Breaking Zen: FDA Denies Vanda’s Petition on FANAPT 3-Year Exclusivity; Approves Generic

December 4, 2016

By Kurt R. Karst

Wikipedia (oh that font of knowledge and easy reference that it is for us bloggers) describes schizophrenia as a mental disorder characterized by, among other things, “failure to understand what is real.”  That pretty much sums up FDA’s impressions of a September 2016 Citizen Petition (Docket No. FDA-2016-P-2654) submitted by Vanda Pharmaceuticals Inc. (“Vanda”) requesting that the Agency refuse to approve any ANDA referencing Vanda’s FANAPT Tablets, 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 mg, until the expiration of a period of 3-year exclusivity on May 26, 2019 stemming from a May 26, 2016 approval of FANAPT under a supplemental NDA (S-015) for maintenance treatment of schizophrenia. FDA initially approved FANAPT on May 6, 2009 under NDA 022192 for the acute treatment of schizophrenia in adults, and then later removed the word “acute” to make FANAPT’s labeling more consistent with other similar drug products. FDA, in the Agency’s November 28, 2016 Denial Response to Vanda once again discusses the metes and bounds of 3-year exclusivity, but in a rather interesting context. We should also note that on the same day the petition response was handed down, FDA approved Inventia Healthcare Private Limited’s ANDA 207231 for Iloperidone Tablets, 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg. 

As noted above, Vanda’s Citizen Petition is the result of FDA’s May 26, 2016 approval of a supplemental NDA for maintenance treatment of schizophrenia, which supplement contained the results of a clinical study known as “REPRIEVE.” The REPRIEVE study demonstrated that FANAPT “is more effective than a placebo in preventing or delaying relapse when administered for longer than six weeks,” according to Vanda, and “provided valuable new information about the use of Fanapt for treating schizophrenia.”  Because the REPRIEVE supplemental NDA met the requirements for 3-year exclusivity, FDA granted it.  The exclusivity is coded in the Orange Book as “M-180,” which is defined in an addendum to the publication to mean “INFORMATION ADDED TO THE LABELING REGARDING THE ADDITION OF MAINTENANCE TREATMENT IN PATIENTS WITH SCHIZOPHRENIA.”

With the approval of S-015, FDA added information to the labeling of FANAPT concerning maintenance treatment. But other labeling information was removed.  Specifically, the following information in Section 1 (Indications and Usage) and Section 2.3 (Dosage and Administration; Maintenance Treatment) was removed from labeling:

The effectiveness of FANAPT in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use FANAPT for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.3)]

Although there is no body of evidence available to answer the question of how long the patient treated with FANAPT should be maintained, it is generally recommended that responding patients be continued beyond the acute response. Patients should be periodically reassessed to determine the need for maintenance treatment.

According to FDA, “[t]his language was deleted to make labeling more accurate, given the addition of information about the REPRIEVE study and maintenance treatment, and consistent with FDA’s approach to schizophrenia treatments in general.” Vanda, however, saw things differently, and argued that FDA’s grant of 3-year exclusivity should be a total bar to ANDA approval, both because of the scope of the 3-year exclusivity granted and because of the inability of an ANDA applicant to carve-out protected information.  According to Vanda:

The removal of the limitation on maintenance treatment satisfies the applicable legal standards for eligibility for three-year exclusivity to the same extent as the addition of information about Fanapt’s efficacy for maintenance treatment. Both types of changes “derive[] from” the REPRIEVE study and that study “relate[s] to” those changes because REPRIEVE is the sole source of reliable clinical evidence supporting the efficacy of iloperidone for maintenance treatment.  Without the REPRIEVE results, there would be no basis for statements describing the efficacy of iloperidone for maintenance treatment, nor would there be support for deleting statements describing the lack of such efficacy data. Because “there are no other data available that could support approval of” these labeling changes made in Supplement 15, REPRIEVE is “essential to approval” of the changes. The direct and logical link between REPRIEVE and the labeling changes is the kind of “substantive relationship between new clinical studies and changes in the supplement” that is required for both types of changes to be covered by three-year exclusivity. . . .

Because Fanapt’s three-year exclusivity covers both the addition and omission of labeling information relating to maintenance treatment, no ANDA referencing Fanapt may be approved before the expiration of three-year exclusivity because no generic iloperidone product can bear approvable labeling. Fanapt’s three-year exclusivity precludes ANDA labeling from omitting statements describing the lack of evidence of safety and efficacy for maintenance treatment.  At the same time, however, ANDA labeling may not include those statements because they are now inaccurate, and because their inclusion would violate the “same labeling” requirement. . . .

