Noteworthy Takeaways From FDA’s 180-Day Exclusivity Forfeiture Decision on Generic EDLUAR

By Kurt R. Karst –      

We recently came across what we think is a pretty interesting FDA Exclusivity Letter Decision on 180-day exclusivity for generic versions of EDLUAR (zolpidem tartrate) Sublingual Tablets, 5 and 10 mg (NDA 021997; approved on March 13, 2009). The 180-day exclusivity forfeiture provision at play in the case is our old friend FDC Act § 505(j)(5)(D)(i)(IV), which we’ve blogged about on many, many occasions over the nearly 10 years this blog has been around.  

By way of background, 180-day exclusivity eligibility is forfeited under FDC Act § 505(j)(5)(D)(i)(IV) 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).

Section 1133 of the 2012 FDA Safety and Innovation Act (“FDASIA”) also addressed FDA’s application of FDC Act § 505(j)(5)(D)(i)(IV) with respect to certain ANDA cohorts. In particular, under FDASIA § 1133(a), for an ANDA submitted to FDA between January 9, 2010 and July 9, 2012 initially containing a Paragraph IV certification (or that is amended during that time to first contain a Paragraph IV certification), the time to obtain timely tentative approval (or final approval if tentative approval is not warranted) is 40 months during the period of July 9, 2012 and September 30, 2015, and not 30 months, and 36 months during the period of October 1, 2015 and September 30, 2016, and not 30 months.

Shortly after the enactment of FDASIA, we made the observation that the provision extending the 30-month period to 36 months seemed pretty useless. At the time, we wrote that “the 36-month extension date is inapplicable (absent an applicable 505(q) citizen petition, or some change in review that occurs during the last 6 months of the 36-month period making the forfeiture provision irrelevant).  By the time this provision takes effect on October 1, 2015, the youngest ANDA to which it could apply – i.e., an ANDA submitted to FDA on July 9, 2012 – will be nearly 39 months old.  If such an ANDA is tentatively approved on September 30, 2015 when the tentative approval period is still 40 months, there would not be a forfeiture.  If, however, that same ANDA is tentatively approved one day later, on October 1, 2015, there would be an automatic forfeiture.”

It turns out, however, that FDA found some utility for the 36-month tentative approval provision under FDASIA § 1133(a) after all. FDA explains the Agency’s interpretation in a footnote in its June 2, 2016 Exclusivity Letter Decision with respect to Par Formulations Private Limited’s (“Par’s”) ANDA 201509 for generic EDLUAR:

For applications submitted between January 9, 2010, and July 9, 2012 containing a Paragraph IV certification (or amended to first contain a paragraph IV certification during that period of time), and approved or tentatively approved during the period of time beginning on July 9, 2012, and ending on September 30, 2015, section 1133 of the Food and Drug Administration Safety and Innovation Act (FDASIA) (P.L. 112-144) extends this period to 40 months. For applications submitted between January 9, 2010, and July 9, 2012 (or amended to first contain a paragraph IV certification during that period of time), and approved or tentatively approved during the period of time beginning on October 1, 2015, and ending on September 30, 2016, section 1133 of FDASIA extends this period to 36 months.  In addition, if an application was submitted between January 9, 2010, and July 9, 2012 containing a Paragraph IV certification (or amended to first contain a paragraph IV certification during that period of time), and FDA has not approved or tentatively approved the application but must consider whether the applicant has forfeited exclusivity because a potentially blocked application is ready for approval, FDA will apply the 36-month period if it makes the forfeiture determination between the period of time beginning on October 1, 2015, and ending on September 30, 2016.  For all other applications, the 30-month period set forth in FD&C Act section 505(j)(5)(D)(i)(IV) applies.

