On May 21, 2007, the New England Journal of Medicine published a meta-analysis of the heart attack and death rates from 42 Avandia trials completed before or after drug approval, that showed a 43% excess incidence of heart attack in Avandia patients. Dr Steven Nissen, Chairman of the Department of Cardiovascular Medicine at Cleveland Clinic and Immediate Past-President of the American College of Cardiology, and statistician, Kathy Wolski, MPH conducted the study.
"The FDA is on notice," he said in a statement, "that we have reached the end of our rope on their stonewalling of investigations into their failures to keep Americans safe from dangerous drugs and poisonous foods."
Avandia was approved on May 25, 1999, and the primary FDA reviewer of the clinical trials submitted recommended approval because the data showed the drug to be effective in reducing blood sugar, however, he also noted that the clinical trials raised questions about Avandia's effect on the heart.
Specifically he noted the "increase in body weight" and "undesirable effects on serum lipids [cholesterol] is cause for concern."
Because of these concerns, the reviewer recommended "a postmarketing study to address these concerns needs to be a condition of approval," which never took place.
On June 6, 2007, the US House Committee on Oversight and Government Reform held a hearing to review the FDA's role in evaluating the safety of Avandia, during which Committee Chairman Henry Waxman (D-Cal) stated, "The medical reviewer did everything right," but unfortunately at that point the FDA dropped the ball.
He noted that the FDA and Glaxo did agree on a post-market study called ADOPT, but it
was designed to show whether Avandia provided long-term control of blood sugar levels, not to assess whether the drug increases the risk of heart attacks.
Subsequently, the FDA received many more warnings about a link between Avandia and heart attacks. In March 2000, Dr John Buse wrote a letter to the FDA to request "cardiovascular safety trials in high-risk populations."
Dr Buse, head of endocrinology at the University of North Carolina, testified at the hearing and told lawmakers that in 1999, after he drew attention to the Avandia heart risks, the company warned him that it might try to hold him accountable for the drop in stock value.
During phone calls, he testified, "it was mentioned on two occasions that there were some in the company who felt that my actions were scurrilous enough to attempt to hold me liable for a loss in market capitalization."
"In the end," he told the Committee, "I offered to help the company with further studies and signed a clarifying statement drafted by SKB [SmithKline Beecham], which was to be used with the investment community."
In February 2003, the World Health Organization issued a warning about the potential cardiac risks associated with all glitazones (TZDs), drugs in the same class as Avandia.