FDA’s Ruling on Generic ZITHROMAX 180-Day Exclusivity: A Little Something for Everyone!

Every once in a while we come across an instance in which FDA’s Paragraph IV Patent Certifications List does not comport with our own 180-Day Exclusivity Tracker.  Either the date on FDA’s list is different from the date we have (perhaps because of a change FDA made in a subsequent version of the List), or FDA’s List simply does not identify a drug and date listing that we believe should be there.  That, of course, piques our interest; and it leads to research so that we can get clarification.  The “old antibiotic” Azithromycin for Oral Suspension, both 100 mg/5 mL and 200 mg/5 mL strengths, which are generic versions of Pfizer, Inc.’s (“Pfizer’s”) ZITHROMAX (approved under NDA 050710 on October 19, 1995), are two such drug products.

As folks might recall, nearly a decade ago Congress passed the QI Program Supplemental Funding Act of 2008 (“the QI Act”).  The QI Act amended the FDC Act to add new § 505(v) – “Antibiotic Drugs Submitted Before November 21, 1997” – to create Hatch-Waxman benefits for so-called “old antibiotics.”  “Old antibiotics” are antibiotic active ingredients (and derivatives of such ingredients) included in an application submitted to FDA for review prior to November 21, 1997, the date of enactment of the FDA Modernization Act.  The 1984 Hatch-Waxman Amendments excluded antibiotic drugs, which were then approved under FDC Act § 507, from the Act’s patent and non-patent market exclusivity provisions (except for the availability of a patent term extension).  Section 4(b)(1)of the QI Act includes three transition provisions: one on Orange Book patent listing; one on patent certifications; and another on 180-day exclusivity for each ANDA applicant that not later than 120 dates after enactment of the QI Act (i.e., February 5, 2009) amended a pending application to contain a Paragraph IV certification to a newly listed antibiotic drug patent.  ZITHROMAX, approved in 1995, is one of several “old antibiotics.”

Lupin Limited (“Lupin”) submitted ANDA 065488 to FDA on April 12, 2007, prior to the enactment of the QI Act, and after FDA had already approved ANDAs for generic versions of Azithromycin for Oral Suspension, 100 mg/5 mL and 200 mg/5 mL. But with the passage of the QI Act, Pfizer submitted information on U.S. Patent No. 6,268,489 (“the ‘489 patent”), expiring on July 31, 2018, to FDA for listing in the Orange Book.  Lupin amended its ANDA on January 29, 2009 to include a Paragraph IV certification to the ‘489 patent, thus becoming a first applicant eligible for 180-day exclusivity.  But because of FDA’s interpretation of the statute, and the failure-to-obtain-timely-tentative-approval-within-30-months-of-submission forfeiture provision at FDC Act § 505(j)(5)(D)(i)(IV) in particular, Lupin was at risk of a forfeiture of 180-day exclusivity eligibility just a few months after its Paragraph IV certification to the ‘489 patent, on October 12, 2009.

FDC Act § 505(j)(5)(D)(i)(IV) provides that a first applicant’s eligibility for 180-day exclusivity is forfeited if:

The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.

The 2007 FDA Amendments Act clarified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition, the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final agency action on the petition (inclusive of such beginning and ending dates) . . . .” (FDC Act § 505(q)(1)(G)).

Under FDC Act § 505(j)(5)(D)(i)(IV), the date the 30-month period begins is the date of ANDA submission. The statute does not specifically reference the date of the submission of a Paragraph IV certification.  Thus, the statute leaves open the possibility that an ANDA is initially submitted to FDA without a Paragraph IV certification, thereby beginning the 30-month period, and is only later amended to include the first Paragraph IV certification to an Orange Book-listed patent covering the Reference Listed Drug (“RLD”).  That opens the possibility that an ANDA applicant could simultaneously qualify and forfeit eligibility for 180-day exclusivity (see our previous post here).  Section 1133 of the 2012 FDA Safety and Innovation Act (“FDASIA”) addressed this issue in part (see our previous post here); however, the provision does not apply to Lupin ANDA 065488 because of its “vintage” as a 2007 ANDA amended with a Paragraph IV certification in January 2009.  Thus, FDA had to tentatively approve (or approve) ANDA 065488 on or before October 12, 2009 to make forfeiture under FDC Act § 505(j)(5)(D)(i)(IV) a non-issue.  That didn’t happen (and none of the other five 180-day exclusivity forfeiture provisions came into play).  In fact, FDA never tentatively approved ANDA 065488 and did not approve the application until May 15, 2015.

