No False Starts: FDA Prevails in Eisai Challenge Over NCE Exclusivity Start Dates for BELVIQ and FYCOMPA

October 1, 2015

By Kurt R. Karst –

On September 30, 2015, Judge Randolph D. Moss of the U.S. District Court for the District of Columbia issued his highly-anticipated decision in a lawsuit lodged by Eisai Inc. (“Eisai”) last August challenging FDA's April 2014 denial of a Citizen Petition (Docket No. FDA-2013-P-0884) requesting that the Agency conclude that the 5-year New Chemical Entity (“NCE”) exclusivity start dates for Eisai's BELVIQ (lorcaserin HCl) Tablets (NDA 022529; approved on June 27, 2012) and FYCOMPA (perampanel) Tablets (NDA 202834; approved on October 22, 2012) are triggered only when FDA-approved labeling incorporating the final DEA Controlled Substances Act (“CSA”) scheduling permits commercial marketing of the drug products, and not on the date of NDA approval.  In granting FDA's Motion for Summary Judgment and denying Eisai's Motion for Summary Judgment, Judge Moss concluded that despite some good arguments put forth by Eisai, FDA's interpretation of the Agency's own controlling regulation defining the term “date of approval” is not plainly erroneous or inconsistent with that regulation.  “This case . . . turns on the meaning, not the wisdom, of an FDA regulation implementing the Hatch-Waxman Amendments,” writes Judge Moss.  “Under that regulation—the validity of which Eisai does not challenge—the exclusivity period for a new drug begins when the FDA issues its letter approving the drug, even if the drug’s manufacturer must await DEA’s scheduling determination before it can bring the drug to market.  The regulation does provide for an exception under limited circumstances.  But the FDA has interpreted that exception narrowly, and the Court is bound to defer to the agency’s reasonable interpretation of its own regulation.  Because Eisai’s drugs do not qualify for the exception under the FDA’s interpretation of its regulation, the FDA and its co-Defendants are entitled to summary judgment.”

There's a lot of background to Eisai's case against FDA, which we've reported on in previous posts (here, here, and here) and that we won't repeat here.  (Eisai even unsuccessfully challenged DEA in court before challenging FDA – see our previous post here.)  The regulation at issue in the case is in 21 C.F.R. § 314.108(a), which defines the term “date of approval” to mean:

the date on the letter from FDA stating that the new drug application 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. “Date of approval” refers only to a final approval and not to a tentative approval that may become effective at a later date. [(Emphasis added)]

Eisai alleged in its Complaint that FDA violated the FDC Act and the Administrative Procedure Act (“APA”) in multiple respects by using the BELVIQ and FYCOMPA NDA approval dates as the triggering events to start the NCE exclusivity periods, thereby possibly accelerating the timing of future generic competition for BELVIQ and FYCOMPA.  According to Eisai:

[C]onsistent with FDA’s regulation—21 C.F.R. §314.108(a)—the governing statute, and clear congressional intent, market exclusivity for BELVIQ® and FYCOMPA® should have been triggered when labeling incorporating the final CSA schedule permitted legal marketing of the products.  FDA’s letters approving the products as safe and effective reinforce this requirement.  FDA’s letters make clear that the products’ labeling would need further revisions once CSA scheduling was complete. . . .  Thus, after CSA scheduling, a revision to the labeling was expressly required before the product could be legally marketed.  Therefore, the date of the approval letters cannot be considered the triggering date for market exclusivity purposes.

As to Eisai's argument that the company should prevail because the FDA letters approving BELVIQ and FYCOMPA contained language that should have brought the drugs within the exception to 21 C.F.R. § 314.108(a) (highlighted above), thereby delaying the official approval date, it was a close call for the court.  “The question here is whether the NDA approval letters themselves 'expressly required' that approval.”  If so, wrote Judge Moss, “then the drugs should have fallen within the exception in § 314.108(a), even as the FDA construes the regulation, and should have received an official approval date that reflected that later approval. This is a close question on the facts.”  

As the court read FDA's BELVIQ and FYCOMPA approval letters, “both expressly require Eisai to revise the labels, but neither expressly requires that the FDA approve those edits.  It is true that the letters require the sort of label revision that the FDA must presumptively approve under its regulations. But only an express requirement of FDA “approval” triggers the exception in 21 C.F.R. § 314.108(a), at least as the FDA construes that exception, and the letters say nothing about approval” (emphasis in original; citation omitted).  This is a fine, but not insignificant distinction, as noted by Judge Moss. “Because those letters did not facially contain an 'express[] require[ment]' that the FDA approve of additional labeling requirements and because Eisai understood that, in fact, the FDA would not need to approve of any additional labeling requirements before the company could take the drugs to market, the Court concludes that the FDA’s decision to consider the date of approval for both Belviq and Fycompa as the date found on their NDA approval letters was not arbitrary or capricious.” 

