US FDA: Safety Reporting Requirements for Combination Products

In this new era, where different therapeutic realms converge, the emergence of combination products has revolutionized the healthcare landscape by providing more innovative treatment options to treat the unmet medical needs of patients. However, with great power comes great responsibility. Continuously monitoring these products and ensuring they are safe to use is paramount in order to mitigate patient harm. As a result, reporting adverse events (AEs) is highly valued. The role that regulatory agencies play in implementing regulations and guidelines to deliver compliance is crucial. For example, the US FDA’s guidance document on “Post-marketing Safety Reporting (PMSR) for Combination Products” provides clarification on the Combination Products PMSR Final Rule to ensure effective PMSR [1].

Guidance for Industry and FDA Staff: Reporting Safety of Combination Products After Marketing

The guidance focuses on two main factors for reporting: Application Type and Applicant Type.

The Application Type is determined by the combination product’s primary mode of action (PMOA). It helps categorize the product based on its main function.

Within the applicant type, there are two subcategories: combination product applicants and constituent part applicants. The former typically possess the marketing authorisation (MA) for the entire combination product, while the latter typically holds the license for one of the constituent parts. This division allows the combination product to be utilized according to its intended purpose.

Application Type-Based Reporting Requirements

Both applicants of Combination Products and applicants of Constituent Parts must fulfil the safety reporting obligations relevant to the particular application type under which their product obtained marketing authorization services. The following regulations apply based on the application type [2]:

NDAs/ANDAs: Combination Product and Constituent Part Applicants holding New Drug Applications (NDAs) or Abbreviated New Drug Applications (ANDAs) must comply with the safety reporting requirements described in 21 CFR Part 314.
BLAs: Combination Product and Constituent Part Applicants with Biologics License Applications (BLAs) must oblige to the safety reporting requirements described in 21 CFR Parts 600 and 606.
Device Applications: Combination Product and Constituent Part Applicants submitting Device Applications must adhere to the safety reporting requirements outlined in 21 CFR Parts 803 and 806.

Constituent Part-Based Reporting Requirements

In addition to the reporting requirements based on application type, Combination Product Applicants have additional safety reporting obligations associated with the constituent parts. The specific requirements depend on the types of constituent parts and the application type:

1. Combination products containing a device as the constituent part:

– Five-day reporting requirements.

– Malfunction reporting requirements.

– Correction and removal of reporting and recordkeeping requirements for events that do not require a report.

2. Combination products containing a drug as the constituent part:

– Field alert reporting (FAR) requirements.

– Fifteen-day reporting requirements.

3. Combination products containing a biological product as the constituent part:

– Biological product deviation reporting (BPDR) requirements.

– Fifteen-day reporting requirements.

Information Sharing Requirements

Constituent Part Applicants have the obligation to share certain information with other Constituent Part Applicant(s) associated with the combination product. Within five calendar days of receipt, they must share initial information on the below-mentioned events:

– Fatalities or life-threatening injuries.

– Adverse experiences.

Reporting under Separate Applications

Suppose a Combination Product Applicant markets the constituent parts of the product under separate applications. In that case, they must comply with each application type’s specific PMSR requirements. Reports should clearly explain the relationship of the event to the constituent part and the combination product as a whole.

Conclusion

Safety reporting requirements are vital for Combination Product and Constituent Part Applicants to ensure the ongoing monitoring and reporting of safety events. By understanding and complying with these requirements, applicants can contribute to the safety and well-being of patients using their products. It is essential to refer to the relevant sections of the 21 CFR Part 4 for detailed information on the specific reporting needs based on application types and constituent parts.

References and Further Reading

[1] US FDA. Post-marketing Safety Reporting for Combination Products- Guidance for Industry and FDA Staff. 2019

[2] Code of Federal Regulations. Title 2 Chapter I, Subchapter A, Part 4, Subpart B- Postmarketing Safety Reporting for Combination Products. 2023

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