FDA apparently settled on this interpretation earlier this year. Indeed, there are a handful of ANDA approval letters, starting with ANDA 201970 for Rasagiline Mesylate Tablets, 0.5 mg and 1 mg (approved on March 15, 2016), that include text similar to the paragraph above.  Other affected ANDAs include ANDA 202103 for Dasatinib Tablets, 20 mg, 50 mg, 70 mg, and 100 mg (approved on June 10, 2016), ANDA 202402 for Ibuprofen Lysine Injection, 20 mg/2 mL (10 mg/mL) single-dose vials (approved on March 30, 2016), and ANDA 202349 for Estradiol Valerate Tablets, 1 mg and 3 mg, Estradiol Valerate and Dienogest Tablets, 2 mg/2 mg and 2 mg/3 mg (approved on May 5, 2016).

With respect to generic EDLUAR, Par ANDA 201509 was submitted to FDA on April 29, 2010 containing a Paragraph IV certification to Orange Book-listed patents on the Reference Listed Drug (“RLD”). As the first substantially complete ANDA submitted to FDA containing a Paragraph IV certification, Par qualified as a “first applicant” eligible for 180-day exclusivity.  Because ANDA 201509 was submitted to FDA within the FDASIA § 1133(a) “window,” the augmented 40-month and 36-month timeframes for obtaining tentative approval applied.  The 40-month period came and went.  And then something triggered FDA to assess Par’s eligibility for 180-day exclusivity.  As FDA explains in a footnote in the Agency’s Exclusivity Letter Decision, “[b]ecause FDA has not approved or tentatively approved Par’s application, but now must determine whether Par has forfeited exclusivity because a potentially blocked application is ready for approval, FDA will apply the 36-month period described in section 1133 of FDASIA.” 

Applying the 36-month date, FDA was then tasked with determining under FDC Act § 505(j)(5)(D)(i)(IV) whether or not there was, as of April 29, 2013 (i.e., 36 months after April 29, 2010), a “change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.”  And that’s where FDA’s Exclusivity Letter Decision provides another noteworthy takeaway.  FDA lays out the Agency’s policy on “hot pursuit” (à la Roscoe P. Coltrane) vis-à-vis the exception provision at FDC Act § 505(j)(5)(D)(i)(IV).  Here’s what FDA says in the decision: 

[T]he labeling review for ANDA 201509 was found acceptable on July 30, 2012. FDA approved changes to the RLD labeling (NDA 021997) on April 19, 2013, ten days before the 36-month forfeiture date.  These changes included new safety information relating to zolpidem tartrate, including several changes to the “Dosage and Administration” section of the RLD labeling.  Despite these changes to the RLD labeling, Par did not submit a labeling amendment to ANDA 201509 to address these changes until October 21, 2013, six months after the approval of the RLD labeling updates.  In fact, Par’s July 22, 2013 request for final approval of ANDA 201509 noted that “[t]here has been no change in Labeling. . . .”

FDA generally will presume that the failure to obtain tentative approval or approval was caused by a change in or review of approval requirements if, at the forfeiture date, the evidence demonstrates that the sponsor was actively addressing the change in or review of approval requirements (or FDA was considering such efforts), and these activities precluded tentative approval (or approval) at that time. Where the evidence fails to demonstrate that the sponsor was actively addressing the change in or review of approval requirements, and these activities precluded tentative approval (or approval) at the forfeiture date, FDA generally does not presume that the failure was caused by a change in or review of approval requirements.

Without any evidence that Par was in hot pursuit to address the RLD labeling changes, FDA concluded that Par forfeited eligibility for 180-day exclusivity:

We conclude that there were changes to the requirements for approval with respect to labeling, as outlined above. Changes to the RLD labeling required Par to revise its labeling. However, we do not find that these labeling changes caused Par’s failure to obtain tentative approval by the forfeiture date.  At the 36-month date of April 29, 2013, Par had not yet submitted an amendment to address the RLD labeling updates approved on April 19, 2013, and no evidence indicates that Par was actively addressing the labeling deficiencies that resulted from the change in approval requirements at that time.  Par’s submission related to the labeling changes was almost 6 months after the forfeiture date.  The six-month lag between the change in approval requirements with respect to labeling and Par’s labeling amendment supports an inference that Par was not actively addressing the labeling changes at the forfeiture date.  Therefore, we conclude that the RLD labeling changes were not a cause of Par’s failure to obtain tentative approval.