Eisai Says FDA Erroneously Triggered NCE Exclusivity Start Dates Before DEA Controlled Substance Scheduling Permitted Marketing

By Kurt R. Karst –      

Five-year New Chemical Entity (“NCE”) exclusivity issues are hot – really HOT – these days!  Not only are there three Citizen Petitions pending at FDA requesting that the Agency interpret the FDC Act to grant 5-year exclusivity for a fixed-dose combination drug product containing both a never-before-approved active moiety (i.e., an NCE or new molecular entity) and a previously approved active moiety (see our previous posts here and here, and a recent Novartis comment here), but just recently, Representative Jason Chaffetz (R-UT) introduced H.R. 2985, the Combination Drug Development Incentive Act of 2013.   That bill, which is reportedly backed by POZEN Inc., would amend the FDC Act’s exclusivity provisions to allow for 5-year exclusivity for new drug combinations, regardless of whether or not such a combination contains an NCE (see our previous post here).  Now there’s a new issue that Eisai Inc. (“Eisai”) has raised in a Citizen Petition (Docket No. FDA-2013-P-0884): Did FDA erroneously trigger 5-year NCE exclusivity for BELVIQ (lorcaserin HCl) Tablets (NDA No. 022529) and FYCOMPA (perampanel) Tablets (NDA No. 202834) before the drugs were scheduled by the Drug Enforcement Administration (“DEA”) under the Controlled Substances Act (“CSA”), and thus, before commercial marketing could occur?

FDA approved BELVIQ on June 27, 2012 as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with a certain initial body mass index, and awarded a period of NCE exclusivity that is shown in the Orange Book as expiring on June 27, 2017.  A few months later, on October 22, 2012, FDA approved FYCOMPA for the treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged 12 years and older, and awarded a period of NCE exclusivity that is shown in the Orange Book as expiring on October 22, 2017. 

Both lorcaserin HCl and perampanel, the active ingredients in BELVIQ and FYCOMPA, respectively, are controlled substances that require scheduling by the DEA under the CSA.  The approval letters for both drug products make it clear that neither drug product can be commercially marketed until DEA schduling of each drug product is complete and labeling is amended to include the appropriate CSA scheduling logo.  Specifically, the approval letters state, under a heading titled “CONTROLLED SUBSTANCE SCHEDULING”:

The final scheduling of this product under the [CSA] is currently proceeding, but not yet complete as of the date of this letter.  We remind you that . . . you agreed not to market this drug until the [DEA] has made a final scheduling decision.  We further note that, when the scheduling is finalized, you will need to make appropriate revisions to the package insert, the patient package insert and the carton and immediate-container labels through supplementation of your NDA.  This would include the statements detailing the scheduling of [BELVIQ or FYCOMPA] in the labeling, as required under 21 CFR 201.57(a)(2) and (c)(10)(i).

This prohibition is grounded in Form FDA 356h, which must accompany regulatory submissions to marketing applications, and that includes a certification that states, in relevant part: “If this application applies to a drug product that FDA has proposed for scheduling under the [CSA], I agree not to market the product until the [DEA] makes a final scheduling decision.”

DEA did not made a decision on the scheduling of lorcaserin until May 8, 2013, when it published a final rule, effective on June 7, 2013, placing the drug into Schedule V.  The DEA has not yet published even a proposed rule with respect to the scheduling of perampane, although, according to Eisai, DEA has had a scheduling recommendation from the U.S. Department of Health and Human Services since late January 2013. 

It is unclear why there is such a delay between drug approval and scheduling.  Eisai notes in the petition that, “[i]n the past, new controlled substances had been scheduled shortly after the time FDA sent a letter approving the drugs as safe and effective,” but that for unexplained reasons “the lag between scheduling and NDA approval has grown longer and longer,” such that “drugs are now often determined by FDA to be safe and effective long before they are scheduled and able to be marketed.”

Whatever the reasons might be for the delays in DEA scheduling, thereby allowing the marketing of BELVIQ and FYCOMPA, NCE exclusivity for both products has been ticking away, according to the Orange Book.  But that’s not only unfair, says Eisai in its petition, but it is legally incorrect.  According to Eisai, NCE exclusivity should begin to run on the date a company can legally market its drug product, and expire 5 years thereafter. 

