FDA Seeks Comment on Generic Dexmedetomidine HCl Injection (PRECEDEX) Approval

By Kurt R. Karst –      

It’s been quite some time since FDA established a public docket soliciting comment on an ANDA approval/Hatch-Waxman issue.  But FDA revived the process earlier this week when the Agency issued a “Dear NDA/ANDA Applicant” letter (Docket No. FDA-2014-N-0087) concerning approval of generic versions of Hospira, Inc.’s (“Hospira’s”) PRECEDEX (dexmedetomidine HCl) Injection, 100 mcg (base)/mL packaged in 200 mcg(base)/2 mL single-dose vials, which FDA approved on December 17, 1999 under NDA No. 021038. 

PRECEDEX is currently approved in three strengths and for two indications: (1) sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting; and (2) sedation of non-intubated patients prior to and/or during surgical and other procedures.  FDA’s Orange Book currently lists two patents for the 100 mcg (base)/mL packaged in 200 mcg(base)/2 mL single-dose vials strength at issue: (1) U.S. Patent No. 4,910,214 (“the ‘214 patent”), which expired on July 15, 2013, but was subject to a period of pediatric exclusivity that expired earlier this week on January 15, 2014; and (2) U.S. Patent No. 6,716,867 (“the ‘867 patent”), which expires on March 31, 2019, but is subject to a period of pediatric exclusivity that expires on October 1, 2019.  The ‘214 patent is listed in the Orange Book as a drug product (formulation), drug substance (active ingredient), and method-of-use patent.  The ‘867 patent is listed in the Orange Book as a method-of-use patent with a “U-1472” patent use code, which is defined in an Orange Book addendum as: “INTENSIVE CARE UNIT SEDATION, INCLUDING SEDATION OF NON-INTUBATED PATIENTS PRIOR TO AND/OR DURING SURGICAL AND OTHER PROCEDURES.” 

The PRECEDEX Orange Book patent listings were not always as they appear today.  Information on another patent – U.S. Patent No. 5,344,840 (“the ‘840 patent”) – was listed for the drug in November 2008.  The ‘840 patent, which expired on September 6, 2011 (and well before FDA’s March 12, 2013 grant of pediatric exclusivity), was listed as a method-of-use patent with a “U-912” patent use code, which is defined as: “SEDATION OF NON-INTUBATED PATIENTS PRIOR TO AND/OR DURING SURGICAL AND OTHER PROCEDURES.”  In addition, the ‘867 patent was, until earlier this month, listed with a “U-572” patent use code defined as “INTENSIVE CARE UNIT SEDATION.”  That’s right . . . . there was a change to the patent use code for the ‘867 patent.  And that change may be the reason why FDA did not approve any ANDAs on January 15, 2014 for generic PRECEDEX when pediatric exclusivity applicable to the ‘214 patent expired and that contain a “section viii” statement to omit (i.e., “carve out”) from proposed labeling information protected by the ‘867 patent.

We’ve seen patent use code changes before.  Indeed, in Caraco Pharmaceutical Laboratories, Ltd. v. Novo Nordisk A/S, 132 S. Ct. 1670 (2012), the U.S. Supreme Court considered a use code change in the context of PRANDIN (repaglinide) Tablets and ruled that “[a] generic manufacturer may employ the counterclaim provision [of the FDC Act] to force correction of a use code that inaccurately describes the brand’s patent as covering a particular method of using a drug” (see our previous post here).  But the FDC Act’s counterclaim provision is not at issue in the case of PRECEDEX.  In fact, that provision (at FDC Act §505(j)(5)(C)(ii)(I) for ANDAs and at FDC Act § 505(c)(3)(D)(ii)(I) for 505(b)(2) applications) is inapplicable in the case of a “section viii” carve-out, because the statute requires “a patent infringement action against the [ANDA] applicant.” 

Given the unique situation relative to generic PRECEDEX, FDA is seeking comment on three sets of questions.  FDA’s questions raise some pretty interesting issues, including whether an ANDA “carve-in” is permissible, and whether a patent use code change can be considered late-listed.  Specifically, FDA is soliciting comment on the following questions:

1.  Does the breadth of the new use code description for the ‘867 patent foreclose ANDA applicants from gaining approval for any of the approved indications (or for any subset of those indications) before the ‘867 patent expires?  For example, would it be permissible as a scientific, regulatory, and legal matter for an ANDA applicant to submit a statement under 21 U.S.C. §355(j)(2)(A)(viii) and a corresponding carve out that results in an approval for a subset of the second approved indication, i.e., an approval explicitly limited to procedures outside of an intensive care setting?  In this context, is it acceptable to add new words to the approved indication to limit the indication to exclude only that portion of the indication that is covered by the use code (i.e., to exclude sedation of non-intubated patients in the ICU setting only)?  If you believe a carve out of this type is permissible, if you wish, you may submit a side by side of the indication section of the labeling for dexmedetomidine hydrochloride injection showing the carve out that you believe would be acceptable.

2.  Whether the fact that Hospira changed the use code information outside of the 30-day window after the patent issued means that the use code change is late listed as to any ANDAs pending with a section viii statement at the time the use code was changed?  See 21 C.F.R. § 314.53(c), (d).  If so, would any ANDA with an existing section viii statement be entitled to retain that statement (and corresponding carve out) under 21 C.F.R. § 314.94(a)(12)(vi), notwithstanding the change in use code?

3.  What relevance, if any, to a determination of whether the use code change was timely submitted is the fact that Hospira previously listed the ‘840 patent with very similar use code information to that now listed for the ‘867 patent, and did not change the use code for the ‘867 patent until after the ‘840 patent expired?  

Initial comments are due to FDA by the close of business on January 24, 2014.  Commenters submitting in the initial comment period may respond to comments from other commenters, and must submit those responses to FDA by the close of business on January 31, 2014. 

It is unclear how long after January 31, 2014 it will take FDA to make a decision and issue a letter decision.  If history is any indication of future events, then FDA’s decision on the questions raised in the Agency’s solicitation and FDA’s decision on pending ANDAs may end up in court in the not too distant future.