By Kurt R. Karst –
It was just a couple of weeks ago that we published a post titled “Abuse-Deterrence and 3-Year Exclusivity: FDA Decisions Further Elucidate Scope and a ‘Route of Abuse’ Approach to Exclusivity.” Among other things, we discussed Egalet US, Inc.’s ARYMO ER (morphine sulfate) Extended-release Tablets, which FDA approved on January 9, 2017 under NDA 208603, and FDA’s statement accompanying the ARYMO ER NDA approval, titled “Impact of Exclusivity on Approval of Arymo ER.” In that statement, FDA briefly explains that although intranasal route of abuse clinical studies were conducted with ARYMO ER (as well as intranasal route of abuse clinical studies), 3-year exclusivity FDA granted in connection with the approval of Inspirion Delivery Technologies, LLC’s MORPHABOND (morphine sulfate) Extended-release Tablets (NDA 206544) – identified in the Orange Book with a M-189 exclusivity code (i.e., “LABELING DESCRIBING THE EXPECTED REDUCTION OF ABUSE OF SINGLE-ENTITY EXTENDED-RELEASE MORPHINE BY THE INTRANASAL ROUTE OF ADMINISTRATION DUE TO PHYSICOCHEMICAL PROPERTIES”) – prevented the Agency from approving ARYMO ER with labeling describing abuse-deterrence via the intranasal route of abuse. To make that determination, however, FDA must have previously determined the metes and bounds of 3-year exclusivity for MORPHABOND. To that end, we stated in our February 9th post: “We’re pretty certain that FDA (and the CDER Exclusivity Board) put together a Letter Decision on the ARYMO ER-MORPHABOND exclusivity issue, but we’re still waiting to get a copy of that determination. We’ll post it once we get it.” Well, that time is now . . . . And the memorandum prepared by the CDER Exclusivity Board is probably the most interesting read yet on 3-year exclusivity and abuse deterrence.
Titled “Scope of 3-Year Exclusivity for MorphaBond (NDA 206544),” the November 16, 2016 CDER Exclusivity Board Memorandum delves into not only FDA’s views on the scope of 3-year exclusivity granted in connection with the approval of NDA 206544, but also details FDA’s decision-making process on how to handle abuse-deterrence exclusivity more generally. As to the former issue, FDA concludes (on page 12 of the memorandum) that “the scope of Morphabond’s exclusivity is limited to the condition of approval supported by Study M-ARER-002: labeling describing the expected reduction of abuse of a single-entity ER morphine by the intranasal route of administration due to physicochemical properties.” But it’s the discussion that follows after the next sentence – i.e., “We describe below the reasons for adopting this approach” – that’s the most important part of the memorandum. There, FDA describes how the Agency came to adopt a so-called “route of abuse” approach to 3-year exclusivity after wrestling with other possible approaches.
Below are the relevant paragraphs from the CDER Exclusivity Board Memorandum that sum up the Agency’s thinking on the matter. We’ve omitted the footnotes, but we’ll return to one of them in a moment.
Although neither the regulation, nor the preambles to the 1989 [Hatch-Waxman] Proposed Rule or the final rule governing exclusivity63 expressly contemplated how exclusivity would be determined for AD opioids, the preamble to the 1989 Proposed Rule states that, “[i]f the innovation is a new use, then exclusivity protects only that labeling claim and not the active ingredients, dosage form, or route of administration.” The Board believes that the circumstances of the MorphaBond approval, while not the same, may be analogized to the approval of a “new use” where the Agency represents in approved labeling its finding that a drug product, for example, is safe and effective to treat a new indication. Similarly, in this instance, approved labeling for MorphaBond represents the Agency’s finding that MorphaBond is expected to reduce abuse of single-entity ER morphine by the intranasal route of administration due to physicochemical properties. Accordingly, the Board believes that the exclusivity for MorphaBond should protect labeling describing this claim.
This scope of exclusivity is defined by two primary characteristics: (1) the abuse route (intranasal); and (2) the type of abuse deterrence employed (physicochemical properties). The Board notes that these characteristics are consistent with concepts discussed in the AD Opioids Guidance, which describes the categories of AD products (e.g., physical/chemical barriers, antagonist) and types of abuse routes (e.g., intranasal, intravenous, oral). The Board believes that this scope of exclusivity is also consistent with the applicable statutory and regulatory provisions, and it balances the goals of the Hatch-Waxman Amendments’ 3-year exclusivity provisions.
We note that the statute does not expressly describe the scope of exclusivity for 3-year exclusivity, providing FDA discretion to make exclusivity determinations in a manner consistent with the statutory language and intent of Congress. In making its determination that the scope of exclusivity in this instance should be defined as described above, the Board nonetheless considered but declined to adopt both broader and narrower potential approaches to the scope of exclusivity.
A broader scope of exclusivity (for example, one covering abuse deterrence generally) would be inconsistent with the scope of Study M-ARER-002, which was intended only to measure the ability to deter abuse of single-entity ER morphine via the intranasal route due to the drug’s physicochemical properties. Likewise, this broader approach to exclusivity would be inconsistent with the MorphaBond labeling, which (consistent with the AD Opioids Guidance) describes the specific AD properties and the specific routes of abuse that the product has been demonstrated to deter.
A narrower approach to the scope of exclusivity – for example, exclusivity limited to the specific formulation in MorphaBond, or the specific technology MorphaBond uses to deter intranasal abuse – would be inappropriate in this circumstance. As noted above, this approach to exclusivity is not compelled by the statute: FDA generally has taken the position that exclusivityprotected “conditions of approval” may nevertheless overlap between drugs despite certain differences in formulation or other aspects. Thus, FDA has recognized that the scope of exclusivity for the innovation(s) represented by the approval and supported by clinical studies may reach beyond the specific formulation of the drug product approved in an application or supplement.
