Once again, the FDA is shown to be complicit in turning a blind eye when a drug manufacturer, in this case, GlaxoSmithKline, concealed documented risks of heart attacks linked to its adjunctive diabetes drug, Avandia (rosiglitazone), putting of patients in harm’s way.
Gardiner Harris reports that a fierce debate has been brewing for years within the FDA about “what to do about Avandia:” inasmuch as the preponderance of evidence shows patients taking the drug suffer cardiac harm.
Once again, a detailed Senate Finance Committee investigation reveals the true magnitude of the potentially deadly cardiac risks involving Avandia, whose sales reached $3.2 billion in 2006, but whose deadly risks the manufacturer, GlaxoSmithKline, concealed from patients and physicians for YEARS.” See Senate Finance Committee Press Release packet:
The report, overseen by Senator Max Baucus, a Democrat, and Senator Charles E. Grassley, a Republican., examined 250,000 internal GSK documents, concluded that instead of issuing a warning—as is a drug manufacturer’s duty--“G.S.K. executives attempted to intimidate independent physicians, focused on strategies to minimize or misrepresent findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that a competing drug might reduce cardiovascular risk.”
See Senate Finance Committee letter to FDA Commissioner (below).
The Committee packet posted on its website includes a comprehensive benefit-risk assessment report (2008. 75 pp.) by FDA safety officers, Dr. David Graham and Dr. Kate Gelperin.
They report that the preponderance of evidence showed that "there was no evidence that rosiglitazone [Avandia] confers any unique health benefit over pioglitzone [Actos] while there was strong evidence that [Avandia] confers an increased risk of AMI [acute myocardial infarction] and heart failure compared to [Actos]. The evidence led these expert FDA safety officers to conclude that the drug “should be removed from the market” inasmuch as an estimated 500 heart attacks and 300 cases of heart failure would be averted EVERY MONTH, if patients took another diabetes drug.” See Finance Committee packet Attachment B: http://finance.senate.gov/press/Gpress/2010/prg022010a.pdf
Avandia’s cardiac risk was in evidence as early as November 2003, when GSK completed a study in which “diabetics given Avandia had far more heart problems than those given placebos.” European regulators ordered GSK to conduct a study to examine Avandia’s heart risks, but when the study showed harm (2004), GSK conducted a meta-analysis which it submitted to the FDA in 2005, and updated in 2006. The analysis showed that “Avandia increased the risks of serious heart problems by nearly a third.”
However, despite the totality of evidence, from company studies, from adverse event reports filed with FDA’s Medwatch, and from FDA safety evaluations corroborating Avandia’s deadly cardiac risks, the agency continued to drag its feet, “negotiating” with GSK, rather than pulling the drug off the market or, at the very least, issuing public warnings.
Even worse, in 2007, after the New England Journal of Medicine published a report warning of the cardiovascular risk for patients taking Avandia; and after warnings were issued in several countries--including Canada, the European Union, and Australia--that Avandia was CONTRAINDICATED in patients with acute coronary syndrome; FDA officials, in collusion and collaboration with GSK, approved an unethical and exploitative clinical trial—TIDE, which is on-going.
The trial does not meet the ethical principle of equipoise—requiring that so far as is known, the benefit-risk of each comparator were equal. The accumulated evidence showed that Avandia posed far higher risks than Actos. Furthermore, the FDA-approved trial allows the enrollment of very high risk patients with ischemic heart disease—for whom Avandia is contraindicated in several countries
See: Attachment C: http://finance.senate.gov/press/Gpress/2010/prg022010a.pdf
The Informed Consent form given to patients is deceptive by commingling the risks of Avandia with the comparator drug, Actos, which does not pose the cardiac risk that Avandia does.
See Finance Committee Attachment D: http://finance.senate.gov/press/Gpress/2010/prg022010a.pdf
Corporate tactics of intimidation are, once more, in evidence:
The Senate Finance Committee report states that “GSK executives intimidated independent physicians” who suggested in public that Avandia might have serious risks. It’s difficult to tell whether GSK took a leaf from Merck’s tactics of intimidation—such as, Merck’s physician “hit list” of doctors who publicly raised concerns about Vioxx cardiac risks—or whether intimidation of honest physicians is but “the norm and practice” within the pharmaceutical industry.
