Long and Strong for 10 Years: FDA Determines that 2007 Teva ANDA for Generic CIALIS Escapes 180-Day Exclusivity Forfeiture

Please clear your mind of any premature thoughts and allusions that are untoward or prurient in nature. The title of this post refers only to an unusually extended time for one ANDA applicant to obtain tentative approval for a generic version of an erectile dysfunction drug, yet escape forfeiture of 180-day exclusivity eligibility.  With that said, here we are again with another FDA 180-day exclusivity forfeiture decision concerning the often-cited failure-to-obtain-timely-tentative-(or final)-approval forfeiture provision at FDC Act § 505(j)(5)(D)(i)(IV).  The latest decision we obtained from FDA is interesting as it concerns so-called “split strengths” with different 30-month dates and different bases for determining that 180-day exclusivity for those split strengths was not forfeited.

By way of background, FDC Act § 505(j)(5)(D)(i)(IV) 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 Eli Lilly and Company’s (“Lilly’s”) CIALIS (tadalafil) Tablets, 2.5 mg, 5 mg, 10 mg, and 20 mg, containing a Paragraph IV certification was submitted to FDA on November 21, 2007 (5 mg, 10 mg and 20 mg) and October 14, 2008 (2.5 mg). Those ANDA submissions were made by Teva Pharmaceuticals USA, Inc. (“Teva”) under a single ANDA – ANDA 090141 – and qualified the company as a “first applicant” eligible for a period of 180-day exclusivity.  Thirty months after the November 21, 2007 (5 mg, 10 mg and 20 mg) and October 14, 2008 (2.5 mg) submissions was May 21, 2010 and April 14, 2011, respectively, but several more years went by without an FDA approval action on the ANDA.  Finally, FDA tentatively approved ANDA 090141on March 10, 2017, and granted final approval on May 22, 2018 (just one day after the May 21, 2018 expiration of a period of pediatric exclusivity associated with U.S. Patent No. 5,859,006 listed in the Orange Book for CIALIS.)

As to 180-day exclusivity, FDA’s approval letter affirms Teva’s eligibility for exclusivity for all strengths, but (frustratingly) says nothing about the Agency’s basis for granting such exclusivity in light of the failure to obtain timely tentative approval:

With respect to 180-day generic drug exclusivity, we note that Teva was the first ANDA applicant to submit a substantially complete ANDA with a paragraph IV certification for Tadalafil Tablets USP, 2.5 mg, 5 mg, 10 mg, and 20 mg. Therefore, with this approval, Teva is eligible for 180 days of generic drug exclusivity for Tadalafil Tablets USP, 2.5 mg, 5 mg, 10 mg, and 20 mg. This exclusivity, which is provided for under section 505(j)(5)(B)(iv) of the FD&C Act, will begin to run from the date of the commercial marketing identified in section 505(j)(5)(B)(iv). Please submit a correspondence to this ANDA informing the Agency of the date you begin commercial marketing. Please submit correspondence to this ANDA notifying the Agency within 30 days of the date of the first commercial marketing of this drug product or the RLD.  If you do not notify the Agency within 30 days, the date of first commercial marketing will be deemed to be the date of the drug product’s approval. See 21 CFR 314.107(c)(2).

We knew there had to be more to FDA’s decision, so we obtained a copy of the Agency’s November 9, 2017 .  Apparently FDA was forced to make the determination early, prior to approving Teva’s ANDA, in light of approval decisions that needed to be made on subsequent Paragraph IV ANDAs.

According to FDA, different changes or approval requirement reviews imposed after the November 21, 2007 (5 mg, 10 mg and 20 mg) and October 14, 2008 (2.5 mg) ANDA submission dates nullified the 30-month period under FDC Act § 505(j)(5)(D)(i)(IV) for each strength. As to the 5 mg, 10 mg and 20 mg strengths under Teva ANDA 090141, FDA cites a change in chemistry review requirements:

On April 15, 2010, approximately one month and six days before the 30-month forfeiture date of May 21, 2010 for the 5 mg, 10 mg, and 20 mg strengths, Teva submitted a chemistry amendment in response to FDA’s October 9, 2009 chemistry deficiencies. . . . FDA’s review of Teva’s April 15, 2010 amendment . . . extended past the 30-month forfeiture date of May 21, 2010 for the 5 mg, 10 mg, and 20 mg strengths.  FDA completed its review on October 15, 2010, which was after the 30-month forfeiture date of May 21, 2010 for the 5 mg, 10 mg, and 20 mg strengths but approximately six months before the 30-month forfeiture date of April 14, 2011 for the 2.5 mg strength.

