No Good Precedent Goes Overlooked: FDA is Asked to Reset FUSILEV Approval and Exclusivity Dates Because of Proprietary Name Review

By Kurt R. Karst –      

We were wondering how long it might be until a company went running to FDA to request that the Agency reset the date of approval of its NDA, as well as any unexpired marketing exclusivity, as the result of a proprietary name review issue FDA identified in a footnote to an April 30, 2014 denial of two  Citizen Petitions requesting that the Agency reset the 5-year New Chemical Entity (“NCE”) exclusivity periods for drug products because of delays in the controlled substance scheduling process.  It took one company, Spectrum Pharmaceuticals, Inc. (“Spectrum”), less than 6 months to make its appeal to FDA.  In an October 13, 2014 Citizen Petition (Docket No. FDA-2014-P-1615), Spectrum requests that FDA update the Orange Book to state that the company’s FUSILEV (levoleucovorin) for Injection drug product approved under NDA 020140 was approved 129 days after the date currently listed in the publication – on July 14, 2008 rather than March 7, 2008 – and that the period of 7-year orphan drug exclusivity expires 129 days later than currently listed – on July 14, 2015 instead of March 7, 2015.  (Spectrum’s October 13th petition follows a September 30th Citizen Petition [Docket No. FDA-2014-P-1649] from the company requesting that FDA not approve ANDAs for generic FUSILEV that omit certain labeling information – see our updated Generic Drug Labeling Carve-Out Scorecard.)

As we previously reported (here, here, and here), Eisai Inc. (“Eisai”) and UCB, Inc. submitted Citizen Petitions (Docket Nos. FDA-2013-P-1397 and FDA-2013-P-0884) to FDA in 2013 requesting that the Agency conclude that the NCE exclusivity start dates for BELVIQ (lorcaserin HCl) Tablets (NDA No. 022529), FYCOMPA (perampanel) Tablets (NDA No. 202834), and VIMPAT (lacosamide) Tablets (NDA No. 022253) are triggered only when FDA-approved labeling incorporates the final Drug Enforcement Administration Controlled Substances Act scheduling decision to permit commercial marketing of the drug products, and not on the date of NDA approval.  In denying the petitions, FDA addressed the petitioners’ argument that the Agency’s regulation at 21 C.F.R. § 314.108(a) defining “date of approval” supports a later NCE exclusivity start date.  That regulation defines “date of approval” as follows:

Date of approval means 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)]

According to FDA, the approval letters for BELVIQ, FYCOMPA, and VIMPAT do not “expressly require” approval of labeling or other materials, and therefore, the regulation is not applicable to the approval of those drugs.  To make the point about the limited nature of the “expressly required” exception in the regulation, FDA says the following in footnote 92 of the petition denial:

The highlighted language is an exception to the general rule, and FDA has always construed that exception narrowly.  PhRMA, in a comment supporting Petitioners, has argued that this exception can only have been intended to apply to scheduling situations (despite the fact that it has never been applied to such situations).  PhRMA comment at 5-6.  FDA is aware of one situation, which did not involve scheduling, in which this narrow exception has been applied.  In that case, the letter announcing the approval of the NDA contemplated the later submission of a trade name that FDA would have to review and approve prior to marketing, and FDA determined that the approval date was the date when the trade name was approved. The drug involved in that case was Razadyne ER (NDA 021615). . . .

That footnote – and the RAZADYNE ER (galantamine hydrobromide) Extended-release Capsules precedent in particular – is at the heart of Spectrum’s October 13th petition.  (It also plays an important role in the lawsuit Eisai filed against FDA earlier this year after the Agency denied the company’s petition – see our previous post here – and in Eisai’s recent Motion for Summary Judgment in that case.)

FDA initially approved NDA 021615 for RAZADYNE ER on December 22, 2004.  The drug, however, was approved without a proprietary name after FDA rejected name proposals because of concerns about medication errors.  The NDA sponsor ultimately (i.e., 101 days after the  December 22, 2004 approval, or April 1, 2005) found a proprietary name that passed muster at FDA and then asked the Agency to revise the NDA approval date.  FDA acquiesced and issued a letter in June 2006 with the following rationale: 

FDA’s December 22, 2004 action letter stated that, because of medication errors associated with the use of the trade name Reminyl for the approved galantamine hydrobromide immediate release product, J&J would not market the extended release product until a new trade name had been reviewed and approved by FDA. 

We have reviewed your letter and the NDA record, and concluded that the action letter of December 22, 2004, should be considered an approvable letter as described in 21 CFR 314.110.  In light of the concerns about medication errors expressed in that letter, it is reasonable to conclude that Razadyne ER was not approved until April 1, 2005, when the Agency completed its review of the proposed new trade name, found it acceptable, and conveyed this information to J&J.

As a result, FDA also amended the Orange Book to reflect the new NDA approval date, and reset the period of 3-year exclusivity for  RAZADYNE ER to expire on April 1, 2008 instead of December 22, 2007. 

According to Spectrum, the regulatory history of FUSILEV is strikingly similar to that of RAZADYNE ER.  FDA and Spectrum were unable to come to terms on a proprietary name for the proposed Levoleucovorin drug product, which led to the approval letter issued on March 7, 2008 providing

for the use of Levoleucovorin for Injection, 50 mg/10 mL or 10 mg/mL for rescue after high-dose methotrexate therapy in osteosarcoma and to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists.

The letter goes on to state that

A decision on the acceptability of your proposed trade name will be made by the Division of Medication Error Prevention and will be communicated to you at a later date.  Accordingly, you may submit a post-approval labeling supplement with inclusion of the accepted trade name. Until then, you may not use any trade name on the labels and labeling, but may only use the established name.

On July 14, 2008 – 129 days after the original March 7, 2008 approval letter was issued – FDA sent Spectrum a letter approving a supplement providing “for a proprietary name, Fusilev, and revised labeling to include the proprietary name.”  Spectrum subsequently began marketing the drug with the FUSILEV name. 

Spectrum says that there is no reason for FDA to treat FUSILEV and the circumstances surrounding the proprietary name review and approval of the drug any different than in the case of RAZADYNE ER.  But a decision is needed fast, says Spectrum.  The March 7, 2015 date currently listed in the Orange Book for the expiration of a period of orphan drug exclusivity, and that could mean ANDA approval, is approaching quickly.