By Kurt R. Karst —
Beginning in 1999, around the time FDA issued a (still) draft guidance document on 505(b)(2) applications, and lasting until about 2009, this blogger taught an introduction to drug law course at FDA to FDAers. The focus of my talk was – surprise, surprise – Hatch-Waxman. Each time I arrived at the section of the talk on 505(b)(2) applications I would take a poll of participants: “How many of you have heard of the 505(b)(2) NDA?” In 1999, 15 years after the enactment of the Hatch-Waxman Amendments, which created the 505(b)(2) NDA, and 8 years after two of my colleagues wrote what might be the first analysis of the statutory provision (see Sasinowski FJ, Scarlett T. Reliance on Phantom ANDAs to Access NDA data. Reg Affairs. 1991;3: 467-482), only a few hands in an audience of about 50 participants would be raised. By 2009, almost every participant raised a hand. That significant change in the familiarity with the 505(b)(2) NDA tracks industry’s use of the approval route – and which increase continues today. Ahh, but with greater use comes greater controversy. . . (just as as Uncle Ben would say to Peter Parker) with great power comes great responsibility. And that’s where we begin our story today.
In a recent response to a March 2014 citizen petition (Docket No. FDA-2014-P-0318) submitted by Antares Pharma, Inc. (“Antares”), and the subtext of which might be “make sure you get your publicly available facts straight when petitioning FDA,” FDA denied Antares’s request that the Agency refrain from approving (and withdraw) any 505(b)(2) application submitted by Medac Pharma, Inc. (“Medac”) directed to a methotrexate drug product for subcutaneous injection if such application does not reference Antares’ single-dose auto-injector OTREXUP (methotrexate) Injection, 10 mg/0.4 mL, 15 mg/0.4 mL, 20 mg/ 0.4 mL and 25 mg/0.4 mL, and that FDA order Medac to submit a new application citing OTREXUP as a listed drug (that would, of course, include certifications to any patents listed in the Orange Book for OTREXUP).
FDA approved OTREXUP on October 11, 2013 under NDA No. 204824 for severe rheumatoid arthritis including polyarticular juvenile idiopathic arthritis, and for symptomatic control of severe, recalcitrant, disabling psoriasis in adults who are not adequately responsive to other forms of therapy. That 505(b)(2) NDA, which was submitted to FDA on December 14, 2012, is identified in the Orange Book as the Reference Listed Drug (“RLD”) for an injectable methotrexate solution with a subcutaneous route of administration.
Meanwhile, Medac was developing its own methotrexate injection drug product – a prefilled pen available in 10 strengths called RASUVO (methotrexate) Injection – for the same uses as OTREXUP. Medac submitted its 505(b)(2) NDA No. 205776 for RASUVO to FDA just a few weeks before FDA approved OTREXUP – on September 10, 2013. And notwithstanding Antares’ petition to stop the approval of RASUVO, FDA approved NDA No. 205776 on July 10, 2014. Enter FDA’s intervening NDA approval policy. . . .
FDA’s regulation at 21 C.F.R. § 314.101(d)(9) states that “FDA may refuse to file an application if . . . . [t]he application is submitted as a 505(b)(2) application for a drug that is a duplicate of a listed drug and is eligible for approval under section 505(j) of the act.” 21 C.F.R. § 314.101(d)(9). FDA explained how the Agency interprets this regulation in a June 2004 response to a citizen petition (Docket No. FDA-2003-P-0338). In that case, which concerned a then-pending 505(b)(2) application for Loratadine Tablets, 10 mg, FDA determined that an intervening NDA approval for the same drug product does not bar the Agency from approving a pending 505(b)(2) application. Specifically, FDA ruled that 21 C.F.R. § 314.101(d)(9) “bars 505(b)(2) applications for products eligible for approval under section 505(j) of the Act only if the product described in a 505(b)(2) application may be approved via section 505(j) at the time of the application’s submission” (emphasis added). A 505(b)(2) application submitted to FDA before the approval of another NDA – an intervening NDA – that would otherwise render the 505(b)(2) application drug product a duplicate of an approved drug is, according to FDA, unaffected by the intervening NDA approval.
More recently, FDA discussed the Agency’s intervening NDA approval policy as part of a May 17, 2012 decision granting a citizen petition to designate VELTIN (clindamycin phosphate and tretinoin) Gel, 1.2%/0.025% (NDA No. 050803) as a second RLD in the Orange Book. A comment submitted to FDA contended, among other things, that VELTIN could have been submitted via an ANDA given the intervening approval of NDA No. 050802 for ZIANA (clindamycin phosphate and tretinoin) Gel, 1.2%/0.025%. According to FDA, however:
Because there were no pharmaceutically equivalent products approved at the time that Veltin was submitted, it would not have been appropriate for the Veltin application to be submitted as a 505(j) application. Although we approved the Ziana NDA while the Veltin application was under review, our policy is that we do not require applicants to withdraw and resubmit applications if another pharmaceutically equivalent drug product is subsequently approved. Therefore, the 505(b)(2) NDA was an appropriate pathway for Veltin’s application.
Under othercircumstances, FDA has decided (Docket No. FDA-2008-P-0329) that the intervening approval of an NDA after the submission of an ANDA made pursuant to an approved suitability petition, and where the NDA approval renders the pending ANDA a duplicate of an approved drug, requires the generic applicant to submit a new ANDA citing the newly approved NDA drug product as the RLD.
Given the longstanding FDA policy on intervening NDA approvals as a result of the Agency’s interpretation of 21 C.F.R. § 314.101(d)(9), why would Antares petition FDA? Antares’ petition requests may have been triggered by a January 27, 2014 Medac press release announcing FDA’s acceptance of the RASUVO 505(b)(2) NDA. That press release did not mention FDA’s PDUFA goal date for acting on the NDA. Ok, so without a PDUFA date, one might speculate that FDA slipped up and accepted the RASUVO 505(b)(2) NDA after the October 11, 2013 approval of OTREXUP. But not long after Antares submitted its petition to FDA, Medac made known in a press release the PDUFA date for the application: “the PDUFA date for Rasuvo is July 10, 2014.” Based on a standard 10-month review, that meant the RASUVO 505(b)(2) NDA was submitted to FDA on September 10, 2013. But the petition was not withdrawn.
Although Antares raised in its petition, among other things, choice of listed drug and pharmaceutical equivalence issues, all FDA needed to deny the petition was to answer one very simple question: “Is September 10, 2013 before October 11, 2013.” According to FDA:
Antares’ claims are based on a number of erroneous assumptions, the first and foremost of which is the date of submission of Medac’s NDA. Contrary to what Antares asserts, Medac submitted its application not after Otrexup was approved on October 11, 2013, but before Otrexup’s approval, that is, on September 10, 2013. FDA’s policy is that when reviewing 505(b)(2) applications, FDA will not require sponsors to withdraw and resubmit applications if pharmaceutically equivalent product is approved after the application is submitted but before it is approved. That is precisely the factual situation here. . . .
Therefore, regardless of whether Otrexup is pharmaceutically equivalent to Medac’s product, Medac was under no obligation to resubmit its application and reference Otrexup. Since it did not rely for approval on Otrexup in its application, Medac also had no obligation to certify any patents listed for Otrexup. The date of submission of a complete 505(b)(2) NDA is the only controlling factor in this instance. Thus, for the purposes of responding to this Petition, the Agency does not need to reach the issue of whether Otrexup is pharmaceutically equivalent to Medac’s product. [(Emphasis in original)]