Graceway Sues FDA Over Generic ALDARA Cream Decisions; Alleges that Petition Response is Contrary to Basic Science, Common Sense, and Precedent

By Kurt R. Karst –   

Although it took a little longer than we expected, late last week, Graceway Pharmaceuticals, LLC (“Graceway”) sued FDA in the U.S. District Court for the District of Columbia requesting declaratory and injunctive relief with respect to the Agency’s January 2010 denial of a Graceway citizen petition and approval of a generic version of Graceway’s ALDARA (imiquimod) Cream, 5%.

As we previously reported, the primary issue raised in the Graceway petition was whether a generic applicant can demonstrate bioequivalence for a multi-indication Reference Listed Drug (“RLD”) with a comparative clinical trial in just one indication.  Graceway requested that FDA refuse to approve ANDAs for generic versions of ALDARA Cream unless such applications contain, among other things, data from bioequivalence studies conducted in patients with each of ALDARA’s three approved indications – actinic keratoses (“AK”), primary superficial basal cell carcinoma (“sBCC”), and external genital and perianal warts/condyloma acuminata (“EWG”). 

FDA has long held (see e.g., Docket No. FDA-1995-P-0044) that a clinical endpoint bioequivalence study in one indication for a multi-indication RLD can suffice as proof of bioequivalence in another indication when the indications are “related” and involve the “same site of action.” 

In 2008, FDA denied a citizen petition raising issues similar to those in the Graceway petition.  In that case, FDA ruled, in the context of approving ANDAs for generic versions of EFUDEX (fluorouracil) Topical Cream, 5%, which is approved for AK and sBCC, 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.”  FDA’s decision was challenged in court, and, as we previously reported, in September 2009, the U.S. District Court for the Central District of California ruled in FDA’s favor, leaving intact FDA’s stellar batting average in bioequivalence decision court challenges.  (The September 2009 decision falls in between FDA wins (here and here) in challenges concerning generic PROGRAF (tacrolimus) and generic ZOSYN (piperacillin sodium; tazobactam sodium) ANDA approval requirements.) 

FDA concluded in the Graceway petition response that a well-designed study in AK will suffice to show bioequivalence of a generic version of ALDARA for all indications.  Just a few weeks later – on February 25, 2010 – FDA approved Nycomed US Inc.’s (“Nycomed’s”) ANDA No. 78-548 with 180-day exclusivity, even though there was a failure to obtain tentative ANDA approval within 30 months of ANDA submission (see our previous post here).  FDA also issued a draft bioequivalence recommendation for applicants seeking approval of an ANDA for Imiquimod Cream, 5%, in which the Agency, consistent with its petition response, recommends a single clinical endpoint bioequivalence study in the treatment of AK.

Graceway alleges in its complaint, which challenges only FDA’s conclusion that a single clinical endpoint bioequivalence study in the treatment of AK suffices to demonstrate bioequivalence in EWG and not FDA’s determination that a single study in AK patients suffices to demonstrate bioequivalence in sBCC, that:

FDA’s decision not to require bioequivalence studies in patients with [EWG] was based on its unsupportable conclusion that genital warts are “related” to and share the same “site of action” as the other two conditions treated by Aldara, both of which result from sun exposure.  This determination was unsupported by – and in fact, contrary to – basic science, common sense, and the agency’s previous actions in similar situations.  While Graceway is not contesting for the purposes of this lawsuit that AK and [sBCC] may be “related” in the sense that both result from sun exposure, neither has anything in common with genital warts, which appear in the pubic area and are caused by an infectious disease – a sexually-transmitted virus. [(internal citation omitted)]

Graceway expands on both the “related to” and “same site of action” criteria supporting a single clinical endpoint study.  The company states that while “[b]oth AK and sBCC involve abnormal proliferations of cells that arise within the epidermis as a result of sun exposure,” “EGW is a contagious disease caused by a virus that has a fundamentally different pathophysiology than AK and sBCC,” and therefore, “EGW is wholly unrelated to either AK or SBCC.”  In addition, Graceway relies on a March 2009 FDA citizen petition response (Docket No. FDA-2004-P-0215) concerning DERMA-SMOOTHE/FS (fluocinolone acetonide 0.01 % topical oil) in which the Agency noted that skin that is penetrated by “terminal” (i.e., coarse, thick) hairs may have different absorption properties than skin that is penetrated by “vellus” (i.e., thinner, finer) hairs.  According to Graceway:

EGW occurs at a different anatomical location and on different types of skin than AK and sBCC.  While AK and sBCC usually occur on the face, head, and extremities, EGW by definition occurs in the pubic area, an area that is comprised of very different types of skin (e.g., vaginal tissues, the penis, the anus, and the scrotum). . . .  Because FDA itself has recognized [in Docket No. FDA-2004-P-0215] the difference in absorption properties between the types of skin located at the different sites of action for EGW and AK, comparative clinical testing is required in patients with EGW as well as AK before bioequivalence can be shown for the product as a whole.

As a result, Graceway alleges that FDA violated the Administrative Procedure Act, the FDC Act, and the Agency’s implementing regulations in denying the company’s petition and in approving ANDA No. 78-548.  Graceway asks the court for declaratory relief, including a declaration that FDA’s petition response and ANDA approval were unlawful, as well as injunctive relief, including enjoining FDA from approving any further ANDAs for Imiquimod Cream, 5%, until bioequivalence is demonstrated based on a clinical endpoint study in EWG patients and rescinding the approval of ANDA No. 78-548.