FDA Denies Petitions Alleging Erroneous Triggering of NCE Exclusivity Start Date Before DEA Controlled Substance Scheduling Permitted Marketing; Litigation to Follow?

By Kurt R. Karst –      

Earlier this week, FDA issued its highly anticipated (well, at least for this blogger) Consolidated Response to two Citizen Petitions (Docket Nos. FDA-2013-P-1397 and FDA-2013-P-0884) submitted to the Agency last year by Eisai Inc. (“Eisai”) and UCB, Inc. (“UCB”) arguing that FDA erroneously triggered the periods of 5-year NCE exclusivity for Eisai’s BELVIQ (lorcaserin HCl) Tablets (NDA No. 022529) and FYCOMPA (perampanel) Tablets (NDA No. 202834), and UCB’s VIMPAT (lacosamide) Tablets (NDA No. 022253) before the drugs were scheduled by the Drug Enforcement Administration (“DEA”) under the Controlled Substances Act (“CSA”), and thus, before commercial marketing could occur.  Eisai has already shown a willingness to litigate over CSA scheduling decisions for perampanel (see our previous posts here, here, and here), so we wouldn’t be surprised if there’s a lawsuit against FDA coming down the pike.  

As we previously reported on the Eisai petition, Eisai asked 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 scheduling permits commercial marketing of the drug products, and not on the date of NDA approval.  The situation arose because, in recent years, DEA has been slow to issue scheduling decisions for controlled substances undergoing FDA review; however, recent legislation (see our previous post here) is intended to address the delay.  Eisai offers two potential solutions to address any “shortening” of the NCE exclusivity period (by virtue of not marketing until DEA scheduling is final).  First, if a Changes Being Effected (“CBE”) supplement is used to reflect DEA’s scheduling decision, “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,” says Eisai.    Alternatively, “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.”  UCB’s petition adopts the arguments in Eisai’s petition.  An important difference between the positions of Eisai and UCB is that while neither BELVIQ and FYCOMPA are the subject of a pending ANDA (according to FDA’s Paragraph IV Certification List), there are several ANDAs pending at FDA for generic VIMPAT.

FDA, in its Consolidated Response, shot down both of the arguments raised by Eisai and UCB in one fell swoop, stating: “The legal and regulatory framework on exclusivity and drug approvals contemplate only a single date of approval for determining when exclusivity begins for an NDA.  For each NDA at issue, that date is the date that FDA completes its review and issues an approval letter.”  More specifically, FDA, pointing to the so-called “bar clause” at FDC Act § 505(j)(5)(F)(ii) (ANDA) and § 505(c)(3)(E)(ii) (505(b)(2) application) governing NCE exclusivity, says:

The 5-year NCE exclusivity provision clearly contemplates a single date of approval for determining when an exclusivity period begins.  The bar clause prevents the submission of any ANDA or 505(b)(2) application that “refers to the drug for which the [505(b)] application was submitted,” and this bar on submission lasts for “five years from the date of the approval of the [505(b)] application.”  Thus, the FD&C Act provides that exclusivity runs from the date FDA issues an approval letter for an application, unless the approval has a delayed effective date.  [(Emphasis in original)]

Turning to the drug approval provisions, FDA states:

The statutory and regulatory provisions governing drug approvals contemplate only full approvals of NDAs, except when [tentative approval standards for ANDAs and 505(b)(2) applications apply].  Neither the statute nor FDA’s regulations provide for, or envision, conditional or two-tiered approvals.  The FD&C Act specifically directs the Agency to approve a product unless one of the delineated bases in [FD&C Act § 505(d)] applies.  Similarly, . . . 21 CFR 314.105(a) concerns the approval of NDAs, and states that FDA “will approve an application and send the applicant an approval letter if none of the reasons in [21 CFR] 314.125 for refusing to approve the application applies.”  

From there, it was relatively easy for FDA to put the two together and reject petitioners’ arguments:

Petitioners’ argument that their NDAs were both approved and not approved on the date FDA issued their approval letter is not supportable.  Nor, upon analysis, is there support for their assertion that their NDAs were not approved at all before DEA scheduling was completed.  There was never any confusion about when the NDAs in question were approved by FDA.  For each of the drugs in question, the approval letter was titled, in bold and all capital letters, “NDA APPROVAL”.  Each letter clearly stated that the NDA “is approved, effective on the date of this letter.”  FDA regulations [at 21 CFR 314.107(a)] are clear that . . . an “approval becomes effective on the date of issuance of the approval letter.”   [(Emphasis in original)]

Eisai had used for support in its petition the fact that the NDA approval letters for its drug products include an agreement with FDA that the company will not market its product until DEA scheduling is completed and appropriate labeling revisions are made, and noted that this agreement – a prohibition on marketing – is grounded in Form FDA 356h.  Form FDA 356h, which must accompany regulatory submissions to marketing applications, 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.”  But FDA says that this committment, which, to the Agency’s knowledge, has never been broken by an NDA sponsor, applies only after (and can only be broken after) NDA approval.

Finally, Eisai had argued that because FDA’s regulations at 21 C.F.R. § 314.108 (implementing the FDC Act’s NCE exclusivity provisions) 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), “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” (i.e., marketed in interstate commerce) (emphasis in original).  And in the case of BELVIQ and FYCOMPA, says Eisai, because of the need to submit and obtain approval for revised labeling, their situation falls within the emphasized text at 21 C.F.R. § 314.108 above.  Not so says FDA:

[T]he approval letters for the drugs at issue here do not “expressly require” approval of labeling or other materials.  The [approval] letters do not even impliedly require such approval, as FDA has generally permitted products of this type to be marketed after submission of a [CBE] supplement as soon as scheduling occurs (and before FDA approves that supplement).  This is because FDA has already evaluated the abuse potential of the drug and recommended placement in a schedule; thus it need not evaluate labeling that references the final DEA scheduling order after that order issues.

So, there you have it.  All of the cards are now laid on the table.  The next move goes to Eisai and UCB.