FDA’s consistent failure to act in the public interest continues unabated under the Obama administration, much as it did under the Bush Administration. Avandia--and an untold number of other drugs that damage the heart--continue to be aggressively marketed, killing thousands of consumers: FDA officials continue to diddle.
Vera Hassner Sharav~~~~~~~~~~~~~~~~~
Senate United States
Committee on Finance
Via Electronic Transmission
The Honorable Margaret A. Hamburg, MD
Food and Drug Administration U.S.
1 White Oak Building
10903 New Hampshire Avenue
Silver Spring, MD 20993
Dear Commissioner Hamburg:
As senior members of the United States Senate and Chairman and Ranking
Member of the Committee on Finance (Committee), we have a duty under the
Constitution to conduct oversight into the actions of executive branch agencies, including
the Food and Drug Administration (FDA). In this capacity, we must ensure that FDA
properly fulfill their mission to advance the public’s welfare, safeguard the nation’s drug
supply, and protect patients participating in clinical trials.
We recently released a report raising concerns about Avandia, a diabetes drug
made by GlaxoSmithKline (GSK). We began this inquiry after the New England Journal
of Medicine published a study in May 2007 warning of the possible cardiovascular risk of
Our report was based on a review of hundreds of thousands of pages of internal
GSK documents and concluded:
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 (pioglitazone) might reduce cardiovascular risk.
In 2007, the FDA asked GSK to perform a cardiovascular safety trial, called
TIDE (Thiazolidinedione Intervention With Vitamin D Evaluation), to compare Avandia
to other diabetes treatments such as ACTOS (piolglitazone). According to
clinicaltrials.gov, the TIDE trial is currently recruiting patients. [ATTACHMENT A]
In response to several document requests made to the FDA, we received and
reviewed an analysis conducted by two FDA safety officials. It is our understanding that
this analysis, conducted in October 2008, reviewed all available studies comparing
rosiglitazone (Avandia) to pioglitazone (ACTOS). The analysis by these FDA officials
raise some alarms. For instance, they wrote:
[T]here is no evidence that rosiglitazone confers any unique health benefits over
pioglitazone while there is strong evidence that rosiglitazone confers an increased
risk of [heart attacks] and heart failure compared to pioglitazone.
Even more alarming, they concluded that “any proposed head-to-head trial of
rosiglitazone vs. pioglitazone would be unethical and exploitative.”
Two days after releasing this analysis, one of these same safety officers reviewed
the protocol for the TIDE trial. This safety officer wrote that because of cardiovascular
concerns with Avandia “the safety of the study itself cannot be assured, and is not
acceptable.” [Attachment C]
After reading these documents, we would like to know what steps the FDA has
taken to protect patients in the TIDE trial, and why this trial is allowed to continue. We
would also like to know if the Office for Human Research Protection (OHRP) was
notified about the safety concerns of the TIDE trial identified by the FDA. Further, we
were alarmed to learn that the warnings from these safety officers do not appear to be
addressed in the consent form that was handed out to patients that were enrolled in the
study. [Attachment D]
We look forward to hearing from you by no later than March 4, 2010. All
documents responsive to this request should be sent electronically in PDF format to
Brian_Downey@finance-rep.senate.gov. If you have any questions, please do not
hesitate to contact Chris Law (Senator Baucus) or Paul Thacker (Senator Grassley) at
Max Baucus Charles E. Grassley
Chairman Ranking Member
THE NEW YORK TIMES
February 20, 2010
Controversial Diabetes Drug Harms
Concludes Heart, U.S.
By GARDINER HARRIS
Hundreds of people taking Avandia, a controversial diabetes medicine, needlessly suffer heart attacks and heart failure each month, according to confidential government reports that recommend the drug be removed from the market.
