Last Minute Dissolution Testing Requirement Avoids Forfeiture of 180-Day Exclusivity for Generic COREG CR Staggered Strengths

As folks know by now, each month we pore over the latest Orange Book Cumulative Supplement in an effort to keep our popular 180-Day Exclusivity Tracker as current as possible, and to look for interesting precedents. One recent entry in particular caught our attention.  It was for ANDA 090132 for Carvedilol Phosphate Extended-Release Capsules, 10 mg, 20 mg, 40 mg and 80 mg, a generic version of SmithKline’s COREG CR Extended-Release Capsules (NDA 022012).  The Orange Book Cumulative Supplement showed the addition of periods of “PC” exclusivity (i.e., 180-day patent challenge exclusivity) expiring on May 7, 2018 for all four strengths covered under the ANDA now owned by Sun Pharmaceutical Industries Inc. (“Sun”) (formerly owned by Mutual Pharmaceutical Company, Inc. (“Mutual”)).  What made the entry of 180-day exclusivity interesting is that FDA’s October 25, 2017 letter approving the ANDA included the Agency’s all-too-familiar 180-day exclusivity “punt” language:

With respect to 180-day generic drug exclusivity, we note that Sun was the first ANDA applicant for Carvedilol Phosphate Extended-Release Capsules, 10 mg, 20 mg, 40 mg and 80 mg, to submit a substantially complete ANDA with a paragraph IV certification. Therefore, with this approval, Sun may be eligible for 180 days of generic drug exclusivity for Carvedilol Phosphate Extended-Release Capsules, 10 mg, 20 mg, 40 mg and 80 mg. The Agency notes that Sun failed to obtain tentative approval of its ANDA within 30 months after the date on 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 Sun’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 Sun begins commercial marketing of Carvedilol Phosphate Extended-Release Capsules, 10 mg, 20 mg, 40 mg and 80 mg, or (b) at any time prior to the expiration of the ‘156 patent if Sun has not begun commercial marketing.

FDA’s Orange Book entry showing the addition of 180-day exclusivity could mean only one thing: that the Agency was forced into a position of determining whether or not eligibility for 180-day exclusivity was forfeited, and FDA determined that it was not. (We’ve referred to this type of decision as a “punt return,” as opposed to a “fumble return” – see our previous posts here, here, and here.)

FDA’s “punt return” determination was confirmed by FDA’s December 6, 2017 tentative approval of Impax Laboratories, Inc.’s (“Impax’s”) ANDA 204717 for Carvedilol Phosphate Extended-Release Capsules, 10 mg, 20 mg, 40 mg, and 80 mg. FDA stated in that tentative approval letter:

[W]e are unable to grant final approval to your ANDA at this time. Prior to the submission of your ANDA, another applicant or applicants submitted a substantially complete ANDA providing for Carvedilol Phosphate Extended-Release Capsules, 10 mg, 20 mg, 40 mg, and 80 mg, and containing a paragraph IV certification. Your ANDA will be eligible for final approval on May 7, 2018, which is the date that is 180 days after the commercial marketing date identified in section 505(j)(5)(B)(iv) of the FD&C Act.

While these facts are nice to have, we wanted to know more! What was the basis of FDA’s “punt return” determination?  So we obtained a copy of FDA’s exclusivity determination to satisfy our curiosity.    It shows that FDA ruled on November 3, 2017 – about a month before tentatively approving Impax ANDA 204717 – that Mutual (now Sun) maintained eligibility for exclusivity for all four strengths because of a change in the requirements for approval with respect to showing bioequivalence.