. . . FDA generally will presume that the failure to obtain tentative approval of approval was caused by a change in or review of approval requirements if, at the 30-month 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.  At the 30-month forfeiture date for the 5 mg, 10 mg, and 20 mg strengths, FDA was considering Teva’s efforts to address the change in requirements for approval. . . .  Accordingly, this change was a cause of Teva’s failure to obtain tentative approval or approval by the 30-month forfeiture date of May 21, 2010 for the 5 mg, 10 mg, and 20 mg strengths.  However, this change was not a cause of Teva’s failure to obtain tentative approval or approval by the 30-month forfeiture date of April 14, 2011 for the 2.5 mg strength, as FDA determined that Teva had adequately addressed the change in approval requirements . . . on October 15, 2010, approximately six months before the 30-month forfeiture date of April 14, 2011 for the 2.5 mg strength.

But as to the 2.5 mg strength under Teva ANDA 090141, FDA cites a change in CIALIS labeling that caused Teva’s failure to obtain timely tentative approval for that strength:

After the ANDA amendment was submitted for addition of the 2.5 mg strength on October 14, 2008, labeling changes were approved for the RLD on February 1, 2010. The RLD labeling changes provide for:

updates under Recent Major Changes in the HIGHLIGHTS OF PRESCRIBING INFORMATION and revisions to CONTRAINDICATIONS (4.2) and WARNINGS AND PRECAUTIONS (5.11) sections of the Physician Insert, and to the Patient Package Insert, to achieve consistency with the ADCIRCA labeling and to replace a previous contraindication. The updated labeling provides for a revised warning against use of CIALIS with other phosphodiesterase (PDE5) inhibitors including ADCIRCA.  ADCIRCA also contains tadalafil and is indicated for the treatment of pulmonary arterial hypertension.  In addition, the updated labeling replaces a previous contraindication in patients with known serious hypersensitivity to tadalafil.

. . . . The evidence [] demonstrates that there was a change in approval requirements related to labeling, which were imposed after the amendment for the 2.5 mg strength was submitted.  The evidence further demonstrates that Teva had addressed the change in approval requirements and FDA was reviewing the response to such change at the 30-month forfeiture date of April 14, 2011 for the 2.5 mg strength.  Specifically, on March 22, 2010, approximately seven weeks after the RLD labeling change and one year and 23 days prior to the 30-month forfeiture date of April 14, 2011, Teva submitted an unsolicited labeling amendment with “an updated package insert and patient package insert . . . in accord with the most current labeling of the reference-listed drug Cialis® Tablets, approved on February 1, 2010.”  FDA’s review of Teva’s March 22, 2010 unsolicited labeling amendment extended past the 30-month forfeiture date of April 14, 2011.  FDA completed its review of the March 22, 2010 amendment on October 31, 2011, approximately six months and 17 days after the 30-month forfeiture date of April 14, 2011. . . .  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 30-month 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.  In this case, FDA was considering Teva’s efforts to address the RLD labeling change of February 1, 2010, at the 30-month date.  Accordingly, this change was a cause of Teva’s failure to obtain tentative approval or approval by the 30-month forfeiture date of April 14, 2011 for the 2.5 mg strength.

Teva reportedly launched all strengths approved under ANDA 090141 on September 27, 2018, thereby triggering 180-day exclusivity. The number of tentatively approved ANDAs for generic CIALIS indicates that after that exclusivity expires on or about March 26, 2019, stiff competition (just an innocent reference to Cheap Trick) among generic competitors will likely ensue.