The reports, obtained by The New York Times, say that if every diabetic now taking Avandia were instead given a similar pill named Actos, about 500 heart attacks and 300 cases of heart failure would be averted every month because Avandia can hurt the heart. Avandia, intended to treat Type 2 diabetes, is known as rosiglitazone and was linked to 304 deaths during the third quarter of 2009.
“Rosiglitazone should be removed from the market,” one report, by Dr. David Graham and Dr. Kate Gelperin of the Food and Drug Administration, concludes. Both authors recommended that Avandia be withdrawn.
The internal F.D.A. reports are part of a fierce debate within the agency over what to do about Avandia, manufactured by GlaxoSmithKline. Some agency officials want the drug withdrawn because they believe there is a safer alternative; others insist that studies of the drug provide contradictory information and that Avandia should continue to be an option for doctors and patients. GlaxoSmithKline said that it had studied Avandia extensively and that “scientific evidence simply does not establish that Avandia increases” the risk of heart attacks.
The battle has been brewing for years but has been brought to a head by disagreement over a new clinical trial and a Senate investigation that concluded that GlaxoSmithKline should have warned patients earlier of the drug’s potential risks.
Avandia was once one of the biggest-selling drugs in the world. Driven in part by a multimillion-dollar advertising campaign, sales were $3.2 billion in 2006. But a 2007 study by a Cleveland Clinic cardiologist suggesting that the drug harmed the heart prompted the F.D.A. to issue a warning, and sales plunged. A committee of independent experts found in 2007 that Avandia might increase the risk of heart attack but recommended that it remain on the market, and an F.D.A. oversight board voted 8 to 7 to accept that advice.
Hundreds of thousands still take the medicine, although some top endocrinologists say they have sworn off the drug.
Since 2007, more studies have been done. In a December 2009 internal memorandum, Dr. Janet Woodcock, director of the F.D.A.’s drug center, wrote that “there are multiple conflicting opinions” about Avandia within the agency, and she ordered officials to assemble another advisory committee, expected this summer, to reconsider whether the drug should be sold.
“I await the recommendations of the advisory committee,” the agency’s commissioner, Dr.
Margaret Hamburg, said Friday night. “Meanwhile, I am reviewing the inquiry made by Senators Baucus and Grassley and I am reaching out to ensure that I have a complete understanding and awareness of all of the data and issues involved.”
The bipartisan multiyear Senate investigation — whose results are expected to be released publicly on Monday but which were also obtained by The Times — sharply criticizes GlaxoSmithKline, saying it failed to warn patients years earlier that Avandia was potentially deadly.
“Instead, G.S.K. executives attempted to intimidate independent physicians, focused on strategies to minimize or misrepresent findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that a competing drug might reduce cardiovascular risk,” concludes the report, which was overseen by Senator Max Baucus, a Montana Democrat, and Senator Charles E. Grassley, an Iowa Republican.
Mr. Baucus said of the report, “Patients trust drug companies with their health and their lives, and GlaxoSmithKline abused that trust.”
In response, GlaxoSmithKline said that it disagreed with the Senate investigation’s conclusions. The company said that it could not comment on internal F.D.A. documents but that “the official ruling from F.D.A. is that Avandia remain on the market.”
In the wake of the controversy, agency officials ordered GlaxoSmithKline to undertake a study comparing how many heart attacks, strokes and heart-related deaths occur among patients given either Avandia, Actos or a placebo. Studies suggest that Actos, made by Takeda, lowers blood sugar as well as Avandia but without hurting the heart as much.
But Dr. Graham and Dr. Gelperin, working in the F.D.A.’s office of surveillance and epidemiology, argued in two separate internal reports that the new GlaxoSmithKline study, called TIDE, is “unethical and exploitative” because patients given Avandia face far greater risks than those given Actos, with no promise of any additional benefit. The trial may include patients who have had heart attacks or chest pains even though some foreign drug authorities have warned against Avandia’s use by precisely such patients, the reports note.
“Although the proposed TIDE trial is motivated by a desire for definitive answers regarding the cardiovascular safety of the drug rosiglitazone, the safety of the study itself cannot be assured and is not acceptable,” one of the reports concludes.
