Excuses, Excuses! A Round-Up of Exceptions Under the Failure to Obtain Timely Tentative Approval 180-Day Exclusivity Forfeiture Provision

By Kurt R. Karst –     

The recent lawsuit filed against FDA in the U.S. District Court for the District of Columbia in which Mylan Laboratories Limited and Mylan Pharmaceuticals Inc. are challenging FDA’s decision that Ranbaxy Inc. is eligible for 180-day exclusivity for its generic versions of DIOVAN (valsartan) Tablets (see our previous post here) got us thinking about the instances in which FDA determined that 180-day exclusivity was not forfeited under FDC Act § 505(j)(5)(D)(i)(IV) because of some “extenuating circumstance.”  Under that provision added by the 2003 Medicare Modernization Act (“MMA”), 180-day exclusivity eligibility 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. [(Emphasis added)]

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 [FDA] 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).  The 2012 FDA Safety and Innovation Act made further changes with respect to the application of FDC Act § 505(j)(5)(D)(i)(IV) to certain ANDAs (see our previous post here).

So what are the various types of changes or reviews that have excused a first applicant’s failure to obtain a timely tentative approval (or final approval when tentative approval is not warranted)?  We compiled a list of the 15 public cases, as well as an honorable mention.  We think there might be somewhere in the neighborhood of 20 instances; however, FDA has not yet, for one reason or another, made all of them public.  In some cases, FDA’s approval letter specifically states the reason for excusing the failure to obtain timely tentative approval.  In other cases, the approval letter is rather opaque and required additional investigative research to uncover the reason for excusing the failure to obtain timely tentative approval.   

(1) ANDA No. 078548; Approved on 2/25/2010 – Imiquimod Cream, 5% (ALDARA)

This is, to our knowledge, the first final approval in which FDA excused an applicant’s failure to obtain timely tentative approval and granted 180-day exclusivity.  FDA’s ANDA Approval Letter merely states that “the agency has determined that the failure to obtain tentative approval within 30 months was caused by the agency’s ongoing review of the requirements for approval of Imiquimod Cream, 5%. . . .”  The approval of ANDA No. 078548 coincides with FDA’s publication of a draft bioequivalence guidance for Imiquimod Cream, 5%, and is likely the basis for FDA’s proffered “ongoing review of the requirements for approval” of the drug.

(2) ANDA No. 040445; Approved on 3/31/2010 – Metaxalone Tablets, 800 mg (SKELAXIN)
 
FDA’s ANDA Approval Letter states that “during the entire time the ANDA was under review, the agency had pending before it a citizen petition that created a review of the appropriate labeling for generic metaxalone in light of certain patent-protected language in the labeling of the RLD,” and, as a result, 180-day exclusivity was not forfeited.  As we previously discussed, the citizen petition identified by FDA in the approval letter was submitted to the Agency in March 2004 (FDA Docket No. FDA-2004-P-0426) and concerns certain labeling carve-out issues. 

(3) ANDA No. 078179; Approved on 10/13/2010 – Zolpidem Tartrate Extended-release Tablets, 6.25 mg (AMBIEN CR)
 
In yet another instance of an opaque decision, FDA’s ANDA Approval Letter merely states that the failure to obtain timely tentative approval “was caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application was filed.”  It seems likely that the “change in or a review of the requirements for approval” of the ANDA was due to a change in the bioequivalence requirements.  On the same day FDA approved ANDA No. 078179, the Agency issued a Citizen Petition Decision (Docket No. FDA-2007-P-0182) establishing certain partial AUC bioequivalence requirements for generic versions of AMBIEN CR.

(4) ANDA No. 090229; Approved on 11/26/2010 – Levocetirizine Dihydrochloride Tablets, 5 mg (XYZAL)     
 
In this case, FDA’s ANDA Approval Letter provides some additional information on the “change in or a review of the requirements for approval” of the ANDA that excused the failure to obtain timely tentative approval.  The letter states:

The agency has determined that there was a change in the requirements for approval of this ANDA.  Specifically, the labeling of the RLD changed after submission of the ANDA.  The agency has also determined that this change was the cause of your not obtaining tentative approval of the ANDA within 30 months after the date on which it was filed.

