FDA Prevails in Challenge to Generic ACETADOTE Approval; Court Grants Summary Judgment

By Kurt R. Karst – 

In a decision handed down on September 30, 2013 (but not unsealed until last Friday), the U.S. District Court for the District of Columbia rebuffed a challenge by Cumberland Pharmaceuticals Inc. (“Cumberland”) to FDA’s approval of a generic version of Cumberland’s acetaminophen overdose treatment, ACETADOTE (acetylcysteine) Injection, 200mg/mL, which is approved under NDA No. 021539.  In granting FDA’s Motion for Summary Judgment and denying Cumberland’s Motion for Summary Judgment (reply briefs here and here), the court found FDA’s November 7, 2012 denial of a May 18, 2012 Citizen Petition (Docket No. FDA-2012-P-0507) sumitted by Cumberland and simultaneous approval of InnoPharma, Inc.’s (“InnoPharma”) ANDA No. 200644 for a generic version of ACETADOTE did not violate the Administrative Procedure Act (“APA”).

As we previously reported, Cumberland sued FDA requesting 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 from the market the EDTA-containing version of ACETADOTE. 

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FDC Act (21 C.F.R. § 314.122 and § 314.161), an ANDA for a generic version of a listed drug that has been voluntarily withdrawn from sale is to be accompanied by a petition seeking a determination as to whether the listed drug was widrawn for safety or effectiveness reasons, and FDA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 May 2012 Citizen petition requested that FDA not approve any ANDAs for generic ACETADOTE containing EDTA.  Cumberland argued that the EDTA-containing version of ACETADOTE was discontinued for safety reasons.  Specifically, Cumberland alleged that “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 November 2012 petition response that available data “do not provide a reasonable basis upon which to conclude that the original, EDTA-containing formulation of Acetadote was unsafe.”   FDA further states that EDTA is a component in several currently marketed drug products – some with higher quantities of EDTA than in “old” ACETADOTE – and 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, granted pursuant to 21 C.F.R. § 314.99(b), of FDA’s so-called “exception excipient” regulations at 21 C.F.R. § 314.94(a)(9)(iii) 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. 

As reflected in the more than 1,800-page administrative record, FDA’s decision on EDTA-containing Acetylcysteine Injection (captured in the Agency’s November 2012 Citizen petition response), was reached after significant debate within FDA.  FDA’s Division of Gastroenterology and Inborn Errors Products (“Gastroenterology Division”) initially recommended in a July 1, 2011 memorandum that the Agency “not accept ANDAs for acetylcysteine injection based on the discontinued formulation” because of concerns about allergic reactions and syncope.  In subsequent meetings to discuss the review of the safety of EDTA-containing Acetylcysteine Injection, representatives from FDA’s Office of Generic Drugs and Office of New Drugs raised concerns with the Gastroenterology Division’s July 2011 opinion.  Specifically, they contended that the Gastroenterology Division’s opinion “appears inconsistent with Agency precedent and potentially unsupportable” because:

(1) there was no recall of the original formulation;
(2) the amount of edetate in Acetadote is comparable to that in approved and currently-marketed propofol products;
(3) the FDA allows both propofol products that contain and do not contain edetate;
(4) there are a number of other products containing edetate in various amounts on the market; and
(5) “[t]here are concerns about drug shortages and the potential problems of having a single supplier of this product.”

Given these concerns, the Gastroenterology Division was asked to reconsider its initial opinion. 

In a subsequent opinion, the Gastroenterology Division determined that “[o]n re-examination of the electronic records of letters and reviews for this NDA, there is no definitive evidence that this [postmarketing commitment] was prompted by specific safety concerns,” and that while “[t]here are potential safety concerns . . . associated with [edetate,] . . . none of these concerns rises to the level that would enable us to conclude that the old formulation of Acetadote[] (with [edetate]) was withdrawn for reasons of safety.”  In reaching this opinion, the Gastroenterology Division acknowledged that “exclusively marketing a non-[edetate] containing product would be preferable because it would eliminate even the potential for risk from [edetate],” but the Division reasoned that “there is a risk to the U.S. population in having only a single source of Acetadote[] available for treating [the] life[-]threatening condition of acetaminophen poisoning (i.e., concerns about future drug shortages, which could be devastating in this case).”

