FDA recently finalized the guidance document, Postmarketing Safety Reporting for Combination Products (“PMSR Guidance”). The PMSR Guidance addresses compliance with the final rule on postmarketing safety reporting (PMSR) requirements, 21 C.F.R. Part 4, Subpart B (“PMSR final rule”), for combination products. This is a complicated area, so the guidance is welcome.
The PMSR Guidance begins with discussion of the different types of combination products because PMSR requirements vary depending on the combination product type. A “single-entity” combination product is a product composed of two or more regulated components. A “co-packaged” combination product includes two or more separate products packaged together. A “cross-labeled” combination product is a drug, device or biological product packaged separately from other constituents and, 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.” PMSR Guidance at 3.
The PMSR final rule applies to two types of applicants: Combination Product Applicants and Constituent Part Applicants. When there is a single marketing authorization for a combination product, or multiple authorizations held by the same entity, the applicant of the marketing authorization(s) is a Combination Product Applicant. In the case of cross-labeled combination products where different applicants hold marketing authorizations for the different constituent parts, these applicants are Constituent Part Applicants. It is important to note that a company is a Constituent Part Applicant “only if that entity holds an application to market that product as a constituent part of a combination product.” Id. at 6.
Both Combination Product Applicants and Constituent Part Applicants are required to submit application type-based reports. Additionally, constituent part-based reporting requirements are applicable to Combination Product Applicants and information sharing is required for Constituent Part Applicants. For Combination Product Applicants, additional reporting requirements are based on the constituent types. For example, a single-entity or co-packaged combination product approved in an NDA that includes a drug and device constituent is subject to safety reporting requirements described in 21 C.F.R. Part 314 for the drug and also to five-day reporting requirements, malfunction reporting requirements and correction and removal reporting requirements described in 21 C.F.R. Part 803 and 21 C.F.R. Part 806 for the device. The guidance uses the term “Individual Case Safety Reports” (ICSR) to describe a “report of an event experienced by an individual user of a combination product, including adverse events and malfunctions.” Id. at 10.
The PMSR Final Rule and PMSR Guidance describe an approach for streamlined reporting. Where reports can be submitted in the same manner and satisfy all applicable requirements, including submission timelines, a single report may be used to comply with more than one reporting requirement. The PMSR Guidance clarifies that “in the same manner” means that a report is “submitted in the same way (e.g., electronic, paper submission) and to the same recipient group within FDA (e.g., via a common electronic gateway).” Id. at 23.
There are not many substantive changes in the final PMSR Guidance compared to the draft. Expanded discussions are provided for five-day reports, malfunction reports and combination product ICSRs for foreign events or experiences to offer greater clarity.
The final rule was published in December 2016, establishing an effective compliance date for application type-based PMSR requirements as January 19, 2017. The final rule also established a compliance date of July 19, 2018 for constituent part-based PMSR requirements and associated recordkeeping. However, FDA has issued Immediately in Effect Guidance, Compliance Policy for Combination Product Postmarketing Safety Reporting, first in March 2018 and subsequently in April 2019, but is delaying enforcement. FDA does not intend to enforce requirements for constituent part-based PMSR requirements, the submission process for constituent part-based ICSRs or recordkeeping requirements until the following dates:
- July 31, 2020, for Combination Product Applicants using the FDA Adverse Event Reporting System (FAERS) and Electronic Medical Device Reporting System (eMDR) to report ICSRs
- January 31, 2021, for Combination Product Applicants using the Vaccine Adverse Event Reporting System (VAERS) to report ICSRs
The delayed enforcement should give Combination Product Applicants time to update procedures and infrastructure to allow for the increased reporting requirements.
Overall, the PMSR Guidance provides detailed explanations and numerous helpful examples for navigating the complex requirements for postmarketing safety reporting for the various combination product types for both Combination Product and Constituent Part Applicants.