The change in RLD labeling appears to be a reference to a NDA supplement FDA approved amending the labeling for XYZAL “for the relief of symptoms associated with seasonal allergic rhinitis (SAR) in children 2 years of age and older, and for the relief of symptoms of perennial allergic rhinitis (PAR) and treatment of uncomplicated skin manifestations of chronic idiopathic urticaria (CIU) for children 6 months of age and older.”

(5) ANDA No. 090505; Approved on 12/28/2010 – Doxycycline Hyclate Delayed-release Tablets, 75 mg and 100 mg (DORYX)

(6) ANDA No. 090431; Approved on 12/28/2010 – Doxycycline Hyclate Delayed-release Tablets, 75 mg and 100 mg (DORYX)
     
Although only one of the two approval letters is available, we assume the basis for each exclusivity decision is the same.  FDA’s Approval Letter for ANDA No. 090505 states in a footnote that:

A citizen petition that was subject to section 505(q) of the Act was submitted that required the agency to review the requirements for approval for Doxycycline Hyclate Delayed-release drug products. . . . Furthermore, the requirements for approval were changed when the RLD was approved for a scored tablet configuration; [the ANDA sponsor] was required to change to a scored tablet and conduct additional dissolution testing.

The referenced citizen petition (Docket No. FDA-2008-P-0586) was submitted in November 2008.  In May 2009, FDA issued a Citizen Petition Decision partially granting and partially denying the petition. 

(7) ANDA No. 090738; Approved on 4/18/2011 – Cyclobenzaprine HCl Extended-release Capsules, 15 mg and 30 mg (AMRIX)
 
FDA has not yet posted the approval letter for ANDA No. 090738, but we have been able to piece together the facts.  This is a case in which FDA changed the ANDA bioequivalence requirements after the submission of the first ANDA containing a Paragraph IV certification.  According to FDA’s Paragraph IV Certifications List, the first ANDA for generic AMRIX was submitted to FDA on August 11, 2008.  Shortly after the submission of ANDA No. 090738, FDA issued a draft bioequivalence guidance with recommendations that presumably differed from what was submitted in ANDA No. 090738. 

(8) ANDA No. 078854; Approved on 6/7/2011 – Clobetasol Propionate Topical Shampoo, 0.05% (CLOBEX)

FDA’s Approval Letter for ANDA No. 078854 is pretty straightforward.  It states that the first applicant’s failure to obtain timely tentative approval was excused, because “during its bioequivalence review, the agency asked [the first applicant] to perform comparative vasoconstrictor bioassay studies; the agency later told [the first applicant] the agency was reviewing the appropriateness of vasoconstrictor bioassay studies for topical corticosteroid drug products that are applied to the hirsute scalp.”  FDA issued a draft bioequivalence guidance for this drug in February 2011.

(9) ANDA No. 077159; Approved on 3/30/2012 – Irbesartan Tablets, 75 mg, 150 mg, and 300 mg (AVAPRO)

FDA’s ANDA Approval Letter states: “Toward the end of the 30-month period described in section 505(j)(5)(D)(i)(IV), FDA changed the approval requirements for Teva’s proposed product.  As a result, Teva was required to perform additional testing and include an additional drug substance specification prior to approval.”  FDA stated the same basis in a related Citizen Petition Decision issued on the same day FDA approved ANDA No. 077159.

(10) ANDA No. 090869; Approved on 5/17/2012 – Ropinirole HCl Extended-release Tablets, 2 mg, 4 mg, 6 mg, and 8 mg (REQUIP XL)

Acknowledging that “size matters,” FDA’s ANDA Approval Letter states that the failure to obtain timely tentative approval was caused by “a review of ANDA approval requirements with respect to the size of certain solid oral dosage form products.”  As we previously reported, FDA has issued letters to companies with pending ANDAs stating that the applications are not approvable because of tablet size differences when compared to the corresponding strengths of the RLD.  According to the Performance Goals and Procedures letter accompanying the Generic Drug User Fee Amendments of 2012, FDA has agreed to evaluate drug product physical attributes on patient acceptability, including tablet size and shape, “to provide better guidance to applicants on how these physical attributes should be controlled and compared to the RLD.”

(11) ANDA No. 077707; Approved on July 19, 2012 – Methylphenidate HCl Extended-release Capsules (CD), 10 mg, 20 mg, and 30 mg (Once Daily) (METADATE CD)

(12) ANDA No. 078873; Approved on July 19, 2012 – Methylphenidate HCl Extended-release Capsules (CD), 40 mg (Once Daily) (METADATE CD)

The Approval Letters for both ANDA No. 077707 and ANDA No. 078873 use identical language describing the basis for excusing the applicants’ failure to obtain timely tentative approval: “A citizen petition was submitted that required the agency to review the requirements for approval for generic drug products for which Metadate CD is the RLD.”   

