Mark Kramer answers 5 questions on combination products and the regulatory hurdles manufacturers can face.
1. What is a combination product?
A combination product is a combination of different types of regulated products, i.e., a drug and a device, a drug and a biologic, a device and a biologic, or a combination of a drug, device and biologic. FDA recognizes 3 types of combination products, where the components are (1) physically/chemically combined into a single entity (like a drug-coated catheter), (2) packaged together, or (3) separate products brought together through their labeling (“cross labeling”). The US is unique in recognizing cross labeled components as combination products, and these sometimes raise challenging regulatory issues.
2. How does FDA determine the assignment of a combination product to a lead Agency Center?
The assignment of a combination product is based on its “primary mode of action” (PMOA), which is the most important therapeutic action of a combination product. For example, a drug-device combination for which the greatest contribution to the overall intended therapeutic effects is provided by its device component, while the drug plays a subordinate role, would be assigned to CDRH. FDA also has an “assignment algorithm” to handle situations where the PMOA of a combination product cannot be determined with reasonable certainty.
3. What are the most important things to accomplish in a Request for Designation?
The formal process for determining combination product assignment is called a “Request for Designation.” The requirements for an RFD are specified in the regulation, but this brief submission, limited to 15 pages by regulation, must clearly explain your product and its composition, its intended use, how your product works, its PMOA, any data to substantiate the PMOA, and your recommendation for product assignment.
4. What kind of marketing applications are submitted for a combination product?
Most combination products (particularly single entity combinations) are reviewed under a single marketing application, typically the type of application commonly submitted to the lead Center (NDA to CDER, BLA to CBER, 510(k) or PMA to CDRH). Some combinations, particularly cross labeled products, may have separate applications covering the various components of the product (e.g., NDA for drug component and a 510(k) or PMA for device component).
5. What are FDA’s expectations for key postmarketing requirements for combination products?
FDA proposed new GMP and postmarketing reporting regulations for combination products in late 2009. These regulations have not yet been finalized, but the proposals provide a creative framework intended to avoid the need for manufacturers to fully comply with both sets of requirements that would otherwise apply to the individual components of the combination product. The proposed rules would require manufacturers to comply with one basic set of requirements, as well as specific, additional provisions to ensure that any unique requirements attributable to the “other” component are preserved. The proposed rules are available at http://edocket.access.gpo.gov/2009/pdf/E9-23519.pdf and http://edocket.access.gpo.gov/2009/pdf/E9-22850.pdf.
Mark D. Kramer, RAC, is President, Regulatory Strategies Inc., a regulatory consultancy specializing in medical devices and combination products. He has more than 25 years’ experience in regulatory affairs, including 17 years at the US Food and Drug Administration in positions in CDRH and culminating in his position as Director of FDA’s Office of Combination Products from 2002 to 2007. From 2007-2010, Mark was Vice President, Regulatory Affairs and Chief Regulatory Strategist at GE Healthcare, where he had executive responsibility for US, Canadian and Latin American regulatory affairs for the medical device business. Mark is on the Board of Directors of the Regulatory Affairs Professional Society (RAPS), and served as Chair of the Wisconsin RAPS Chapter from 2007-2010. For more information or to reach Mark, visit www.regulatorystrategies.net.