FDA Precedent on Tramadol NDA Resubmission Shows Agency Efforts to Dull the Pain of a Statutory Prohibition

By Kurt R. Karst –      

It’s a quiet news week here in the U.S. with the Independence Day holiday approaching.  But the news void has given us an opportunity to catch up on a few items we put on a backburner and intended to tackle at some point.  First up off the backburner is the statutory provision added by the December 2003 Medicare Modernization Act (“MMA”) prohibiting ANDA and 505(b)(2) sponsors from amending a pending application to change the Reference Listed Drug (“RLD”) (in the case of an ANDA) or a listed drug relied on for approval (in the case of a 505(b)(2) NDA).

The MMA amended the FDC Act to add Section 505(j)(2)(D)(i), which states that “[a]n applicant may not amend or supplement an [ANDA] to seek approval of a drug referring to a different listed drug from the listed drug identified in the application as submitted to [FDA].”  The parallel provision applicable to 505(b)(2) applications is located at FDC Act § 505(b)(4)(A) and states that “[a]n applicant may not amend or supplement [a 505(b)(2) application] to seek approval of a drug that is a different drug than the drug identified in the application as submitted to [FDA].” 

Way back in November 2008, we posted on an FDA citizen petition decision (Docket No. FDA-2008-P-0329) in which the Agency was asked to determine that any company with a pending ANDA for a proposed Venlafaxine HCl Extended-Release Tablets drug product be required to submit to FDA a new ANDA citing another company’s approved Venlafaxine HCl Extended-Release Tablets drug product as the appropriate RLD, and that FDA require any such ANDA applicant to conduct new bioequivalence studies comparing its proposed drug product to a different approved drug product.  FDA granted the petition.  In explaining the statutory prohibition on amending a pending ANDA to change RLD (FDC Act § 505(j)(2)(D)(i)), FDA also explained the Agency’s interpretation of the parallel provision applicable to 505(b)(2) applications (FDC Act § 505(b)(4)(A)):

We note that our interpretation of § 505(b)(4)(A) of the Act, also added by the MMA, for 505(b)(2) applications is influenced by and intended to be consistent with section 505(j)(2)(D)(i) regarding ANDAs.  Accordingly, a 505(b)(2) applicant may not amend or supplement a 505(b)(2) application to seek approval of a drug that relies on the Agency’s finding of safety and/or effectiveness for a drug that is different from the drug identified in a previous submission of the application.

FDA’s November 2008 citizen petition decision was the first time the Agency publicly explained FDC Act § 505(b)(4)(A).  But we wondered . . . had FDA already been faced with a scenario in which a 505(b)(2) applicant sought to amend a pending 505(b)(2) application?  And if so, how did FDA handle that case?  Well, it turns out that FDA did have a case.

Back in June 2006, Cipher Pharmaceuticals (“Cipher”) submitted a 505(b)(2) NDA for Tramadol HCl Extended-release Capsules, 100 mg, 200 mg, and 300 mg (referred to as “Cip-Tramadol ER” in various FDA documents) for the management of moderate to moderately severe chronic pain in adults, and that cited ULTRAM (tramadol HCl) Tablets (NDA No. 020281) as the listed drug relied on for approval.  FDA completed its review of the NDA but did not approve the application; rather, FDA issued an “approvable” decision.  FDA explained in a May 2, 2007 letter that, among other things, “[i]t will be necessary for the sponsor to perform at least one additional adequate and well-controlled clinical trial that clearly demonstrates efficacy for their drug product.” 

After a post-action meeting in May 2007, Cipher filed for formal dispute resolution.  In January 2008, FDA denied Cipher’s formal dispute resolution request and reiterated the need for additional clinical trial data.  But FDA provided Cipher a way out of conducting a new study – the company could cite NDA No. 021692 for ULTRAM ER (tramadol HCl) Extended-release Tablets as an additional listed drug and bridge its proposed product to ULTRAM ER. 