Judge Moss then turned to whether or not FDA reasonably construed the exception to its regulation defining “date of approval.”

[I]n run-of-the-mill cases, the date of approval is simply the “date on the letter from the FDA stating that the new drug application is approved.”  There is little room for the agency to interpret this clear rule, and its interpretation is not at issue here.  There is room, however, to interpret the exception to the general rule, which applies when “approval of [final printed] labeling or other materials” is “expressly required.”   The regulation is entirely silent as to who must “expressly require[ ]” labeling approval, where that requirement must appear, or even what constitutes an “express require[ment].”  [(Emphasis in original)]

But after analyzing the text of 21 C.F.R. § 314.108(a), FDA's intent behind the regulation, and the statutory purpose of NCE exclusivity, Judge Moss decided that FDA had a reasonable interpretation of its regulation:

Although the extent to which the current regulatory scheme comports with the incentive structure that the Hatch-Waxman Amendments put in place raises difficult issues, the question presented here is a narrow one: Is the FDA’s interpretation of the exception to its “date of approval” regulation “plainly erroneous or inconsistent with the regulation.”  The answer to that question is relatively straightforward.  The FDA has reasonably construed the exception to mean that the requirement for further FDA approval must appear in the letter itself.  

Before turning to prior FDA practice and some other miscellaneous arguments Eisai raised, Judge Moss addressed a lingering “interpretive question”: “What rational basis might plausibly exist to confer different effective periods of exclusivity on new drugs based on whether a requirement for further FDA approval of labeling or other materials is expressly mentioned in the approval letter itself or simply mandated by statute or regulation.” The answer, said Judge Moss,

is that the approval letters signify completion of the FDA’s process for reviewing and approving a manufacturer’s NDA. . . .  Some requirements that may remain after the FDA sends such a letter are ministerial and do not affect the finality of that approval. In those circumstances—including when the manufacturer will have to finalize a label to reflect DEA scheduling—the FDA does not need to consider further any aspect of the NDA and so it treats its “approval” as final.  In other cases, however, the requirements that remain are substantial and will require further substantive review and approval.  In those cases, the agency expressly requires further action in its approval letter as a signal that the FDA has concluded that its process is not yet completed.  Although not the only method that the FDA might use to differentiate applications that require no further substantive review from those that still demand some significant approval, the approach the FDA has adopted is a reasonable one.  The operative statute makes it necessary for th e FDA uniformly to define the “date of approval,” and the agency drew that line in a reasonable place. The Court, accordingly, concludes that the FDA’s interpretation of 21 C.F.R. § 314.108(a) is not “plainly erroneous or inconsistent with the regulation,” and it thus defers to that interpretation.  [(Emphasis in original; citation omitted)

Finally, Judge Moss addressed a precedent Eisai raised concerning FDA's decision to reset the NDA approval and NCE exclusivity dates of RAZADYNE ER (galantamine hydrobromide) Extended-release Capsules (NDA 021615).  Eisai argued that FDA's decision on RAZADYNE ER is inconsistent with FDA's construction of 21 C.F.R. § 314.108(a) as applied to BELVIQ and FYCOMPA.  (The RAZADYNE ER precedent was also raised by another company in a citizen petition – see here – that FDA later denied – see here.)  But Judge Moss found instead that the RAZADYNE ER precedent helps to define the contours of the exception under § 314.108(a):

The Razadyne letter thus reveals where the FDA draws the line for the § 314.108 exception.  Its interpretation is strict enough that merely mentioning regulatory obligations that, in turn, give rise to a requirement to obtain approval of a label change is insufficient to trigger the exception.  But it is accommodating enough that language expressly referring to an obligation to submit labeling-related materials for “review” qualifies for the exception.  The agency did not need to draw the line in this place—it could have adopted an interpretation of the exception under which both Eisai and the sponsor of Razadyne qualified, and it likely could have adopted an interpretation under which neither qualified.  The conclusion it actually reached, however, reasonably relies on a real—even if modest—textual difference in the letters the FDA issued, and it warrants deference. 

There's more in Judge Moss' decision as to additional arguments Eisai raised in the litigation against FDA.  But it's getting late in the night, so we'll leave it to you to peruse the remainder of the decision (pages 28-31).

We'll know in the coming weeks whether or not Eisai's bid to reset the NCE exclusivity start dates for BELVIQ and FYCOMPA will continue on with an appeal to the U.S. Court of Appeals for the District of Columbia Circuit.  In the meantime, we note that Congress is considering legislation – H.R. 639, the Improving Regulatory Transparency for New Medical Therapies Act – that would, among other things, amend the FDC Act to delay the effective date of approval (and therefore, delay the start of applicable exclusivity and other deadlines keyed to an approval date) of a drug, biological product, or animal drug for which FDA recommends scheduling under the CSA until the Department of Justice issues a final interim scheduling rule for the product.