Evelyn Pringle June 18, 2007
The FDA has ignored repeated warnings about the potential cardiac risks associated with the diabetes drug Avandia, and medical experts predict Americans will likely pay a heavy price for trusting its negligent watchdog because US doctors wrote 13 million Avandia prescriptions in 2006 alone, according to IMS Health a medical information tracking firm.
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 very same day, the Chairman of the US House Energy and Commerce Committee’s Oversight Subcommittee, Representative Bart Stupak (D-Mich), stated, in essence, that the Avandia debacle was the last straw.
“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."
"Heart disease due to atherosclerosis," he wrote, "is a major cause of morbidity and mortality in patients with type 2 diabetes, and it cannot be assumed that treatment with [Avandia] will decrease the risk."
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 a letter he wrote to the firm at the time, which was distributed at the hearing, Dr Buse said: "Please call off the dogs. I cannot remain civilized much longer under this kind of heat."
"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.
A year later a review in the New England Journal of Medicine stated that "data about the effects of TZDs on cardiovascular disease are urgently needed."
Yet despite all these warnings, Rep Waxman pointed out, the FDA never required Glaxo to conduct an adequate post-market study to assess Avandia's heart risks.
Dr Nissen testified at the hearing and told the panel, "The same 42 trials that we included in our analysis are available to the company and to the FDA."
"Because both of these organizations have access to raw patient data," he said, "they can perform more statistically powerful analyses, which can help clarify the extent of the risk."
Dr Nissen said Glaxo has reported the basic results of their own meta-analysis on their clinical trials website, "which confirms a statistically significant increase in heart-related complications in patients who received Avandia."
He also noted that the FDA recently announced that their own internal analysis of patient-level data confirms an “approximately 40%” excess of heart related complications.
"However," he added, "neither the GSK, nor FDA analyses have been published, and it is therefore not possible to directly compare the results for all three analyses."
Also at the hearing was Dr Bruce Psaty, a professor of medicine and epidemiology at the University of Washington. Dr. Psaty wrote an editorial that accompanied Dr Nissen’s analysis in the NEJM.
In August 2006, he testified, Glaxo provided the FDA and the European equivalent of the FDA with the results of several studies, including a meta-analysis similar to Dr Nissen’s. "By October 2006," he pointed out, "the product labels in Europe were revised to include this information."
"The US product label," Dr Psaty noted, "still does not identify heart attack as a potential adverse reaction in the general population of diabetics."
"The primary measure of regulatory success is the timeliness of information, warnings, or withdrawals," he said. "With Avandia, FDA failed to warn or inform in a timely fashion."
"Late and incomplete evaluations of the health risks and benefits of drugs such as Avandia," he said, "create confusion and uncertainty among patients, physicians, and policy makers."
"If sponsors do not voluntarily initiate large long-term trials of public health importance," he said, "then the FDA needs the authority to insist that they do so in a timely fashion."
Attorney Karen Barth Menzies, who has been litigating pharmaceutical cases against Glaxo for years, attended the hearing and also said the FDA needs the authority to force companies to conduct specific post-marketing studies and stop drug makers from designing studies that produce confusing results like with Avandia.
“This is one of the ways drug companies ignore potential risks,” she said, “and the FDA cannot force a drug company to conduct a specific study that actually studies the safety risks for which there has been a signal.”
“Instead,” she said, “as Glaxo did here, the drug companies do the post-marketing studies as a way to increase market share by designing studies that focus on efficacy as compared to the competitor’s drugs.”
“Sure,” she told the panel, “the study may show that one drug is better than another regarding efficacy, but it isn’t designed to show whether a drug is associated with a particular safety risk.”
“The latter question is not one the drug companies will spend money to answer,” Ms Menzies noted.
"If there is a lesson from the events of the last weeks and years," Dr Buse told the panel, "perhaps it is that upon filing a New Drug Application, pharmaceutical manufacturers should make every effort to develop an adequately-powered independently-executed study that examines clinically meaningful endpoints such as heart attack or loss of vision."
"In parallel with regulatory approval," he stated, "such a study should be reviewed with attention to design, oversight, funding plan and timeline, recognizing that such studies are very expensive and will take many years to complete."
"Direct to consumer advertising and medical marketing," he added, "should be constrained until such studies are completed."
Dr Psaty also told the Committee that: "Direct-to-consumer advertising increases demand for drugs, some of which, like Avandia, may have been incompletely evaluated."
At the hearing, FDA Commissioner Andrew von Eschenbach announced that the FDA has asked the drug makers to add a black box warning about the risk of congestive heart failure to the labels of Avandia and Actos.
(Written as part of a series on Avandia sponsored by Baum Hedlund's Pharmaceutical Litigation Department)