Under the statutory failure to obtain-timely tentative (or final) approval forfeiture provision at FDC Act § 505(j)(5)(D)(i)(IV), 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 ANDA Paragraph IV Certifications List, the first ANDA containing a Paragraph IV certification for Carvedilol Phosphate Extended-Release Capsules was submitted to FDA on November 19, 2007 (80 mg), on December 21, 2007 (40 mg), and on March 18, 2008 (10 mg and 20 mg). In fact, it was Mutual that qualified as the sole “first applicant” for all four strengths based on its original ANDA submission and subsequent strength amendments.  Thus, as FDA states in the Agency’s exclusivity determination, “Mutual had 30 months to obtain tentative approval or approval for the purposes of section 505(j)(5)(D)(i)(IV) of the Act.  Thirty months from the submission of the original ANDA containing the 80 mg strength is May 19, 2010.  Thirty months from the submission of the new strength amendment for the 40 mg strength is June 21, 2010. Thirty months from the submission of the new strength amendment for the 10 and 20 mg strengths is September 18, 2010.”

FDA never tentatively approved Mutual ANDA 090132, and did not approve the ANDA until nearly ten years after it was submitted to the Agency. Nevertheless, FDA determined that eligibility for 180-day exclusivity was not forfeited.  And although there was a Citizen Petition (Docket No. FDA-2010-P-2016) that FDA considered during the pendency of ANDA 090132 (and that the Agency responded to in October 2010), the Agency says that “[t]here is no evidence that FDA’s consideration of this petition, itself, caused a delay in approval or tentative approval of Mutual’s ANDA.”  Thus, FDC Act § 505(q)(1)(G) did not come into play.

So this is a case of pure consideration of what was going on at the 30-month periods under FDC Act § 505(j)(5)(D)(i)(IV). To that end, FDA identified new dissolution testing requirements imposed after the submission of Mutual ANDA 090132 – and, in fact, just a few to several months before the 30-month forfeiture dates – that provide a basis for review changes and approval requirements:

At the time ANDA 090132 was submitted, FDA did not require that applicants conduct dissolution testing using ethanol for ANDAs for modified-release drug products. In February 2010, after the submission of ANDA 090132 but several months prior to the 30-month forfeiture dates for this ANDA, the Agency published a draft product-specific guidance for Carvedilol Phosphate Extended Release Capsules (referencing NDA 022012, Coreg CR (Carvedilol Phosphate) Extended Release Capsules, 10 mg, 20 mg, 40 mg, and 80 mg).’ Due to concerns of dose dumping from this drug product when taken with alcohol, the draft product-specific guidance stated that applicants should also conduct dissolution testing using various concentrations of ethanol in the dissolution medium.” On May 14, 2010, approximately three months after the publication of the draft product-specific guidance and prior to the 30-month forfeiture dates for this ANDA, Mutual submitted an amendment which purported to address the new dissolution testing described in the Agency’s draft product-specific guidance for Carvediol Phosphate Extended Release Capsules. At the 30-month forfeiture dates for this ANDA, the dissolution data for ANDA 090132 was still under review.  The Agency found the dissolution testing adequate on March 16, 2011.

Accordingly, FDA concluded that Mutual (Sun) did not forfeit eligibility for 180-day exclusivity because of the change and because Mutual remained in hot pursuit of ANDA approval by addressing the FDA changes:

We conclude that there was a change in the requirements for approval with respect to bioequivalence, as outlined above, and that this change was a cause of Mutual’s failure to obtain tentative approval by the forfeiture dates. After the submission of Mutual’s ANDA, in the February 2010 draft product-specific guidance, the Agency advised applicants to conduct additional dissolution testing using various concentrations of ethanol in the dissolution medium for Carvedilol Phosphate Extended Release Capsules. Mutual actively addressed this change in the requirements for approval before the 30-month forfeiture dates for this ANDA when it submitted its May 14, 2010 amendment containing information to address the new dissolution testing described in the February 2010 draft product-specific guidance. As of the 30-month forfeiture dates for this ANDA, the Agency was still reviewing Mutual’s dissolution information.  Based on these facts (including, among other things, that Mutual had been actively addressing the change in approval requirements and that FDA was reviewing Mutual’s efforts at the 30-month forfeiture dates), we conclude that the requirement to comply with the new dissolution testing using various concentrations of ethanol in the dissolution medium was a cause of Mutual’s failure to obtain tentative approval by the forfeiture date.