FDA Issues Draft Guidance to Advance Development of Combination Products


On Tuesday, February 5th, FDA published a draft guidance explaining the principles for premarket review of combination products, including how to determine which type of premarket submission is appropriate. These submissions include new drug applications (NDAs) or abbreviated new drug applications (ANDAs) for drug-led combination products; stand-alone or biosimilar biologics license applications (BLAs) for biologic-led combination products, and 510(k), De Novo, or premarket approval (PMA) applications for device-led combination products.

The draft guidance, entitled “Principles of Premarket Pathways for Combination Products,” is part of the FDA’s effort to implement Section 3038 of the 21st Century Cures Act (“Cures Act”). This section, enacted in December 2016, substantially amended section 503(g) of the Federal Food, Drug, and Cosmetic (FD&C) Act and is the principal section specifically addressing combination products. “General themes of these amendments include enhancing clarity, predictability, efficiency, and consistency of premarket regulatory expectations for combination products, including by ensuring that Agency components and staff coordinate appropriately on premarket review of these products, and that Agency thinking is aligned in conducting these reviews.”

Combination Products

In a recent statement, Scott Gottlieb, M.D., Commissioner of the FDA, stated that “because combination products often combine a drug or biologic with a device, these products can sometimes be more complex to develop—and it can be less clear to innovators on how to best engage the regulatory process to advance these innovations.”

Combination products are any “product composed of two or more different types of medical products (i.e., a combination of a drug, device, and/or biological product with one another).” Included in the combination products are drugs, devices, and biological products which are referred to as “constituent parts.”

Under 21 CFR 3.2(e), combination products include:

  • A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity
  • Two or more separate products packaged together in a single package or unit and comprised of drug and device products, device and biological products, or biological and drug products.
  • A drug, device, or biological product packaged separately that, according to its investigational plan or proposed labeling, is intended for use only with an approved, individually specific drug, device, or biological product where both are required to achieve the intended use, indication, or effort and where upon approval of the proposed product the labeling of the approved product would need to be changed
  • Any investigational drug, device, or biological product that is packaged separately and, according to its proposed labeling, is intended for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect

Combination products will be assigned to an Agency Center that will have primary jurisdiction (i.e “the lead”) for premarket review and regulation of that combination product.

The assignment to the lead Center is based on a determination of which constituent part of the combination product provides the primary mode of action (PMOA). For example, if the PMOA of a device-biological product combination product is attributable to the biological product, primary jurisdiction for the regulation of the combination product will be the Center responsible for premarket review of a biological product. Therefore, the Agency Center with primary jurisdiction will work with other Agency Centers to ensure adequate premarket review.

Interacting with the FDA

The lead Center is a Sponsor’s primary point of contact and the focal point for the FDA to present their views to the Sponsor. The Cures Act ensures that meetings between the FDA and Sponsors are attended by review staff from each Center, as appropriate. Premarket approval and procedures for the lead Center are available, and the FDA suggests that Sponsors utilize the procedures, such as pre-submissions meetings and other mechanisms for obtaining Agency feedback.

“Sponsors may request in writing the participation of representatives of the Office of Combination Products (OCP) in meetings regarding their products, or to have OCP otherwise engage on regulatory matters concerning the product.”  OCP can assist sponsors in identifying appropriate points of contact, resolving substantive issues, or otherwise facilitating interactions with the FDA and collaboration among Agency components.

Premarket Regulation of Combination Products

In its draft guidance, FDA emphasizes that drugs, devices, and biological products retain their discrete regulatory identities when they are constituent parts of a combination product. Therefore, premarket requirements for demonstrating the safety and effectiveness of a combination product is applicable to the statutory and regulatory requirements of its constituent parts.

FDA states that a single application for a combination product is generally appropriate with regards to premarket authorization pathways. Furthermore, the Agency believes that this single application will eliminate unnecessary duplication of multiple applications and will streamline submissions and communication with FDA. To assess the safety and effectiveness of a combination product in a single application, a similar evaluation that would be submitted if each constituent part were reviewed under separate submissions should be included.

