Purpose: This report describes the Food and Drug Administration's review of data and analyses leading to the approval of the oral iron chelator, deferasirox for the treatment of chronic iron overload due to transfusional hemosiderosis.
Experimental Design: The FDA reviewed findings of a controlled, open-label, randomized multicenter phase III study of deferasirox vs deferoxamine in 586 patients with beta-thalessemia and transfusional hemosiderosis. The study results as well as the results of the FDA review of chemistry, preclinical pharmacology, and supportive studies are described.
Results: Following 48 weeks of treatment in the phase III study, patients' liver iron concentrations (a key endpoint variable) had decreased an average of 2.4 mg of iron (Fe)/g dry weight (dw) and 2.9 mg Fe/g dw in the deferasirox and deferoxamine groups, respectively, despite continued blood transfusions in both cohorts. Deferasirox was associated with serum creatinine increases in approximately a third of patients. Common adverse events included gastrointestinal symptoms and skin rash. Other data provided supportive evidence of deferasirox safety and efficacy.
Conclusions: The FDA granted deferasirox accelerated approval on November 2, 2005, for use in treating chronic iron overload due to transfusional hemosiderosis in patients ≥ 2 years of age. The sponsor must obtain clinical data demonstrating the drug's long-term safety and effectiveness.
Clinical studies demonstrated that orally administered deferasirox could decrease LIC in a dose-related manner and provided definitive evidence of this agent's efficacy and safety over a 1-year period.
In the confirmatory clinical study, the dose assignment procedures and primary endpoint (a comparison between the two cohorts of "success" in reducing LIC) presented unique challenges in data interpretation. The challenges generally related to two study design limitations: a dosage-tailoring paradigm limited to one study (the deferoxamine group) and the lack of a clinically verifiable basis for estimation of the noninferiority margin incorporated into the study's primary endpoint definition.[16,17] The FDA review of the confirmatory study's findings required consideration of these inherent limitations in study design. Hence, FDA considered the totality of the clinical data, rather than focusing solely upon the somewhat arbitrarily defined primary endpoint.
The standard for FDA approval is demonstration of safety and efficacy. There is no legal requirement for comparative safety and efficacy; ie, a new drug neither has to be more safe and effective nor "noninferior" in safety and efficacy than existing therapies—in this case, deferoxamine. The decrease in LIC baseline to end of study among deferasirox-treated patients became the primary evidence of effectiveness, and the totality of preclinical and clinical data showed that deferasirox administration decreased markers of iron overload in a dose-related manner over a 1-year period.
The data were reviewed at the September 29, 2005, meeting of the FDA Blood Products Advisory Committee. A critical discussion at that meeting concerned the "clinical meaningfulness" of a decrease in LIC, the main measure for assessing drug efficacy in the confirmatory and supportive clinical studies. Advisory Committee members uniformly acknowledged that a reduction in LIC was acceptable as a major determinant of treatment effect. While acknowledging some controversy surrounding the correlation of LIC with iron content within the heart, committee members generally supported the contention that deferasirox-induced alterations in LIC provided a clinically meaningful indication of the drug's therapeutic benefit.
An important limitation of this assessment is that the benefit was observed only over a short (1-year) period (the confirmatory study's duration), during which time important safety concerns were demonstrated. Some of these, such as deterioration in renal function, were strongly predicted by preclinical tests. Others, such as evidence of liver damage and gastrointestinal disturbance, were predicted to a lesser extent by animal testing but may correlate with deferasirox's known metabolic pathway.
On November 2, 2005, the FDA granted deferasirox accelerated approval for the treatment of chronic iron overload due to blood transfusions in patients ≥ 2 years of age. Full prescribing information is available at the FDA website.
The accelerated approval pathway is generally pursued for drugs whose major treatment effects were determined based on alterations in surrogate endpoints (substitute endpoints likely to predict clinical benefit) rather than endpoints that show direct clinical benefit. In the case of deferasirox, however, the accelerated pathway was prompted by the need to obtain long-term data verifying the drug's safety and clinical benefits. The accelerated approval regulations allow this pathway in situations in which a study drug's major treatment effects were shown to affect a clinically meaningful endpoint (such as a change in LIC) but where additional clinical data are necessary to verify the drug's long-term benefit.
Marketing approval of deferasirox presents a new option for Americans with transfusional hemosiderosis, especially patients intolerant of deferoxamine. Over a 1-year period, deferasirox was shown to effectively lower body iron stores with acceptable toxicity. Management of this toxicity either through alterations or interruptions of deferasirox dose necessitates regular monitoring of patients' serum creatinine and liver enzyme values. Additionally, serum ferritin monitoring is recommended to detect evidence of under or overchelation.
Important questions remain regarding the use of chelation therapy, especially prophylactically in patients showing little or no evidence of iron overload. Since the available clinical data for deferasirox were obtained only from patients who had clear evidence of transfusional hemosiderosis at baseline, these data are insufficient to support the drug's prophylactic use in the absence of such manifestations. Additional questions remain regarding the possible coadministration of deferasirox with deferoxamine, an important consideration given the different pharmacokinetic and pharmcodynamic effects of the two drugs and the potential for additive benefit. These and other important issues must be explored in subsequent clinical studies.
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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