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FDA Advisors Question Study Data Submitted for Dialysis Therapy
The FDA’s Oncologic Drugs Advisory Committee (ODAC) has questioned the clinical meaningfulness of data supporting the use of Triferic (soluble ferric pyrophosphate, Rockwell, Inc.) as an iron replacement and treatment for the maintenance of hemoglobin levels in kidney patients undergoing renal dialysis.
The panel’s opinion comes 1 day ahead of a scheduled meeting of independent experts, who will discuss the product and recommend whether it should be approved.
While the FDA is not obligated to follow the recommendations of its advisory committees, it usually does so.
Triferic was submitted for FDA review as a parenteral iron agent for use in the chronic treatment of iron loss and in the maintenance of hemoglobin, and to reduce the use of erythropoiesis-stimulating agents (ESAs), in adults with hemodialysis-dependent chronic kidney disease (HDD-CKD). The product is supplied as single-use 5-mL ampoules, each containing 27.2 mg of elemental iron (5.44 mg iron/mL) in water for injection.
The efficacy of Triferic was evaluated in two randomized, controlled, phase III clinical trials of identical design (SFP-4 and SFP-5) in 305 and 294 adults, respectively, with HDD-CKD for the proposed indication for the treatment of iron loss or iron deficiency to maintain hemoglobin. The patients received Triferic in dialysate at a concentration of 110 mcg iron/L or placebo (i.e., standard dialysate without Triferic) during each hemodialysis for 3 or 4 times per week.
Randomized treatment was planned to continue for up to 48 weeks. However, only a minority of patients completed the full 48 weeks, partly because of a protocol-mandated change in anemia management (involving changes in ESA and/or iron dosing).
The FDA submission also included data from a phase II study designed to support a labeling statement for the reduction of ESA use in these patients. In this multicenter, randomized, double-blind, placebo-controlled trial, 103 iron-replete patients with HDD-CKD received either Triferic or placebo during dialysis.
The results showed that the subjects receiving Triferic had a mean 12.5% increase in the ESA dose compared with a mean 42.2% increase in the placebo group, but the differences between the two treatment groups did not reach statistical significance (P = 0.098). The secondary efficacy endpoint analysis showed a similar distribution of changes in the prescribed ESA dose between the Triferic and placebo groups (P = 0.915).
The FDA advisors noted that the primary issues regarding efficacy for the “treatment of iron loss of iron deficiency to maintain hemoglobin in adult patients with hemodialysis-dependent stage 5 chronic kidney disease” centered on the fact that although treatment in the two pivotal trials (SFP-4 and SFP-5) was intended to extend to up to 48 weeks, in both studies fewer than 20% of patients in either treatment group (Triferic or placebo) completed 48 weeks of dosing, and approximately 50% of patients completed no more than 20 weeks. Consequently, the advisors said, there was a considerable amount of “missing data” due to discontinuation of study drug by the end of the treatment period.
“The large proportion of patients with early withdrawal from study treatment necessitates examination of the study data to assess the impact of the early discontinuation of patients on the validity and robustness of the efficacy results,” the panel commented.
Further, with regard to the proposed labeling statement “to reduce the prescribed dose of ESAs required to maintain desired hemoglobin levels,” the FDA advisors pointed out that data from only a single, exploratory phase II study were provided.
The committee asked: “Considering the limitations of [this] study, is there substantial evidence to support the desired claim?”
Source: FDA; November 5, 2014.