FDA Racks Up Another Win in Bioequivalence Litigation; This Time Over Generic EFUDEX

By Kurt R. Karst –      

Consistent with recent wins concerning generic PROGRAF (tacrolimus) and generic ZOSYN (piperacillin sodium; tazobactam sodium) Injection (here and here), the U.S. District Court for the Central District of California recently ruled that FDA’s April 2008 denial of a citizen petition and decision to approve Spear Pharmaceuticals, Inc.’s (“Spear’s”) ANDA No. 77-524 for a generic version of Valeant Pharmaceuticals International’s (“Valeant’s”) EFUDEX (fluorouracil) Topical Cream, 5%, did not violate the Administrative Procedures Act (“APA”).

EFUDEX (also known as 5-FU) is a locally-acting antineoplastic drug product FDA first approved in July 1970 for the topical treatment of multiple actinic or solar keratoses (“AK”).  In 1976, FDA approved the drug for a second indication – for the topical treatment of superficial basal cell carcinomas (“sBCC”) when conventional methods are impractical.  As we previously reported, in December 2004, Valeant submitted a citizen petition to FDA requesting that the Agency not approve any ANDA for a generic version of EFUDEX Cream unless the application contains data from an adequately designed comparative clinical study conducted in sBCC subjects.  Specifically, Valeant argued in the company’s petition that:

The inadequate treatment of sBCC can lead to serious complications for patients, including the growth of their cancer. In that light, . . . is critical that FDA not make assumptions about whether a proposed generic product will be safe and effective in treating sBCC, based on a showing of comparable efficacy in patients with AK. These two conditions occur at different sites of drug action and exhibit different growth patterns. Comparable absorption of a drug to one site of action does not demonstrate comparable absorption to another, more difficult to reach site of action. Similarly, comparable efficacy in an easier to treat condition does not demonstrate comparable efficacy in a more difficult to treat condition. 

For these reasons, FDA must not allow onto the market generic versions of Efudex Cream until a demonstration of bioequivalence has been made, at a minimum, in patients with sBCC.

On April 11, 2008, FDA denied Valeant’s petition and approved Spear’s ANDA.  Citing judicial precedent upholding FDA’s authority to determine the appropriate methods to determine bioequivalence, the Agency stated in its petition response that “even when clinical trials are needed, it has not been the Agency’s policy to require that bioequivalence be shown in every indication if drug release from the dosage form and appearance at the or sites of activity has been demonstrated.”  Furthermore, FDA concluded that “an AK bioequivalence study is sufficient to establish that the generic topical 5-FU formulation will be available in the epidermis and the upper dermis to act on both AK and sBCC lesions to an extent that is comparable to Efudex Cream.” 

Valeant promptly sued FDA in the U.S. District Court for the Central District of California for declaratory and injunctive relief pursuant to the APA.  Spear intervened in the case.  After discovering a “potential conflict of interest . . . that could cause it to revisit the approval status of the ANDA,” FDA issued an Administrative Reconsideration and Stay of Action to Spear staying the approval of ANDA  No. 77-524.  After resolving that issue, FDA reaffirmed the approval of the Spear ANDA.  Valeant moved for summary judgment on the basis that FDA – specifically, the Office of Generic Drugs (“OGD”) – failed to defer to the views of scientists within the Division of Dermatology and Dental Products in FDA’s Office of New Drugs (“OND”), who had determined that a study in AK patients alone was insufficient to establish bioequivalence, but rather that “both AK and sBCC should be studied to yield independent confirmation of bioequivalence for these indications.”  FDA and Spear also moved for summary judgment (here and here) on the basis that FDA’s approval action was proper under the APA, in that “the authorized decision maker in connection with Spear’s original approval was [OGD], not the dermatologists in [OND] . . . .”

In granting FDA’s and Spear’s summary judgment motions, the court commented that:

Valeant has offered no evidence that the FDA actually ignored the opinions of its dermatology experts.  The FDA simply did not defer to those opinions. . . .  [D]eference is owed to the decisionmaker authorized to speak on behalf of the agency, not to each individual agency employee. . . .  In this case, the authorized decision maker in connection with Spear’s original approval was the Office of Generic Drugs, not the dermatologists in the Office of New Drugs . . . . [(internal quotation and citation omitted)]

The district court’s decision leaves intact FDA’s stellar batting average in bioequivalence decision court challenges.  Courts have uniformly held that FDA’s bioequivalence determinations fall squarely within the broad discretion of the Agency – see, e.g., Glaxo Group v. Leavitt, AMD 06-469 (D. Md., Mar. 6, 2006) (Davis, J.) (unpublished opinion); Schering Corp. v. FDA, 51 F.3d 390 (3d Cir. 1995); Schering Corp. v. Sullivan, 782 F. Supp. 645 (D.D.C. 1992), vacated as moot sub nom. Schering Corp. v. Shalala, 995 F.2d 1103 (D.C. Cir. 1993); Somerset Pharms., Inc. v. Shalala, 973 F. Supp. 443 (D. Del. 1997); Bristol-Myers Squibb Co. v. Shalala, 923 F. Supp. 212 (D.D.C. 1996); Fisons Corp. v. Shalala, 860 F. Supp. 859 (D.D.C. 1994).

Interestingly, FDA has been asked to rule on another bioequivalence issue similar to that raised by Valeant in its citizen petition, but this time in the context of ALDARA (imiquimod) Cream, 5%, which is approved for AK, sBCC, and External Genital Warts (“EGW”).  Earlier this year, Graceway Pharmaceuticals, LLC ("Graceway") submitted a citizen petition to FDA requesting that the Agency refrain from approving any ANDAs for a generic version of ALDARA Cream unless an ANDA contains data from bioequivalence studies conducted in patients with each of ALDARA’s approved conditions, including sBCC and EWG, and pharmacokinetic studies under maximal use conditions in patients with EGW and AK.  Graceway states in its petition that “[t]he straightforward application of FDA’s reasoning in the Efudex matter mandates that an ANDA for a generic version of Aldara contain data from a bioequivalence study in patients with EGW and a separate study in patients with sBCC.”