Wednesday, May 23, 2007

Rosiglitazone (Avandia) - FDA x Glaco Smith Kleine

FDA Issues Safety Alert on Avandia

ROCKVILLE, MD -- May 21, 2007 -- The U.S. Food and Drug Administration (FDA) is aware of a potential safety issue related to Avandia (rosiglitazone), a drug approved to treat type 2 diabetes. Safety data from controlled clinical trials have shown that there is a potentially significant increase in the risk of heart attack and heart-related deaths in patients taking Avandia. However, other published and unpublished data from long-term clinical trials of Avandia, including an interim analysis of data from the RECORD trial (a large, ongoing, randomized open label trial) and unpublished reanalyses of data from DREAM (a previously conducted placebo-controlled, randomized trial) provide contradictory evidence about the risks in patients treated with Avandia. Patients who are taking Avandia, especially those who are known to have underlying heart disease or who are at high risk of heart attack should talk to their doctor about this new information as they evaluate the available treatment options for their type 2 diabetes. FDA's analyses of all available data are ongoing.

FDA has not confirmed the clinical significance of the reported increased risk in the context of other studies. Pending questions include whether the other approved treatment from the same class of drugs, pioglitazone, has less, the same or greater risks. Furthermore, there is inherent risk associated with switching patients with diabetes from one treatment to another even in the absence of specific risks associated with particular treatments. For these reasons, FDA is not asking GlaxoSmithKline, the drug's sponsor, to take any specific action at this time. FDA is providing this emerging information to prescribers so that they, and their patients, can make individualized treatment decisions. "FDA remains committed to assuring that doctors and patients have the latest information available to make treatment and medication use decisions. In this case, FDA is carefully weighing several complex sources of data, some of which show conflicting results, related to the risk of heart attack and heart-related deaths in patients treated with Avandia," said Steven Galson, M.D., M.P.H., director of FDA's Center for Drug Evaluation and Research. "We will complete our analyses and make the results available as soon as possible. FDA will take the issue of cardiovascular risk associated with Avandia and other drugs in this class to an Advisory Committee as soon as one can be convened." Avandia was approved in 1999 for treatment of type 2 diabetes, a serious and life threatening disease that affects about 18 to 20 million Americans. Diabetes is a leading cause of coronary heart disease, blindness, kidney failure and limb amputation.

Since the drug was approved, FDA has been monitoring several heart-related adverse events (e.g., fluid retention, edema and congestive heart failure) based on signals seen in previous controlled clinical trials of Avandia alone and in combination with other drugs, and from postmarketing reports. FDA has updated the product's labeling on several occasions to reflect these new data, most recently in 2006. The most recent labeling change for Avandia also included a new warning about a potential increase in heart attacks and heart-related chest pain in some individuals using Avandia. This new warning was based on the result of a controlled clinical trial in patients with existing congestive heart failure. Recently, the manufacturer of Avandia provided FDA with a pooled analysis (meta analysis) of 42 randomized, controlled clinical trials in which Avandia was compared to either placebo or other anti-diabetic therapies in patients with type 2 diabetes. The pooled analysis suggested that patients receiving short-term (most studies were 6-months duration) treatment with

Avandia may have a 30-40 percent greater risk of heart attack and other heart-related adverse events than patients treated with placebo or other anti-diabetic therapy. These data, if confirmed, would be of significant concern since patients with diabetes are already at an increased risk of heart disease. Avandia is manufactured by GlaxoSmithKline, which is based in Research Triangle Park, N.C. SOURCE: FDA

Title: GlaxoSmithKline Responds to NEJM Article on Avandia
GlaxoSmithKline Responds to NEJM Article on Avandia

