FDA: carta al NEJM sobre Rosiglitazona

To the Editor: In his Perspective article (Aug. 30 issue),1 Dr. Rosen discusses the recent Food and Drug Administration (FDA) advisory committee meeting on rosiglitazone. He also calls for approval of antidiabetic drugs based on long-term clinical outcomes, not on the surrogate of glycated hemoglobin, a measure of glycemic control. Although he does not describe a specific study, we assume he is suggesting that approval should require evidence that cardiovascular events, a major long-term complication of diabetes mellitus, are reduced. This change could have major implications for the availability of treatments for type 2 diabetes. All drugs currently approved for the treatment of diabetes are indicated to improve glycemic control. Reductions in glycated hemoglobin levels directly reflect improved glycemic control, leading to a lessening of hyperglycemic symptoms, including polydipsia, polyuria, and blurred vision. In this respect, the FDA views a reduction in the level of glycated hemoglobin as a well-validated surrogate for a beneficial effect on the immediate clinical consequences of diabetes.

There are reasonably strong data supporting a reduced risk of microvascular complications with improved long-term glycemic control,2,3 although not for most individual drugs, and no drug carries a claim for such an effect. Clear evidence of a reduced risk of macrovascular complications in type 2 diabetes associated with any antidiabetic agent has yet to be established.4 Because patients with type 2 diabetes have progressive worsening of glycemic control over time, long-term trials will probably need to compare one drug within a multidrug regimen with other available therapies, making demonstration of the effect of any single drug a formidable task.

A proposal to base future approvals on evidence of long-term cardiovascular benefit would significantly delay the availability of new drugs for the treatment of diabetes and might make development of new drugs impossible. One would also need to question why existing therapies, all lacking such evidence of benefit, should persist. This concern does not minimize the importance of determining whether the treatment of diabetes with antidiabetic drugs reduces long-term cardiovascular complications. Such an effect is, after all, one of the major intents of the treatment of diabetes.

A separate issue raised in the case of rosiglitazone, but one that is not limited to treatments for diabetes, is whether a drug might have adverse cardiovascular effects. For rosiglitazone, the recommendations of the advisory committee are currently under consideration by the FDA. The FDA considers cardiovascular safety matters during premarketing review and postmarketing activities, particularly when there is a safety signal that raises a concern. For this very reason, we recently requested a phase 3 clinical outcome trial of an investigational antidiabetic drug on the basis of safety concerns noted in preclinical and phase 2 studies, despite evidence of an effect on glycemic control.

We agree that a better understanding of the cardiovascular benefits and risks of antidiabetic drugs is needed. For new antidiabetic drugs, a reasonable approach might be to approve new entities on the basis of improved glycemic control and to ensure that well-designed, long-term studies comparing the new treatment with established therapy, with cardiovascular outcomes as end points of interest, are conducted in a timely manner after approval. This approach merits further discussion.


Hylton V. Joffe, M.D., M.M.Sc.
Mary H. Parks, M.D.
Robert J. Meyer, M.D.
John K. Jenkins, M.D.
Robert Temple, M.D.
Food and Drug Administration
Silver Spring, MD 20993-0002
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This letter (10.1056/NEJMc076347) was published at www.nejm.org on August 29, 2007.

References

  1. Rosen CJ. The rosiglitazone story — lessons from an FDA advisory committee meeting. N Engl J Med 2007;357:844-846. [Free Full Text]
  2. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-986. [Free Full Text]
  3. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853. [Erratum, Lancet 1999;354:602.] [CrossRef][ISI][Medline]
  4. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-865. [Erratum, Lancet 1998;352:1558.] [CrossRef][ISI][Medline]
To the Editor: I believe that the Perspective article by Dr. Rosen about the July 30 committee meeting to advise the FDA on myocardial ischemic events during treatment with rosiglitazone leaves readers with a misconception about the committee’s advice. Dr. Rosen states that the committee concluded that rosiglitazone “was associated with a greater risk of myocardial ischemic events than placebo, metformin, or sulfonylurea.” Although the adv

Original post by Rubén Roa and software by Elliott Back


Octubre 24, 2007 · Escrito en Farmaceuticas ·  

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