In a Veloxis-Like Analysis, FDA Rules That EMBEDA 3-Year Exclusivity Does Not Block MORPHABOND 505(b)(2) Approval

By Kurt R. Karst –  

There are few things this blogger likes more (workwise at least) than having a hot cup of joe in the morning while reading through an FDA exclusivity decision. (Reading through the latest edition or supplement to the Orange Book while enjoying some coffee is also right up there on the top of the list.)  This blogger recently had one of those enjoyable  experiences after coming across a “new” – that is, “new” insofar as the decision was just publicly released – exclusivity decision buried in an FDA Approval Package (Summary Basis of Approval) for Inspirion Delivery Technologies, LLC’s (“Inspirion’s”) MORPHABOND (morphine sulfate) Extended-release Tablets, 15 mg, 30 mg, 60 mg, and 100 mg. FDA approved MORPHABOND under a 505(b)(2) NDA (NDA 206544) on October 2, 2015 for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

In an October 1, 2015 Exclusivity Letter Decision, the CDER Exclusivity Board examines whether or not a period of 3-year exclusivity the Agency apparently granted after approving  a Supplemental NDA (S-016) for AlPharma Pharmaceuticals, LLC’s (“AlPharma’s”) EMBEDA (morphine sulfate and naltrexone HCl) Extended-release Capsules (NDA 022321) should block the approval of MORPHABOND. We say “apparently” because the Orange Book does not show any unexpired period of 3-year exclusivity for EMBEDA in connection with the October 17, 2014 approval of S-016. That supplement revised the EMBEDA labeling to describe the results of data from in vitro and in vivo abuse potential studies. In any case, the 3-year exclusivity applicable to EMBEDA, which is approved for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate, expires on October 17, 2017. 

The 505(b)(2) NDA for MORPHABOND was submitted to FDA in September 2014 and relies on FDA’s safety and effectiveness findings for MS CONTIN (morphine sulfate) Extended-Release Tablets (NDA 019516; approved on May 29, 1987), for which the Orange Book does not identify any unexpired period of patent or non-patent exclusivity. So, if the listed drug cited in the MORPHABOND 505(b)(2) NDA is not EMBEDA, then why are we even talking about a potential block on the approval of MORPHABOND?  Because, FDA interprets the FDC Act’s 3-year exclusivity provisions to apply regardless of a reliance tether.  This interpretation became clear within the past two years in the context of FDA’s consideration – and later court challenge – concerning Veloxis Pharmaceuticals, Inc.’s  (“Veloxis’”) 505(b)(2) application (NDA 206406) for ENVARSUS XR (tacrolimus) Extended-release Tablets.  In that case, FDA’s  determination, which was upheld in court, was that a period of 3-year exclusivity FDA granted in relation to an original NDA for a single-entity drug product for certain conditions of use blocked the approval of NDA 206406 for the protected conditions of use.  You can read up on that FDA decision and district court case here and here.

The EMBEDA-MORPHABOND exclusivity analysis differs from the Veloxis case analysis in two important respects. First, unlike EMBEDA, which contains two active ingredients, MORPHABOND contains only a single active ingredient.  Second, the period of 3-year exclusivity applicable to EMBEDA was granted in the context of a Supplemental NDA instead of an Original NDA.  Also, we should note that for those folks hoping that FDA might opine of the scope of EMBEDA’s 3-year exclusivity as it relates to abuse-deterrent formulations, you’re out of luck.  FDA states pretty early in the Agency’s 18-page Letter Decision that “[t]his memorandum only discusses whether the 3-year exclusivity for Embeda should block the approval of the MorphaBond NDA, and does not address the scope of Embeda’s exclusivity nor whether MorphaBond is eligible for its own period of exclusivity or the scope of any such exclusivity.” Oh well . . . another day perhaps.  But we have more on that below. 

For Supplemental NDAs, FDC Act § 505(c)(3)(E)(iv) provides the following with respect to 3-year exclusivity:

If a supplement to an application approved under subsection (b) [of this section] is approved after [September 24, 1984,] and the supplement contains reports of new clinical investigations (other than bioavailabilty [sic] studies) essential to the approval of the supplement and conducted or sponsored by the person submitting the supplement, the Secretary may not make the approval of an application submitted under subsection (b) [of this section] for a change approved in the supplement effective before the expiration of three years from the date of the approval of the supplement under subsection (b) [of this section] . . . .