Cipher took FDA up on its offer, but there were a couple of catches.  Because FDC Act § 505(b)(4)(A) precludes a 505(b)(2) applicant from amending its pending application to change listed drug, FDA required the company to submit a new NDA – NDA No. 022370 – containing appropriate patent certifications to any patents listed in the Orange Book as covering the approved listed drugs cited in Cipher’s new NDA.  FDA’s decision and the consequences of a new NDA submission are documented in a memorandum (included in FDA’s Summary Basis of Approval for NDA No. 022370) that states, in part:

We interpret section 505(b)(4)(A) of the Food, Drug, & Cosmetic Act (FD&C Act), added by the Medicare Modernization Act, in a manner consistent with its counterpart provision at section 505(j)(2)(D)(i), such that an applicant may not amend a 505(b)(2) application to seek approval of a drug that relies on the Agency's finding of safety and/or effectiveness for a drug that is different from the drug identified in a previous submission of the application.  This interpretation also is informed by amendments to section 505(c)(3) of the FD&C Act which limit the availability of a 30-month stay of approval in certain circumstances involving amendments and supplements.  Accordingly, the identification of Ultram ER as an additional listed drug relied upon is not the type of change that may be made in an amendment to a 505(b)(2) application such as a response to an approvable letter.

You may elect to withdraw and resubmit your 505(b)(2) application to identify Ultram ER as an additional listed drug relied upon.  Under these circumstances, a resubmission of your application that identifies an additional listed drug relied upon and otherwise complies with section 736(a)(1)(C) of the FD&C Act would not be subject to new user fees.  The Division intends to review a resubmission of this type using the same review timeframe goal that would have applied to a complete response to the approvable letter.  We note that the regulatory requirements for a 505(b)(2) application (including, but not limited to, an appropriate patent certification or statement) apply to each listed drug upon which a sponsor relies.  Therefore, we cannot consider this complete response to our action letter.  The review clock will not start until we receive a complete response or a new NDA submission.  If you decide to resubmit your application as a new NDA, the review clock would be the equivalent of a Class 2 resubmission and would have a six-month review clock.

Cipher submitted NDA No. 022370 to FDA on April 14, 2008.  At that time, there were two patents listed in the Orange Book for the listed drugs relied on by Cipher: (1) U.S. Patent No. 6,339,105 (“the ‘105 patent”), a method-of-use patent listed for ULTRAM, the pediatric exlusivity for which expires on April 12, 2020; and (2) U.S. Patent No. 6,254,887 (“the ‘887 patent”), a drug substance patent listed for ULTRAM ER that expires on May 10, 2014.  Cipher submitted the 505(b)(2) equivalent of a “section viii” statement to the ‘105 patent carving out of its proposed labeling the protected use.  Instead of challenging the ‘887 patent in a Paragraph IV certification, however, Cipher submitted a Paragraph III certification, seeking approval of NDA No. 022370 on May 10, 2014.

Perhaps as a result of the Paragraph III certification to the ‘887 patent, FDA assigned a standard 10-month review of NDA No. 022370 instead of the 6-month review identified in the above-quoted FDA memorandum.  At the end of the review period, in February 2009, FDA tentatively approved NDA No. 022370. 

Cipher ultimately changed its mind and decided to challenge the ‘887 patent in a Paragraph IV certification submitted as an amendment to its NDA on or about September 15, 2009.  Cipher was timely sued for patent infringement in the U.S. District Court for the Eastern District of Virginia (Case No. 2:09-cv-00544-RBS-JEB).  The lawsuit triggered a 30-month litigation stay on the approval of NDA No. 022370.  But the parties were able reach an agreement and the court entered a consent judgment in late December 2009 in favor of Cipher and dismissing the patent infringement lawsuit (see here).  That decision terminated the 30-month litigation stay and cleared the path for Cipher to request final NDA approval, which FDA granted on May 7, 2010.

Although the approval of NDA No. 022370 took several twists and turns, it is instructive as to how FDA would likely handle future cases in which FDC Act § 505(b)(4)(A) is implicated.  Clearly, FDA recognizes the potentially draconian effects of the statutory provision and wants to dull them to the extent possible.