FDA More Than Doubles the Number of Orphan Drug Designation Revocations Overnight

By Kurt R. Karst –      

An FDA decision to revoke designation of a drug (or a biological product) as an orphan drug is a rare event.  (Though it’s not as rare as revocation of orphan drug exclusivity, which has happened only once – see our previous post here).  Until recently, we were aware of only three orphan drug designation revocations in the 30-plus year history of the Orphan Drug Act.  That number more than doubled in April 2016 when FDA revoked four orphan drug designations for various drugs for the treatment of hypertension in pediatric patients.

FDA’s orphan drug regulations (21 C.F.R. § 316.29(a)) 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.

Prior to April 2016, we were aware of only three orphan drug designation revocations.  In each of these three cases (shown below), orphan drug designation was revoked because FDA determined that the drug “had not been eligible for orphan drug designation at the time of submission of the request.”  (We also note that in 2011, FDA denied a citizen petition seeking the revocation of orphan drug designation for MAKENA (hydroxyprogesterone caproate) Injection, 250 mg/mL (then known as GESTIVA).)  Specifically, FDA previously rescinded orphan drug designation for:

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).

The four new instances of orphan drug designation revocations that recently appeared on FDA’s Orphan Drug Designations and Approvals database are:

• Valsartan Oral Solution – Designated as an orphan drug on October 28, 2015 for the “treatment of hypertension in pediatric patients 0 through 16 years of age” (Carmel Biosciences)
• Lisinopril Oral Solution – Designated as an orphan drug on January 27, 2015 for the “treatment of primary hypertension with complications and secondary hypertension in pediatric patients (ages 0 through 16 years of age” (BioRamo, LLC)
• Lisinopril Oral Solution – Designated as an orphan drug on October 14, 2015 for the “treatment of hypertension in pediatric patients 0 through 16 years of age” (Silvergate Pharmaceuticals, Inc.)
• Enalapril Maleate (Powder for Oral Solution) – Designated as an orphan drug on January 30, 2013 for the “treatment of hypertension in pediatric patients” (Silvergate Pharmaceuticals, Inc.)

The four new revocations share several similarities.  There are the obvious similarities of indication and timeframe of designation.  But also note that in each instance FDA’s Orphan Drug Designations and Approvals database identifies the dosage form of the designated drug.  That’s unusual and likely indicates that orphan drug designation was granted based on a plausible hypothesis of clinical superiority (perhaps “greater safety” or “major contribution to patient care”) because FDA had previously approved the same drug (i.e., active moiety) for the same rare disease. 

As to FDA’s basis for revoking orphan drug designation for the four drugs above, we suspect that FDA stumbled upon some information that the Agency believed supported withdrawal and then determined that each drug “had not been eligible for orphan drug designation at the time of submission of the request” because the United States prevalence of pediatric hypertension exceeded the 200,000 person cut-off.