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News Articles >> FDA Scientist Graham Calls Glaxo Avandia..
FDA Scientist Graham Calls Glaxo Avandia Trial Useless
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| July 30, 2007. By Evelyn Pringle |  RSS  Del.icio.us  Seed Newsvine  Facebook |
Washington, DC: World-renowned cardiologist Dr Steven Nissen and statistician Kathy Wolski of the Cleveland Clinic posted a study online on May 21, 2007, to warn the public that the diabetes drug Avandia (rosiglitazone) increased the risk of heart attacks by 43% and the risk of death from cardiovascular causes by possibly 64%.
A print edition of the study was also published in the June 14, 2007 issue of the New England Journal of Medicine. The authors noted that their study was limited by a lack of access to original source data, which would have enabled time-to-event analysis, but said: "Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes."
Dr Curt Furberg, a health policy professor at Wake Forest University, and University of Washington epidemiologist Dr Bruce Psaty, wrote an accompanying editorial in the NEMJ urging regulatory action by the FDA.
"During the market life of rosiglitazone," they wrote, "tens of millions of prescriptions for the drug have been written for patients with type 2 diabetes."
"Insofar as the findings of Nissen and Wolski represent a valid estimate of the risk of cardiovascular events," they noted, "rosiglitazone represents a major failure of the drug-use and drug-approval processes in the United States."
"Indeed," they said, "at the time of approval of rosiglitazone, the evidence from 26-week studies of expected health benefits was at best mixed."
The doctors were no doubt referring to the FDA's review of the clinical trials in 1999, by Dr Robert Misbin, who noted Avandia's adverse effects in an April 2, 1999 report that specifically warned that 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."
"My concern about deleterious long term effects on the heart," he advised, "should be addressed by requiring the Sponsor to provide adequate information in the label about changes in weight and lipids."
"A postmarketing study to address these issues needs to be a condition of approval," Dr Misbin wrote.
The same day that the Nissen report appeared online, the FDA issued a pubic health alert stating: "Safety data from controlled clinical trials have shown that there is a potentially significant increase in the risk of heart attack and heart-related deaths in patients taking Avandia."
However, in the same alert the agency began a clear campaign of damage control for Avandia maker GlaxoSmithKline and said, "other published and unpublished data from long-term clinical trials of Avandia provide contradictory evidence about the risk of ischemic cardiovascular events in patients taking Avandia."
But as it turns out, some of the "contradictory evidence" referred to was Glaxo's own analysis of an ongoing company sponsored clinical trial called RECORD that is basically useless, according to FDA scientist Dr David Graham.
In documents posted on the FDA web site on July 26, 2007, in advance of an FDA advisory panel meeting, Dr Graham states: "Contrary to an FDA Alert issued on May 21, 2007, the results of an interim analysis of RECORD do not provide "contradictory evidence" in support of RSG's (Avandia) cardiovascular safety."
"Rather, the results of this interim analysis suffer from a profound lack of statistical power, made worse by multiple deficiencies in design that guarantee an optimistically biased underestimation of RSG's coronary heart disease risks," he advised.
Dr Grahams says the design of RECORD cannot address Avandia's specific cardiovascular risk because it does not include a placebo group and the trial is unreliable because it was "open label," meaning doctors and patients knew which drug the patients were taking.
"The open-label nature of the study," he wrote, "substantially increases the likelihood of bias in how outcomes are identified, labeled, classified, and reported."
The design of RECORD renders it "useless," he says, as an objective measure of cardiovascular safety. "Its results cannot be trusted because they are too subject to bias."
Furthermore he wrote, "RECORD is incapable of credibly or reliably excluding clinically meaningful increases in cardiovascular risk associated with RSG use, and should play no role in FDA's benefit-risk determinations for this drug."
He says the design is so unreliable that even the final results of the trial due out in 2009, should also not be used in any consideration of risk or benefit associated with Avandia.
In fact, he goes so far as to say that the study is so useless that it should not be allowed to continue. "The design and statistical power limitations of RECORD," he wrote, "are such that it is probably unethical to continue the study because it cannot produce scientifically reliable or valid results."
Under the Bush administration's FDA, Dr Graham is one of the few scientists brave enough to speak out against the wrong-doing of the pharmaceutical industry, which is largely credited with financing Bush's move to Washington.
And true to form, Dr Graham's highly critical report on Glaxo's RECORD study is buried about half way down in a pile of more than 400 briefing documents posted on the internet by FDA management.
However, the Bush Administration's well-embedded protection racket operating under cover of the FDA may soon be dismantled because in May 2007, the Senate passed the Food and Drug Administration Revitalization Act, and the House passed the Food and Drug Administration Amendments Act of 2007 in July 2007. The House and Senate are now in conference to resolve the differences between the two bills.
Both bills address the fundamental problem at the FDA of the lack of equality between the pre-approval Office of New Drugs and post-approval Office of Surveillance and Epidemiology. The Office of New Drugs approves drugs and the Office of Surveillance monitors and assesses the safety of the drugs once they are on the market.
Last fall, the Government Accountability Office reported that the Office of New Drugs
basically controls what drug safety information becomes known because it sets the agenda and chooses the presenters at FDA's advisory meetings and recommended that the role of the Office of Surveillance be clarified because the office is supposed to be the expert on post-marketing safety issues.
On July 26, 2007, in a speech on the Senate floor, Senator Charles Grassley (R-Iowa), ranking member of the Senate Finance Committee and one of Dr Graham's staunchest supporters, tried to get his fellow Senators to recognize the importance of correcting the imbalance within the FDA by following the recommendations of the GAO.
"I have seen time and time again," he advised, "in my investigations that serious safety problems that emerge after a drug is on the market do not necessarily get prompt attention from the Office of New Drugs, the office that approves drugs to go on the market in the first place. "
He said they saw it with Vioxx and more recently with Avandia, where the FDA has disregarded and downplayed warnings from its own best scientists. "We saw evidence of that," he noted, "in the way FDA treated Dr. Andrew Mosholder's findings on antidepressants and Dr. David Graham's findings on Vioxx."
Senator Grassley noted that his review of the agency's handling of Avandia has unearthed similar concerns. "Not only did the FDA disregard the concerns and recommendations from the office responsible for post-marketing surveillance," he told his fellow Senators, "but I have found that it also attempted to suppress scientific dissent."
In the past two months, he stated, "I've had to write to the FDA regarding the suppression of dissent from not one but two FDA officials involved in the review of Avandia."
Senator Grassley said, "FDA employees dedicated to post-marketing drug safety should be able to express their opinions in writing and independently without fear of retaliation, reprimand, or reprisal."
In light of the many allegations that reviewers are coerced into changing their scientific findings, he said, it is critical that the provision that states that a scientific review of a drug application must not be changed by FDA managers or the reviewer once it is final, survives the legislative conference process.
Under this provision, when an agency scientist like Dr Graham issued a report critical of a drug or a company's clinical trials, it would not be subject to dilution by politically appointed officials at the top of the FDA.
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