FDA Rescinds Orphan Drug Exclusivity for Wilate; A First-of-its-Kind Decision

By Kurt R. Karst –      

There’s a first time for everything!  And on August 8th, 2012, FDA decided, for the first time since the enactment of the Orphan Drug Act, to rescind a period of 7-year orphan drug exclusivity.  The decision came in the form of a response granting in part and denying in part a citizen petition (Docket No. FDA-2011-P-0213) CSL Behring (“CSL”) submitted to FDA in March 2011 requesting that the Agency: (1) revoke the orphan drug designation and the period of orphan drug exclusivity FDA subsequently granted to Octapharma USA, Inc. (“Octapharma”) for the December 4, 2009 approval of WILATE (von Willebrand Factor/Coagulation Factor VIII Complex (Human)) under BLA No. 125251 “for the treatment of spontaneous or trauma-induced bleeding episodes in patients with severe von Willebrand disease (VWD) as well as patients with mild or moderate VWD in whom the use of desmopressin is known or suspected to be ineffective or contraindicated;” and (2) “refrain from making any orphan drug designations and approval decisions based on hypothetical claims of superiority.”  FDA decided not to revoke orphan drug designation for WILATE, and also denied CSL’s request regarding “hypothetical claims of superiority.”

WILATE is the “same drug” as HUMATE-P (Antihemophilic Factor/von Willebrand Factor Complex (Human)) for orphan drug purposes.  That is, FDA considers them to be “chemically the same drug” and for the same orphan indication.  FDA approved HUMATE-P on April 1, 1999 for the same orphan disease as WILATE.  Because WILATE is the “same drug” as HUMATE-P, the issue of “clinical superiority” comes into play – for obtaining orphan drug designation and for obtaining orphan drug exclusivity.

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.”  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 petition response (as well in the Agency’s 2011 proposed rule – see our previous post here):

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 WILATE, FDA designated the drug as an orphan drug in April 2007 after determining that there was a plausible hypothesis of clinical superiority.  Specifically, FDA determined that WILATE “may be safer than [HUMATE-P] in a substantial portion of the target population due to its two dedicated viral inactivation steps compared to a single dedicated viral inactivation step for [HUMATE-P].”  After approving WILATE, FDA allowed Octapharma to make its case for a demonstration of clinical superiority, and on June 24, 2010, FDA determined that WILATE “appeared to be clinically superior to [HUMATE-P] because of greater viral safety,” and, in fact, “had been shown to be clinically superior to [HUMATE-P] within the meaning of the FDA’s orphan drug regulations . . . .”  As such, FDA granted a period of 7-year orphan drug exclusivity retroactive to December 4, 2009 when FDA approved WILATE.

CSL subsequently contacted FDA and questioned the evidentiary support for FDA’s exclusivity decision.  FDA requested that CSL raise its concerns in a citizen petition, which CSL submitted in March 2011.  CSL’s main premise is that the evidence Octapharma presented to FDA to support clinical superiority of WILATE over HUMATE-P does not meet the applicable regulatory standards. 

After reanalyzing available evidence, FDA concluded that WILATE had not, in fact, been demonstrated to be clinically superior to HUMATE-P due to greater safety.  According to FDA, “the record does not contain sufficient evidence to support a finding that Wilate is clinically superior to Humate due to its ‘[g]reater safety in a substantial portion of the target population.’”  Accordingly, FDA withdrew its clinical superiority determination, and, as a result, rescinded the orphan drug exclusivity for WILATE. 

FDA decided not to rescind orphan drug designation for WILATE, however.  FDA’s orphan drug regulations provide three independent bases under which orphan drug designation can be revoked – if FDA finds that: 

(1)  The request for designation contained an untrue statement of material fact; or

(2)  The request for designation omitted material information required by [21 C.F.R. Part 316]; or

(3)  FDA subsequently finds that the drug in fact had not been eligible for orphan drug designation at the time of submission of the request therefor. [(21 C.F.R. § 316.29(a))] 

FDA rarely rescinds orphan drug designation.  We are aware of only three instances:

(1) Papaverine – On February 6, 1992, OOPD designated Pharmedic Co.’s papaverine topical gel for the “treatment of sexual dysfunction in spinal cord injured patients.”  FDA revoked the designation on September 16, 1993 after additional information showed that the potential target population of the drug could be significantly larger than originally stated.

(2) Methylnaltrexone – On June 17, 1996, FDA designated the University of Chicago’s methylnaltrexone for the “treatment of chronic opioid-induced constipation unresponsive to conventional therapy.”  FDA revoked the designation on January 9, 1998 after new information indicated that the drug could be used in a significantly larger patient population.

(3) Pancreatic Enzymes – On January 23, 2002, FDA designated Altus Biologics Inc.’s TheraCLEC-Total, a microbially-derived pancreatic enzyme product containing amylase, lipase, and protease, as an orphan drug for the “treatment of exocrine pancreatic insufficiency.”  FDA revoked the designation on June 28, 2007 based on information showing that the drug could be used in a significantly larger patient population – specifically HIV/AIDS patients who suffer from fat malabsorbtion (see our previous post here).

In each of these cases, orphan drug designation was revoked because FDA determined (see 21 C.F.R. § 316.29(a)(3)) that the drug “had not been eligible for orphan drug designation at the time of submission of the request.”  In 2011, FDA denied a petition seeking the revocation of orphan drug designation for MAKENA (then known as GESTIVA), which is another orphan drug the orphan drug exclusivity of which has been in the news as of late (see here).

With respect to the orphan drug designation for WILATE, FDA concluded that although WILATE’s “hypothesis of clinical superiority has not been demonstrated to be true,” that does not mean that the plausible hypothesis of clinical superiority “was implausible ‘at the time the [designation] request was submitted.’  The salient fact is that, at the time Octapharma advanced it, the designation request presented a plausible hypothesis.”  As such, according to FDA, none of the grounds in FDA’s regulation to rescind designation apply.

FDA also denied CSL’s second request concerning “hypothetical claims of superiority,” because “‘hypothetically plausible’ is the very standard that the Agency applies to designation requests under its orphan drug regulations.”

Octapharma submitted comments to the petition docket advancing several arguments.  Among other things, Octapharma claimed that the company has “a Constituionally-protected interest” in the orphan drug exclusivity FDA granted for WILATE, and that FDA may not rescind exclusivity without providing the company an opportunity to defend its exclusivity interest at a formal hearing.  FDA reiterated the Agency’s position that “a manufacturer has no property right in its orphan-drug exclusivity that would entitle it to the sort of process to which Octapharma claims it is entitled.”