These concerns, in internal reports dated October 2008 but not made public until now, were later overruled by other agency officials, and GlaxoSmithKline is currently enrolling patients in the TIDE trial. The trial is not expected to be completed until 2020, although the company is hoping to report some results to the F.D.A. by 2014. The company’s patent on Avandia expires in 2012, and generic versions will probably swallow most remaining profits.
In a letter sent Thursday to Dr.
, the Food and Drug Administration commissioner, Mr. Baucus and Mr. Grassley asked “what steps the F.D.A. has taken to protect patients in the TIDE trial” and said the trial’s patients had never been told about the concerns raised by the agency’s own safety officers. Hamburg
Mr. Grassley said the internal agency battle showed that the agency needed to be restructured to give more power to safety officials like Dr. Graham and Dr. Gelperin over their counterparts who approve medicines and deal more directly with drug makers.
“It doesn’t make any sense to have these experts who study drugs after they have been on the market for several years under the thumb of the officials who approved the drug in the first place and have a natural interest in defending that decision,” Mr. Grassley said. “The Avandia case may be the most alarming example of the problem with this setup.”
The question of when and how to communicate possible drug risks has long bedeviled drug makers and regulators. Hints are common that drugs may cause injuries; thousands of drug injury reports pour into the Food and Drug Administration every week. For example, Avandia ranked first among all prescribed drugs in the number of serious, disabling and fatal problems — including 304 deaths — reported to the agency in the third quarter of 2009, according to an analysis done by the Institute for Safe Medication Practice, a drug safety oversight group.
But companies say that such reports do not offer proof of a problem and that highlighting them can scare patients away from needed treatment, so they often argue that more certainty is needed before alarms are raised. GlaxoSmithKline said a “vast majority” of the recent reports regarding Avandia was related to litigation.
The Senate investigation — the result of years of digging through more than 250,000 internal company documents — concludes that GlaxoSmithKline and by extension the F.D.A. delayed far too long in this process.
In November 2003, for instance, the company completed a study in which diabetics given Avandia had far more heart problems than those given placebos. Two months later, the World Health Organization sent the company an alert linking Avandia to heart ailments. In a June 2004 meeting, the company’s Global Safety Board said a hard look should be taken at all Avandia clinical trials for more signs of heart problems, documents show.
European regulators had earlier ordered GlaxoSmithKline to conduct a study — called the Record trial — to examine Avandia’s heart risks because hints of these problems appeared in the company’s earliest trials.. But the Senate report shows that by at least 2004, company executives were aware that the Record trial was going so poorly that it would never answer the heart question with any kind of certainty.
So company executives gathered dozens of Avandia studies and sifted their combined data. Called a meta-analysis, this combined look found first in 2005 and in an updated look in 2006 that Avandia increased the risks of serious heart problems by nearly a third, the Senate investigation shows. Because two-thirds of diabetics die of heart problems, this was hugely worrying.
In 2005, executives revealed the results of their meta-analysis to the F.D.A., and in 2006 they provided the agency with the underlying data.
Two large company-sponsored trials — called Dream and Adopt — were published near the end of 2006, and each provided more hints that Avandia hurts the heart, the documents show. In a March 2007 meeting of the company’s Diabetes Franchise Cardiology Advisory Board, advisers called the safety worries found in these many studies “disquieting.” Negotiations with agency officials about how and whether to alert the public continued.
Meanwhile, the company continued to market and advertise Avandia aggressively. The Senate inquiry concludes that the company threatened doctors who suggested in public that Avandia might have serious risks.
In 1999, for instance, Dr. John Buse, a professor of medicine at the
, gave presentations at scientific meetings suggesting that Avandia had heart risks. GlaxoSmithKline executives complained to his supervisor and hinted of legal action against him, according to the Senate inquiry. Dr. Buse eventually signed a document provided by GlaxoSmithKline agreeing not to discuss his worries about Avandia publicly. The report cites a separate episode of intimidation of investigators at the Universityof North Carolina . