Posted: 07 Aug 2015 05:47 AM PDT
By Kurt R. Karst –
There are few things this blogger relishes more in his practice than getting his hands on FDA exclusivity decisions. (It’s like being given and then unwrapping a holiday gift.) We don’t mean the “decisions” that most people see in ANDA approval letters or that are published in the Orange Book. Those “decisions” are interesting, but they aren’t usually terribly helpful because of their opacity. We mean the decisions underlying those “decisions”; the decisions that explain why FDA granted (or denied) exclusivity to an application sponsor. Those decisions aren’t published by FDA. You have to know what you’re looking for, and then ask for them.
We try to publicize FDA exclusivity decisions when we can. After all, those FDA decisons should be freely available and in the public domain so that folks understand FDA’s current thinking. Nobody likes stumbling around in a dark room. The lights need to be turned on – or, at the very least, you need a night light. Sometimes we cannot provide the actual FDA decision, so, when possible, we put up a post explaining what we know, as we did here and here. Sometimes we can provide the actual FDA decisional memorandum. We did that last year when we obtained a copy of FDA’s decision on 180-day exclusivity forfeiture for Risedronate Sodium Tablets (ACTONEL) (see our previous post here). More recently, we publicized FDA’s various decisions on the scope of 3-year new clinical investigation exclusivity made available after the unsealing of litigation documents in a lawsuit involving extended-release Tacrolimus (see our previous post here). In some instances, we’re in the dark as much as everyone else, because FDA has decided not to decide on exclusivity – sometimes for many months (as in the case of AURYXIA (ferric citrate) Tablets approved under NDA 205874), and sometimes for years (as in the case of SURFAXIN (lucinactant) Intratracheal Suspension approved under NDA 021746).
Over the past few weeks we’ve come across three exclusivity decisions: two concerning 180-day exclusivity forfeiture, and another concerning 3-year exclusivity. The two 180-day exclusivity forfeiture decisions are interesting reads, but not overly noteworthy. One FDA Memorandum provides FDA’s rationale for determining that 180-day exclusivity for Linezolid Injection 2 mg/mL (packaged in 600 mg/300 mL single-use flexible plastic containers), a generic version of ZYVOX, was not forfeited because of a change in or review of the requirements that prevented tentative approval within 30 months of ANDA submission (FDC Act § 505(j)(5)(D)(i)(IV)). Another FDA Memorandum goes into the “better late than never” category and explains FDA’s rationale for determining that 180-day exclusivity for Valsartan Tablets, 40 mg, 80 mg, 160 mg, and 320 mg (DIOVAN) was not forfeited under FDC Act § 505(j)(5)(D)(i)(IV). That decision led to litigation that was resolved in late 2012 (see our previous post here).
Our best “find” is 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. That NDA Supplement included a “drug liking” study and proposed the addition of “labeling language describing the results of pre- and post-marketing data from in vitro and in vivo abuse potential studies to the DRUG ABUSE AND DEPENDENDCE section of the Package Insert.” The NDA Supplement approval was the first approval for a drug with abuse-deterrent labeling claims. (Then in draft form – see our previous post here – today final guidance – “Abuse-Deterrent Opioids — Evaluation and Labeling” provides FDA’s current thinking about the studies that should be conducted to demonstrate that a particular drug product formulation has abuse-deterrent properties.)
The approval of NDA 022272/S014 had been on our radar for a while. It was on our list of drug products for which an exclusivity decision was pending (and delayed). We’re not entirely certain why it took FDA so long to make a decision, or what finally prompted the Agency to act, but when we saw the addition of a period of 3-year exclusivity for NDA 022272 in the February 2015 Orange Book Cumulative Supplement (published in mid-March) coded as “M-153” and defined as “ADDITION OF INFORMATION REGARDING THE INTRANASAL ABUSE POTENTIAL OF OXYCONTIN” we were immediately interested to know what FDA had to say. (Orange Book exclusivity codes are defined in an appendix to the publication. FDA has explained that “[e]xclusivity codes with an ‘I’ prefix (‘I-###’) are suggestive of new indication exclusivity, exclusivities for ‘new dosing schedules’ are assigned a ‘D-###’ code, whereas exclusivities that do not neatly fall into either of these two categories are assigned a ‘miscellaneous’ use code ‘M-###.’”)