The referenced citizen petition (Docket No. FDA-2004-P-0290) was submitted in May 2004 and was responded to on the same day FDA approved ANDA No. 077707 and ANDA No. 078873.  FDA’s Citizen Petition Decision establishes certain partial AUC bioequivalence requirements for generic versions of METADATE CD.

(13) ANDA No. 200435; Approved on 9/25/2012 – Amlodipine, Hydrochlorothiazide, and Valsartan Tablets, 5 mg/12.5 mg/160 mg, 5 mg/25 mg/160 mg, 10 mg/25 mg/160 mg, and 10 mg/25 mg/320 mg (EXFORGE HCT)
 
In a second instance in which tablet size formed the basis for excusing an applicant’s failure to obtain timely tentative approval, FDA’s ANDA Approval Letter states: “[T]he agency has determined that the failure to obtain tentative approval within the 30-month period was caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application was filed, specifically a review of ANDA approval requirements with respect to tablet size.”

(14) ANDA No. 090040; Tentatively Approved on 3/15/2011 – Doxercalciferol Injection, 2 mcg/mL (HECTOROL)

In this case, FDA only tentatively approved the first applicant’s ANDA and that tentative approval letter is not yet posted on FDA’s website.  Nevertheless, FDA addressed the issue of 180-day exclusivity forfeiture for this drug in a September 20, 2011 Citizen Petition Decision (Docket No. FDA-2010-P-0632).  In that response, FDA stated:

When a change in formulation for a listed drug referenced requires an ANDA applicant to respond (either by seeking approval for a change in formulation or by seeking a determination that the old formulation was not withdrawn for safety reasons and a waiver) we will consider this a “change in or review of the requirements for approval” within the meaning of 505(j)(5)(D)(i)(IV) of the FD&C Act.

FDA issued the Citizen Petition Decision on the same day the Agency tentatively approved ANDA No. 091101, which was submitted by a subsequent applicant.  

(15) ANDA No. 077492; Tentatively Approved on 10/25/2007 – Valsartan Tablets, 40 mg, 80 mg, 160 mg and 320 mg (DIOVAN)
 
As we noted at the top of this post, FDA’s determination that Ranbaxy did not forfeit 180-day exclusivity eligibility for generic DIOVAN for failure to obtain timely tentative approval is the subject of current litigation.  FDA's Tentative Approval Letter states:

This letter does not address issues related to the 180-day exclusivity provisions under section 505(j)(5)(B)(iv) of the Act, except to note that for purposes of sections 505(j)(5)(B)(iv) and 505(j)(5)(D)(i)(IV), the agency regards the change in the USP monograph for Valsartan, published on May 1, 2007, . . . to be a change in the requirements for approval imposed after the date on which your ANDA was filed.

FDA recently filed under seal a Motion to Dismiss or, in the Alternative, for Summary Judgment in the litigation initiated by Mylan.  Similarly, Ranbaxy has filed (also under seal) a Motion for Summary Judgment.

And that brings us to our honorable mention . . . .

ANDA No. 077532; Approved on 5/7/2008 – Acarbose Tablets, 25 mg, 50 mg, and 100 mg (PRECOSE)
 
FDA ruled in a Letter Decision that a change in bioequivalence requirements resulted in a delay in obtaining a tentative approval.  Specifically, FDA stated:

Throughout the relevant period, FDA identified the 100-mg strength tablet in the Orange Book as the drug product to be used in a bioequivalence study.  Cobalt initially conducted its bioequivalence study using that strength of the drug, but was informed by FDA on August 8, 2006, that its in vivo bioequivalence using the 100 mg strength was not acceptable. After further study by Cobalt, it relied upon a different strength of acarbose tablets for its in vivo bioequivalence study.  This change in requirements for bioequivalence data necessitated a longer review of the Cobalt ANDA.

But because FDA also determined that exclusivity was forfeited under the failure-to-market (FDC Act § 505(j)(5)(D)(i)(I)) forfeiture provisions, we do not count Acarbose Tablets as a true failure to obtain timely tentative approval precedent.