Although FDC Act § 505(c)(3)(E)(iv) differs somewhat from FDC Act § 505(c)(3)(E)(iii) concerning Original NDAs, FDA says that the Agency “has taken a consistent approach to both types of applications in determining eligibility for 3-year exclusivity and scope.” From there, FDA lays out the two-step inquiry to determine the blocking effect of another sponsor’s period of 3-year exclusivity, both generally, and in the context of a combination drug product:

[I]n order to determine that a 505(b)(2) NDA is blocked because it seeks approval for a “change approved in a supplement” during another applicant’s 3-year exclusivity period, the 505(b)(2) NDA must be for a drug with the same active moiety as the drug with exclusivity. . . . If the 505(b)(2) application for a single-entity drug seeks approval for the same drug (active moiety) to which exclusivity has attached, then the second aspect of the scope inquiry applies.  To determine whether the 505(b)(2) NDA is barred, FDA must also determine what exclusivity-protected change was approved in the supplement.  To do so, FDA examines the conditions of approval supported by the new clinical investigations (other than bioavailability studies) that were essential to approval of the supplement.  If the 505(b)(2) NDA for a single-entity drug is for the same drug for the same exclusivity-protected change approved in the supplement, it will be blocked. . . .

[I]n determining whether a 505(b)(2) NDA is seeking approval for a “change approved in a supplement” to a fixed-combination and is therefore blocked by 3-year exclusivity for the supplement, FDA similarly limits its inquiry to applications that contain the same combination of active moieties as in the fixed-combination and examines the scope of the new clinical investigations essential to the approval and that were conducted or sponsored by the applicant. If the 505(b)(2) NDA is not seeking approval for a fixed-combination with the same combination of active moieties as the combination with exclusivity, it is not seeking approval for a change approved in the supplement and therefore cannot be blocked.

Based on that last paragraph in particular, you know the outcome of FDA’s EMBEDA-MORPHABOND exclusivity analysis. But here it is in FDA’s own words:

The change approved in the supplement (S-016) for Embeda is the change in conditions of approval for the drug containing the combination of active moieties approved in the Embeda NDA. Thus, the change approved in the supplement only bars approval of other 505(b)(2) NDAs for drugs containing the combination of active moieties approved in Embeda and that otherwise seek approval for the same exclusivity-protected conditions of approval as Embeda.  Because MorphaBond does not contain the combination of active moieties approved in Embeda, any approval of MorphaBond is not an approval for the “change approved in the supplement” (i.e., S-016) for which Embeda currently has exclusivity and no additional inquiry is required.  Therefore, we recommend that the exclusivity awarded to Embeda for S-016 should not block approval of MorphaBond.

Harkening back to an earlier note in the Letter Decision concerning the scope of EMBEDA’s exclusivity (quoted above), FDA states that “[i]f both Embeda and MorphaBond contained the same combination of the two active moieties morphine and naltrexone, we would need to evaluate the nature of the change approved in the NDA supplement and would need to determine which new clinical investigations were essential to approval of S-016.” But FDA did not have to go there. “We need not reach this aspect of the scope of inquiry here, however,” says FDA, “because Embeda and MorphaBond do not contain the same combination of active moieties.”

In addition to FDA’s statutory analysis and conclusion, the Agency discusses several other reasons supporting its determination. With respect to abuse-deterrence, FDA notes that the Agency’s “recommendation in this case is also consistent with the Agency’s efforts to foster the development of AD opioid products more generally. Because the science of abuse deterrence is still evolving and the Agency does not yet know which AD technologies will ultimately prove most effective in deterring opioid abuse, the Agency believes that, when the statute and regulations permit it, it is in the interest of public health to encourage development of multiple AD alternatives.”

Is FDA signaling with this comment how the Agency might determine, and what factors might affect, the scope of 3-year exclusivity for an abuse-deterrent drug product supported by clinical studies? Maybe. . . maybe not.  We hesitate to read too much into this FDA comment.  The fact is that FDA will only make an evaluation and determination when the Agency is faced with a hard set of facts.