Guest Column | March 13, 2019

FDA Guidance On Premarket Pathways For Combo Products — What It Does (And Doesn't) Say

By Kate Cook, Greenleaf Health

biosimilar industry

Last month, the FDA published the draft guidance “Principles of Premarket Pathways for Combination Products.”  The document describes what a combination product is and how to interact with the FDA when developing a combination product, and it identifies some of the principles the agency uses in determining what type of premarket submission should be made.  As a general rule, combination products are reviewable under a single application, and the marketing application type submitted should generally coincide with the primary mode of action of the combination product.  However, “(i)n limited cases, an application type associated with the statutory authorities applicable to the non-lead constituent part ... may be needed.” 

As usual, the devil is in the details, and some of the most significant details are provided in the “Annex” appended to the draft guidance.  There, the FDA suggests that whenever a drug constituent part is added to a Class II device for the first time, the combination product could not be found to be substantially equivalent to the predicate device because of the new technological characteristics and intended use.  The same result occurs for subsequent submissions after a combination product is cleared under a 510(k) if the sponsor wishes to significantly change the claims made for the drug constituent part or to change the drug constituent part by swapping one active ingredient for another.  In each of these cases, the sponsor would have to seek a de novo classification or file a premarket approval application (PMA) for the new combination product.   The FDA’s discussion of these examples suggests that the agency intends to sharply narrow the use of 510(k) submissions for combination products and to increase de novo classification and PMA submissions. 

Combination Product Defined

There are three basic types of medical products: biological products, drugs, and medical devices.  The laws and regulations governing each type developed at different times, although in recent years there have been significant harmonization efforts, particularly for biological products and drugs.  A combination product is a product composed of two or more of these three types, such as a biological product distributed in a prefilled syringe (a biological product-device combination product) or a drug-coated cardiac stent (a drug-device combination product).  Appropriate regulation for combination products must address safety and effectiveness issues for both components.

Premarket Interactions With The FDA

The document stresses that the lead FDA center — i.e., the Center for Biologics Evaluation and Research, the Center for Device and Radiological Health, or the Center for Drug Evaluation and Research — is a combination product sponsor’s point of contact, and it will typically be responsible for presenting the FDA’s views to the sponsor.  Communications by the lead center should be considered communications on behalf of all the centers involved in the review.  The FDA will ensure that meetings between the agency and the sponsor are attended by review staff from each center involved, as warranted by the meeting topics.  The FDA has made important improvements by implementing these principles for premarket interactions.  Better cross-center coordination has led to fewer last-minute surprises during combination product development. 

Premarket Submissions For Combination Products

A single application for a combination product will generally be adequate, and the type of that single application will generally be an application associated with the combination product’s primary mode of action.  However, there may be multiple types of applications associated with a product’s primary mode of action, and the FDA will have to determine whether the application type preferred by the sponsor is adequate.  On page 5, the FDA states that the application type must support a review that is similar “to that which would be applied to each constituent part if they were reviewed under separate applications.”  It is important to note that decisions about the types of premarket submissions are made by the centers involved in the review.  The draft guidance references the FDA’s Inter-Center Consult Request Process in footnote 14, explaining that “(d)ecisions with respect to which application type is appropriate and whether a single or separate applications are appropriate will generally require consultation and alignment between the lead and non-lead center.”

The FDA addresses concerns that its approach may appear to be excessively burdensome, stating, “It bears noting that the data and information needed to address safety and effectiveness questions related to the non-lead constituent part of a combination product may differ from the data and information needed to obtain marketing authorization for that article as a stand-alone product that is not part of a combination product.”  As an example, for a device-led combination product that uses a drug coating for antibiotic or anti-inflammatory effects, the drug constituent part may have short-term local exposure at a low dose.  This would raise questions of safety and effectiveness that are different than those that would need to be addressed in an NDA application for the same active ingredient when it is intended for chronic administration for systemic absorption at a higher dose.  The FDA also notes that premarket review can be streamlined when the combination product’s sponsor has a right of reference to the data supporting the FDA’s prior approval of a constituent part or can rely on the FDA’s prior findings of safety or effectiveness of a drug constituent part.      

