iSpeak Blog

Combination Products Post Marketing Safety Reporting

Monique L. Sprueill, PMP
Susan W. Neadle, FRAPS, FAAO
Combination Products Post Marketing Safety Reporting


Patients are demanding more innovation from drug companies for delivery of therapeutics, ease of use, and affordability. Combination Products are integral to our industry. Per the Globe Newswire Global Forecast, the Drug Device Combination Product market is expected to reach 177.7 billion USD by 2024. We have a responsibility to safely meet patients’ expectations, continuously improve and monitor the production and use of these products.

There is currently a strong focus on Postmarketing Safety Reporting (PMSR) requirements for Combination Products. Increased efforts have been made to understand the evolving global regulations and to determine the best compliance strategies.

Combination products consist of any combination of a drug, a device, and a biological product. Each drug, device, and biologic product included in a combination product is referred to as a “constituent part” of the combination product. The FDA assigns a product to a lead center based on the primary mode of action (PMOA) of a combination product, however all applicable centers coordinate with each other and the Office of Combination Products, as appropriate, for post market safety reporting.

Guidance for Industry and FDA Staff: Postmarketing Safety Reporting for Combination Products

The FDA released the Guidance for Industry and FDA Staff: Postmarketing Safety Reporting (PMSR) for Combination Products, Final Guidance in July 2019 to clarify expectations of the 2016 Combination Products PMSR Final Rule. Per this document, PMSR obligations are based on (1) Application Type and (2) Applicant Type:

(1) Application Type is based on the combination product’s PMOA.

(2) Applicant Types are designated as Combination Product Applicants and Constituent Part Applicants. A Combination Product Applicant is the legal entity that holds the marketing authorization for a combination product. A Constituent Part Applicant of a combination product is the holder of the license for a constituent part, that in its application, indicates it is to be used as part of a combination product in order to achieve its intended use. Often, the applicants for the constituent parts in a cross-label combination product are Constituent Part Applicants.

Combination Product Applicants as well as Constituent Part Applicants must comply with reporting requirements based on their role. The applicants are required to understand who will perform which tasks for submissions, streamline reporting when possible and maintain records for the required time period.

A Constituent Part Applicant must share information in the event of death, serious injury per 21 CRF 803.3 and Adverse experiences per 21 CFR 314.80 or 600.80, with the other Constituent Applicants within 5 calendar days from receipt of information.

Combination Product Applicants are required to follow 21 CFR 4.102(c)1 for submission of NDA/ANDA/BLAs. A Combination Product which has a Drug PMOA must also comply with 5 and 30 day reports for Malfunctions. Additionally, they would comply with the 806 regulations for Corrections and Removals. Combination Product Applicants who file BLA or Device applications also must comply to Field Alert Reporting (FAR) and fifteen-day reporting requirements per 21 CFR 4.102(c)2 , 314.81 and 314.80. For those who submit for combination products that contain a Biological Product Constituent part, they are subject to Biological Product Deviation reporting and the fifteen-day reporting requirements per 21CFR 600.14, 606.171 and 600.80.

Both, the Combination Product Applicant and the Constituent Applicant must adhere to safety reporting requirements per 21 CFR Part 314, 600, 606, 803 and 806. A Constituent Part Applicant must adhere to the safety reporting applicable for their constituent part of the combination product, plus information sharing requirements. For example, the Constituent Part Applicant who holds the PMA for a device constituent part of a device-biologic cross-label combination product must comply with safety reporting under parts 803 and 806, as well as information sharing with the biologic Constituent Part Applicant. The biologic Constituent Part Applicant must adhere to reporting under parts 600 and 606, and information sharing requirements with the device Constituent Part Applicant of the combination product.

The Combination Product Applicant must adhere to safety reporting requirements applicable based on the constituent parts in their combination product (e.g., if a drug-device combination product, 21 CFR Parts 314, 803 and 806 all apply).

Another important aspect of the Final Rule on Combination Products PMSR is the expectation for reporting of certain events, even if those events occur on product outside the United States (OUS). This is referred to as same-similar reporting. If a malfunction that meets the definition of US reportability occurs on a constituent part of a combination product OUS, one is expected to report against the US-marketed combination products that have the same-similar constituent part. Logistical aspects of this added reporting complexity must be addressed, along with considerations of global reporting implications.

Useful Tools for Postmarketing Safety Reporting (PSMR)

Pharma companies are updating their digital strategies to manage data more efficiently and ensure integrity is maintained. The expectation is that companies will have the appropriate technology in place to support electronic reporting, information sharing and records retention.

The FDA has updated their systems to process combination product reports. By July 2020, it is expected that Combination Product Applicants will utilize the FDA Adverse Event Reporting System (FAERS) and Electronic Device Reporting System (eMDR). By the end of January 2021, the Vaccine Adverse Event Reporting System (VAERS) will be ready to receive Individual Case Safety Reports (ICSRs).


More companies are collaborating to produce Combination Products. These partnerships provide patients with more innovative and affordable options. The Guidance for Industry and FDA Staff: Postmarketing Safety Reporting for Combination Products provides an outline for managing the safety reporting process after market approval3 .

ISPE Combination Products Community of Practice

ISPE is committed to connecting professionals to drive continuous improvement and innovation. The ISPE Combination Products Community of Practice (COP) was started in March 2019. This group consists of Pharmaceutical Professionals who work with Medical Devices, Pharmaceuticals and Combination Products. We meet monthly to share knowledge, review regulations, align on best practices and develop expertise. By actively participating in this COP, we collectively work together to better understand and determine how to respond to evolving regulations. We welcome new members and hope that you will consider participating in this group. The Combination Products COP Leader, Susan Neadle, will speak both at the Sessions on Innovations in Drug Delivery and Combination Products Evolving Trends, accompanied by members of the CoP and FDA for an active panel discussion, on October 28th at the 2019 ISPE Annual Meeting in Las Vegas. Join us as we share insights on Combination Products.