FDA Says No 180-Day Exclusivity Forfeiture for Generic LIALDA Based on Changed Bioequivalence Recommendations

March 8, 2018By Kurt R. Karst

For this blogger, paging through and poring over FDA exclusivity determinations is about as much fun as sitting down with a hot cup of coffee and reading the Sunday newspaper. We recently came across an interesting FDA decision on 180-day exclusivity for generic LIALDA (mesalamine) Delayed-release Tablets, 1.2 g, approved under NDA 022000, that we thought was worth sharing. It concerns the familiar failure to obtain-timely tentative (or final) approval forfeiture provision at FDC Act § 505(j)(5)(D)(i)(IV), which states that 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)).

According to FDA’s Paragraph IV Certifications List, the first ANDA for a generic version of LIALDA containing a Paragraph IV certification was submitted to FDA on December 16, 2009. That submission was made by Zydus Pharmaceuticals (USA), Inc. (“Zydus”) under ANDA 091640 and made the company a “first applicant” eligible for a period of 180-day exclusivity. Thirty months after that ANDA submission was June 16, 2012, but several more years went by without an FDA approval action on the ANDA. Finally, on June 5, 2017, FDA approved Zydus ANDA 091640 after the company responsed to a December 2016 Complete Response Letter. As to 180-day exclusivity, FDA’s approval letter says that the Agency decided to “punt” on whether or not exclusivity would be available to Zydus:

With respect to 180-day generic drug exclusivity, we note that Zydus was the first ANDA applicant for Mesalamine Delayed-Release Tablets USP, 1.2 g, to submit a substantially complete ANDA with a paragraph IV certification. Therefore, with this approval, Zydus may be eligible for 180 days of generic drug exclusivity for Mesalamine Delayed-Release Tablets USP, 1.2 g. This exclusivity, which is provided for under 505(j)(5)(B)(iv) of the FD&C Act, would begin to run from the date of the commercial marketing identified in section 505(j)(5)(B)(iv). The Agency notes that Zydus failed to obtain tentative approval of this ANDA within 30 months after the date of which the ANDA was filed. See section 505(j)(5)(D)(i)(IV) of the FD&C Act (forfeiture of exclusivity for failure to obtain tentative approval). The Agency is not, however, making a formal determination at this time of Zydus’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 Zydus begins commercial marketing of Mesalamine Delayed-Release Tablets USP, 1.2 g, or (b) at any time prior to the expiration of the ‘720 patent if Zydus has not begun commercial marketing. Please submit correspondence to this ANDA informing the Agency of the date commercial marketing begins.

But just a few months later, apparently FDA was put into a position of having to resolve whether or not Zydus forfeited eligibility for 180-day exclusivity (presumably because a subsequent Paragraph IV applicant became eligible for full approval). Upon review of the Zydus ANDA file, FDA resolved this exclusivity punt in favor of Zydus. And, in doing so, FDA confirmed that it is when the Agency communicates to a particular ANDA applicant a prior determination on bioequivalence standards that counts (here, from a Citizen Petition Response), and not necessarily when an issue is decided by the Agency, for purposes of the failure to obtain timely tentative (final) approval forfeiture provision.

As initially submitted, Zydus ANDA 091640 contained, among other things, the results of a clinical endpoint bioequivalence study. But just 8 months after the submission of ANDA 091640, FDA changed course. In an August 20, 2010 Citizen Petition Response (Docket Nos. FDA-2010-P-0111 and FDA-2008-P-0507) concerning mesalamine extended-release products, FDA ruled that:

in light of new data from PK and comparative clinical endpoint studies in modified-release mesalamine products, as well as recent developments in regulatory science concerning the analysis of PK data, the Agency . . . no longer recommends comparative clinical endpoint studies to show bioequivalence for these products. Rather, . . . applicants should show bioequivalence to certain NDAs for mesalamine extended-release products (Asacol and Pentasa) through a combination of PK studies and in vitro dissolution testing.

According to an October 25, 2017 FDA Exclusivity Determination for Zydus ANDA 091640, this change in bioequivalence standard was not communicated to Zydus until a couple of years later:

In its February 23, 2012 bioequivalence review for ANDA 091640, FDA determined that the principles described in the Citizen Petition Response should apply to generic versions of Lialda as well and that Zydus must conduct comparative PK studies (under both fasting and fed conditions) and in vitro dissolution studies to demonstrate bioequivalence instead of the in vivo studies Zydus had previously conducted. This change in bioequivalence requirements for approval, which required Zydus to plan and conduct additional studies, was first communicated to Zydus as Bioequivalence Comments on March 13, 2012, three months before the forfeiture date of June 16, 2012 for ANDA 091640. Zydus later received a Complete Response Letter for this ANDA on March 13, 2013, which included the same bloequivalence deficiencies communicated in the Agency’s March 13, 2012 Bioequivalence Comments.

Zydus promptly responded to the March 2013 Complete Response Letter in October 2013, and, as noted above, eventually obtained ANDA approval in June 2017. But it was Zydus’ active pursuit to address the bioequivalence deficiencies communicated by FDA in March 2012 (and based on an August 2010 Citizen Petition Response) that saved the company from forfeiting eligibility for 180-day exclusivity. According to FDA:

On October 23, 2013, Zydus responded to the Agency’s March 13, 2013 Complete Response Letter, which included information to address the bioequivalence deficiencies communicated in the Agency’s March 13, 2012 Bioequivalence Comments and March 13, 2013 Complete Response Letter for ANDA 091640. A review of this information shows that Zydus’s application was not ready for approval at the forfeiture date due, in part, to the fact that while Zydus’s application was pending there was a change in the bioequivalence studies expected for approval. At the time of the forfeiture date of June 16, 2012, Zydus was actively addressing the bioequivalence deficiencies described above and communicated to Zydus in the March 13, 2012 Bioequivalence Comments, and Zydus had not yet demonstrated bioequivalence under the new methodology as of the June 16, 2012 forfeiture date. . . .

Based on these facts, we conclude that Zydus failed to obtain tentative approval within 30 months and this failure was caused by a change in the requirements for approval. As described above, Zydus was actively addressing the change at the forfeiture date. We conclude that Zydus’s efforts to comply with the new bioequivalence methodology for modified-release mesalamine products, which methodology was revised while Zydus’s application was pending, was a cause of its failure to obtain tentative approval by the June 16, 2012 forfeiture date.

We’ve said it before, and we’ll say it again: timing is everything when it comes to Hatch-Waxman. That’s certainly true in the case of Zydus ANDA 091640, where a Citizen Petition Response issued shortly after ANDA submission that changed bioequivalence standards was not determinative of 180-day exclusivity forfeiture, but rather when FDA communicated the substance of that petition decision to a particular ANDA applicant requesting new bioequivalence data and information.