By Rose Pagano and Suzanne M. Sensabaugh, MS, MBA

The FDA recently released a final guidance concerning postmarketing safety reporting for combination products.  This is relevant for combination product applicants, whose products are made of two or more different types of medical products. The final rule on postmarketing safety reporting requirements (PMSR) was issued in 2016. This guidance provides advice on how to comply with this rule.

Specifically, a combination product is comprised of any combination of a drug, device, and biological product. Each component is considered to be a constituent part of the combination product. These combination products are reviewed and regulated by the assigned Agency center that has primary jurisdiction. This assignment to a particular center is determined according to the constituent part that provides the primary mode of action (PMOA) for the combination product. The “primary mode of action” is defined as the single mode of action that makes the greatest contribution to the overall intended therapeutic effects of the combination product. However, despite PMOA, agency centers will work together to determine appropriate PMSR policies.

The combination product PMSR final rule refers to combination products that could undergo premarket review by FDA. This includes “Combination Product Applicants” and “Constituent Part Applicants.” The final rule included application type-based reporting requirements, constituent part-based reporting requirements, information sharing, submission process, streamlined reporting, and recording retention. Application type-based reporting requirements apply to combination product applicants and constituent part applicants, while constituent part-based reporting requirements apply to only combination product applicants.  

A combination product applicant is when the applicant possesses the only application or all applications for a combination product. Conversely, a constituent part applicant is when the applicant has an application for a constituent part of a combination product and other parts are classified under other applications by another applicant. Each drug, device, and biological product included in a combination product is referred to as a “constituent part” of the combination product.

Additionally, there are certain safety reporting requirements these applicants must follow. The New Drug Application (NDA),  Abbreviated New Drug Application (ANDA), and Biologics License Application (BLA) for a combination product that has a device constituent part needs to follow the five-day reporting requirements, malfunction reporting requirements, and correction and removal reporting and recordkeeping requirements for instances that do not need a report. The BLA or Device Application should also obey field alert reporting requirements and fifteen-day reporting requirements.

Another difference between constituent part applicants and combination product applicants is in the recordkeeping requirements. Constituent part applicants need to follow particular recordkeeping requirements concerning their reporting and information sharing. They must retain reporting-related records for the time periods based on the class of constituent part and preserve information-sharing records (copy of information, dates information was received, and who shared the details). Combination product applicants should retain PMSR records for the longest time period required. For example, drug-biologic combination product records should be kept for 10 years.

The FDA provides  timelines for submitting reports for combination product applicants. Combination product applicants follow the timelines associated with the report type. An exception is for combination products that receive marketing authorization  under a Device Application. In this case, fifteen-day reports can be submitted within 30 calendar days. These applicants need to submit Individual Case Safety Reports (ICSRs) following the necessary requirements for their designated review center.


At HartmannWillner LLC, we understand the regulatory requirements for the development of combination products and their postmarketing reporting requirements. With our help, you can insure that FDA requirements are met.  Contact us today to learn more about our services and how we can help you.

Suzanne M. Sensabaugh is a regulatory affairs consultant and a cGMP consultant who has advanced the development of over 130 biologics, biosimilars, and combination products since 2009. She can be reached at