The U.S. Food and Drug Administration, FDA, released a final guidance on postmarketing safety reporting for combination products to further clarify what a combination product is and how applicants can comply with the rules on postmarketing safety reporting requirements (PMSR).
The FDA says that although the PMSR regulations for drugs, devices and biological products have many similarities, each set of regulations establishes distinct safety reporting requirements, including standards and timeframes. Therefore, this guidance explains which combination products are impacted by the PMSR requirements, how to submit reports, recordkeeping requirements, and how to avoid duplications when submitting safety information to the agency.
What is a Combination Product?
According to the FDA, "a combination product is a product composed of any combination of a drug, a 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".
A combination product includes the following products:
Single-entity combination products. These products are composed of two or more 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. Examples of “single-entity” combination products include prefilled syringes, transdermal patches, or drug-eluting stents.
Co-packaged combination products. These products contain 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. Examples of “co-packaged” combination products include surgical and first-aid kits.
Cross-labeled combination products. These products are drugs, devices, or biological products packaged separately that are according to the investigational plan or proposed labeling intended for use only with an approved individually specified drug, device, or biological product. Both are required to achieve the intended use, indication, or effect. Upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose.
Investigational drugs, devices, or biological products packaged separately that are, according to the labeling, for use only with another individually specified investigational drug, device, or biological product. Both are required to achieve the intended use, indication, or effect.
What safety reporting requirements apply to a Combination Product or Constituent Part?
BothCombination Product Applicants and Constituent Part Applicants must meet the safety reporting requirements associated with the application type under which their combination product or constituent part received marketing authorization.
In addition to application type-based reporting requirements, onlyCombination Product Applicants are also subject to certain safety reporting requirements associated with the constituent parts of the combination product. The reports should address how the event is related to the constituent part and the combination product as a whole to the extent such information is available.
Constituent Part Applicants must share with the other Constituent Part Applicant(s) for the combination product, within 5 calendar days from receipt, initial information received on the following events associated with the combination product: - Deaths or serious injuries, - Adverse experiences.
In addition, the guidance provides examples for drug application combination products and device application combination products with detailed flowcharts, explaining which safety reports are required under the PMSR rule, and discusses the content for these reports, and when they are due to the FDA.
To ensure applicants have sufficient time to make necessary adjustments, the agency does not intend to enforce the additional constituent part-based PMSR requirements until July 2020 for most combination products, and until January 2021 for vaccine combination product.