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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.
The Cooley's Anemia Foundation testified before the US Food and Drug Administration (FDA) for the approval of the iron chelator deferasirox (Exjade) because of the dire need within the thalassemia community for an alternative to treatment by subcutaneous infusion of deferoxamine for the removal of transfusional iron overload.
Individuals born with thalassemia have been struggling for decades to maintain their health and extend their lives utilizing deferoxamine. For most, the burdensome method of administering deferoxamine has had a significant detrimental effect on their ability to maintain compliance with treatment; the drug is safe, but the method of administration seriously impacts its effectiveness.
In addition to the sheer physical difficulty of complying with deferoxamine treatment, many patients often experience psychosocial complications related to the drug and its administration. They feel "chained" to the infusion pump, which affects the image they have of themselves and of how they relate to the world around them. Living with this chronic disease makes them feel different from those around them, as if they do not fit in. The fact that their daily therapy has been more visible and obvious than simply taking an oral compound has added to their self-consciousness. They seek to hide the fact that they have an illness and develop a heightened sense of guilt or shame as a result. This contributes to the difficulty of maintaining compliance, further diminishing the efficacy of the prescribed chelation treatment.
The data pertaining to deferasirox that was submitted to the FDA indicated that efficacy would not be an issue. The Foundation and the thalassemia community looked to the FDA to verify this assessment. More importantly, we looked to the agency to evaluate the drug's safety profile and provide an independent assessment of the data. As long as deferasirox could be determined to be safe, we believed that the relative ease of administration would ensure significantly increased rates of compliance within the patient population.
The decision by the FDA to grant accelerated approval to deferasirox for use in the treatment of patients over the age of 2 with chronic iron overload due to blood transfusions was greeted with hope by members of the thalassemia community, who were excited that a new era of oral chelation had finally reached the United States.
Although this patient population in the United States is small, their needs are great and can vary significantly from patient to patient. Thus, there is a demand for a menu of drugs for alleviating transfusional hemosiderosis, from which physicians may tailor treatment that suits the needs of each patient. We know from experience in other countries, which have for some time had access to an oral chelating alternative, that the existence of options results in more effective treatment.
The approval of deferasirox is an important step forward in making individualized treatment regimens possible in this country. Physicians now have the option of two chelating agents; ideally, they will one day have even more options, as do doctors in Europe, who can choose between deferoxamine, deferasirox, and deferiprone when determining the most appropriate method of removing excess iron from an individual patient.
The thalassemia community commends the FDA for granting accelerated approval to deferasirox, so that patients could begin reaping the benefits of this alternative therapy as quickly as possible. We now depend upon the FDA to remain vigilant in monitoring the follow-up studies recommended as a result of that approval.
The data that were presented to the FDA support the decision for approval; however, preapproval studies almost inevitably leave some questions unanswered. In this instance, the possibility that the drug may in some way contribute to the elevation of serum creatinine levels in some patients deserves to be explored, especially given the high incidence of diabetes among this particular population. In addition, the pediatric registry should provide a larger source of data regarding the effect of the drug on younger patients, and the study focusing on patients with liver iron concentrations < 7 mg Fe/g dw is necessary to determine long-term effects on this patient subset.
Because iron-related cardiac complications are the leading cause of death among this population, specific data about deferasirox's effect in this area is important if doctors are to prevent or treat this complication. We commend the FDA for requesting that the manufacturer provide data on the heart in its phase IV trials. Studies focusing on the coadministration of deferoxamine and deferasirox are also vital, as the possibility that this could result in a substantially greater reduction of iron stores could have considerable significance in patient outcomes.
The recommended studies and appropriate follow-up can provide valuable information that can assist the medical community in utilizing deferasirox in a manner that will provide the greatest benefits to patients.
Deferasirox is still a "young" drug; what effect, if any, long-term studies will have upon cumulative safety and efficacy data is unknown. Carefully designed and monitored studies that look at these and the other issues discussed above are important to the continued survival of the patient population. It is incumbent upon the FDA to ensure that these studies are conducted in the most complete and yet expedient manner.
We recognize that the FDA has in the past been criticized for not demanding that phase IV studies and data submissions meet established deadlines. We will work to push the agency to provide the necessary oversight in this area. It is not acceptable that the study design and follow-up be delayed for any reason.
Novartis is to be applauded for pursuing this alternative chelation option at what must have been considerable expense. And the FDA is to be applauded for recognizing the urgent need for such an alternative. During this critical evaluation period, we hope that all parties will act with vigilance and tenacity to demonstrate that positive outcomes will be realized by the thalassemia patient community, as well as other communities affected by transfusional iron overload.
Gina Cioffi, Esq
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.
1. Borgna-Pignatti C, Cappellini MD, De Stefano P, et al: Cardiac morbidity and mortality in deferoxamine- or deferiprone-treated patients with thalassemia major. Blood 107:3733-3737, 2006.
2. Wood JC, Tyszka JM, Carson S, et al: Myocardial iron loading in transfusion-dependent thalassemia and sickle cell disease. Blood 103:1934-1936, 2004.
3. Drug Safety: Improvement Needed in FDA's Postmarket Decision-making and Oversight Process (Report to Congressional Requesters), pp 1-62. Washington, DC; US Government Accountability Office (GAO-06-402); March 2006.