All for One and One for All – FDA Denies Graceway Petition on Generic ALDARA Cream

By Kurt R. Karst –      

Late last month, FDA denied a citizen petition submitted by Graceway Pharmaceuticals, LLC (“Graceway”) requesting that the Agency refuse to approve Abbreviated New Drug Applications (“ANDAs”) for generic versions of Graceway’s ALDARA (imiquimod) Cream, 5%, unless such applications contain, among other things, data from bioequivalence studies conducted in patients with each of ALDARA’s approved conditions – actinic keratoses (“AK”), primary superficial basal cell carcinoma (“sBCC”), and external genital and perianal warts/condyloma acuminata (“EWG”) – and pharmacokinetic studies under “maximal use” conditions in patients with EGW and AK.  ALDARA is approved under NDA No. 20-723.

The primary issue raised in the Graceway petition – whether an generic applicant can demonstrate bioequivalence for a multi-indication Reference Listed Drug with a comparative clinical trial in just one indication – was the topic of another citizen petition FDA denied in 2008.  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 in September 2009, the U.S. District Court for the Central District of California ruled in FDA’s favor. 

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.”  FDA disagreed, and concluded that a well-designed study in AK will suffice to show bioequivalence of a generic version of ALDARA:

[T]here is a reasonable scientific basis for concluding, and the Agency has in fact concluded, that the successful demonstration of equivalent drug delivery in AK is sufficient to show bioequivalence.  This conclusion is based on considerations including the following: (a) the site of topical imiquimod action is the same for all three conditions, (b) all three conditions are “related” in that they are responsive to topical treatments, such as imiquimod, that enhance local and cell-mediated immunity, (c) treatment success is dependent upon the induction of an effective host immune response in immunocompetent individuals, and (d) the stratum corneum is the primary barrier to topical drug delivery.

More generally, FDA commented that:

For a drug product with multiple indications, one aspect of appropriate study design is the choice of which indication or indications to study.  It is the Agency’s policy to require only those studies necessary to assess bioequivalence – if bioequivalence can be shown for a multiindication drug with a comparative clinical trial in just one indication, the other indications need not be studied. . . .

[W]hen the site of action is the same for all indications of a multi-indication drug, there is generally no need to conduct a comparative clinical study in more than one of those indications to show bioequivalence.  That is, clinical endpoint data from one indication showing equivalent drug delivery at the site of action are suffcient when all indications share the same site of action.  The question then becomes which indication or indications should be studied.  The answer will depend on the specific product.  For some products there may be a scientific basis for concluding that a study in one indication would be significantly more sensitive or discriminating than a study in any of the other indications, whereas for other products this may not be the case.

Whether Graceway will challenge FDA’s decision in court is unclear.  Regardless, we note that courts have uniformly held that FDA’s bioequivalence determinations fall squarely within the broad discretion of the Agency.

FDA is expected to rule on a second Graceway petition later this month.  In that petition, Graceway requests that FDA not approve any ANDA or 505(b)(2) application for a generic version of ALDARA Cream that substitutes another ingredient(s) for isostearic acid, unless the applicant has demonstrated that any substituted inactive ingredient does not affect the safety of the drug product by providing certain data, and that if such data are from animal or clinical investigations (other than bioavailability and bioequivalence studies), FDA should refuse to approve an ANDA and require the submission of a 505(b)(2) application.