Author: John Lockwood, Senior Director, US Head of MedTech
Combination products play an integral role in healthcare. While these products can combine two or more regulated products, typically, these are understood to be drug-device or biologic-device combinations.
What makes the area more complex than most is determining the regulatory path. The US Food and Drug Administration makes this decision based on the product’s primary mode of action (PMOA) – that is, the part of the product that provides the most important therapeutic action.
If a drug is determined to be the PMOA, then the product is regulated through the Center for Drug Evaluation and Research (CDER), or the Center for Biologic Evaluation and Research (CBER) when the PMOA is related to a biologic. If, however, the PMOA is driven by the actions of the device component, then the Center for Devices and Radiological Health (CDRH) would have primary jurisdiction.
If the PMOA is not necessarily obvious, the agency will assign the combination product based on two criteria. First; which FDA center regulates other combination products with similar questions of safety and effectiveness, and second; which FDA center has the most expertise pertinent to critical safety and effectiveness questions about the product.
The role of the OCP
Another key player in the process is the Office of Combination Products (OCP). It is OCP that performs what is called a designation review. This occurs when a sponsor either asks for a Request for Designation (RFD) or instead wants non-binding feedback using the Pre-Request for Designation request process. Both processes provide feedback regarding whether the product is a drug, device, biological product, or combination product and/or which FDA center would be assigned primary jurisdiction.
OCP is also responsible for developing FDA guidance for industry on combination products and, under the Medical Device User Fee and Modernization Act of 2002 (MDUFMA), ensuring review times are met in line with governmental requirements, which are reported to congress.
Ultimately the role of OCP is more one of oversight, with the review itself being carried out by CDER/CBER or CDRH.
A push for informal assignment
While companies can request the more formal RFD, our experience has found that in the past couple of years the FDA has been pushing companies to take advantage of the less restrictive Pre-RFD. The difference between the two processes largely relates to the length of submission and depth of regulatory analysis that a sponsor must provide. For example, RFDs cannot exceed 15 pages, but no such length requirement exists for Pre-RFD submissions.
Product quality and safety
The FDA has issued specific guidance for combination products with regard to Good Manufacturing Practices (GMP)v. As with any medical device or medicinal product, the FDA expects that a combination product will be manufactured following GMP guidelines. Often these are drug delivery devices, so the company’s quality system will be based on the drug GMPs, but they would also need to have the device QSRs addressed as part of their quality system as well. This includes adequate vendor qualification and purchasing controls for activities, CAPA, and design control. Some of these activities are often outsourced.
When it comes to safety management of the product, adverse event reporting would depend on the type of product. With a combination product that is marketed as a single entity, such as a drug-eluting stent, the applicant of the combination product would be responsible for reporting to the FDA center affected by the reportable event. If the combination product is made up of two or more separate products packaged together (for example, drug and syringe), then the applicant would report separately for each constituent part in accordance with the requirements and processes associated with the application type for that constituent part.
Managing the regulatory process with combination products requires understanding the different aspects of the product, its PMOA, and the specific requirements of the FDA center managing the review process.