Diabetes Drugs Must Now Clear Cardiovascular Hurdle, Says FDA

December 18, 2008

December 18, 2008 (Silver Spring, Maryland) — The Food and Drug Administration is now recommending that all new drugs developed for the treatment of type 2 diabetes show that they do not increase the risk of cardiovascular events.

The recommendation is included in a new guidance document issued this week by the agency and emerges after concerns have been raised about the cardiovascular safety of drugs in this field, especially the thiazolidinediones (TZDs), including rosiglitazone (Avandia, GlaxoSmithKline). The new standard is effective immediately and affects all drugs and biologics currently in development.

Last July, the Endocrinologic and Metabolic Drugs Advisory Committee voted overwhelmingly in favor of requiring sponsors to conduct long-term clinical trials or provide equivalent evidence ruling out an unacceptable cardiovascular safety risk. Based on that two-day meeting, the FDA is now asking sponsors for more stringent clinical trials that collect data on cardiovascular end points, as well as studies that include real-world patients likely to be seen in clinical practice.

"To obtain sufficient end points to allow a meaningful estimate of risk, the phase 2 and phase 3 programs should include patients at higher risk of cardiovascular events, such as patients with relatively advanced disease, elderly patients, and patients with some degree of renal impairment," the FDA states in the guidance document. "Because these types of patients are likely to be treated with the antidiabetic agent, if approved, this population is more appropriate than a younger and healthier population for assessment of other aspects of the test drug's safety."

The report, from the Center for Drug Evaluation and Research (CDER), recommends that sponsors establish an independent cardiovascular end points committee to prospectively assess cardiovascular events during all phase 2 and phase 3 trials. These events should include cardiovascular mortality, MI, and stroke and can include hospitalization for acute coronary syndrome, urgent revascularization procedures, and possibly other end points.

Glycemic control, as measured by changes in glycated hemoglobin levels, remains an acceptable primary efficacy end point for approval of drugs to treat hyperglycemia, the agency states. Studies, however, will likely be longer and more expensive, in order to provide sufficient data on cardiovascular risk for these new therapies.

In a briefing with reporters yesterday, Dr Mary Parks, director of the division of metabolism and endocrinology products, said the FDA has sent out more than 100 letters to drug companies informing them of the recommendations. The new guidance applies to all unapproved drugs, but the agency is working on another guidance document to evaluate the cardiovascular safety of drugs already approved.

In addition to showing cardiovascular safety, the agency is asking companies to provide comprehensive data collection that will allow for appropriate meta-analyses to be performed at the time of their completion. The document is nonbinding, meaning companies are not required to follow the new guidelines, although the FDA guidance is "suggested or recommended."

  1. Food and Drug Administration. FDA announces new recommendations on evaluating cardiovascular risk in drugs intended to treat type 2 diabetes. December 17, 2008. Available at: https://www.fda.gov/bbs/topics/NEWS/2008/NEW01928.html.



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