FDA – Study on Iron Species in Healthy Subjects with Generic and Reference Sodium Ferric Gluconate

After intravenous administration, iron colloid particles are processed by phagocytes and iron ions are delivered to the lysosomes within the cell as part of the intracellular labile iron pool. The phagocyte uptake and biodistribution of iron complex particles depend upon their physicochemical properties. If iron is not needed immediately, it is stored in the form of ferritin or hemosiderin. When the iron is needed in the body, iron is released from the cell and transferrin binds iron ions and delivers them to their destination. If transferrin is oversaturated or if the iron complex product is so unstable that iron is spontaneously released at a rate that exceeds transferrin binding capacity, non-transferrin bound iron (NTBI) is formed in the plasma. NTBI can be toxic to cells as it acts as a catalyst in the formation of free radicals from reactive oxygen species.

In March 2011, FDA approved the first generic sodium ferric gluconate iron complex Nulecit™, an alternative to Ferrlecit®. FDA’s approval of generic iron complex products was based on equivalence in formulation composition (qualitatively and quantitatively the same), product physicochemical characteristics, as well as equivalence in in vivo pharmacokinetic. Products that meet these approval standards should have no significant difference in NTBI.

Since 2008 there are multiple reports about the safety and efficacy of generic iron colloid products on the European and Asian markets. These products have caused public concerns and have been cited in several citizen petitions that question FDA’s equivalence recommendations for iron sucrose and sodium ferric gluconate complex in sucrose injection. On March 17, 2011, the European Medicines Agency published the Reflection Paper on Non-Clinical Studies for Generic Nanoparticle Iron Medicinal Product Applications. This paper suggested that generic iron formulations could have higher levels of labile iron, leading to the formation of a greater amount of nontransferrin-bound iron in vivo than the RLD that would potentiate oxidative stress and inflammation and result in direct cellular damage and possibly increasing the risk of atherosclerotic disease. This paper concluded that “Comparative data from non-clinical studies on the time-dependent iron content in the major target organs may be used to support the claim of essential similarity of generic and reference nanoparticle iron medicinal products”.

To confirm the agency’s approval criteria and bridge the gap between equivalence standards from FDA and EMA, well controlled and prospective studies that compare NTBI levels between brand and generic in healthy subjects may be needed.

Objective:
The objective of this study is to conduct in vivo studies to compare plasma total iron (TI), transferrin bound iron (TBI), non-transferrin bound iron (NTBI) levels and oxidative stress after i.v. administration of RLD and generic sodium ferric gluconate injections in healthy subjects. This study is part of post-market surveillance on approved generic products, which can help address potential concerns regarding the quality of generic iron complex products and support the Agency’s review standards.

Detailed Descriptions:
A prospective, randomized, 2-way crossover study to compare plasma TI, TBI, NTBI levels in healthy subjects treated with generic and reference sodium ferric gluconate injections is preferred. Utilize in vitro and in vivo biomarkers such as malondialdehyde, heme-oxygenase-1 (HO-1) RNA or others to evaluate the oxidative stress and toxicity caused by generic and RLD products.

1. Collect marketed brand and generic sodium ferric gluconate products and compare them in terms of potency, impurity, and other drug product quality attributes.

2. Develop bio-analytical methods to determine plasma TI, TBI, and NTBI concentrations.

3. Conduct a prospective, randomized, 2-way crossover study to compare plasma TI, TBI, NTBI levels in healthy subjects treated with generic and RLD. Monitor TBI, total iron binding capacity and serum ferritin level during washout period to ensure iron storage and transport has returned to baseline.

4. Evaluate the oxidative stress and toxicity caused by generic and RLD using in vitro and in vivo biomarkers.

5. Monitor any side effects or adverse reactions during the study period.

6. Conduct statistical analysis to determine whether there are any significant differences between generic and RLD in NTBI level and others.