When FDA finally did approve Lupin ANDA 065488, the Agency decided that it didn’t have to address 180-day exclusivity. Instead, FDA included in the ANDA approval letter its standard “punt” language on 180-day exclusivity:

With respect to 180-day generic drug exclusivity, we note that Lupin was the first ANDA applicant for Azithromycin for Oral Suspension USP, 100 mg/5 mL and 200 mg/5 mL, to submit a substantially complete ANDA with a paragraph IV certification. Therefore, with this approval, Lupin may be eligible for 180 days of generic drug exclusivity for Azithromycin For Oral Suspension USP, 100 mg/5 mL and 200 mg/5 mL.  This exclusivity, which is provided for under section 505(j)(5)(B)(iv) of the Act, would begin to run from the date of the commercial marketing identified in section 505(j)(5)(B)(iv).  The agency notes that Lupin failed to obtain tentative approval of this ANDA within 30 months after the date on which the ANDA was filed. . . .  The agency is not, however, making a formal determination at this time of Lupin’s eligibility for 180-day generic drug exclusivity.  It will do so only if a subsequent paragraph IV applicant becomes eligible for full approval (a) within 180 days after Lupin begins commercial marketing of Azithromycin for Oral Suspension USP. 100 mg/5 mL and 200 mg/5 mL, or (b) at any time prior to the expiration of the ‘489 patent if Lupin has not begun commercial marketing.

Lupin did not begin commercial marketing, and ultimately another ANDA applicant became eligible for approval, thereby requiring FDA to determine whether there would be a “punt return” (see our previous post here), or a “fumble return” (see our previous post here).

In a March 1, 2016 Letter Decision, FDA concluded that there was “a change in or a review of the requirements for approval of [ANDA 065488 ] imposed after the date on which the application [was] filed,” and that Lupin did not forfeit eligibility for 180-day exclusivity pursuant to FDC Act § 505(j)(5)(D)(i)(IV).

As an initial matter, although Pfizer had submitted a Citizen Petition to FDA in October 2006 (Docket No. FDA-2006-P-0448) concerning Azithromycin for Oral Suspension, thereby potentially bringing FDC Act § 505(q)(1)(G) into play, that petition, which FDA denied in August 2011, was specific to action on another generic drug manufacturer’s ANDA. As such, FDA determined that the Citizen Petition “did not delay FDA’s review of ANDA 065488.”

As of the 30-month forfeiture date (i.e., October 12, 2009), FDA had already reviewed much of ANDA 065488; however, both the chemistry and labeling reviews were pending.  But there was a saving grace in there for Lupin.  According to FDA’s March 1, 2016 Letter Decision (some of which is redacted), the Agency communicated certain chemistry deficiencies to Lupin that the company responded to in June 2009.  FDA’s review of those responses extended to March 2010, when the Agency communicated additional chemistry deficiencies.  “Based on these facts, we have determined that there was a change in requirements for approval related to [REDACTED] which Lupin had been actively addressing and FDA was reviewing at the 30-month forfeiture date, and that this change was a cause of Lupin’s failure to obtain tentative approval by the 30-month forfeiture date.”

FDA’s handling of 180-day exclusivity for Azithromycin for Oral Suspension, 100 mg/5 mL and 200 mg/5 mL, while not groundbreaking, is nevertheless a nice example of the interaction of various and step-wise amendments to the FDC Act affecting 180-day exclusivity and how FDA deals each of them. We also see in FDA’s decision a reiteration of the “hot pursuit” requirement to escape forfeiture under FDC Act § 505(j)(5)(D)(i)(IV) (see our previous post here).  Finally, there’s the reminder that FDA’s Paragraph IV Certifications List, while an immensely helpful and important tool, is not perfect.  FDA knows this from experience, and thus provides a disclaimer on the Agency’s website that the List “should be used for reference only. The Agency will make every effort to ensure the accuracy of the information disclosed in this list.  However, any discrepancies or disparities should be discussed with the Division of Filing Review at 240-402-8859, before making any decisions based on this information.”