PHILADELPHIA, PA -- May 21, 2007 -- GlaxoSmithKline today issued the following response to an article in the New England Journal of Medicine (NEJM) on Avandia® (rosiglitazone maleate), a widely used and highly effective treatment for type 2 diabetes: GSK strongly disagrees with the conclusions reached in the NEJM article, which are based on incomplete evidence and a methodology that the author admits has significant limitations. The NEJM paper is based on an analysis of summary information that combines a number of studies -- a meta-analysis -- which is not the most rigorous way to reach definite conclusions about adverse events. Each study is designed differently and looks at unique questions: for example, individual studies vary in size and length, in the type of patients who participated, and in the outcomes they investigate. The data compiled from these varied studies is complex and can be conflicting. Importantly, the editorial in the NEJM states: "A few events either way might have changed the findings for myocardial infarction or for death from cardiovascular causes. In this setting, the possibility that the findings were due to chance cannot be excluded. In their discussion, the authors properly emphasize the fragility of their findings." In contrast to a meta-analysis, the most scientifically rigorous way to examine the safety and benefits of a medicine is to conduct large scale, long-term clinical trials in patients with the disease. Several trials of this type have been ongoing for many years. To date concerns regarding patient safety have not been identified by the independent Safety Monitoring Boards for these trials. Several trials have completed and the results published. For example, GSK's long-term, landmark study 'ADOPT' (A Diabetes Outcome Progression Trial) - one of the longest clinical trials in people with type 2 diabetes to date - directly compared both the safety and effectiveness of Avandia with other oral anti-diabetic medicines in over 4,300 patients studied for up to 6 years. Data from ADOPT showed that the overall risk of serious, cardiovascular events (CV death, myocardial infarction, and stroke, or MACE endpoint) for patients on Avandia was comparable to metformin and sulfonylurea (glyburide) -- two of the most commonly used medicines to treat type 2 diabetes. ADOPT showed comparable rates of cardiovascular deaths: Avandia -- 5 reports out of 1,456 patients, or 0.34%; metformin -- 4 out of 1,454, or 0.28%; and glyburide -- 8 out of 1,441 or 0.56%. The ADOPT clinical trial did show a small increase in reports of myocardial infarction among the Avandia -treated group ( Avandia : 24 out of 1,456 or 1.65%) vs metformin (20 out of 1,454 or 1.38%) vs glyburide (14 out of 1,441 or 0.97%); however, the number of events is too small to reach a reliable conclusion about the role any of the medicines may have played in this finding. Importantly, ADOPT also demonstrated that Avandia was superior to metformin and sulfonylurea regarding long-term control of blood sugar over five years, which is a key goal in managing diabetes to avoid the long-term complications of the disease. In another long-term study, DREAM -- which followed over 5,200 patients at high risk of developing of type 2 diabetes for a period of three to five years -- Avandia monotherapy showed no increase in cardiovascular risk when compared to placebo. Furthermore, in 2000, GSK initiated RECORD -- a large, long-term clinical trial in people with diabetes -- which has been prospectively designed to look at cardiovascular outcomes. The independent Safety Monitoring Boards responsible for overseeing the safety of this trial monitors patients closely, and in its regular operations has not found any safety risk that would interrupt continuation of the study. In addition, in a comprehensive analysis of patients in a US managed care database of more than 33,000 people with diabetes -- performed by independent investigators - there was no difference in ischemic cardiovascular events (including myocardial infarction) among patients taking Avandia -containing regimens versus other oral anti-diabetic medicines. The totality of the data show that Avandia has a comparable cardiovascular profile to other oral anti-diabetic medicines. GSK stands firmly behind the safety of Avandia when used appropriately, and we believe its significant benefits continue to outweigh any treatment risks. Because Avandia has been shown to control blood sugar for longer than other standard oral anti-diabetic medicines, it is an important treatment option for physicians who often need to prescribe two or three medicines to help their patients maintain their blood sugar levels. Type 2 diabetes is chronic, relentlessly progressive and life threatening; yet, two-thirds of diabetic patients suffer with uncontrolled disease. If left uncontrolled, diabetes can lead to heart disease, and is the leading cause of blindness, kidney disease and non-traumatic amputations in the US. GSK has consistently shared its data on Avandia from meta-analyses and controlled studies with the FDA and other regulatory agencies. Data is also posted publicly on the company's Clinical Trial Register. We continue to work closely with regulatory authorities and physicians to keep them fully informed so they can make the best decisions for patients based on both the safety and benefit of the medicine. SOURCE: GlaxoSmithKline

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