Importantly, the Board believes that a specific-formulation or specific-technology scope of exclusivity would be inconsistent with the scope of Study M-ARER-002. In this case, Study MARER-002 supported approval of MorphaBond as the first single-entity ER morphine product with labeling describing intranasal AD properties. Thus, the labeling describing the expected reduction of abuse of single-entity ER morphine by the intranasal route of administration due to physicochemical properties is the “innovation” represented by the approval of MorphaBond and supported by a new clinical investigation (Study M-ARER-002, the only clinical investigation (that is not a bioavailability study) submitted to MorphaBond’s NDA). In addition, a narrow specific-formulation or specific-technology scope of exclusivity potentially would have a very limited effect on subsequent 505(b)(2) applications and ANDAs (which might propose different formulations and excipients than MorphaBond), potentially undermining the purpose of 3-year exclusivity.
Footnote 69 in the Memorandum is inserted as part of FDA’s discussion of why a narrower and formulation-specific approach to the scope of 3 year exclusivity is inappropriate (at least in the context of MORPHABOND). That footnote states:
The Board previously considered the scope of exclusivity recognized for NDA 022272/S-14 requesting approval of labeling describing AD properties of reformulated OxyContin. Although the Board drafted a memorandum and recommendation for the scope of exclusivity of OxyContin, no ANDA or 505(b)(2) application potentially affected by this exclusivity was ready for final approval during the exclusivity period. Further, the Board’s thinking on the issues related to 3-year exclusivity for AD opioids has evolved as reflected in this memorandum.
We suspect that FDA drafted a memo detailing why a formulation-specific approach to abuse-deterrence exclusivity might be appropriate. (At least that’s how we interpret FDA’s reference to evolved thinking.) And we further suspect that such memorandum was prepared in the context of FDA’s consideration of the approval of Collegium Pharmaceuticals, Inc.’s NDA 208090 for XTAMPZA ER (oxycodone) Extended-release Capsules. But because of another block on the approval of NDA 208090 (i.e., a 30-month litigation stay), and perhaps some foot-dragging along the way, FDA ultimately did not have to deal with the potential effect of a period of 3-year exclusivity applicable to OXYCONTIN on the approvability of XTAMPZA ER. That M-153 exclusivity applicable to OXYCONTIN expired on April 16, 2016, shortly before FDA approved NDA 208090 for XTAMPZA ER on April 26, 2016.
Although FDA ultimately adopted a “route of abuse” approach to 3-year exclusivity over a more narrow formulation-specific approach, there’s some history to support a more narrow approach. Consider, for example, DIPRIVAN (propofol injectable emulsion), 1% (10 mg/mL). On January 4, 1999, FDA approved ANDA 075102 for Propofol Injectable Emulsion, 1% (10 mg/mL), notwithstanding a period of 3-year exclusivity applicable to DIPRIVAN that was scheduled to expire on June 11, 1999. The period of 3-year exclusivity applicable to DIPRIVAN was based on FDA’s approval of a supplemental NDA for a version of the drug product formulated with EDTA as a preservative. FDA determined that the ANDA sponsor, whose drug product was formulated with sodium metabisulfite as the preservative in place of EDTA, was not subject to the exclusivity applicable to the EDTA-formulated version of DIPRIVAN because the scope of 3-year exclusivity was limited to the drug product formulation.
FDA’s decision was unsuccessfully challenged in court. In upholding FDA’s grant of 3-year exclusivity as relating only to the clinical investigations for EDTA, and not to preservatives in general, the court ruled that the 3-year exclusivity FDA granted:
extends only to the change approved in the supplement. Zeneca’s NDA supplement sought authority to add EDTA to Diprivan. The clinical investigations it submitted to the FDA with that supplement were necessitated by specific concerns related to EDTA, not to preservatives in general. Thus, the exclusivity applies to propofol products including EDTA, not to propofol products with other preservatives.
Zeneca Inc. v. Shalala, No. 99-307, 1999 WL 728104, at *13 (D. Md. Aug. 11, 1999), aff’d, 213 F.3d 161 (4th Cir. 2000) (internal quotes omitted).
More recently, FDA approved multiple 505(b)(2) NDAs for pharmaceutically equivalent testosterone gel drug products containing different penetration enhancers, and granted each sponsor a period of 3-year exclusivity. FDA’s decision that the first 505(b)(2) application approved with a period of 3-year exclusivity – i.e., NDA 202763, approved on February 14, 2012 with a period of “new product” exclusivity that expired on February 14, 2015 – did not block the approval of a subsequent 505(b)(2) application – i.e., NDA 203098, approved on January 31, 2013 with a period of “new product” exclusivity that expired on January 31, 2016 – appears to be due to the Agency’s determination that the scope of each applicant’s 3-year exclusivity was limited to the clinical trial data supporting approval of the particular penetration enhancer formulation tested.
Absent a successful challenge to FDA’s rejection of a formulation-specific approach to 3-year exclusivity in favor of a “route of abuse” approach to 3-year exclusivity, this all now seems to be water under the bridge. Nevertheless, it would be enlightening to see how FDA (perhaps in a memorandum not yet made public) squares these examples with the Agency’s current position. But like trying to find out how many licks it takes to get to the center of a Tootsie Pop, the world may never know.