Avandia Heart Attack Risk, Questions Remain

Washington, DCToday is a milestone for GlaxoSmithKline's Avandia. According to various sources it was May 25, 1999 that Avandia received regulatory approval for the treatment of Type 2 diabetes. However, much has happened in the ten years since Avandia first surfaced with so much promise: various studies and other analyses pointing to heart attack and various other side effects associated with Avandia.

Those side effects earned the drug—eight years after its introduction—a Black Box warning for heart attack concerns, together with a ton of bad press. However Avandia continues on the market. Calls for the complete removal of Avandia from the market have not been heeded.

Indeed, a spokesperson for the US Food and Drug Administration (FDA), which is reviewing Avandia, makes the point that Avandia may have been given too harsh a ride in the court of public opinion. Janet Woodcock, director of the FDA's drug-review division, was quoted in the Wall Street Journal earlier this year as saying Avandia had been "convicted without a trial."

Few argue against the effectiveness of Avandia for the treatment of Type 2 diabetes. The problems rest with the side effects, an issue that rose to the height of public consciousness two years ago this month with the publication of a study by noted Cleveland cardiologist Dr. Steven Nissen that revealed a 43 percent higher risk of cardiovascular events for Type 2 diabetes patients taking Avandia.

Dr. Nissen's study is well known, triggering congressional investigations and fostering a black box warning for Avandia some months later.

However, what is not as widely known are various events that surrounded the release of Dr. Nissen's study in the New England Journal of Medicine (NEJM) in May of 2007.

According to a report in the Wall Street Journal that appeared earlier this year, Dr. Nissen's study was slated to be released in NJEM May 21st 2007, and was supposed to be kept confidential until then. However, as the Wall Street Journal reported a doctor reviewing the study for the Journal released a copy to the Avandia manufacturer May 3rd. The doctor, who admitted later that releasing the document to GlaxoSmithKline (Glaxo) was done in error, had ties to the manufacturer. Dr. Steven Haffner, according to the report, had been a Glaxo consultant with regard to Avandia since 2000 and received $433,000 in compensation from Glaxo beginning in 2000 to August 2007.

As a result of obtaining the copy, it has been reported that a team of Glaxo scientists visited Dr. Nissen and attempted to persuade him to revisit his concerns prior to the publication of the study.

"They never revealed that they had obtained a copy of our manuscript and had concluded that our findings were irrefutable," Dr Nissen said in comments published in the Wall Street Journal in January. "Instead, they attacked the validity of the study and the motives
of both the authors and the NEJM."

Indeed, the manufacturer's public denouncements of Dr. Nissen's research appeared to contradict Glaxo's own findings. It has been reported that a meta-analysis conducted by Glaxo arrived at conclusions similar to those found by Dr. Nissen. A letter published in the Lancet May 30th, 2007 over the signature of Glaxo Chief Medical Officer Ronald Krall revealed that "GlaxoSmithKline did similar meta-analyses in 2005 and 2006 and found hazard ratios in the same direction."

The Lancet letter, together with a subsequent response in the NEJM following the release of Dr. Nissen's study suggested a public acknowledgement of the findings after the initial NEJM study was published.

However, there is evidence that Glaxo was aware of the similar findings with regard to risk for cardiovascular events and was considering how to best explain it.

"The numbers are the numbers, the analysis is very similar to our own." This, according to an email from Glaxo's senior consultant days before the damning study was published. The author, Dr. Moncef Slaoui who served as Glaxo's director of research, noted to various executives in a May 8, 2007 email obtained by the Wall Street Journal that "FDA, Nissen and GSK all come to comparable conclusions regarding increased risk for ischemic events, ranging from 30 percent to 43 percent!" (exclamation used by the author of the statement)

Dr. Slaoui noted that while Glaxo could not undermine the results, perhaps the company could find a way of explaining them?

Not long after a Glaxo spokesperson noted that Dr. Saloui had used imprecise language in his internal email, but was more precise in written testimony to Congress when he indicated Glaxo did not agree with the conclusions of Dr. Nissen and regarded his methodololy as having significant limitations.

It has been reported that Glaxo fully disclosed its findings to the FDA.

For its part the FDA has been reviewing the data from a meta-analysis conducted by Glaxo in 2005. However according to the Wall Street Journal the data was in the FDA' s hands the year prior to the release of Dr. Nissen's study, but made no comment.

The FDA became the subject of a Congressional hearing with regard to the handling of Avandia.

While sales of Avandia continue to be off-pace since the release of the NEJM study, Glaxo and the FDA are both standing behind the drug as an effective and valued treatment for Type 2 diabetes. There are no plans to remove Avandia from the market in an effort to mitigate the possibility of heart attack and other side effects associated with Avandia.