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FDA denies Remodulin® Citizen Petition; Treprostinil Injection ANDAs can proceed with labeling carve-out

Last week, FDA announced the latest in a line of decisions demonstrating the agency’s continued support for approval of generic drugs with labeling that “carves-out” information protected by a brand drug’s patents or marketing exclusivity.

Section 505(j)(2)(A)(i) of the Food, Drug and Cosmetic Act requires that an Abbreviated New Drug Application (ANDA) contain “information to show that the conditions of use prescribed, recommended, or suggested in the labeling proposed for the new drug have been previously approved” for the brand or reference listed drug (RLD).  The Act also requires that an ANDA contain information to show that the labeling proposed for the new generic is “the same” as the labeling for the approved RLD, except for certain permitted changes such as labeling differences to reflect the different manufacturers.  Other permitted differences in labeling include “omission of an indication or other aspect of labeling protected by patent or accorded exclusivity under section 505(j)(5)(F) of the act.” 21 C.F.R. § 314.94(a)(8)(iv).  However, those labeling differences must “not render the proposed [ANDA] product less safe or effective than the listed drug for all remaining non-protected conditions of use.”  21 C.F.R. § 314.127(a)(7).

It is well-established that an ANDA applicant may carve-out patent- or exclusivity-protected labeling without violating the “same labeling” requirement.  FDA addresses carve-out issues “on a case-by-case basis depending on whether the legal and medical standards for ANDA approval are satisfied given the specific facts presented.”  FDA has generally construed these provisions liberally and approved generics with patent- or exclusivity-protected labeling carved out.  Previous decisions include carve-outs for Lyrica; Altace; Marinol; and Camptosar.  The agency’s latest decision, issued last week, involved Remodulin® (treprostinil) Injection; the carve-out decision is here.

United Therapeutics Corp. (UTC) holds the new drug application (NDA) for Remodulin®.  Remodulin® can be administered via subcutaneous infusion; it can also be administered via intravenous infusion, using one of three diluents:  Sterile Diluent for Flolan® or Sterile Diluent for Epoprostenol Sodium (collectively, “Sterile Diluent for Flolan”); Sterile Water for Injection (“sterile water”); or 0.9% Sodium Chloride Injection (“saline solution”).  UTC submitted information to FDA for listing a patent in the Orange Book for intravenous administration of Remodulin® using Sterile Diluent for Flolan.  In a citizen petition filed on October 15, 2013, UTC argued that Sterile Diluent for Flolan had safety benefits in comparison with sterile water or saline solution and that no ANDA for Remodulin® should be permitted to carve the patent-protected Sterile Diluent for Flolan information from labeling.

FDA, however, denied UTC’s petition.  The agency carefully reviewed the data UTC offered and was unconvinced that intravenous infusion of Remodulin® using Sterile Diluent for Flolan,  rather than sterile water or saline solution, protected patients from bloodstream infection.  As a result, assuming it receives final approval, a generic treprostinil drug may proceed to market without the patent-protected Sterile Diluent for Flolan® information from the Remodulin® labeling.

The Remodulin® decision and the others that have preceded it show that FDA scrutinizes any claims by the NDA holder that patent- or exclusivity- protected labeling cannot be carved out of a proposed generic’s labeling.  After careful analysis, FDA frequently finds that labeling omissions due to patent or other exclusivity will not render a generic drug less safe or effective than the RLD.

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