After providing the necessary background and going through the criteria for granting 3-year exclusivity (i.e., an application for a previously approved active moiety containing “reports of new clinical investigations (other than bioavailability studies),” that were “essential to approval” of the application, and that were “conducted or sponsored by” the applicant), the CDER Exclusivity Board addresses the issues at hand: “The issues before the Board in this instance are the scope of exclusivity and the assignment of an appropriate exclusivity code in the Orange Book that best characterizes this exclusivity.” Here’s what the Board has to say about those two issues:
FDA’s decision was 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 U.S. District Court for the District of Maryland ruled in Zeneca Inc. v. Shalala, No. CIV.A. WMN–99–307, 1999 WL 728104 (D. Md. Aug. 11, 1999), aff’d, 213 F.3d 161 (4th Cir. 2000), that the 3-year exclusivity FDA granted:
With all of the “abuse-deterrent” drug products in development these days (including products that are or will be the subject of 505(b)(2) applications), and given FDA’s recent explanation of the scope of 3-year exclusivity (above and in recent memorandaunsealed in litigation against FDA), interest (and concern) over the scope of a particular period of 3-year exclusivity seems to be growing. Indeed, the concern was so great that late last year two companies exchanged waivers of 3-year exclusivity for their competing single-entity, extended-release hydrocodone drug products (see here). Those mutual waivers occurred shortly after at least one of the companies met with FDA's Office of Chief Counsel on October 21, 2014 (see here)
There are few things this blogger relishes more in his practice than getting his hands on FDA exclusivity decisions. (It’s like being given and then unwrapping a holiday gift.) We don’t mean the “decisions” that most people see in ANDA approval letters or that are published in the Orange Book. Those “decisions” are interesting, but they aren’t usually terribly helpful because of their opacity. We mean the decisions underlying those “decisions”; the decisions that explain why FDA granted (or denied) exclusivity to an application sponsor. Those decisions aren’t published by FDA. You have to know what you’re looking for, and then ask for them.
We try to publicize FDA exclusivity decisions when we can. After all, those FDA decisons should be freely available and in the public domain so that folks understand FDA’s current thinking. Nobody likes stumbling around in a dark room. The lights need to be turned on – or, at the very least, you need a night light. Sometimes we cannot provide the actual FDA decision, so, when possible, we put up a post explaining what we know, as we did here and here. Sometimes we can provide the actual FDA decisional memorandum. We did that last year when we obtained a copy of FDA’s decision on 180-day exclusivity forfeiture for Risedronate Sodium Tablets (ACTONEL) (see our previous post here). More recently, we publicized FDA’s various decisions on the scope of 3-year new clinical investigation exclusivity made available after the unsealing of litigation documents in a lawsuit involving extended-release Tacrolimus (see our previous post here). In some instances, we’re in the dark as much as everyone else, because FDA has decided not to decide on exclusivity – sometimes for many months (as in the case of AURYXIA (ferric citrate) Tablets approved under NDA 205874), and sometimes for years (as in the case of SURFAXIN (lucinactant) Intratracheal Suspension approved under NDA 021746).
Over the past few weeks we’ve come across three exclusivity decisions: two concerning 180-day exclusivity forfeiture, and another concerning 3-year exclusivity. The two 180-day exclusivity forfeiture decisions are interesting reads, but not overly noteworthy. One FDA Memorandum provides FDA’s rationale for determining that 180-day exclusivity for Linezolid Injection 2 mg/mL (packaged in 600 mg/300 mL single-use flexible plastic containers), a generic version of ZYVOX, was not forfeited because of a change in or review of the requirements that prevented tentative approval within 30 months of ANDA submission (FDC Act § 505(j)(5)(D)(i)(IV)). Another FDA Memorandum goes into the “better late than never” category and explains FDA’s rationale for determining that 180-day exclusivity for Valsartan Tablets, 40 mg, 80 mg, 160 mg, and 320 mg (DIOVAN) was not forfeited under FDC Act § 505(j)(5)(D)(i)(IV). That decision led to litigation that was resolved in late 2012 (see our previous post here).
Our best “find” is 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. That NDA Supplement included a “drug liking” study and proposed the addition of “labeling language describing the results of pre- and post-marketing data from in vitro and in vivo abuse potential studies to the DRUG ABUSE AND DEPENDENDCE section of the Package Insert.” The NDA Supplement approval was the first approval for a drug with abuse-deterrent labeling claims. (Then in draft form – see our previous post here – today final guidance – “Abuse-Deterrent Opioids — Evaluation and Labeling” provides FDA’s current thinking about the studies that should be conducted to demonstrate that a particular drug product formulation has abuse-deterrent properties.)
