First Post-FDAAA “New Active Ingredient” Election and Grant of NCE Exclusivity Made With the Approval of FETZIMA

By Kurt R. Karst

If you wait around long enough, almost any scenario feasible under the FDC Act with respect to Hatch-Waxman exclusivity is bound to happen. Nearly six years after the September 2007 enactment of the FDA Amendments Act (“FDAAA”), one company’s drug product has finally qualified for the election at FDC Act § 505(u), and the company elected for its drug product to be treated as a “new active ingredient” and was granted 5-year New Chemical Entity (“NCE”) exclusivity. Specifically, we’re talking about FETZIMA (levomilnacipran) Extended-release Capsules, 20 mg, 40 mg, 80 mg and 120 mg, which FDA approved on July 25, 2013 under NDA No. 204168 for Major Depressive Disorder (“MDD”). Levomilnacipran is a stereoisomer – an enantiomer – of the previously approved racemate, milnacipran HCl. FDA approved milnacipran as SAVELLA Tablets, 12.5 mg, 25 mg, 50 mg, and 100 mg, under NDA No. 022256 on January 14, 2009. SAVELLA is approved for the management of fibromyalgia.

By way of background, a molecule may exist in two “mirror image” forms. The two forms of such molecules are called “enantiomers.” A “racemate” is a mixture of two enantiomers in equal amounts. For some drugs, one enantiomer may have markedly different pharmacological effects than the other. (For more on stereoisomers, see FDA’s 1992 policy statement, Development of New Stereoisomeric Drugs.) In promulgating rules implenenting the Hatch-Waxman Amendments, FDA had initially taken the position that the Agency would not grant NCE exclusivity for an enantiomer when the racemate had previously been approved. See 59 Fed. Reg. 50,338, 50,359 (Oct. 3, 1994). In January 1997, FDA announced in a Federal Registernotice that the Agency was reconsidering that position and requested comments. Years went by, however, and FDA remained mum on where things stood with the potential reconsideration.

When FDA did not act, Congress in the 2007 FDAAA passed a change in the law, reauthorized in the 2012 FDA Safety and Innovation Act, that permits sponsors of enantiomers to elect to claim “new active ingredient” status and be awarded 5-year NCE exclusivity when new indications are developed for the enantiomers. Specifically, Congress amended the statute to add FDC Act § 505(u), titled “Certain Drugs Containing Single Enantiomers.” There are several limitations that come with such an election. The enantiomer drug cannot rely on studies of the racemate, and approval must be based on full reports of new clinical investigations. In addition, the sponsor agrees not to seek, for 10 years, approval of the enantiomer for a use in a “therapeutic category” for which the racemate is approved, or for a use for which any other enantiomer of the racemate is approved. For purposes of determining the “therapeutic category” of a drug, the statute references a list developed by the United States Pharmacopeia and as in effect on September 27, 2007. A copy of that list is available here. (Although subsequent versions of the list provide more granularity in terms of therapeutic categories, and could, therefore, lead to a greater likelihood of exclusivity-qualifying enantiomers, the list, unless amended by FDA by regulation, is static under the statute.) Finally, the labeling of the enantiomer drug for which “new active ingredient” status is elected must “include a statement that the non-racemic drug is not approved, and has not been shown to be safe and effective, for any condition of use of the racemic drug.”

When FDA posted on its website in July the approval letter and labeling for FETZIMA, we had an inkling that the approval might be precedent setting with respect to NCE exclusivity. After all, the labeling includes the following in the “Indications and Usage” section:

FETZIMA, a serotonin and norepinephrine reuptake inhibitor (SNRI) is indicated for the treatment of major depressive disorder (MDD). The efficacy of FETZIMA was established in three 8-week, randomized, double-blind, placebo-controlled studies in adult patients with a diagnosis of MDD [ see Clinical Studies (14)].
Limitation of Use: FETZIMA is not approved for the management of fibromyalgia. The efficacy and safety of FETZIMA for the management of fibromyalgia have not been established.

Now that the Orange Book has been updated with the latest Cumulative Supplement, our suspicion has been confirmed: 5-year NCE exclusivity was granted. (The July Orange Book Cumulative Supplement took a little longer than usual to get posted this month because of some glitches in new software that is being used by FDA.) The exclusivity is identified as “NCE*”,which is defined in an Orange Book addendum to mean: “NEW CHEMICAL ENTITY (AN ENANTIOMER OF PREVIOUSLY APPROVED RACEMIC MIXTURE. SEE SECTION 505(U) OF THE FEDERAL FOOD AND DRUG COSMETIC ACT).”

How long it might be until FDC Act § 505(u) gets used again remains to be seen. As noted above, the static nature of the therapeutic category list may be an obstacle. Sponsor interest is another factor. A 2012 report from the Government Accountability Office says that FDA has received very few inquiries regarding FDC Act § 505(u) (see our previous post here).