The document also provides a discussion of application pathways for drug-led combination products (NDA or ANDA), biological product-led combination products (traditional BLA or biosimilar application), and device-led combination products (510(k), de novo classification request, and PMA).  In footnote 12, the FDA signals that a 510(k) submission will be of limited use for many combination products: “For example, if an independent showing of safety and effectiveness would be needed for any constituent part then 510(k) would likely not be appropriate.” The FDA warns on page 10, “Generally, a device that is not combined with a drug or biologic constituent could not be successfully used as a predicate for a 510(k) for a device-led combination product.  This is because the addition of the drug or biologic constituent would likely result in a new intended use and/or constitute a different technological characteristic that raises different questions of safety and effectiveness as compared to the predicate.” 

Interestingly, the draft guidance omits any discussion of the use of the humanitarian device exemption for combination products — possibly because under this pathway, marketing is authorized under a “probable benefit” standard that is viewed as lower than the standard for marketing authorization applicable to the other device applications, as well as lower than the drug and biological product standards.  If this is the case, the FDA may have determined that an HDE marketing authorization cannot assure that a drug or biological product constituent part has been shown to be safe and effective when used in that combination product.

Annex: Examples Of Device-Led Combination Products

The last seven pages of the draft guidance are devoted to discussing examples of device-led combination products.  Each example assumes that the sponsor has a right of reference to a previously approved NDA, which provides supporting data for the drug constituent part.  The approved drugs discussed in the examples are antimicrobial drugs for intravenous administration, indicated for the treatment of acute bacterial skin and skin structure infections.  Several of the examples signal that the FDA no longer intends to follow established guidances such as its Guidance for the Content of Premarket Notifications for Conventional and Antimicrobial Foley Catheters, which provides a clear pathway for 510(k) submissions for antimicrobial Foley catheters.  Missing from the draft guidance is a summary of the reasons why the FDA is making these changes.

In the first example, the sponsor intends to add an antimicrobial coating for the first time to a previously classified (Class II) device type (Combination Product #1).  The purpose of adding the antimicrobial to this device is to prevent infections associated with the surgical procedure and continued use of the product.  The FDA states that the addition of the drug means that the combination product would be found to be not substantially equivalent (NSE) to the Class II predicate device, because the drug component changes the intended use of the device and because the addition of the drug is a significant technological change.  The sponsor’s first hope for a path forward would be a de novo classification; if the product does not meet the requirements for de novo classification, a PMA would be required. 

In the second example, the sponsor does not intend to change the design or manufacturing of Combination Product #1, but instead intends to propose a new anti-inflammatory indication for the product, due to the pharmacological properties of the drug constituent part.  The FDA states that this additional claim could not be reviewed under the 510(k) pathway; the combination product with the new claim would be found to be NSE to Combination Product #1.  

In the final example, the sponsor intends to replace the antimicrobial coating in Combination Product #1 with a different antimicrobial drug constituent part.  In this situation, the FDA states that the resulting combination product would be NSE to Combination Product #1:

As the new product contains a different active ingredient from [Combination Product #1], it would not be within the same type, and would thus be NSE.  Even if the special controls did not specify a particular active ingredient, a product with a different active ingredient from a predicate would differ significantly in features such as design and materials, which would likely raise different questions of safety and effectiveness and cause the product to be NSE. 

The FDA’s discussion of these three examples suggests that the FDA wants to break with established practices and narrow the scope of combination product review under 510(k).  If finalized, this will likely result in a large number of de novo classifications and, possibly, more PMAs. 

About The Author:

Kate Cook is executive VP of drug and biological products at Greenleaf Health, Inc.  She joined Greenleaf after a long career at the FDA, including 15 years in the Office of Chief Counsel, five years in the Office of the Center Director at the FDA’s Center for Biologics Evaluation and Research, and one and a half as associate director for regulations and policy at the FDA’s Center for Devices and Radiological Health. You can contact her at