Yesterday, FDA issued two new items to help clarify combination products: 1) a Final Rule published in the Federal Register entitled, “Current Good Manufacturing Practice Requirements for Combination Products” and 2) a Draft Guidance entitled, “Guidance for Industry and FDA Staff:
Submissions for Postapproval Modifications to a Combination Product Approved Under a BLA, NDA, or PMA”, also announced in the Federal Register.
The Final Rule is intended to clarify which good manufacturing practice (“CGMP”) requirements apply when drugs, devices, and biological products are combined to create combination products. The Rule also provides a mechanism that FDA describes as “transparent and streamlined regulatory framework” for companies to use when demonstrating compliance with CGMP requirements for “single-entity” and “co-packaged” combination products. “Single-entity” combination products are two or more regulated components, e.g., drug/device, biologic/device, drug/biologic/device, which are physically, chemically, or otherwise combined or mixed and produced as a single-entity. Two or more separate products packaged together in a single package or as a unit and comprised of two or more regulated products is a “co-packaged” combination product. The Final Rules started as a Draft Guidance announced on October 4, 2004 (69 FR 59239), entitled “Current Good Manufacturing Practices for Combination Products.” Based on comments and FDA’s own internal review, FDA decided that “rulemaking was warranted” and issued Proposed Rules on September 23, 2009 (74 FR 48423).
The concept behind the CGMP Rule is simple for parts that are separately manufactured and marketed: each of the constituent parts of a combination product are subject only to the CGMP regulations applicable to that part, e.g., drug, biologic, or device. The two categories of combination products mentioned above, however, “single-entity” and “co-packaged” are slightly different due to the possibility for overlapping CGMP requirements for the different regulated components. Companies have two basic options for these types of products: 1) demonstrate compliance with the specifics of all CGMPs to each of the parts, or 2) demonstrate compliance with the specifics of either the drug CGMPs at 21 C.F.R. Parts 210 and 211 or the quality system (“QS”) regulation at 21 C.F.R. Part 820 rather than both, for drug/devices under certain conditions. For combination products including biologics, the specific regulations are 21 C.F.R. parts 600 through 680, and for product including any human cell, tissue, and cellular tissue-based products, the regulations are 21 C.F.R. Part 1271.
FDA acknowledged that the Final Rule is essentially the same as the Proposed Rule. According to FDA , it received 25 sets of comments on the Proposed Rule. Many of the comments appeared directed at having FDA explain whether these are new rules or just an explanation of what FDA has been doing all along. FDA generally explained the latter, indicating that, for the most part, products already on the market do not need to be reanalyzed for compliance with the Final Rule. That being said, because the Final Rule includes measures to streamline compliance with CGMPs, FDA thought it may be worthwhile for companies to modify their approaches taken for some current single-entity or co-packaged products to save resources. FDA declined to extend the effective date for the Final Rule beyond 180 days from publication, i.e., July 22, 2013, because, as FDA explained, the Final Rule does not present any new requirements, and FDA will be issuing companion guidances to help industry understand compliance expectations. FDA also declined to form an entirely new combination CGMP policy or a different mechanism for reporting adverse events for “cross-labeled” combination products, as some commentators had suggested. Yet FDA stated that it did not believe it would be appropriate for FDA to issue guidance until the rule was final.
The combination Guidance that published on the same day addressed the underlying principles to determine the type of marketing submission required for postapproval changes to already-marketed combination products approved as a new drug application (“NDA”), a biologics license application (“BLA”) or a device premarket approval application (“PMA”). The guidance does not apply to combination products approved as other applications, e.g., device premarket notification submission (510(k) applications) or over-the-counter (“OTC”) drugs. In particular, the Guidance includes tablets to help determine the type of submission that FDA would require.
In general, for combination products, FDA assigns a lead FDA Center with primary jurisdiction over the product, which is based on the primary mode of action (“PMOA”) of the combination product or other criteria when the PMOA “cannot be determined with reasonable certainty.” In the past, uncertainty arose when only one of the components in a combination product was modified with regard to which FDA Center would be the lead. Not surprisingly, the submission type should correlate to the application type of the lead FDA Center, regardless of whether the change is for the same product type. The chart referenced in the Federal Register Notice may be used largely to identify what the submission will be called, e.g., NDA Prior Approval Supplement, BLA Prior Approval Supplement, PMA 180-day Supplement, or PMA Panel-Track. The Guidance also includes a host of helpful list of guidances to consult in the submission process for product modifications.
Together, the Final Rule and Guidance appear to be a start in the right direction for manufactures to gain greater insight how to maintain combination products over time. As more companies seek to manufacture single-entity or co-packaged combination products to meet additional needs, e.g., treatments with multiple modes of action or genetic or other screening diagnostics copackaged with treatment options, these types of documents will be increasingly important to track and be utilized to increase efficient marketing of these products.