How Effective is a “Depomed Threat” at Resolving an Orphan Drug Clinical Superiority Dispute?

By Kurt R. Karst – 

The legal world is chock-full of tests, doctrines, and processes named after a particular case or court decision.  It’s kind of a legal short-hand; a lexicon of legal eponyms.  There’s the “Winter Standard” for preliminary injunctions in federal courts; the “Lemon Test” for cases involving the establishment clause of the First Amendment; the “Central Hudson Test” for analyzing commercial speech regulations; the “Walker Process” for antitrust claims; the “Park Doctrine” for prosecutions against corporate officials under the FDC Act . . . . and on and on . . . .  Today, we offer up a potential addition to the legal lexicon of eponyms: the “Depomed Threat.”  Recent precedent suggests that it might be an effective tool for some companies with orphan drug designations.

The case namesake of the “Depomed Threat” is Depomed, Inc. v. HHS, — F. Supp. 2d –, 2014 WL 4457225 (D.D.C. Sept. 5. 2014).  In that decision, the U.S. District Court for the District of Columbia granted Depomed Inc.’s (“Depomed’s”) Motion for Summary Judgment and ordered FDA to recognize orphan drug exclusivity for GRALISE (gabapentin) Tablets “without requiring any proof of clinical superiority or imposing any additional conditions on Depomed.”  You see, FDA designated GRALISE as an orphan drug for the treatment of Post-Herpetic Neuralgia (“PHN”) based on a plausible hypothesis that GRALISE may be clinically superior to NEURONTIN (gabapentin) for the management of PHN, but FDA refused to grant Depomed a period of orphan drug exclusivity after approving the GRALISE NDA because Depomed had not  demonstrated clinical superiority over NEURONTIN by showing greater efficacy, greater safety, or a major contribution to patient care.  Depomed challenged FDA in court arguing, among other things, that the orphan drug designation was sufficient and that a demonstration of clinical superiority was not necessary to obtain orphan drug exclusivity (see our previous posts here and here). 

When the Depomed decision came out in September 2014, we commented that the decision, which finds that “the plain language of the exclusivity provisions of the Orphan Drug Act requires the FDA to recognize exclusivity for any drug that the FDA has designated and granting marketing approval” (emphasis added), would have far-reaching implications for FDA’s orphan drug program (and perhaps beyond).  Among other things, we thought the decision might mean a rewrite of some of FDA’s orphan drug regulations.

FDA initially appealed the District Court decision to the U.S. Court of Appeals for the District of Columbia Circuit, and then quickly dropped the appeal (see our previous post here).   But FDA didn’t stop there.  To our surprise, FDA issued a notice, styled as a “clarification of policy,” doubling-down on the Agency’s clinical superiority orphan drug regulations (see our previous post here).  In the policiy clarification, FDA states:

In consideration of any uncertainty created by the court’s decision in Depomed, the Agency is issuing this statement.  It is the Agency’s position that, given the limited terms of the court’s decision to GRALISE, FDA intends to continue to apply its existing regulations in part 316 to orphan-drug exclusivity matters.  FDA interprets section 527 of the FD&C Act and its regulations (both the older regulations that still apply to original requests for designation made on or before August 12, 2013, as well as the current regulations) to require the sponsor of a designated drug that is the “same” as a previously approved drug to demonstrate that its drug is “clinically superior” to that drug upon approval in order for the subsequently approved drug to be eligible for orphan-drug exclusivity.

In other words, FDA seemingly blows off the district court decision as a one-off case that applies only to the facts of Depomed.  We speculated at the time that this might be “FDA’s way of drawing out another lawsuit from an affected sponsor so that the Agency can have another crack to relitigate the issue in court.”  After all, we were aware of several orphan drug designations based on a plausible hypothesis of clinical superiority.  Now that we are a year separated from the Depomed decision, however, we have a different take on things. 

What changed our perspective?  One of those several orphan drug designations mentioned above:  Eagle Pharmaceuticals, Inc.’s (“Eagle’s”) RYANODEX (dantrolene sodium) for Injectable Suspension. 

According to FDA’s Orphan Drug Designations and Approvals Database, FDA designated the drug as an orphan drug on August 16, 2013 for the “[t]reatment of malignant hyperthermia syndrome.”  FDA approved RYANODEX (NDA 205579) on July 22, 2014 for “the treatment of malignant hyperthermia in conjunction with appropriate supportive measures and for the prevention of malignant hyperthermia in patients at high risk.”  But FDA did not update the Orange Book to show a grant of orphan drug exclusivity for RYANODEX until the publication of the February 2015 Cumulative Supplement. 

Why the delay?  We think FDA might have had to do some thinking to come up with a way to justify a demonstration of clinical superiority to avoid a Depomed-like lawsuit.

We’ll spare you the long story of the quest to designate RYANODEX as an orphan drug.  Here’s the short story . . . .  It starts back in October 2003 with an orphan drug designation request.  FDA subsequently took the position that the predecessor-in-interest to Eagle, Lyotropic Therapeutics, had to provide a plausible hypothesis as to why RYANODEX was clinically superior to the non-orphan designated DANTRIUM IV (dantrolene sodium for injection) (NDA 018624), which is also approved for malignant hyperthermia treatment.  After a lot of back-and-forth over the years – even FDA’s Office of Chief Counsel had to step in at one point (see here) – FDA ultimately granted orphan drug designation on August 16, 2013 based on a plausible hypothesis of greater safety vis-à-vis DANTRIUM IV.  Specifically, Eagle hypothesized that RYANODEX was safer than previously approved dantrolene sodium formulations because it requires a substantially smaller diluent volume and has a substantially lower amount of mannitol. 

