FDA Issues Exclusivity Decision for EMEND; Agency Reverses Course and Grants NCE Exclusivity

By Kurt R. Karst –      

Following FDA’s decision, reflected in the October 2009 Orange Book Cumulative Supplement (page A-28), to grant 5-year New Chemical Entity Exclusivity (“NCE”) for EMEND (fosaprepitant dimeglumine) Injection, the Agency has issued an exclusivity determination explaining its decision.  Fosaprepitant is a phosphamide derivative (a type of covalent derivative) and a pro-drug of the previously-approved active ingredient in EMEND (aprepitant) Capsules (NDA No. 21-549).

Under the FDC Act, FDA grants 5-year exclusivity for NCEs.  An NCE is a drug that contains no “active moiety” that has been approved by FDA in another NDA.  An “active moiety” is defined in FDA’s regulations at 21 C.F.R. § 314.108(a) to mean “the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.”  In addition, FDA stated in the preamble to the Agency’s 1989 proposed regulations implementing the Hatch-Waxman Amendments that “[a] compound (other than an ester) that requires metabolic conversion to produce an already approved active moiety is considered a ‘new molecular entity,’ . . . and will be considered a new chemical entity entitled to 5 years of exclusivity. 

Thus, for purposes of determining whether a particular drug product is eligible for 5-year NCE exclusivity, FDA’s Exclusivity Summary completed for each NDA approval asks the following about the chemical structure of a drug:

Has FDA previously approved under section 505 of the Act any drug product containing the same active moiety as the drug under consideration?  Answer “yes” if the active moiety (including other esterified forms, salts, complexes, chelates or clathrates) has been previously approved, but this particular form of the active moiety, e.g., this particular ester or salt (including salts with hydrogen or coordination bonding) or other non-covalent derivative (such as a complex, chelate, or clathrate) has not been approved.  Answer “no” if the compound requires metabolic conversion (other than deesterification of an esterified form of the drug) to produce an already approved active moiety.

According to FDA’s exclusivity determination memorandum, which was added to the Summary Basis of Approval for EMEND (NDA No. 22-023):

Emend for Injection under FDA’s interpretation of 21 CFR § 314.108 should have been classified at the time of approval as an NCE. . . .  Fosaprepitant dimeglumine is a pro-drug phosphoramide derivative of aprepitant.  A phosphoramide is a compound in which one or more of the OR groups of phosphoric acid have been replaced with covalent bonds to an amino or substituted amino group.  Fosaprepitant dimeglumine is neither an ester, salt (including a salt with hydrogen or coordination bonds), nor other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule aprepitant.  It is a covalent phosphoramide derivative.  As a non-ester covalent derivative of aprepitant, under 21 CFR § 314.108, fosaprepitant dimeglumine is a new chemical entity entitled to 5 years of exclusivity.

Fosaprepitant is not the first instance in which FDA has reversed an exclusivity decision.  In October 2004, FDA informed the sponsor of VITRASE (hyaluronidase) Injection that contrary to the Agency’s earlier decision to grant 3-year exclusivity for the product, “[a]fter reviewing information and data regarding hyaluronidase drug products . . . the Agency has decided that 5-year exclusivity is appropriate because we have inadequate information to determine whether any active moiety in Vitrase is the same as any previously approved active moiety.”