FDA has issued a proposed rule that defines a combination product as being either one that is physically combined or copackaged, and also, one established by cross-labeling where the components are separately manufactured or packaged, but expressly labeled for use with each other (See 21 CFR3.2(e)(1)-(4)).
Furthermore, the constituent parts of the combination (drug, biologic, or device) retain their individual cGMP requirements when combined during manufacturing; thus, a manufacturer combining a drug and device must demonstrate compliance with drug cGMPs and also design controls provisions. Companies developing combination products, particularly those containing devices, need to be especially cognizant of the new proposed rule (74 Fed. Reg. 48,429, September, 2009).
At the end of September, FDA issued extensive risk evaluation and mitigation strategies (REMS) guidance with examples of REMS elements. Instructions on how to modify approved REMS were also provided. The importance of this guidance for biotech/biopharma companies is multifold. First, there are an ever-increasing number of pharmaceutical products and classes of products now being subjected to REMS regulatory requirements. Companies need to anticipate whether their product will be subjected to REMS and plan for it.
Second, though FDA adamantly denies any correlation, many believe that therapeutic products that provide clinical benefit but have some FDA-perceived safety risks can more easily be approved/licensed when subjected to REMS.
In fact, the guidance allows that a proposed REMS can be submitted in the original drug application, as a supplement to an existing application or as an amendment to an original application. A senior FDA official has said that the REMS requirement might affect priority drugs disproportionately as compared to standard NDA applications as FDA is less likely to impose REMS on a drug that does not offer a clinical advantage over an approved drug. It is interesting to note that priority-rated NDAs continue to get reviewed and approved much faster that standard NDAs.
Pharmaceutical companies developing new products obviously favor those indications that will receive priority-rated NDAs, given the faster approval times. In choosing such indications, companies now need to consider the implications of having to comply with REMS guidance.
Although most pharmaceutical executives are frustrated by REMS, it does have its benefits, as acknowledged by a biopharma executive under a consent decree requiring dissemination of REMS-mandated information. The executive said that he did not mind the requirements to disseminate such information to physicians since it actually enhanced the companies’ ability to interact and build creditability with the prescribing physicians.