manufacturer of each constituent part, highlighting an important, yet frequently omitted, component of a complete regulatory strategy: the master service agreement (MSA), quality agreement (QA), and other contracts between the manufacturers of the constituent parts.

How To Link The Constituent Information?

As stated, when allowed by regulation, and subject to specifics regarding the relationship between the constituent parts and their respective manufacturers, it is best practice to utilize a single marketing authorization application for a given combination product. The most likely scenario is a drug-led application (due to the primary mode of action being attributed to the drug), such as an NDA,16 ANDA,17 or BLA18 in the U.S. or a marketing authorization application (MAA)19 in the EU or its member state(s).

The drug or biologic application should fully incorporate information regarding the device constituent or reference this information, as appropriate. The mechanism for referencing device information once again depends on the region in which the filing will occur and the relationship between the manufacturers of the constituents. For example, in the EU, inclusion of the CE declaration of conformity and other notified body20 certificates regarding the device manufacturer is an appropriate method. Whereas in the U.S., obtaining a letter of authorization (LOA)21 from the device manufacturer for a respective 510(k), MAF, or DMF, may be appropriate.

Labeling of the constituent parts must also link together, as evident by the very definition of a cross-labeled or referenced combination product. This includes physical and packaging labeling of the constituent(s), regional required labeling such as U.S. prescribing information (PI)22 or EU summary of product characteristics (SmPC),23 and the device instructions for use (IFU).24,25

How To Demonstrate The Constituent Parts Work Together Safely And Effectively?

In preparing a regulatory strategy for combined use combination products, it is easy to forget one of the most important questions, since the focus tends to be on the individual constituent parts: How to document or demonstrate that the constituent parts work together safely and effectively?

Regardless of region, business agreements, or other details, any submission determined by a given regulatory strategy must contain evidence that the constituent parts not only meet their respective requirements but will work together to achieve the intended use26 (intended purpose27) and/or indication28,29 of the final product.

Moreover, submissions must demonstrate that unintended, potentially negative, interactions between the two have been identified, assessed, and properly mitigated. Companies frequently overlook key topics required for the final combined product, including, for example, human factors, design controls, and risk management. This is the gap that needs to be addressed. Acknowledging, and bridging, the gap between pharmaceutical development practices and current cGMPs and device development practices and cGMPs is the key to an appropriate submission strategy and a successful submission.

Underestimating the importance of developing a thorough submission strategy, early in the process of developing a combination product (including the often-forgotten plan for demonstrating compliance with all applicable regulations, specifically those that require assessment of the interaction of the constituent parts) is a common mistake that costs companies time, effort, and money. Identifying planned regions and countries, understanding the respective recognition and/or regulation of cross-labeled, referenced, or combined use combination products in those regions, identifying the status of the constituents, and defining clear roles and responsibilities between the respective manufacturing partners or applicants are critical steps in defining the framework for regulatory, and commercial, success. In short, always remember to mind, and bridge, the gap.

References

  1. U.S. 21 CFR 3.2(e)
  2. Regulation (EU) 2017/745 Article 1 (9)
  3. U.S. 21 CFR 3.2(g)
  4. Regulation 2001/83/EC Article 1 (2)
  5. U.S. 21 CFR 3.2(f)
  6. Regulation (EU) 2017/745 Article 2 (1)
  7. Health Canada Policy, Drug/Medical Device Combination Products, 2006/03/01
  8. Regulation (EU) 2017/745 Article 1 (43)
  9. U.S. Food, Drug, & Cosmetics Act, Section 510(k)
  10.  U.S. Food, Drug, & Cosmetics Act, Section 515
  11. U.S. 21 CFR Part 814.3(d)
  12. U.S. 21 CFR Part 314.420
  13. U.S. 21 CFR Part 3.2(m)
  14. Regulation (EU) 2017/745 Article 1 (6), (8), (9), (10)
  15.  MDCG 2022 – 5 Rev. 1 Guidance on borderline between medical devices and medicinal products under Regulation (EU) 2017/745 on medical devices, October 2024
  16.  U.S. Food, Drug, & Cosmetics Act, Section 505
  17.  U.S. Food, Drug, & Cosmetics Act, Section 505(j)
  18.  U.S. Public Health Service Act, Section 351(a)
  19.  Regulation 2001/83/EC Title III, Chapter 1
  20.  Regulation (EU) 2017/745 Article 2 (42)
  21.  U.S. 21 CFR Part 314(g), Part 601.2(g)
  22. U.S. 21 CFR Part 201.56
  23. Directive 2001/83/EC Article 11
  24. U.S. 21 CFR Part 801.5
  25. Regulation (EU) 2017/745 Article 2 (14)
  26. U.S. 21 CFR Part 801.4
  27. Regulation (EU) 2017/745 Article 2 (12)
  28. U.S. 21 CFR Part 201.56
  29.  Directive 2001/83/EC Article 8, Article 11

About The Author:

Lyndsay Sweeney, founder and primary consultant at Splice Regulatory Solutions, brings a fresh and unique perspective to regulatory strategy, writing, and compliance, based on her background in combination product and medical device engineering, project management, and regulatory affairs. Sweeney focuses on regulatory support of innovative product development, submission planning, and execution, leading to safe and efficacious solutions for patients around the world.