By Attorney Jonathan Emord
Author of "The Rise of Tyranny" and,
"Global Censorship of Health Information"
January 10, 2011
If you harbored romantic notions that an Obama FDA would be less controlled by the pharmaceutical industry than a Bush FDA, think again. The case of Avandia proves once again that FDA will sacrifice the health of the American people to defend the economic interests of its favored regulatees, the big drug companies.
In an April 2, 1999 internal memo to his superiors FDA medical reviewer Dr. Robert I. Misbin objected to FDA approval of the GlaxoSmithKline Type 2 diabetes drug Avandia. He expressed concerns “about deleterious long term effects on the heart” from the drug. His criticisms were rejected by the agency’s political appointees. On May 25, 1999, FDA approved the drug for marketing without referencing the heart risks.
For identifying the heart risks, Dr. Misbin was not complimented at FDA. Far from it, he was ostracized and subjected to severe criticism and review by his superiors. He was told, flatly, by one of them that he just did not get it, that FDA was there to serve the industry. In a later interview, Misbin (now deceased) said: “One of my superiors said something to me that I have never forgotten, that we have to maintain good relations with the drug companies because they are our customers.”
In February 2006 another courageous FDA medical reviewer raised objections to the drug. Dr. Rosemary Johann-Liang strenuously urged her superiors to require GlaxoSmithKline to include a black box warning on the drug, alerting people to its heart attack risks. Liang’s supervisor told her that FDA management was “upset with her recommendation” and “decided to act like her review never happened.”
Congresswoman Diane E. Watson (D-CA), a member of the House Energy and Commerce Committee with FDA oversight, was prescribed Avandia for her diabetes. She developed a heart murmur while on the drug. In an Energy and Commerce Committee hearing evaluating the drug, she told the FDA Commissioner that Avandia caused her heart murmur and demanded to know why the agency let such an unsafe drug remain on the market.
A meta analysis published in the May 2007 New England Journal of Medicine associated Avandia with a 43% increased risk of heart attack. In July 2007, an FDA advisory panel with conflicts of interest voted that Avandia did increase the risk of cardiac ischemic attack in Type 2 diabetics but ultimately ruled that the drug should remain on the market.
Under intense pressure from Congress, and having received over 83,000 adverse event reports of heart problems arising from Avandia, FDA reversed itself (not removing the drug from the market, as one would expect, but adding a black box warning over a year after medical reviewer Johann-Liang called for one). The black box warning reduced Avandia’s market position but the drug still achieved $1.2 billion in worldwide sales for 2009.
In February of 2010 Dr. David Graham, FDA’s Associate Director of Drug Safety, recommended that Avandia be taken off the market. Graham said that Avandia causes 500 more heart attacks and 300 more heart failures than its leading competitor, Abbott drug Actos.
In June of 2010, Dr. Graham and his colleagues published a retrospective study in the Journal of the American Medical Association of 227,571 elderly patients. The study compared Avandia to its competitor, the Abbott drug Actos. He concluded that Avandia was associated with “an increased risk of stroke, heart failure, and all-cause mortality and an increased risk of the composite of Acute Myocardial Infarction, stroke, heart failure, or all-cause mortality in patients 65 years or older.” Dr. Graham and his colleagues concluded that compared to patients taking Actos, patients taking Avandia experienced a 27% higher risk of stroke, a 25% higher risk of heart failure, and a 14% higher risk of death. In an interview for webmd.com, he explained that for every 60 older patients taking Avandia instead of Actos there would be one extra heart attack, heart failure, stroke, or death. In that same interview he was quoted as saying: “If you are a patient currently being treated with Avandia, based on the data from our study it would be wise for you to contact your doctor and ask to be switched to a safer alternative.” He added, “even if you have been on Avandia for a while and have not had anything bad happen to you, why take those risks? They are completely unnecessary.” Dr. Graham is a meticulous and conservative FDA scientist but one possessed of tremendous courage, willing to speak out about unsafe drugs the agency has approved despite the ever present threat of agency retaliation.
In July of 2010, FDA reconvened its Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees to reconsider Avandia cardiovascular risks. Following Committee. On July 14, 2010, following two days of deliberations, a majority of the FDA panel voted not to take the drug off the market. On July 20, 2010, it came to light that the panel had members with conflicts of interest, including one who was a paid speaker for GlaxoSmithKline. That paid speaker voted to keep the drug on the market with no change in labeling.
On the eve of the agency’s re-evaluation of the drug, the Senate Finance Committee wrote a letter to FDA Commissioner Margaret Hamburg demanding that she remove the drug from the market. That committee had maintained an ongoing inquiry into Avandia. It found that GlaxoSmithKline withheld studies on Avandia from FDA and the public that called into question the drug’s safety and actively promoted the drug as comparatively safe and efficacious despite the known safety risks. The Committee wrote to Commissioner Hamburg: “The totality of evidence suggests that GSK was aware of the possible cardiac risks associated with Avandia years before such evidence became public . . . Based on this knowledge, GSK had a duty to sufficiently warn patients and the FDA of its concerns in a timely manner. Instead, GSK executives intimidated independent physicians, focused on strategies to minimize findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that the rival drug Actos might reduce cardiovascular risk.”
The Senate Finance Committee based its findings, in part, on internal GlaxoSmithKline emails, revealing high level company awareness of the cardiovascular risks of Avandia as early as 2000. The Committee also identified a GlaxoSmithKline ghostwriting campaign where the company would solicit articles from medical professionals lauding the drug as comparatively safe and effective for publication in medical journals without the journals knowing of the company’s involvement. The Committee faulted FDA for letting the drug remain on the market despite the 83,000 adverse event reports FDA received between 1999 and 2007 tying the drug to cardiovascular risks.
This overwhelming evidence against Avandia would lead any reasonable person to conclude that the drug ought not be on the market, particularly because other drugs that are for the same condition pose far fewer risks. Did Obama’s FDA Commissioner, Margaret Hamburgh (who prides herself on enforcement of the law) demand the drug be removed? Not at all.
She ensured that it could continue to be available to those now on it, and largely limited her restriction of its use to new patients. In other words, she gave GlaxoSmithKline an opportunity to wind down its affairs with Avandia while millions of people worldwide would remain at an elevated risk of heart attacks, heart failure, strokes, and death. And if a patient so suffers, who will account in the law for the homicide? Not Commissioner Hamburg, not GlaxoSmithKline, not anyone responsible. So much for law enforcement, Madam Commissioner.
On September 23, 2010, FDA required GlaxoSmithKline to submit a Risk Evaluation and Mitigation Strategy (REMS) for the drug. Under the REMS, the drug can remain available to patients already taking it with written informed consent. Future patients can receive the drug if they cannot achieve glycemic control on other drugs.
Once again we see that the FDA is a captive of the drug industry. The agency proceeds like a blind jockey atop the drug elephant. Wherever that beast takes it, FDA is sure to go.