Abuse-Deterrence and 3-Year Exclusivity: FDA Decisions Further Elucidate Scope and a “Route of Abuse” Approach to Exclusivity

Questions about the scope of 3-year exclusivity granted by FDA for an abuse-deterrent opioid have been on the rise over the past few years. Initially, FDA was able to punt on some decisions, either because companies exchanged waivers of 3-year exclusivity (e.g., single-entity, extended-release hydrocodone drug products – see here), or because another obstacle, such as a 30-month litigation stay, provided FDA with an excuse for having to address exclusivity.  (Here, we would have included a link to the tentative approval letter for NDA 208090 for XTAMPZA ER (oxycodone) Extended-release Capsules, where FDA states in a footnote that the Agency doesn’t need to address the scope of another sponsor’s 3-year exclusivity because of a 30-month litigation stay; however, as we recently reported, some drug approval information is disappearing from FDA’s website.)  But with the passage of time (and NDA approvals), FDA is being forced to address 3-year exclusivity issues head-on.  And with those decisions, we are learning more about FDA’s interpretation of the scope of 3-year exclusivity in the context of abuse-deterrent opioid drug products, and the development of what we’ll call a “route of abuse exclusivity approach.”

First, there was a March 3, 2015 Memorandum from the CDER Exclusivity Board explaining FDA’s decision to grant a period of 3-year exclusivity with respect to the April 16, 2013 approval of NDA 022272/S014 for OXYCONTIN (oxycodone HCl) Controlled-release Tablets (see our previous post here).  That exclusivity was coded in the Orange Book as “M-153,” which is defined as: “ADDITION OF INFORMATION REGARDING THE INTRANASAL ABUSE POTENTIAL OF OXYCONTIN.”  With the assignment of this exclusivity code, the CDER Exclusivity Board noted that “the scope of 3-year exclusivity in this instance is limited to the addition of information to the [OXYCONTIN] labeling regarding the reduction of abuse via the intranasal route.”

Then there was an October 1, 2015 Exclusivity Letter Decision from the CDER Exclusivity Board examining whether or not a period of 3-year exclusivity the Agency granted after approving a Supplemental NDA (S-016) for AlPharma Pharmaceuticals, LLC’s EMBEDA (morphine sulfate and naltrexone HCl) Extended-release Capsules (NDA 022321) should block the approval of Inspirion Delivery Technologies, LLC’s MORPHABOND (morphine sulfate) Extended-release Tablets (NDA 206544) (see our previous post here).  FDA explained that “the change approved in the [EMBEDA] 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,” and that “[b]ecause 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.”  As such, the CDER Exclusivity Board recommended “that the exclusivity awarded to Embeda for S-016 should not block approval of MorphaBond.”  (Curiously, FDA still has not updated the Orange Book to show a period of 3-year exclusivity granted in connection with the October 17, 2014 approval of S-016 for EMBEDA.)

After approving NDA 206544 for MORPHABOND, FDA updated (eventually) the Orange Book to reflect the grant of a period of 3-year exclusivity expiring on October 2, 2018 and coded as “M-189.” That M-189 code is defined in an Orange Bood addendum as: “LABELING DESCRIBING THE EXPECTED REDUCTION OF ABUSE OF SINGLE-ENTITY EXTENDED-RELEASE MORPHINE BY THE INTRANASAL ROUTE OF ADMINISTRATION DUE TO PHYSICOCHEMICAL PROPERTIES.”  We’ll return to this shortly . . . .

The next exclusivity challenge FDA (i.e., the CDER Exclusivity Board) faced was whether a period of 3-year exclusivity coded in the Orange Book as “NC” (New Combination) for TARGINIQ (oxycodone HCl and naloxone HCl) Extended-release Tablets (NDA  205777) blocked the approval of the 505(b)(2) NDA for TROXYCA (oxycodouc HCl and naltrexone HCl) Extended-release Capsules (NDA 207621).  In an August 19, 2016 Memorandum, the CDER Exclusivity Board concluded as one might expect: “Targiniq’s 3-year exclusivity for the conditions of approval of NDA 205777 is ticd to its specific combination of active moieties, oxycodone and naloxone.  The Board thus recommends that any 3-year exclusivity for Targiniq should not block the approval of Troxyca because Troxyca has a different combination of active moieties, oxycodone and naltrexone.”  Thus, FDA approved NDA 207621 for TROXYCA and granted the sponsor, Pfizer Inc., its own period of 3-year exclusivity (also coded in the Orange Book as “NC”).

As an interesting side note, during FDA’s review of the TROXYCA NDA, several Citizen Petitions were submitted to to the Agency concerning either the approval of TROXYCA (specifically, 505(b)(2) NDA “listed drug” issues) – see Docket No. FDA-2015-P-5108 – or FDA’s approval of abuse-deterrent drug products – see Docket No. FDA-2016-P-1946.  FDA denied both Citizen Petitions – one without comment (here), and another because of the Agency’s inability to resolve “complex scientific issues” (here) – in Letter Decisions included in the relevant petition dockets.  But those denials aren’t the last words from FDA on each petition.  In other memoranda FDA prepared in connection with the approval of TROXYCA, the Agency provides a more fulsome response to the two Citizen Petitions.  Copies of those memos are available here and here.  FDA’s memo concerning Docket No. FDA-2015-P-5108 in particular is worth a read.  There, FDA expands on and clarifies previous Agency statements and decisions concerning a 505(b)(2) applicant’s choice of listed drug.  We’ve discussed some of those previous decisions in posts here and here.

