Cumberland Sues FDA After the Agency Denies Citizen Petition and Approves Generic ACETADOTE

By Kurt R. Karst –      

Earlier this week, Cumberland Pharmaceuticals Inc. (“Cumberland”) filed a Complaint in the U.S. District Court for the District of Columbia challenging FDA’s November 7, 2012 denial of a Citizen Petition (Docket No. FDA-2012-P-0507) and approval of InnoPharma, Inc.’s (“InnoPharma’s”) ANDA No. 200644 for a generic version of Cumberland’s  acetaminophen overdose treatment, ACETADOTE (acetylcysteine) Injection, 200mg/mL, which is approved under NDA No. 021539.  Cumberland alleges that FDA’s actions violate the FDC Act and the Administrative Procedure Act (“APA”) and requests that the court set aside FDA’s approval of ANDA No. 200644 and order FDA not to accept for review or approve any ANDA for generic ACETADOTE containig edetate disodium (“EDTA”).

FDA approved a formulation of ACETADOTE on January 23, 2004 containing the chelating agent EDTA with a postmarketing study commitment that Cumberland “evaluate the potential benefit of [EDTA] on the stability of the drug product.”  Cumberland conducted the evaluation, and on January 10, 2011, FDA approved a Suppemental NDA for an EDTA-free formulaton of ACETADOTE.  Cumberland then withdrew the EDTA-containing version of ACETADOTE from the market. 

After the issuance and Orange Book listing of information on a patent covering EDTA-free ACETADOTE, and subsequent notices of ANDA Paragraph IV certifications, Cumberland learned that FDA had received and was reviewing ANDAs for EDTA-containing versions of generic ACETADOTE.  In addition, in May 2011, a Citizen Petition (Docket No. FDA-2011-P-0339) was submitted to FDA requesting that the Agency make a determination as to whether the discontinued, EDTA-containing version of ACETADOTE was discontinued for reasons of safety or effectiveness.  Under FDA’s regulations implementing the FDC Act (21 C.F.R. § 314.122 and § 314.161), an ANDA for a generic version of a listed drug that has been voluntarily withdrawn from sale is to be accompanied by a petition seeking a determination as to whether the listed drug was widrawn for safety or effectiveness reasons, and FDA must make such a determination before approving an affected ANDA.

Cumberland’s Citizen petition, which was submitted to FDA in May 2012, requests that FDA not approve any ANDAs for generic ACETADOTE containing EDTA.  Cumberland argues that the EDTA-containing version of ACETADOTE was discontinued for safety reasons.  According to Cumberland, “EDTA has generally been associated with adverse events, such as significant drops in serum calcium levels, which might result in fatality, hypokalemia, hypomagnesemia, or hypotension,” “EDTA has also been associated with adverse events such as syncope, and allergic contact dermatitis,” and “[a]llergic reactions to EDTA may lead to a problematic interruption of therapy that occurs while these reactions are treated.”  FDA says in the Agency’s petition response, however, that available data “do not provide a reasonable basis upon which to conclude that the original, EDTA-containing formulation of Acetadote was unsafe,” and notes that EDTA is a component in several currently marketed drug products – some with higher quantities of EDTA than in “old” ACETADOTE.  FDA concludes that “although there is a theoretical safety concern with EDTA in Acetadote . . . . we have insufficient evidence to conclude that the original formulation was withdrawn for reasons of safety.” 

Given FDA’s determination, as well as a waiver of FDA’s so-called “exception excipient” regulations for generic versions of injectable drug products that differ from the RLD in formulation (something other than a permitted difference in preservative, buffer, or antioxidant), FDA was able to approve InnoPharma’s ANDA No. 200644.  (See our prior post concerning a challenge to the approval of generic ZOSYN for a discussion FDA’s excipient regulations.)

Cumberland alleges in the company’s Complaint that:

FDA’s denial of Cumberland’s Citizen Petition and acceptance for review and approval of InnoPharma’s acetylcysteine injection ANDA is in violation of the FDCA because Cumberland’s original EDTA-containing Acetadote® formulation was withdrawn for reasons of safety and replaced by an EDTA-free formulation.  As such, FDA cannot lawfully approve an ANDA under section 505(j)(4)(H) of the FDCA for acetylcysteine injection containing EDTA because the EDTA-containing formulation was withdrawn for reasons of safety.

FDC Act § 505(j)(4)(H) states that FDA must approve an ANDA unless, among other things:

information submitted in the application or any other information available to [FDA] shows that (i) the inactive ingredients of the drug are unsafe for use under the conditions prescribed, recommended, or suggested in the labeling proposed for the drug, or (ii) the composition of the drug is unsafe under such conditions because of the type or quantity of inactive ingredients included or the manner in which the inactive ingredients are included.

FDA’s regulations implementing FDC Act § 505(j)(4)(H), generally, are found in the Agency’s ANDA content and format regulations at 21 C.F.R. 314.94.  Pertinent regulations on inactive ingredient changes for generic parenteral drug products are set forth in 21 C.F.R. § 314.94(a)(9). 

Cumberland also alleges that FDA’s petition denial and ANDA approval “without requiring InnoPharma to demonstrate that an EDTA-containing formulation is as safe as the reference-listed drug . . . is fundamentally inconsistent with the agency’s previous decision to require Cumberland to undertake the postmarketing study of Acetadote® . . . and is thus, arbitrary and capricious.”  Finally, Cumberland alleges that FDA’s waiver of the Agency’s exception excipient regulation permitting the approval of ANDA No. 200644 violates the APA in that it is arbitrary and capricious and otherwise not in accordance with law.