Regulatory Decision Summary for Nat-Lanthanum

Since the binding of dietary phosphorus occurs in the lumen of the stomach and upper small intestine, plasma lanthanum concentrations are not predictive of lanthanum carbonates efficacy, and therefore, the use of a conventional comparative bioavailability approach to demonstrate lanthanum bioequivalence between two products would be meaningless. Furthermore, due to low bioavailability of lanthanum (less than 0.002%), an alternative assessment method is required.

This ANDS followed the approach described in the most recent United States Food and Drug Administration (US FDA) draft guidance document on Lanthanum Carbonate published in May 2017. As per this document, an in vitro approach can be used to replace the conventional human pharmacokinetic in vivo studies in assessing the bioequivalence of two lanthanum immediate-release drug products. In vitro dissolution, phosphate equilibrium binding and phosphate kinetic binding studies are recommended to establish bioequivalence of the test and reference tablets. Alternatively, equivalence can be demonstrated in vivo by conducting a study using pharmacodynamic endpoints in healthy subjects.

In accordance with the in vivo approach described in the aforementioned US FDA draft guidance, the sponsor has conducted and submitted results from a multiple dose two-way crossover pharmacodynamic equivalence study comparing 1 x 1,000 mg NAT-Lanthanum tablets versus 1 x 1,000 mg Fosrenol tablets (Shire Pharma Canada ULC) administered three times a day for three days in 45 healthy adult male volunteers under fed conditions.

The primary pharmacodynamic variable used for equivalence assessment was the average daily urinary phosphate excretion over three days. The difference between the test and the reference formulations in average daily urinary phosphate excretion (least squares [LS] mean and 90% confidence interval [CI]) was estimated and compared with a reference interval representing ±20% of the LS mean value for the reference formulation. As per the protocol, and in accordance with previous studies conducted in support of subsequent entry products submitted to the US FDA, pharmacodynamic equivalence was claimed since the 90% CI was completely contained within the reference interval.

In vivo data were only submitted for the 1,000 mg strength of NAT-Lanthanum tablets. The sponsor has requested a waiver of the requirement to conduct studies with the proposed 250, 500 and 750 mg strengths as per the Therapeutic Products Directorate Policy "Bioequivalence of Proportional Formulations - Solid Oral Dosage Forms" (March 7, 1996).