Once FDA approved RYANODEX (NDA 205579) on July 22, 2014, the Agency had to decide whether or not to grant the orphan drug exclusivity.  But according to a January 15, 2015 memorandum (the memo says 2014, but that’s clearly a typo) from FDA’s Office of Orphan Products Development (“OOPD”), that was going to be a problem: “The review division informed OOPD that there was no data to demonstrate clinical superiority in the NDA submitted by Eagle.”  Uh-oh!

OOPD informed Eagle of the determination from the Division of Anesthesia, Analgesia, and Addiction Products (“DAAAP”), and Eagle responded.  While Eagle “made a case for clinical superiority based on length of time needed to reconstitute and administer Ryanodex compared to the previously approved dantrolene product (1 minute versus 50 minutes), decreased quantity of mannitol in the Ryanodex product, and decreased volume of fluid administered with the Ryanodex product,” Eagle also issued the “Depomed Threat.”  According to OOPD:

It should be noted that Eagle maintained that a demonstration of clinical superiority was not necessary due to the Depomed court decision that stated that a company that had orphan drug designation for a drug or biologic for treatment of a rare disease automatically received orphan exclusivity upon marketing approval per the Orphan Drug Act.

It’s what happened next, after the Depomed Threat was issued, that we find particularly interesting.  (And we imagine the correspondence from Eagle to FDA/OOPD concerning Depomed may have been more strongly worded than what is conveyed in OOPD’s memorandum.)  DAAAP largely dismissed Eagle’s clinical superiority arguments, but OOPD, after consulting with DAAAP, found that there was a major contribution to patient care (the so-called “MC-to-PC” clinical superiority basis) supporting a grant of 7-year orphan drug exclusivity.  Here’s how the OOPD memorandum describes the discussions and conclusion (it’s worth quoting at length from the memorandum):

DAAAP was consulted concerning the sponsors claims of clinical superiority.  With respect to the claim of superiority due to decreased mannitol content and fluid content, it was noted by the review division that mannitol and fluids were part of the supportive care used to maintain the patient and cool down the patient and was thus not acceptable as making Ryanodex superior over the previously approved dantrolene product.  The review division acknowledged that malignant hyperthermia is a medical emergency and as such, a decrease in time to treat should result in improved patient outcome.  However, it was noted that treatment involves a discontinuation of administration of the triggering anesthetic, fluid, mannitol, and dantrolene.  The sponsor provided data from retrospective analysis of cases in which there was delay in administration of dantrolene.  This data showed that there was an increased complication rate with every 15 minute delay in delivery of dantrolene.  However, there was no control over time of diagnosis or timing of the other procedures involved in the treatment of this condition.  The review division concluded that a demonstration of superior efficacy would require controlled prospective studies.  The review division and OOPD met and discussed the concept of a major contribution to patient care which is one aspect of clinical superiority defined under 21 CFR 316.3(b)(3)(iii) (“[i]n unusual cases, where neither greater safety nor greater effectiveness has been shown, a demonstration that the drug otherwise makes a major contribution to patient care.”).  This basis for finding a subsequent drug clinically superior is intended to constitute a narrow category, and its proposed use is not intended to open the flood gates to FDA approval for every drug for which a minor convenience over and above that attributed to an already approved orphan drug can be demonstrated.  The example provided in the orphan regulations for major contribution to patient care was a sponsor developing an oral dosage form where the previously approved drug was available only in a parenteral formulation.

The review division said that in view of the emergency nature of malignant hyperthermia, more rapid treatment should result in improved patient outcome but again, treatment involves multiple interventions including discontinuation of offending agent, administering fluids for support, cooling the patient, administering mannitol for organ support, providing continued anesthesia for surgery, and administering dantrolene.  It was also noted that while the full dose of Ryanodex can be administered in 1 minute and the previously approved dantrolene requires up to 1 hour to reconstitute and administer, the anesthesiologist would not wait until the previously approved dantrolene is totally reconstituted before initiating therapy.  The dantrolene is administered over the 1 hour period as each vial is reconstituted.  It is, therefore, not fully apparent how this delay in administration of the full dose of dantrolene would impact the care of the patient.  The review division did not believe that the requirement to reconstitute up to 10 vials of dantrolene compared to one vial of Ryanodex subjected the patient to increased risk of contamination or dosing error.  However, the review division did note that the ability of the anesthesiologist to reconstitute and administer Ryanodex within one minute allowed the anesthesiologist to concentrate on continued supportive care and treatment of the patient with malignant hyperthermia compared to treatment with the previously approved dantrolene product that required up to one hour to reconstitute and administer, which would not allow the anesthesiologist to fully concentrate on the other aspects of treatment and support of the patient.  This would have an impact on the patient’s care.  The review division believed that this would support a decision that Ryanodex provided a major contribution to patient care. [(Emphasis added)]

That’s a pretty creative and unique basis on which to find clinical superiority.  We’ll add RYANODEX to our growing list of MC-to-PC precedents (see our previous posts here, here, and here).