NDA Approval Date Resets: More Than a One-off

By Kurt R. Karst –  

We love precedents – particularly unusual precedents that are wrapped up in drug approval histories. A couple of years ago we learned about a new precedent concerning the “date of approval” of a drug product.  That term is defined in an FDA regulation (21 C.F.R. § 314.108(a)) 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)]

Way back in April 2014, FDA issued a Consolidated Response to two Citizen Petitions (Docket Nos. FDA-2013-P-1397 and FDA-2013-P-0884) submitted to the Agency in 2013 by Eisai Inc. (“Eisai”) and UCB, Inc. (“UCB”) arguing that FDA erroneously triggered the periods of 5-year New Chemical Entity (“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 under the Controlled Substances Act (“CSA”), and thus, before commercial marketing could occur at that time (prior to the enactment of the Improving Regulatory Transparency for New Medical Therapies Act – see our previous post here).  Buried in the Petition Response (at footnote 92), FDA states that the Agency “is aware of one situation, which did not involve scheduling [of a controlled substance under the CSA], in which this narrow exception [(highlighted in the definition above)] has been applied.” 

The drug at issue in footnote 92 was RAZADYNE ER (galantamine hydrobromide) Extended-release Capsules, approved under NDA 021615. 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,” explained FDA.  We dug into the precedent, which came up again in litigation Eisai brought against FDA (see our previous posts here and here), as well as in a Citizen Petition (Docket No. FDA-2014-P-1615) Spectrum Pharmaceuticals, Inc. (“Spectrum”) submitted to FDA concerning the company’s FUSILEV (levoleucovorin) for Injection drug product approved under NDA 020140, and which petition FDA later denied (see our previous post here). 

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 then reset the period of 3-year exclusivity for RAZADYNE ER to expire on April 1, 2008, instead of on December 22, 2007.

It turns out that RAZADYNE ER is not the only drug product to have its approval date revised.

One day while perusing an old edition of the Orange Book we came across an apparent discrepancy between the date of approval of an NDA listed in the Orange Book versus the date of approval identified on FDA’s Drugs@FDA website. The drug, GLUCOPHAGE (metformin HCl) Tablets, 500 mg and 850 mg, is approved under NDA 020357.  But is the “date of approval” of NDA 020357 March 3, 1995, as shown on Drugs@FDA, or an earlier date, as reflected in older editions of the Orange Book? 

Both strengths of GLUCOPHAGE approved under NDA 020357 were first added to the Orange Book with the December 1994 Cumulative Supplement showing an approval date of December 29, 1994, and an NCE exclusivity expiration date of December 29, 1999 (pages 40 and 79). The December 29, 1994 approval and December 29, 1999 NCE exclusivity expiration dates also appear in the 1995 annual edition (15th edition) (page 3-193 and AD32).  This all seems to make sense.  After all, the FDA letter approving NDA 020357 is date-stamped “DEC 29 1994”.

Fast-forward to 1997, and to the April Orange Book Cumulative Supplement in particular, which shows the following additions and deletions to the Prescription Drug Product List and to the Patent and Exclusivity Data Addendum for NDA 020357:

Why were the dates changed to March 3, 1995 and March 3, 2000? 

Apparently when the GLUCOPHAGE NDA was “approved” on December 29, 1994, it was not approved with agreed upon prescribing information – which was referred to back then as a Patient Package Insert (“PPI”). Instead, the NDA was approved with a commitment from the then-NDA sponsor, Lipha Pharmaceuticals, Inc. (“Lipha”), not to market GLUCOPHAGE until a PPI was agreed to by FDA.  

How do we know about this commitment?

We hunted down a letter from Lipha, dated December 29, 1994, which states, in relevant part: “In accord with our telephone conference of December 29, 1994 with [FDA], we agree that Glucaphage® will not be marketed in the United States without an accompanying Patient Package Insert (PPI). The language of this PPI will be mutually agreed upon by FDA and Lipha Pharmaceuticals, Inc. in the immediate future.” That PPI was presumably approved on March 3, 1995, making that date the official “date of approval” of NDA 020357 for GLUCOPHAGE.  

Given that GLUCOPHAGE was approved with a period of 5-year NCE exclusivity, and, unlike RAZADYNE ER, could be eligible for a Patent term Extension (“PTE”), we wondered (for the sake of completeness) whether or not the revision of the December 29, 1994 approval date for NDA 020357 to an official “date of approval” of March 3, 1995, also affected the PTE calculus. Unfortunately, we cannot find any evidence that a PTE was submitted for a patent covering GLUCOPHAGE. 

Both the RAZADYNE ER and GLUCOPHAGE approval date reset precedents are now artifacts of history . . . so why dredge up old history?  There's the obvious answer: “Because precedents can be important to making and supporting a case for some FDA action.”  But there's more.  Knowing that a second example exists with the approval of GLUCOPHAGE might mean that there are other, more recent examples out there not yet uncovered that may have more immediate implications if found.