Moving on (and with reference back to our placeholder comment on the exclusivity FDA granted for MORPHABOND), FDA provided further clarification and insight into the Agency’s view of the scope of 3-year exclusivity granted in the context of abuse-deterrent drug products when the Agency approved NDA 208603 on January 9, 2017 for Egalet US, Inc.’s ARYMO ER (morphine sulfate) Extended-release Tablets 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.

With that ARYMO ER NDA approval, FDA issued a statement, titled “Impact of Exclusivity on Approval of Arymo ER.” For the sake of posterity (and because we don’t know what information will eventually be scrubbed from FDA’s website), we provide below the text of that FDA statement:

Today, the FDA approved Arymo ER (morphine sulfate extended-release tablets), a new extended-release opioid with abuse-deterrent properties. Arymo ER is approved to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.  Arymo ER is formulated to give it physicochemical properties expected to make abuse by injection difficult. However, abuse by the intravenous, intranasal, and oral routes is still possible.

Expanding access to abuse-deterrent opioids to discourage misuse and abuse is part of the FDA’s Opioid Action Plan, and the pharmaceutical industry has shown significant interest in the development of abuse-deterrent products. Technology is progressing rapidly, and these medications hold promise as their abuse-deterrent qualities continue to improve and as they become more widely available.

As the FDA reviews new drug applications, the agency works through various issues that may arise, including exclusivity. Another product, MorphaBond (morphine sulfate extended-release tablets), has marketing exclusivity for labeling describing the expected reduction of abuse of single-entity extended-release morphine by the intranasal route due to physicochemical properties.  Due to MorphaBond’s marketing exclusivity, no other single-entity extended-release morphine product submitted in an abbreviated new drug application or 505(b)(2) application can be approved for that use at this time.

Because the science of abuse deterrence is still evolving and the agency does not yet know which technologies will ultimately prove most effective in deterring opioid abuse, the agency believes that it is in the interest of public health to encourage development of multiple abuse-deterrent alternatives while continuing to promote and protect innovation.

The details of the FDA’s scientific review of the clinical evidence that supported the approval of Arymo ER are available in the FDA Review Summary, which will be posted to Drugs@FDA following approval. Additional information about Arymo ER is available in the briefing materials from the August 4, 2016, joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee.

What FDA explains above is the Agency’s “route of abuse exclusivity approach.” Although intranasal route of abuse clinical studies were conducted with ARYMO ER (as well as intranasal route of abuse clinical studies), FDA determined that MORPHABOND’s 3-year exclusivity – applicable to “LABELING DESCRIBING THE EXPECTED REDUCTION OF ABUSE OF SINGLE-ENTITY EXTENDED-RELEASE MORPHINE BY THE INTRANASAL ROUTE OF ADMINISTRATION DUE TO PHYSICOCHEMICAL PROPERTIES” (M-189) – prevented the Agency from approving ARYMO ER with labeling describing abuse-deterrence via the intranasal route of abuse.  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.

Finally, we note FDA’s January 17, 2017 approval of Teva Branded Pharmaceutical Products R & D, Inc.’s NDA 207975 for VANTRELA ER (hydrocodone bitartrate) Extended-release Tablets. FDA approved VANTRELA ER 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.  That’s the same indication for which other single-entity hydrocodone bitartrate drug products are approved, and, in particular, HYSINGLA ER (hydrocodone bitartrate) Extended-release Tablets (NDA 206627) and ZOHYDRO ER (hydrocodone bitartrate) Extended-release Capsules (NDA 202880).  FDA granted a period of 3-year exclusivity – coded as “NP” (New Product) – with the October 25, 2013 approval of ZOHYDRO ER.  FDA approved HYSINGLA ER on November 20, 2014, prior to the expiration of exclusivity for ZOHYDRO on October 25, 2016, by virture of a waiver of exclusivity agreed to by the two NDA sponsors (see here).

But what about 3-year exclusivity for HYSINGLA ER? And wouldn’t such exclusivity serve to block the approval of NDA 207975 for VANTRELA ER? After all, FDA’s Exclusivity Summary for NDA 206627 indicates that the Agency should grant a period of 3-year exclusivity based on three clinical studies, including two abuse potential studies (HYD1013 and HYD1014), Purdue conducted to obtain approval of HYSINGLA ER.

Well, FDA has not yet updated the Orange Book to reflect any award of 3-year exclusivity for HYSINGLA ER. The issue is probably still under review at the Agency.  And it could  remain under review until (or if) another single-entity hydrocodone bitartrate drug product comes up for an FDA approval decision.  You see, FDA did not have to make an exclusivity decision when approving  VANTRELA ER because the approval of NDA 207975 was not affected by any exclusivity applicable to HYSINGLA ER.  VANTRELA ER is a 505(b)(1) NDA by virture of a right of reference obtained to certain carcinogenicity data generated for the approval of ZOHYDRO ER.  Because 3-year exclusivity applies with respect to second-in-time 505(b)(2) NDAs (as well as ANDAs), but not 505(b)(1) NDAs, any 3-year exclusivity applicable to HYSINGLA ER could not serve as an obstacle to the approval of NDA 207975 for VANTRELA ER.