FDA Sued After Denying Citizen Petition and Approving Generic EFUDEX Cream ANDA; Agency Will Reconsider ANDA Approval

May 19, 2008

Valeant Pharmaceuticals International’s (“Valeant’s”) EFUDEX (fluorouracil) Topical Cream, 5%, (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.  In December 2004, Valeant submitted a citizen petition to FDA requesting that the Agency not approve any Abbreviated New Drug Application (“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 argues 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 EfudexÒ 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 Pharmaceuticals, Inc.’s (“Spear’s”) ANDA #77-524 for Fluorouracil  Cream, 5%.  Citing judicial precedent upholding FDA’s authority to determine the appropriate methods to determine bioequivalence, the Agency states 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 concludes 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.” 

Two weeks after denying Valeant’s petition and approving Spear’s ANDA, Valeant sued FDA on April 25, 2008 in the U.S. District Court for the Central District of California (Southern Division) for declaratory and injunctive relief pursuant to the Administrative Procedure Act (“APA”).  Specifically, Valeant requests in the company’s complaint that the court declare FDA’s decision to approve ANDA #77-524 unlawful and invalid and order FDA to suspend ANDA approval.  Valeant also seeks a Temporary Restraining Order (“TRO”) compelling FDA to suspend ANDA approval.  (Valiant’s TRO is filed under seal.)  FDA, as the Agency did in its petition response, argues in its TRO opposition memorandum that the Agency has broad discretion to determine the appropriate requirements for a generic applicant to demonstrate bioequivalence.  Furthermore, FDA argues that its petition decision and ANDA approval are entitled to deference under the APA, and that Valeant has not met the requirements to support a TRO.  Spear, which has intervened in the case, makes similar arguments in its TRO opposition papers and also alleges that Valiant’s lawsuit and citizen petition are merely tactics to block or delay generic competition.  (Valiant’s petition was submitted to FDA prior to the enactment of the FDA Amendments Act, which amended the FDC Act to require FDA to take final action on certain petitions that would delay generic drug approval within 180 days after petition submission.)

After submitting its TRO opposition papers, FDA became aware of an “administrative issue” and “an additional issue concerning Spear’s ANDA which, in the agency’s judgment, necessitates administrative reconsideration of the ANDA approval,” and requested that the court stay proceedings and refer the matter to FDA.  On May 14, 2008, FDA issued an “Administrative Reconsideration and Stay of Action” to Spears staying the approval of ANDA #77-524, and the company has since suspended selling the drug product.  FDA hopes to complete its review of these issues and the administrative reconsideration process by May 30, 2008.  Until then, further litigation is stayed.

It is unclear what, exactly, the two issues are that led FDA to suspend the approval of ANDA #77-524.  According to FDA’s Orange Book, EFUDEX Cream, 5%, is not subject to any period of patent or non-patent market exclusivity, so the administrative and scientific issues referred to by FDA would not appear to involve such issues.  We will update you as we learn additional information.

By Kurt R. Karst    


Categories: Hatch-Waxman