FDA Focuses On Combination Products with New Proposed Current Good Manufacturing Practices and Adverse Event Reporting Requirements

The FDA has renewed its focus in a number of areas, including the regulation of combination products. Recently, the Federal Food and Drug Administration ("FDA") has taken significant action with regard to combination products. Specifically, the FDA, on September 22, 2009 issued the draft regulations on current Good Manufacturing Practices ("cGMPs" or "GMPs"). These were followed by the issuance of the proposed adverse event reporting requirements ("Postmarketing Safety Reporting") on September 30, 2009. The products which will be subject to these new regulations are those that meet the definition of a combination product. The FDA defines a combination product as a product comprised of any combination of a drug and device; a device and a biological product; a biological product and a drug; or a drug, device, and a biological product.

The proposed rules on cGMPs for combination products are put forth to "help ensure the manufacturer of safe and effective combination products, by providing a clear and transparent regulatory roadmap for the application of cGMP requirements to these products." Under the proposed rules a combination product that consists of separately packaged constituent parts, for instance a drug packaged separate and apart from a device for delivery of the drug, are each only subject to the cGMP regulations applicable to for each constituent part. So, for the drug part a manufacturer would only have to comply with cGMP regulations for drugs, and for the device part a manufacturer would only have to comply with the Quality System ("QS") regulations for devices. Additionally, under the proposed rule, the manufacturer of a co-packaged or single-entity combination product has two options to demonstrate compliance with the regulations. The first option is for the manufacturer of a co-packaged or single-entity combination product to comply with the cGMPs applicable to each constituent part of the product. For example, if a combination product consists of a drug part and device part, then a manufacturer would be in compliance if it complied with both drug cGMPs and QS regulations for devices. The second option is for a manufacturer to comply with either the drug cGMPs or the QS regulations for devices, rather than both, as well as certain additional specific provisions. For instance, if a manufacturer of a drug/device product complies with drug cGMPs then it must also comply with specific provisions of the QS regulations for devices, including: management responsibility; design controls; purchasing controls; corrective and preventive action; installation; and servicing. In contrast, if a manufacturer of drug/device product complies with QS regulations for devices then it must also comply with specific provisions of the drug cGMPs, including: testing and approval or rejection of components, drug product containers, and closures; calculation of yield; tamper-evident packaging for over-the-counter human drug products; expiration dating; testing and release of distribution; stability testing; special testing requirements; and reserve samples. Further, the proposed rules require when the manufacture of a constituent part does not occur at the same facility as another type of constituent part, the operating system must be shown to comply with all of cGMP regulations applicable to that constituent part.

The proposed rule on Postmarketing Safety Reporting on combination products are put forth "to ensure appropriate ongoing postmarketing surveillance of risks, to ensure the consistency of the agency's postmarket regulation of combination products, [and] to streamline requirements for reporters by avoiding duplicating reporting requirements." Under the proposed rule, a reporter must comply with Postmarketing Safety Reporting associated with the application used to approve or clear the combination product. For instance, if combination product consisting of a drug part and device part is approved under an New Drug Application ("NDA"), the reporter would follow the NDA reporting provisions of the regulations even thought it was a combination product involving drug and device parts. However, the proposed rule also requires a reporter, aside from complying with the reporting provisions associated with an application , to supplement with certain unique reporting requirements. The unique reporting requirements, and correlated follow up reports, are: (1) submission of a "5-day report" related to the device constituent part; (2) submission of a 30-day "malfunction report" related to the device constituent part; (3) submission of a "postmarketing 15-day `Alert report'" connected to a drug or biological constituent product; (4) submission of a 3-day "field alert report; and (5) submission of an expedited "blood fatality report". These five supplemental reports would only be necessary if the report already being submitting does not contain such a report under the reporting provision associated with the application on which approval or clearance is based. Additionally, one very new requirement for combination product manufacturers is that the proposed rule requires if a reporter is not the only reporter on a combination product then it must submit to the FDA and the other reporter any events you learn about within five (5) calendar days of your receipt of information.

These proposed rules should serve not only as a signal of the FDA's new aggressive push to regulation and enforcement but as an opportunity for manufacturers of combination products to have a say in the rule making process. The propose rules present Manufactures a chance to submit their respective positions on these proposed rules by comment. The FDA is accepting comments for the proposed cGMPs for combination products until December 22, 2009, and for Postmarketing Safety Reporting until December 30, 2009. Commenting provides a significant opportunity, which should be seized and not ignored, to participate, and, possibly influence the rule making process occurring for combination products.