In considering whether FDA’s determination that the original, EDTA-containing formulation of ACETADOTE was withdrawn for safety reasons violated the APA, Judge Reggie B. Walton said he was “unconvinced by Cumberland’s attempts to discredit the FDA’s determination.”  Specifically, Judge Walton wrote in his opinion: 

Cumberland’s chief argument in support of its claim that the FDA’s decision is arbitrary and capricious is that the decision is not adequately supported by the evidence before the agency.  Cumberland contends that the FDA reversed its position regarding the safety of edetate-containing Acetadote, pointing to the postmarketing commitment the FDA elicited during the approval process for Acetadote and the July 1, 2011 Gastroenterology Division opinion as evidence that the agency “had, and continues to have, safety concerns about the [edetate]-containing formulation of Acetadote” . . . .  The Court’s review of the administrative record shows that it supports the FDA’s determination that the original formulation of Acetadote was not withdrawn for safety reasons. . . .

Moreover, even if the FDA’s request for the postmarketing commitment was based on safety concerns, such a motivation is not necessarily inconsistent with the challenged determination here.  Having concerns about the safety of an ingredient and even expressing a preference for a formulation that does not contain it is not the same as definitively believing the ingredient to be unsafe or requiring a manufacturer to remove an ingredient. . . .  And, as the FDA points out, it would not have approved Cumberland’s NDA for edetate-containing Acetadote if it had significant concerns regarding the product’s safety.

Cumberland had made much ado about the “about-face” FDA made after the Gastroenterology Division’s initial July 1, 2011 memorandum.  But Judge Walton, citing his earlier decision in Graceway Pharms., Inc. v. Sebelius, 783 F. Supp. 2d 104, 113 (D.D.C. 2011) (see our previous post here), in which there was a disagreement among various FDA components, said that Cumberland’s emphasis on internal debate within FDA is misplaced:

Because the Court’s inquiry here must consider the record in its entirety, the fact that a single memo in the record recommended finding that Cumberland withdrew the original formulation of Acetadote for safety reasons is not dispositive.  Admittedly, the Gastroenterology Division’s July 1, 2011 report is at odds with the FDA’s final conclusion.  However, disagreement among agency staff during the decisionmaking process does not fatally undermine the agency’s final determination, nor does it alone justify according the agency’s final decision less deference than usual.

Cumberland also took issue with two considerations included in the Gastroenterology Division’s later opinion: (1) the possibility of drug shortages if there is only one manufacturer of Acetylcysteine Injection; and (2) FDA’s failure to recall the original formulation of ACETADOTE.  Dispensing with these arguments, Judge Walton wrote that “[w]hile this document is part of the administrative record used to assess whether the FDA’s decision was arbitrary and capricious . . .  this Court’s review of the FDA’s decision must be on the reasons stated for the decision in Dr. Woodcock’s response to the [two] citizen petitions, not other reasons given by agency staff elsewhere in the record.”

Moving on to FDA’s waiver of the Agency’s so-called “exception excipient” regulation at 21 C.F.R. § 314.94(a)(9)(iii) for generic versions of injectable drug products, Judge Walton said that “[h]aving concluded that the Court must affirm the FDA’s determination that the edetate-containing version of Acetadote was not withdrawn for reasons of safety, Cumberland’s objection to the FDA’s grant of a waiver of the regulatory requirement that a proposed ANDA drug contain identical inactive ingredients as the reference listed drug to InnoPharma must also fail.”  The court found FDA’s decision to grant a waiver to InnoPharma pursuant to 21 C.F.R. § 314.99(b) in order to permit the company’s proposed EDTA-containing Acetylcysteine Injection was in accordance with the FDC Act and applicable regulations.

Cumberland had argued that it was arbitrary and capricious for FDA to have granted a waiver to InnoPharma to market an EDTA-containing formulation of Acetylcysteine Injection when the Agency “has consistently preferred that Cumberland, if possible, reduce or remove [edetate] from its product.”  But Judge Walton did not find FDA’s actions inconsistent.  “On the contrary,” wrote Judge Walton, “the FDA is allowing InnoPharma to market an edetate-containing generic version of Acetadote, just as it permitted Cumberland to market an edetate-containing formulation of the drug.”  Seeing no inconsistency in FDA’s treatment of Cumberland and InnoPharma, Judge Walton found FDA’s grant of a waiver to InnoPharma was not arbitrary and capricious.