FDA’s regulations at 21 C.F.R. § 314.108 implementing the FDC Act’s NCE exclusivity provisions at FDC Act §§ 505(j)(5)(F)(ii) (concerning ANDAs) and 505(c)(3)(E)(ii) (concerning 505(b)(2) applications) define the term “date of approval” to mean, in relevant part: “the date on the letter from FDA stating that the [NDA] is approved, whether or not final printed labeling or other materials must yet be submitted as long as approval of such labeling or materials is not expressly required” (emphasis added).  Thus, says Eisai, “the regulation is written to ensure that the effective approval date for purposes of exclusivity is tied to the date that the drug can actually be commercially marketed” (emphasis in original).  And “effective ‘approval’ occurs when the approved drug can be marketed in interstate commerce” (emphasis in original).  This makes sense, says Eisai, and appears to have been the position FDA took in the preamble to the Agency’s 1989 proposed rule implementing the Hatch-Waxman Amendments when FDA commented that “[a] requirement in the approval letter for submission (but not for approval) of final printed labeling or other material that may delay the actual initiation of marketing of the product is not relevant to a determination of the date of approval, so long as the product could be legally marketed.”

Based on this reading of the FDC Act and FDA’s regulations, Eisai asks FDA to conclude that the start date of NCE exclusivity for BELVIQ and FYCOMPA is triggered only when FDA-approved labeling incorporating the final DEA CSA schduling permits commercial marketing of the drug products.  Thus, if a Changes Being Effected (“CBE”) supplement is used, “the day the CBE supplement is submitted with the necessary label changes is the day the sponsor can commercially market the product, and accordingly, should be the date for triggering the NCE exclusivity period.”  Alternatively, says Eisai, “FDA could determine that the date for triggering the NCE exclusivity period is the date the DEA scheduling order becomes effective as this is the date when a CBE supplement could be submitted to permit the sponsor to commercially market the product” (emphasis in oroginal).  This latter determination may be preferable, because it “provides a consistent point for triggering the NCE exclusivity period regardless of when a sponsor decides to take the necessary steps to incorporate the final CSA scheduling into the labeling.”  In either case, the NCE exclusivity for BELVIQ would have been triggered on June 7, 2013, and NCE exclusivity for FYCOMPA would not yet be triggered.

Those of us immersed in Hatch-Waxman might be thinking: “But wasn’t there a court decision a couple of decades ago dealing with the ‘does the date of the NDA approval letter trigger exclusivity issue,’ and doesn’t that decision decide the issue here?”  Yes, there was such a decision; in fact, a pair of decisions, one of which involved scheduling under the CSA of a controlled substance: Norwich Eaton Pharmaceuticals, Inc. v. Bowen, 808 F.2d 486 (6th Cir. 1987) and Mead Johnson Pharmaceutical Group v. Bowen, 838 F.2d 1332 (D.C. Cir. 1988).  We won’t get into the details of each case here, but Eisai says the decisions in both cases are distinguishable from the BELVIQ and FYCOMPA situations, because further action by FDA was not required before the companies could market their drug products in Norwich and Mead.  That is, in those cases, the companies were there own barrier to marketing, and not FDA, as with the marketing of BELVIQ and FYCOMPA.

Eisai goes on to discuss how FDA’s treatment of BELVIQ and FYCOMPA differently than other NCEs is arbitrary and capricious, because other companies will enjoy a full five years of NCE exclusivity for their products, and that it undercuts the intent of the Hatch-Waxman Amendments.  This is also, says Eisai, a problem that can be easily corrected without notice-and-comment rulemaking, and that must be substantively addressed by FDA within the next 5 months (or earlier). 

Interestingly, Eisai makes good use of statements made by FDA in the Agency’s Motion for Stay Pending Appeal filed last May in the PLAN B case concerning exclusivity:

Just this year, FDA publicly advocated against shortening the congressionally-mandated exclusivity period because it would “cause irreparable harm to the regulatory process by undermining the benefits to the public and to FDA of the marketing exclusivity that the [FDC Act] affords to drug sponsors.”  FDA further stated, “such exclusivity provides a critical incentive for drug development that advances FDA’s goal of protecting and promoting public health” and depriving a company, such as Eisai, of its entitled exclusivity period “would stifle rather than encourage innovation, to the detriment of the public.”  Yet, contrary to those assertions, FDA would deprive Eisai of its full statutory five-year exclusivity periods in these instances.

Will those statements come back to haunt FDA in court if the Agency denies Eisai’s petition, or otherwise refuses to update the Orange Book with revised NCE exclusivity expiration dates?  We’ll see.