The marketing application should coincide with the PMOA of the combination product, however “if application coinciding with the PMOA of the combination product (PMOA-based application type) does not enable such an evaluation, the combination product should typically be reviewed in a different PMOA-based application type.”

The draft guidance states that premarket review of a combination product can be “significantly streamlined” where Sponsors are legally authorized to rely on FDA’s prior findings of safety or effectiveness or substantial equivalence with respect to an approved or cleared constituent part, or where the sponsor has a right of reference for another sponsor’s data.

Pathway Availability & Related Considerations

FDA discusses various pathways that are available for combination products based on their PMOA, and considerations for determining the correct pathway, including:

Device -Led Combination Products

  1. Premarket Approval (PMA) Applications
    • Class III devices must obtain FDA PMA approval before they can be legally marketed. The PMA must contain valid scientific evidence to assure that the device or device-led combination product is safe and effective for its intended use(s).
    • Sponsors of device-led combination products should supply sufficient data in PMA applications to demonstrate the safety and effectiveness of the combination product as a whole, which includes all data regarding all constituent part(s).
  2. De Novo Classification Requests
    • If a Sponsor chooses to submit a De Novo request without first submitting a 510(k), the De Novo request may be declined if the Agency identifies a predicate product that could provide a reasonable basis for review of substantial equivalence
    • “Understanding of the biologic or drug constituent parts, including limitations of such understanding, need to be considered when determining the suitability of the De Novo pathway for such device-led combination products.”
  3. Premarket Notification (510(k)) Submissions
    • 510(k) submissions follow a comparative review process, whereas the PMA and De Novo review rely on independent demonstrations of safety and effectiveness.
    • Generally, a device-lead combination drug-biologic constituent could not be used as a predicate for a 510(k), 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.”

Drug-Led Combination Products

  1. New Drug Application (NDA)
    • The NDA must include a demonstration of the safety and effectiveness of the product for the conditions prescribed, recommended, or suggested, among other things in the proposed labeling.
    • A 505(b)(1) NDA contains full reports of investigations of safety and effectiveness that were conducted by or for the applicant. This application may be appropriate for a drug-led combination product that contains a new molecular entity (NME).
    • A 505(b)(2) NDA contains the same reports as 505(b)(1), however the studies were not conducted by or for the applicant, therefore must rely on FDA’s findings of safety and effectiveness. This pathway “should not be used to obtain approval of duplicates of existing drug-led combination products that are eligible for approval under section 505(j) of the FD&C Act.”
  2. Abbreviated New Drug Application (ANDA)
    • In addition to normal ANDA requirements, ANDAs for a drug-led combination product should include sufficient information to demonstrate that the non-lead constituent part is compatible for use with the final formation of the drug’s constituent part.

Biologic-Led Combination Products

  1. Biologics License Applications (BLAs) Submitted under Section 351(a)
    • Stand-alone application which includes all information and data necessary to demonstrate that a biological product is safe, pure, and potent and that the facility meets these standards are included in the application.
    • This pathway is appropriate when the Sponsor is not seeking to rely on FDA’s licensure of another biological product in order to demonstrate biosimilarity to, or interchangeability with a previously licensed biological product.
  2. BLAs for Biosimilar and Interchangeable Biological Products Submitted under Section 351(k)
    • FDA has published guidance indicating the availability of this abbreviated pathway for combination products in the guidance “Questions and Answers on Biosimilar Development and the BPCI Act

At the end of the draft guidance, FDA provides an annex which includes five illustrative examples of device-led combination products. These examples include: antimicrobial coating added for the first time to a previously classified device type, new drug indication added, different method of drug coating, some drug constituent part with a lower concentration, and replacing a drug constituent part with a different antimicrobial.

The FDA is seeking feedback on its draft guidance is accepting written and electronic comments until May 7, 2019.

Are you in the process of developing a combination product? We can help you navigate the sometimes difficult and confusing process of obtaining FDA approval.  To learn more about our services and how we can help you achieve successful interactions with the FDA, contact us today.