Evelyn Pringle July 9, 2007
A February 22, 2006 internal FDA memorandum, obtained by staffers of the Senate Finance Committee, proves that safety officials within the agency recommended that GlaxoSmithKline add a black box warning about congestive heart failure to the label of the diabetes drug Avandia well over a year ago.
The memo also shows that FDA reviewer Dr David Ross recommended a highlighted boxed warning for CHF, a life-threatening condition that occurs when fluid builds up in the lungs causing a severe shortness of breath that requires immediate medical attention.
The memo also recommended that macular edema, a condition that causes swelling of the retina and can lead to blindness, be listed as a serious adverse event on the label.
Although the recommendations were approved by Dr Rosemary Johann-Liang, the Deputy Director of the FDA's Division of Drug Risk Evaluation, they were never added to Avandia's label.
Instead of forcing Glaxo to post warnings to protect Americans, top FDA officials basically demoted Dr Johann-Lang for approving the warnings to begin with.
Congestive heart failure "is a very, very clear adverse reaction syndrome" with Avandia, Dr Johann-Lang told reporter, Rita Rubin, according to an article in USA Today on June 11, 2007. She also noted a concern that some patients might blame symptoms, such as shortness of breath, on the underlying diabetes and mistakenly take more of the drug.
Dr Johann-Lang has now left her position at the FDA for personal reasons, but said in her interview with USA Today, that she might have tried to figure out a way to stay "if the agency had a vision of promoting and protecting public health."
However, her departure does not mean that the misconduct by senior FDA officials will be overlooked. On June 4, 2007, Senator Charles Grassley (R-Iowa) and the Senate Finance Committee sent a letter to the FDA Commissioner Andrew von Eschenbach demanding answers to questions by June 20, 2007, about the retaliation waged against the safety evaluators who tried to warn the public about the risks of Anvandia a year ago.
Although Glaxo downplayed the risks, according to a June 1, 2007 report by Andrea Gerlin for Bloomberg News, the FDA knew about risks associated with Avandia as far back as April 1999, when GlaxoSmithKline executives told the FDA that the drug caused "minimal" cardiovascular side effects and "mild to moderate" fluid buildup,
The agency approved Avandia on May 25, 1999, even though some FDA advisory panel members had recommended that more research should be conducted to detect potential complications.
On February 8, 2001, the FDA Web site shows the agency approved revisions to the Prescribing Information for Avandia to include a new warning regarding cardiac failure and cardiac effects.
But 3 months later, Glaxo sales representatives were "denying the existence of serious new risks associated with Avandia" in presentations at Glaxo's promotional exhibit booth during the Annual American Association of Clinical Endocrinologists Meeting in San Antonio, Texas on May 2-6, 2001, according to a July 26, 2001 FDA letter to Glaxo.
The letter also pointed out that Glaxo had already been warned about this conduct several times. "Your promotional activities that minimize serious new risks are particularly troublesome," it said, "because we have previously objected, in two untitled letters, to your dissemination of promotional materials for Avandia that failed to present any risk information about Avandia or minimized the hepatic risk associated with Avandia."
The untitled letters were sent to Glaxo on June 29, 1999 and October 20, 2000. "Despite your assurance that such violative promotion of Avandia had ceased," the July 2001 letter states, "your violative promotion of Avandia has continued."
In a December 3, 2006 interview, diabetes researcher Rury Holman of Oxford University in the UK, an investigator in the Glaxo study known as ADOPT, told Bloomberg News that the results of that study, which were released in November 2006, were cause for concern.
"These people are early diagnosis, they haven't got complications," he said. "The fact that we're seeing these cardiovascular effects in them we can't deny that."
The concern, he noted, was that a signal emerged in "relatively healthy patients."
In addition, according to the FDA web site, significantly more female patients who received Avandia in the ADOPT study, "experienced fractures of the upper arm, hand, or foot, than did female patients who received either metformin or glyburide."
In an all too familiar pattern with the Bush-controlled industry friendly FDA, Americans were kept in the dark about the risks associated with a drug in what many experts are calling another Vioxx-like disaster.
On May 23, 2007, Reuter's reported that Europe's watchdog, the European Medicines Agency (EMEA), had taken action on the risks of Avandia last year by strengthening the warnings on the drug.
"The situation in Europe is a little bit different to the American situation because," the agency spokeswoman said, "in Europe, Avandia is contraindicated in patients with heart failure anyway and we have warnings about ischemia."
She also referred to a May 2007 study in the New England Journal of Medicine, conducted by Cleveland Clinic cardiologist Dr Steven Nissen, which found Avandia to be associated with a 43% increase in heart attacks and possibly a 64% increase in cardiovascular death. The EMEA spokeswoman explained that "the majority of the studies looked at in the Nissen paper have already been assessed by the (the agency's expert) committee and, partly due to that, the SPC (summary of product characteristics) was updated in 2006."
Only after being boxed in a corner, on June 6, 2007, the Johnny-come-lately, FDA Commissioner von Eschenbach, informed a US House Committee that the FDA is now requesting that a black box warning about CHF be added to the labels of Avandia and another diabetes drug Actos.
However, an extra year with a sleeping US watchdog paid off well for Glaxo. According to a May 21, 2007 USA Today article, doctors in the US wrote 13 million prescriptions for Avandia last year, generating more than $2 billion in sales, according to figures from the data tracking firm IMS Health. Three million prescriptions had already been sold by the end of March 2007.
(Written as part of a series on Avandia sponsored by Baum Hedlund's Pharmaceutical Litigation Department)