One million type two diabetics in the US, and nearly 6 million worldwide, who take Avandia (rosiglitazone maleate) may be putting themselves at an increased risk of heart attack.

Earlier this spring, The New England Journal of Medicine released a study by Dr. Steven Nissen that analyzed the combined results of 42 clinical trials. Their findings indicated that patients on rosiglitazone experienced an increased risk of heart attack by 43% and other cardiovascular-related deaths by 64%.

In the wake of the study results, the FDA requested that Avandia label get a "black box warning," the most serious warning the FDA can request. Additionally, "Safety alert on Avandia" was issued by the FDA which said, in part:

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.

The House Oversight and Government Reform Committee subsequently held a hearing to debate the FDA’s role in evaluating the safety of Avandia. At the hearing, diabetes expert Dr. John Buse testified to feeling intimidated by drug maker GlaxoSmithKline when he expressed misgivings about the drug’s safety as early as 1999.

According to a June 5 article in The New York Times, Buse wrote a letter in March of 2000 to the FDA in which he "criticized [GlaxoSmithKline's] marketing, saying it employed ‘blatant selective manipulation of data’ to overstate the drug’s benefits and understate its risks."

The drug’s detractors claim overagressive marketing, both to doctors and direct to consumers, despite GlaxoSmithKline’s awareness of the risks will provide for failure-to-warn lawsuits similar to those resulting from arthritis drug Vioxx. Avandia’s supporters, however, cite several studies that do not show a correlating increase in risk.

Debate will likely increase, both over the safety of Avandia and the effectiveness of the FDA’s procedures surrounding drug approval, specifically, the lacking requirement for subsequent safety and effectiveness evaluations by drug makers after receiving approval to market their drug.

In an interview with USA Today, former deputy director of the Division of Drug Risk Evaluation, Rosemary Johann-Liang, the burden of proof required to call a drug’s safey into question is greater than that required to show its effectiveness:

The FDA approves diabetes drugs such as Avandia if clinical trials show they meet the "surrogate endpoint," or goal, of lowering blood sugar, [Johann-Liang] says, but then doesn’t require makers to do follow-up studies of whether patients actually feel better and live longer.

On the other hand, Johann-Liang says, "if there is a safety issue with the drug, it must be confirmed. I just don’t think that that’s appropriate." As a result, "we’re not doing things in a timely way."

Sources & Further Reading

• Rubin, Rita. "FDA scientist says she was reprimanded for warning." USA Today. June 10, 2007. <http://www.usatoday.com/news/health/2007-06-10-fda-insider_n.htm>. June 29, 2007.
• "FDA Issues Safety Alert on Avandia." FDA.gov. May 21, 2007. <http://www.fda.gov/bbs/topics/NEWS/2007/NEW01636.html>. June 29, 2007.
• Saul, Stephanie. “Doctor Says Drug Maker Tried to Quash His Criticism of Avandia.” The New York Times. June 2, 2007. <http://www.nytimes.com/2007/06/02/business/02drug.html?…ei=5070>. June 29, 2007.
• Nissen, Steven E., M.D., and Kathy Wolski, M.P.H. “Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes.” The New England Journal of Medicine. Volume 356:2457-2471; June 14, 2007; Number 24. <http://content.nejm.org/cgi/content/short/356/24/2457>. June 29, 2007.
• Hearing on FDA’s Role in Evaluating Safety of Avandia. Committee on Oversight and Government Reform. June 6, 2007. <http://oversight.house.gov/story.asp?ID=1325>. June 29, 2007.