FDA Declares Drug Product Removed for Safety Reasons

Acthar Gel Synthetic (seractide acetate) injection, 80 units/mL and 40 units/mL, was the subject of NDA 017861, approved for Armour Pharmaceuticals on February 21, 1978, but was never marketed by the company.  A Federal Register notice (here) announces the FDA’s determination that the product, that was ultimately withdrawn in 2014, due to failure to submit an Annual Report, was withdrawn for safety reasons.  When a product has never been marketed, the FDA considers the product with the same status as one that has been withdrawn (even though this product was actually eventually withdrawn).  Thus, for permission to submit an ANDA for the product, a person must petition the Agency for a finding that, though the product was never marketed, that failure to market was not for safety or efficacy reasons before an ANDA could be found acceptable.

The FDA describes the reasons for its decision as follows:

“The labeling for ACTHAR GEL SYNTHETIC describes the product as “a highly purified synthetic polypeptide containing thirty-nine amino acids in the sequence described for human corticotropin by Lee, T.H.; Lerner, A.B.; and Buettner-Janusch, Vina (J. Biol Chem, 236:2970- 2974, Nov. 1961)” (Refs. 1 and 2). At the time of ACTHAR GEL SYNTHETIC’s approval, FDA believed the amino acid sequence described by Lee et al. was the correct sequence for human corticotropin and, therefore, that ACTHAR GEL SYNTHETIC was identical to human corticotropin.2 However, since approval, the Agency has learned that ACTHAR GEL SYNTHETIC is not identical to the human corticotropin sequence. We [the FDA] now know that the amino acid sequence described by Lee et al. is a deamidated version of human corticotropin that differs from full length human corticotropin at four positions. The fact that ACTHAR GEL SYNTHETIC has a different amino acid sequence from human corticotropin raises significant safety concerns.  Due to its different amino acid sequence, ACTHAR GEL SYNTHETIC might have a structure or function that is not recognized as endogenous by the immune system.  ACTHAR GEL SYNTHETIC thus poses a higher risk of immunogenicity than a synthetic peptide product that is, in fact, identical to human corticotropin. The health consequences of immunogenicity range from subacute, minor reactions to severe, even deadly, reactions (e.g., anaphylaxis). In addition, frequent stimulation of the immune system could produce antibodies that cross-react with human corticotropin and other closely related endogenous peptides, resulting in the loss of those peptides’ physiological functions.”

There are not many times that the FDA finds that a product, post-approval, that is discontinued from marketing or has never been marketed, was removed from the market for safety or efficacy reasons. It is important to note that this product differs from the human corticotropin in other approved or discontinued Acthar Gel or human corticotropin products found in the Orange Book.  This fact is not lost on the potential implications of the product’s similar names.