A New “Greater Safety” Orphan Drug Clinical Superiority Precedent: PURIXAN

By Kurt R. Karst –      

We like hunting down orphan drug clinical superiority precedents. And although it’s been said that “the thrill is in the chase, never in the capture” (by a Doctor Who character at least), we enjoy the capture just as much as the chase. Earlier this year we put our a scorecard of precedents where FDA determined that an orphan drug is clinically superiority to another drug that is otherwise the same drug for the same orphan condition.  We have two more precedents to add to the scorecard.  Both concern “greater safety” clinical superiority, and put that clinical superiority basis on par with the number of precedents we know of for the so-called Major Contribution to Patient Care (“MC-to-PC”) basis (now seven each). Today, we’re posting on one of those decisions.  We’ll post on the second – and perhaps more interesting precedent – in the coming days. 

We refer to our previous post for a more detailed discussion of orphan drug clinical superiority, but remind folks here that FDA’s orphan drug regulations (21 C.F.R. Part 316) 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. By virtue of showing clinically superior, a drug is not considered the same as a previously approved drug (even if it contains the same active moiety and is approved for the same orphan indication as the previously approved drug), and can be approved notwithstanding a period of orphan drug exclusivity applicable to the previous drug and may obtain its own period of 7-year orphan drug exclusivity.

On August 20, 2012, FDA designated Nova Laboratories Limited’s (“Nova’s”) Mercaptopurine Oral Solution as an orphan drug for the treatment of Acute Lymphoblastic Leukemia (“ALL”) in pediatric patients. Pediatric ALL, which peaks between the ages of 1 and 4 years, is reportedly the most common malignancy diagnosed in children, representing about 23% of childhood cancers.  Nevertheless, in 2012, when Nova requested orphan drug designation, the United States prevalence of pediatric ALL, and, indeed adult and pediatric ALL together, was well below the statutory 200,000 prevalence threshold: about 66,000, according the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program database.

With a drug for a disease that is clearly a rare (orphan) disease, the only obstacle for Nova to overcome seemed to be providing a plausible hypothesis of clinical superiority. You see, FDA previously approved mercaptopurine for the treatment of ALL, including pediatric ALL.  Specifically, FDA approved PURINETHOL (mercaptopurine) Tablets on September 11, 1953 under NDA 009053, which is currently held by Stason Pharmaceuticals.  But the tablet dosage form raised issues for pediatric patients.  According to Nova: 

Presently, a single 50mg strength tablet formulation of [mercaptopurine] is marketed in the United States. Tablet formulations are not acceptable to nearly all pre-school (less than 5 years of age) children and the majority of school-aged children 6-12 years.  As a consequence, children are often given unlicensed liquid formulations of [mercaptopurine] prepared extemporaneously in pharmacies. Alternatively, parents and carers of children are dispensed the tablet form of [mercaptopurine] and therefore have to resort to splitting or crushing the tablet(s) before mixing it into water or food prior to administration.

FDA’s Office of Orphan Products Development agreed with Nova in a July 18, 2012 Memorandum:

The approval by the FDA of mercaptopurine (MF) tablets for the treatment of ALL provides a more than adequate scientific rationale. The issue with this application then becomes whether an oral liquid formulation is clinically superior (i.e., safer or more efficacious) than the approved tablet formulation or a major contribution to patient care. As noted in the November 30, 2009 review of application 09-2863 [from Orbona Pharma Ltd.] for another oral liquid formulation of MP for ALL, there are significant safety issues associated with the use of MP for the treatment ofALL and these safety issues can be compounded when the tablets are manipulated in order to dose pediatric patients.  It is certainly feasible that parents attempting to prepare a dose of MF could accidentally over or underdose their child with serious consequences.  Consequently, an oral iquid formulation of MF would be a “safer” product than the approved tablet formulation by eliminating the need for compounding procedures and thus reducing or avoiding potential serious medication errors. Therefore, for purposes of orphan designation, the sponsor has provided a plausible hypothesis for expecting an oral liquid formulation of MP to be a safer product than the approved tablet formulation of the drug.

FDA ultimately approved Nova’s mercaptopurine drug product for pediatric ALL. In fact, FDA approved the drug for all ALL patients.  Specifically, on April 28, 2014 FDA approved Nova’s NDA 205919 for PURIXAN (mercaptopurine) Oral Suspension, 20 mg/mL, “ for use in pediatric, children, and adult patients for maintenance therapy of [ALL] as part of a combination regimen.” Although PURIXAN was approved for a use broader than the orphan drug designated use (but still an orphan use), FDA granted Nova a period of orphan drug exclusivity that expires on April 28, 2021.