Another Orphan Drug Battle; Depomed Sues FDA Over GRALISE Orphan Drug Exclusivity

By Kurt R. Karst –       

Public turmoil over FDA decisions involving orphan drug exclusivity has been relatively rare in recent years.  That has changed over the past several months.  First there was the lawsuit brough against FDA by K-V Pharmaceutical Company to “restore” orphan drug exclusivity for the pre-term birth drug MAKENA (hydroxyprogesterone caproate) Injection (see our previous post here).  Then there was FDA’s decision – the first ever – to rescind Octapharma USA, Inc.’s orphan drug exclusivity for WILATE (von Willebrand Factor/Coagulation Factor VIII Complex (Human)) (see our previous post here).  And earlier this week, Depomed, Inc. (“Depomed”) filed a Complaint in the U.S. District Court for the District of Columbia challenging FDA’s denial of orphan drug exclusivity for GRALISE (gabapentin) Tablets.

FDA designated GRALISE as an orphan drug in November 2010 for the management of postherpetic neuralgia (“PHN”), and approved the drug product on January 28, 2011 under NDA No. 022544 for the designated indication.  Despite having designated GRALISE as an orphan drug for the approved indication, however, FDA did not grant orphan drug exclusivity.  Why?  Because of issues surrounding what constitutes an “orphan drug” and under what circumstances “clinical superiority” must be shown.

FDA’s orphan drug regulations at 21 C.F.R. § 316.20(a) state that “a sponsor of a drug that is otherwise the same drug as an already approved orphan drug may seek and obtain orphan-drug designation for the subsequent drug for the same rare disease or condition if it can present a plausible hypothesis that its drug may be clinically superior to the first drug” (emphasis added).  Over the years, there has been some confusion as to how FDA interprets the term “orphan drug” in this regulation. 

The term “orphan drug” is specifically defined at 21 C.F.R. § 316.3(b)(10) to mean “a drug intended for use in a rare disease or condition as defined in section 526 of the act.”  But does this mean that an “orphan drug” is any previously approved drug for a rare disease or condition, regardless of whether or not it was designated and approved as an orphan drug?  “Yes,” according to FDA.  In the preamble to FDA’s 2011 proposed orphan drug regulations (see our previous post here), which the Agency says are “intended to clarify regulatory provisions and make minor improvements to address issues that have arisen since” they were promulgated in December 1992, FDA states that “[i]n the absence of a clinical superiority hypothesis, the Agency does not interpret the orphan-drug regulations to permit orphan designation of a drug that is otherwise the same as a drug that is already approved for the orphan use, either where the approved drug received orphan-drug exclusive approval (even after such drug's exclusivity period has run out) or where the approved drug was not previously designated as an orphan drug and thus did not receive orphan exclusive approval” (emphasis added).

FDA’s orphan drug regulations define a “clinically superior” drug as “a drug . . . shown to provide a significant therapeutic advantage over and above that provided by an approved orphan drug (that is otherwise the same drug)” in one of three ways: (1) greater effectiveness as assessed by effect on a clinically meaningful endpoint in adequate and well controlled trials; (2) greater safety in a substantial portion of the target population; or (3) demonstration that the drug makes a major contribution to patient care.  As FDA explains in the recent petition response concerning WILATE orphan drug exclusivity (as well in the preamble to the Agency’s 2011 proposed rule), where clinical superiority is concerned, the standard for obtaining designation is different from the standard for obtaining exclusivity:

Though the sponsor of a subsequent orphan drug must set forth a plausible hypothesis of clinical superiority over the previously approved drug at the designation stage, such a sponsor faces a higher standard at the time of approval.  At approval, the sponsor of a drug which was designated on the basis of a plausible hypothesis of clinical superiority must demonstrate that its drug is clinically superior to the previously approved drug.  Should the sponsor fail to do so, then the subsequent drug will be considered to be the same drug as the previously approved drug, and will not be able to gain marketing approval if the previously approved drug’s orphan-drug exclusive approval period is still running.  Once this exclusivity has expired, the subsequent drug may be approved . . . , but it will not be eligible for orphan-drug exclusivity because the same drug has already been approved for the same orphan indication.

In the case of GRALISE, FDA required a plausible hypothesis of clinical superiority because the Agency previously approved gabapentin for the management of PHN.  Specifically, FDA approved NEURONTIN (gabapentin) for the management of PHN many years ago, but FDA never designated and approved NEURONTIN as an orphan drug.  Nevertheless, FDA considers NEURONTIN an “orphan drug,” and therefore, according to FDA, a company seeking orphan drug designation for its gabapentin product for the management of PHN must meet the Agency’s “clinical superiority” requirements to obtain designation and orphan drug exclusivity.

The information supporting a plausible hypothesis of clinical superiority (greater safety) was provided to FDA and the Agency designated GRALISE as an orphan drug.  According to Depomed, however:

Contrary to the plain language of the Orphan Drug Act and FDA’s regulations, the letter communicating the grant of orphan-drug designation asserted that the approval of Gralise to manage PHN would not automatically lead to orphan-drug exclusivity.  The letter stated that, “should [Depomed] obtain marketing approval for this product, [Depomed] will have to prove clinical superiority . . . in order to obtain seven years of marketing exclusivity.”

Depomed’s Complaint, which seeks declaratory and injunctive relief, alleges that FDA is violating the Administrative Procedure Act by refusing to grant orphan drug exclusivity for GRALISE.  Instead of recognizing orphan drug exclusivity for GRALISE, FDA “placed additional hurdles between Gralise and orphan-drug exclusivity by attempting to impose requirements that are found nowhere in the statute and that exist in regulation only for circumstances not present here,” alleges Depomed.  Depomed previously communicated concerns with FDA’s interpretation of the Orphan Drug Act in comments submitted to the docket established for FDA’s 2011 proposed rule (Docket No. FDA–2011–N–0583).