The COMBAT Act Would Add New Brand and Generic Exclusivity-Stacking Incentives for Abuse-Deterrent Opioid Development

By Kurt R. Karst –      

On April 29, 2016, Represetatives Gerry Connolly (D-VA) and Morgan Griffith (R-VA) announced the introduction of H.R. 5127, the “Curb Opioid Misuse by Advancing Technology (COMBAT) Act.”  The COMBAT Act is the latest effort by Congress to incentivize the development of abuse-deterrent opioids.  The bill also continues a trend of what we’ve termed “exclusivity stacking” that started in 1997 with the creation of 6-month pediatric exclusivity, and which concept has grown in popularity in recent years with the introduction of numerous legislative proposals (see our previous posts here and here).

The COMBAT Act would amend FDC Act §§ 505(c)(3)(E) (applicable to 505(b)(2) NDAs) and 505(j)(5)(F) (applicable to ANDAs) to add a new subsection (vi) to each provision that would extend by 12 months a period of 3-year new clinical investigation exclusivity granted by FDA as a result of the approval of an applicant’s original NDA (either a “full” 505(b)(1) NDA or a 505(b)(2) NDA), or a supplement to an approved NDA, thus delaying approval of a second-in-time 505(b)(2) NDA or an ANDA.  The 12-extension would be awarded if the NDA sponsor “provides documentation to [FDA] demonstrating that the drug that is the subject of the application or supplement— (I) is approved, in whole or in part, on the basis of one or more new clinical abuse potential studies; and (II) is approved with labeling that characterizes the abuse-deterrent properties of the drug product.”

FDC Act §§ 505(c)(3)(E) and 505(j)(5)(F) currently provide that 3-year exclusivity is awarded if an NDA applicant conducts “new clinical investigations” that FDA determines are “essential to the approval” of a marketing application. The statute also defines in general terms the scope of 3-year exclusivity, stating with respect to an original NDA that the exclusivity applies to the “conditions of approval,” and with respect to “a change approved” in the case of an NDA supplement. 

The scope of 3-year exclusivity has been a hot topic in recent years. In June 2015, the U.S. District Court for the District of Columbia ruled in Veloxis Pharmaceuticals, Inc. v. FDA, ___ F.Supp.3d ___, 2015 WL 3750672 (June 12, 2015), that 3-year exclusivity is triggered if there is “an overlap in the conditions of approval between the first-in-time 505(b) drug and the second-in-time 505(b)(2) NDA.” Id. *18 (emphasis in original).  The court also noted that “[t]he effect of [3-year] exclusivity . . . . turns on whether a second-in-time 505(b)(2) NDA shares any conditions of approval with the first-in-time 505(b) drug granted exclusivity.” Id. *25 (see our previous post here).  In other words, a second-in-time 505(b)(2) NDA can be blocked from obtaining approval because of a period of 3-year exclusvity applicable to a first-in-time 505(b) NDA regardless of whether or not the second-in-time 505(b)(2) NDA relies on FDA’s findings of safety or effectiveness for the first-in-time 505(b) NDA.

The COMBAT Act would clarify that the term “new clinical investigations” includes “new clinical abuse potential studies intended to assess the impact of potentially abuse-deterrent properties of drug products in human subjects.” The bill would also direct how FDA must define – in regulations that would need to be promulgated by the Agency – the terms “conditions of approval” and “change approved in the supplement” for purposes of 4-year exclusivity.  Specifically, the bill states that both terms must include, for purposes of a subsequent 505(b)(2) NDA:

any abuse-deterrent properties of a drug product subject to the extension provided by subsection (c)(3)(E)(vi) of such section 505 (as added by subsection (a)), such that [FDA] may not make the approval of an application submitted under subsection (b)(2) of such section 505 effective before the expiration of 4 years from the date of the approval of the application or supplement under subsection (b) of such section 505, including the extension under subsection (c)(3)(E)(vi) of such section 505, unless the application submitted under subsection (b)(2) of such section 505— (A) is approved, in whole or in part, on the basis of one or more new clinical abuse potential studies; and (B) is approved with labeling that characterizes the abuse-deterrent properties of the drug product. [(Emphasis added)]

For purposes of ANDA approval, the bill states that the terms “conditions of approval” and “change approved in the supplement” must include:

any abuse-deterrent properties of a drug product subject to the extension provided by subsection (j)(5)(F)(vi) of such section 505 (as added by subsection (b)), such that [FDA] may not make the approval of an abbreviated application for a drug product submitted under subsection (j) of such section 505 effective before the expiration of 4 years from the date of the approval of the application or supplement under subsection (b) of such section 505, including the extension under subsection (j)(5)(F)(vi) of such section 505.

The COMBAT Act’s scope of exclusivity language applicable to ANDAs is pretty straightforward, but the parallel provision applicable to 505(b)(2) NDAs caught our attention. The text stating “any abuse-deterrent properties of a drug product subject to the extension” appears to reflect the broad scope of 3-year exclusivity recognized by the D.C. District Court in Veloxis, but the “unless” clause appears to narrow the scope of exclusivity, such that a second-in-time 505(b)(2) NDA would not be blocked from obtaining approval because of a period of 3-year exclusivity applicable to a first-in-time 505(b) NDA if the second-in-time 505(b)(2) NDA applicant conducts “new clinical abuse potential studies” leading to abuse-deterrence labeling.  If this interpretation is correct, then the COMBAT Act would effectively create a “carve-out” of the scope of 3-year exclusivity for certain 505(b)(2) NDAs.

So that ANDA applicants are not left in the lurch, the COMBAT Act would also create a 60-day extension to 180-day exclusivity. Specifically, the bill would amend FDC Act § 505(j)(5)(B) to add new subsection (v), which states:

With respect to an [ANDA] described in clause (iv), if such application is approved on or after the date of enactment of the Curb Opioid Misuse By Advancing Technology Act of 2016, the 180-day period specified in such clause shall be extended for an additional period of 60 days if the first applicant submitting the abbreviated application provides documentation to [FDA] demonstrating that the listed drug referred to paragraph (2)(A)(i) and referenced in the abbreviated application— (I) is approved, in whole or in part, on the basis of one or more new clinical abuse potential studies; and (II) is approved with labeling that characterizes the abuse-deterrent properties of the drug product.

Thus, in certain circumstances, 180-day exclusivity would become 240-day exclusivity. In fact, because the Reference Listed Drug (RLD”) cited in an ANDA may not initially be approved with abuse-deterrence labeling, but only after an ANDA is submitted to FDA containing a Paragraph IV certification challenging a patent listed in the Orange Book for the RLD, an ANDA applicant initially anticipating only 180-day exclusivity eligibility may get an unanticipated 60-day windfall (provided such ANDA applicant can demonstrate equivalence under FDA’s tier-based approach – see our previous post here).