Avandia and the Advisory Committee meeting next week   (July 5, 2010)

Avandia (rosiglitazone) is a medication for type 2 diabetes, which was approved by the FDA in 1999. It is in a class of drugs called thiazolidinediones or glitazones, of which three (troglitazone, brand name Rezulin; rosiglitazone; and pioglitazone, brand name Actos) have been approved, and one of which (troglitazone) has been taken off the market because of safety issues (it caused liver damage).

Avandia has been under scrutiny from the FDA and independent researchers because of cardiac risks: congestive heart failure (which had been known as a side effect since its initial approval), and ischemic heart disease (heart attacks). In May 2007, Dr. Steven Nissen, a cardiologist, published a meta-analysis showing that patients taking Avandia had higher risks of heart problems. An FDA Advisory Committee (AdComm for short) met July 30, 2007, and reviewed the safety data on rosiglitazone (Avandia). The AdComm voted 22-1 in favor of keeping Avandia on the market in the U.S.; they also voted 20-3 that there is sufficient data to show that Avandia increases the risk of cardiac ischemia. Some panel members said the drug should remain on the market with restrictions, especially for patients who are also taking insulin. Some panelists said the drug's label should include a so-called "black-box" warning, the most severe the FDA can require, to clearly state that risk. Some suggested the label caution against using the drug together with insulin because doing so may elevate heart risks. The experts also asked that the drug be studied further. Late in 2007, the FDA stated that 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, and a black-box warning was added.

Earlier this year (2010), the FDA reminded everyone that they are continuing to watch the cardiac safety of Avandia, and next week, on July 13 and 14, there will be a joint public meeting of the Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees to "present the totality of new and existing cardiovascular safety data on rosiglitazone."

Dr. Nissen continues to be vocal in his opposition to Avandia. In an editorial " Setting the RECORD Straight, he blasted a big study (called RECORD) that the manufacturer had undertaken to survey the cardiac issues. I listened to him present his viewpoint at the recent American Diabetes Association meeting, and must admit I'm persuaded by his logic. His key point: why should a drug that is known to increase cardiac risk be allowed to stay on the market to treat people with diabetes - who have a high risk of heart disease?

Another well-known medical expert, Dr. Sanjay Gupta, CNN's medical guru, is alerting viewers that Avandia may not be a good choice for them, and hinting that it may not be available in the future.

What will happen on July 13 and 14? The FDA website has clues: "On both days, the committees will focus primarily on the cardiovascular safety of AVANDIA (rosiglitazone maleate) Tablets, GlaxoSmithKline, a drug approved for blood glucose control in adults with type 2 diabetes mellitus. Data specific to rosiglitazone to be presented will include results from the Rosiglitazone Evaluated for Cardiac Outcome and Regulation of Glycemia in Diabetes (RECORD) Trial, observational data, health claims data, and a meta-analysis of controlled clinical trials. In addition, the FDA will present its meta-analysis of several trials of ACTOS (pioglitazone hydrochloride) Tablets, Takeda Pharmaceuticals North America, Inc., another thiazolidinedione for the same indication, in response to public documents comparing the safety of rosiglitazone to pioglitazone based on different meta-analyses performed on each of these two drugs." Background information will be posted on the FDA website shortly before the meeting, and the minutes of the meeting published afterwards.

Will the FDA advise the manufacturer to take Avandia off the market? It's actually a two-step process: the FDA Advisory Committee will review the data, and make a recommendation to the FDA. The FDA usually follows the advice of AdComms, but is not obliged to do so. The FDA could pull the drug, or ask the manufacturer to pull it, or allow it to stay on the market with even more restrictions than at present, or perhaps to remain on the market with no further restrictions on its prescribing.

I think the answer this year is clearer than in 2007: Avandia is a drug that has outlived its usefulness. With the availability of what seems to be a less-risky drug in the same class, and with many new diabetes drugs in other classes that weren't available in 2007, it's time for Avandia to join Rezulin as another failed thiazolidinedione, and become a historical curiosity rather than a marketed drug.