Postmarketing Safety Reporting for Combination Products

What Does FDA Consider a Combination Product?

Accordingly, the U.S. Food and Drug Administration (FDA) defines a combination product that is composed of any combination of a drug and a device; a biological product and a device; a drug, device, and a biological product. Each drug, device, and biological product included in a combination product is referred to as a “constituent part” of the combination product.

If you are working in the development of combination products, you may be aware the FDA issued two new draft guidances in December 2019. The guidances – Requesting FDA Feedback on Combination Products and Bridging for Drug-Device and Biologic-Device Combination Products– were published in response to the 21st Century Cures Act and Prescription Drug User Fee Act VI, respectively. Learn more here.

The two documents clarify best practices for communication during interaction with FDA.  It provides a framework for identifying gaps in development programs that may result from the unique properties of the combination product. And you are best served keeping the lines of communication open with FDA.

Under 21 CFR 3.2(e), a combination product includes:

  • A product composed 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 as a unit and comprising 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 specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect 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 packaged separately that according to its proposed labeling is 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.
chemotherapy drugs

How Does FDA Review and Regulate Combination Products?

A combination product is assigned to an FDA Center that will have primary jurisdiction for that combination product’s regulation. This would include ensuring compliance with postmarketing regulatory requirements. The assignment of a combination product to a lead FDA Center is based on determining which constituent part provides the primary mode of action (PMOA) of the combination product.

Regardless of the PMOA, FDA components will coordinate as appropriate to ensure efficient, effective, and appropriately consistent postmarketing safety reporting (PMSR) policies and review of PMSR information. The lead FDA Center will work with the other centers and the Office of Combination Products (OCP) to address any issues raised and review of the PMSR information.

What Are Considerations for PMSR?

The combination product PMSR final rule addresses combination products that are subject to premarket review by FDA. The entities who are subject to a final rule would include both the Combination Product Applicants and the Constituent Part Applicants.

The list of final rule key points includes:

  • Application type-based reporting requirements which apply to both combination product applicants and constituent part applicants.
  • Constituent part-based reporting requirements which applies to only combination part applicants based on the types of constituent parts included in the combination product.
  • Information sharing rule requires constituent part applicants to share certain postmarketing safety information with each other.
  • Submission process rule specifies how combination product applicants and constituent part applicants must submit PMSR information to the FDA.
  • Streamlined reporting rule offers a way to satisfy certain reporting requirements together in the same report.
  • Records retention rule specifies what records combination product applicants and constituent part applicants must keep and how long to maintain them.

The combination product final rule applies to both the combination product applicants and constituent part applicants. (21 CFR 4.100(a))

How to Submit Combination Product PMSR Information to FDA

Combination product applicants follow the timelines associated with the report type. The exception is for combination products that receive marketing authorization under a device application, 15-day reports under 21 CFR 314.80 or 600.80 can be submitted within 30 days rather than 15 days.

Learn more here.

new medicine discoveries

What Information Should be Included in Combination Product PMSR Reports?

The report must contain all the information required for the report type under the applicable regulations. This includes relevant information on the entire product including each constituent part (21 CFR 4.102).

In situations where the combination product applicant submits multiple types of reports for the same event or product problem, the reports should include references to related PMSR reports. This includes previously filed PMSR reports, consistent with the reporting policies and practices of the lead FDA center.

See also: FDA Postmarketing Safety Reporting for Combination Products

The combination product applicant may contact CDRH’s Division of Industry and Consumer Education (DICE) (, as well as OCP, as needed for assistance in determining the product code that most closely aligns with their device constituent part.

There are also other entities involved in the manufacturing or marketing of a combination product that may have PMSR obligations.

These would include manufacturers, packers, and distributors, whose names appear on the label of over-the-counter combination products not subject to premarket review.

And would also include a drug constituent part, a product that contains a drug or biological product constituent part, or unapproved prescription combination products.

Manufacturers, importers, and user facilities for combination products that include a device constituent part, whether or not subject to premarket review, must comply with requirements.

Since this is an overview on combination products, any of these entities who have questions about reporting requirements should contact the lead FDA Center or OCP for clarification.

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