The approval of NDA 022272/S014 had been on our radar for a while. It was on our list of drug products for which an exclusivity decision was pending (and delayed). We’re not entirely certain why it took FDA so long to make a decision, or what finally prompted the Agency to act, but when we saw the addition of a period of 3-year exclusivity for NDA 022272 in the February 2015 Orange Book Cumulative Supplement (published in mid-March) coded as “M-153” and defined as “ADDITION OF INFORMATION REGARDING THE INTRANASAL ABUSE POTENTIAL OF OXYCONTIN” we were immediately interested to know what FDA had to say. (Orange Book exclusivity codes are defined in an appendix to the publication. FDA has explained that “[e]xclusivity codes with an ‘I’ prefix (‘I-###’) are suggestive of new indication exclusivity, exclusivities for ‘new dosing schedules’ are assigned a ‘D-###’ code, whereas exclusivities that do not neatly fall into either of these two categories are assigned a ‘miscellaneous’ use code ‘M-###.’”)
After providing the necessary background and going through the criteria for granting 3-year exclusivity (i.e., an application for a previously approved active moiety containing “reports of new clinical investigations (other than bioavailability studies),” that were “essential to approval” of the application, and that were “conducted or sponsored by” the applicant), the CDER Exclusivity Board addresses the issues at hand: “The issues before the Board in this instance are the scope of exclusivity and the assignment of an appropriate exclusivity code in the Orange Book that best characterizes this exclusivity.” Here’s what the Board has to say about those two issues:
Exclusivity extends only to the change approved in the supplement for which new clinical investigations were essential, and the Agency interprets the scope of 3-year exclusivity to be related to the scope of the underlying new clinical investigations that were essential to the approval of the supplement. As discussed above, OTR 1018 did not support approval of the original NDA 022272 on April 5, 2010, and was thus not essential to the approval of the specific abuse-deterrent formulation of [reformulated OxyContin (OCR)]. This study only supported the addition of information obtained from the drug liking study to the OCR labeling that indicates that OCR has physicochemical properties that are expected to reduce abuse via the intranasal route. Therefore, the scope of exclusivity in this instance is limited to the addition of this information to Section 9.2 in the labeling.What one might gather from the Board’s memorandum is that the scope of the period of 3-year exclusivity for OXYCONTIN expiring on April 16, 2016 applies to the particular drug product formulation studied in clinical trials, and not broadly to prevent approval of all oxycodone extended-release drug products with abuse-deterrence labeling. That would seem to be consistent with other FDA decisions. For example, on January 4, 1999, FDA approved ANDA 075102 for Propofol Injectable Emulsion, 1% (10 mg/mL), notwithstanding a period of 3-year exclusivity on the reference listed drug, DIPRIVAN, that was not scheduled to expire until June 11, 1999. The period of 3-year exclusivity applicable to DIPRIVAN was based on FDA’s approval of a NDA Supplement 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.
The Board notes generally that the scope of exclusivity should be determined by the nature of the clinical studies done to gain approval of the NDA, not by the exclusivity code that is used as shorthand to describe that approval in the Orange Book. Nevertheless, the Board recommends that when the Orange Book listing is updated to display this exclusivity period, OCR be assigned a unique exclusivity code that reflects the scope of this exclusivity. Given that the scope of 3-year exclusivity in this instance is limited to the addition of information to the OCR labeling regarding the reduction of abuse via the intranasal route, the Board recommends that the following exclusivity code be assigned:
M-###: “Addition of Information Regarding the Intranasal Abuse Potential of OxyContin.”
FDA’s decision was 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 U.S. District Court for the District of Maryland ruled in Zeneca Inc. v. Shalala, No. CIV.A. WMN–99–307, 1999 WL 728104 (D. Md. Aug. 11, 1999), aff’d, 213 F.3d 161 (4th Cir. 2000), 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.More recently, FDA approved multiple 505(b)(2) applications 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 expiring 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 expiring on January 31, 2016 – would seem to be the result of FDA’s determination that the scope of each applicant’s 3-year exclusivity is limited to the clinical trial data supporting approval of the particular penetration enhancer formulation tested.
With all of the “abuse-deterrent” drug products in development these days (including products that are or will be the subject of 505(b)(2) applications), and given FDA’s recent explanation of the scope of 3-year exclusivity (above and in recent memorandaunsealed in litigation against FDA), interest (and concern) over the scope of a particular period of 3-year exclusivity seems to be growing. Indeed, the concern was so great that late last year two companies exchanged waivers of 3-year exclusivity for their competing single-entity, extended-release hydrocodone drug products (see here). Those mutual waivers occurred shortly after at least one of the companies met with FDA's Office of Chief Counsel on October 21, 2014 (see here)
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