Decisive support of Modeling & Simulation for getting drug approval in the context of safety concern on the drug class
Pascal Chanu (1), Bruno Reigner (1), Nathalie Schultze (1), Ronald Gieschke (1), Nicolas Frey (1)
(1) F. Hoffmann-La Roche Ltd, Basel, Switzerland
Background: Exogenous replacement of erythropoietin by the recombinant hormone, epoetin, is a well-accepted therapy for treatment of anemia in patients with chronic kidney disease (CKD). C.E.R.A, is a new erythropoietin stimulating agent (ESA). In April 2006, a Biological License Application (BLA) was submitted to the US-FDA. In 2007, due to reports of cardiovascular risks associated with high hemoglobin (Hb) levels [1,2], the FDA mandated a labeling change for all ESAs, abolishing longstanding dosing instructions based on Hb targets, specifying instead that the drugs should be administered at the lowest level that avoids transfusions and placing a 12 g/dL ceiling on achieved Hb levels. Phase III trials for C.E.R.A., developed in consultation with FDA, used a Hb target range of 11 to 13 g/dL.
Objectives: To explore, using clinical trial simulations, efficacy and safety clinical outcomes of non-tested dosing regimens and dose adjustment rules for C.E.R.A. in support of the SmPC (Summary of Products Characteristics).
Methods: A population pharmacokinetic/pharmacodynamic model [3,4,5] has been developed in NONMEM 5, using data from three Phase III studies in 400 CKD patients. Its predictive performance was assessed with visual predictive checks after implementation of the model and complex Phase III dose adjustment schemes in Trial Simulator 2.2. Exploratory trial simulations were then performed to investigate different starting doses and dose adjustment rules in accordance with latest recommendations.
Results: The model described the time courses of drug concentrations of C.E.R.A and Hb after subcutaneous and intravenous administrations in both ESA-treated and na´ve patients with CKD. Its predictive performance was confirmed by showing that observed results from Phase III studies could be reproduced using simulations for two selected endpoints (Hb time course, occurrence of Hb values > 13 g/dL). Clinical trial simulations were then used to support the proposed starting dose and modified dose adjustment rules: the simulated occurrence of Hb values greater than 13 g/dL was considerably reduced while efficacy was maintained.
Conclusions: The Modeling & Simulation results were supportive to address the safety concern and provided data that were used to support the dosing instructions sections in the labels. C.E.R.A. was approved in 2007 at EMEA and FDA.
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