AMAG Pharmaceuticals ("AMAG") recently filed a Citizen Petition requesting that FDA apply more stringent bioequivalence standards to potential generic versions of its Feraheme® (ferumoxytol) Injection. Feraheme® is a non-biologic complex drug ("NBCD") indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease. Specifically, AMAG requested that FDA: (1) refrain from approving any generic products referencing Feraheme® until post-marketing studies evaluating the therapeutic equivalence another IV iron replacement product to its reference listed drug ("RLD") are complete (Nulecit™ to its RLD Ferrlecit®); (2) require sponsors of generic Feraheme® to show bioequivalence using a comparative study in patients with clinical endpoints; and (3) require generic Feraheme® sponsors to demonstrate bioequivalence using the additional assays being evaluated in the Nulecit™ post-marketing studies.
Ferumoxytol is a colloidal crystal of polynuclear ferric oxyhydroxide encased within a carbohydrate. It is a large, complex chemical entity (approximately 750 kDa) and its chemical structure has not been fully characterized. The carbohydrate serves to encase and sequester the iron moiety until it is taken up by its site of action, the macrophages of the reticular endothelial system ("RES"). In other words, the iron becomes bioavailable only inside the macrophage vesicles. This sequestration function is important because free iron is toxic and causes oxidative stress. Indeed, iron is normally sequestered in the body (e.g. hemoglobin, ferritin) because of this toxicity.
AMAG requests that FDA refrain from approving any generic Feraheme® products until the Nulecit™ post-marketing studies demonstrate that the standards currently established for generic IV iron replacement products are sufficient to therapeutic equivalence. FDA approved Nulecit™ as a generic version of Ferrlecit® in 2011. However, FDA issued a "Sources Sought" notice in April 2013 to determine the availability of third-party businesses to evaluate the therapeutic equivalence of Nulecit™ to Ferrlecit®. In particular, FDA proposed studies of: (1) in vitro phagocytosis to compare RES uptake of generic and RLD; (2) the time-dependent iron content in the major target organs and a comparison of biodistribution in animal models; (3) a prospective, randomized, 2-way crossover study to compare non-transferrin bound iron levels in hemodialysis patients treated with generic and RLD products. AMAG argues that a moratorium on generic approvals of IV iron products is reasonable pending the outcome of these studies. In addition, AMAG requests that FDA require prospective generic applicants perform these studies.