Carving out information about maintenance treatment from the labeling for a generic iloperidone product would leave the product less safe or effective than Fanapt for the remaining, non-protected condition of use: namely, the treatment of adult patients with schizophrenia. A carve-out would leave prescribers with no information about the safety and efficacy of continued treatment for those patients who respond initially to iloperidone—contrary to the requirement that labeling “contain a summary of the essential scientific information needed for the safe and effective use of the drug.” A labeling carve-out should be denied where, as here, the protected information “is necessary to enable physicians to adequately assess the risks and benefits of” the drug product for “the general population” of patients for whom the drug product is indicated.

Or, said another way (by FDA):

You contend that the 3-year exclusivity FDA granted Vanda for the REPRIEVE study results protects both (1) the addition of information to Fanapt’s labeling about the product’s efficacy for maintenance treatment and (2) the deletion of statements describing a lack of evidence for maintenance treatment (Petition at 1, 7). You argue that this exclusivity bars approval of any ANDA that references Fanapt that either includes the maintenance treatment information added in S-015 or omits the prior statements on maintenance treatment limitations (which are no longer in the RLD labeling) (Petition at 10).  You additionally argue that ANDA labeling may not include statements describing the lack of evidence of safety or efficacy for maintenance treatment because they are now inaccurate and their inclusion would violate the “same labeling” requirement (Petition at 10).  Finally, you contend that the new information about maintenance treatment cannot be carved out of generic iloperidone labeling because doing so would render the generic product less safe or effective than Fanapt for the remaining non-protected conditions of use (Petition at 1, 13).  Thus, you argue that the 3-year exclusivity related to the REPRIEVE study prohibits FDA from approving a generic iloperidone referencing Fanapt for any use, including any unprotected use.

With respect to the scope of the 3-year exclusivity FDA granted, FDA disagreed with Vanda’s characterization of it as having two-way effect (a kind of zen moment in Hatch-Waxman). “We disagree with your argument that 3-year exclusivity can cover the deletion of statements from previously approved labeling.”  Here, wrote FDA, “the addition of labeling describing the REPRIEVE study data is the exclusivity-protected change approved in the supplement envisioned by the Hatch-Waxman Amendments.”  Continuing on, FDA said:

This was the labeling supported by “new clinical investigations” that were “essential” to approval of the supplement, within the meaning of section 505(j)(5)(F)(iv). But as the preamble to the 1989 proposed rule for part 314 made clear, it is only the labeling claims on the approved product that describe the REPRIEVE study that are covered by the 3-year exclusivity, not other accompanying changes.  The fact that when adding these claims to the labeling FDA also approved conforming changes – removal of previous statements that would no longer be accurate and that no longer reflected the standard of care for schizophrenia treatment – does not mean that those conforming changes are swept into the scope of exclusivity, or that no ANDA that omits this outdated information can be approved during the 3-year exclusivity period.  FDA does not believe that such conforming deletions are changes for which new clinical investigations are essential.

We were a bit intrigued by FDA’s general statement that 3-year exclusivity does not  cover the deletion of statements from previously approved labeling.  After all, way back in August 2008, we wrote a post titled “FDA Clarifies that 3-Year Exclusivity can be Granted for the Removal of Labeling Information.” In that post, we discussed an instance involving ACZONE (dapsone) Gel, 5% (NDA 021794), in which FDA granted a period of 3-year exclusivity and coded it in the Orange Book as “M-76.”  That exclusivity code is defined as: “REMOVAL OF SCREEN REQUIREMENT IN PTS WITH G6PD DEFICIENCY PRIOR TO INITIATING ACZONE TREATMENT; REMOVAL OF BLOOD COUNT & RETICULOCYTE MONITORING DURING TREATMENT IN G6PD DEFICIENT PTS AND IN PATIENTS WITH HISTORY OF ANEMIA” (emphasis added).  There’s also a “D-121” exclusivity code defined as “CHANGE TO REMOVE 20 MG MAXIMUM DOSAGE RESTRICTION” (emphasis added) related to the approval of a supplemental NDA in October 2009 for FOCALIN XR (dexmethylphenidate HCL) Extended-release Capsules (NDA 021802).  Of course, an exclusivity code is only shorthand for the scope of exclusivity, and each exclusivity scenario must be considered on a case-by-case basis. 

In any case, FDA does go on to address the situation in which the Agency does recognize exclusivity for the deletion of labeling information. “Even if the Agency were to agree that in certain circumstances deletions of information can be protected by exclusivity when supported by new clinical investigations essential to the approval of the deletion (which it does not),” writes FDA, “in this case, the new clinical investigations that earned exclusivity were not essential to the deletions you identify.”

With respect to Vanda’s ANDA labeling carve-out arguments, they fell on deaf ears. “FDA has determined as a scientific matter that it is not necessary to retain the information about the REPRIEVE study that was added in S-015 in the labeling for generic iloperidone to assure safe use,” writes FDA.  “FDA has also determined that generic iloperidone with the protected REPRIEVE study information carved out remains safe and effective for the remaining non-protected conditions of use.  Accordingly, a carve-out of the REPRIEVE study information is permissible in this case.”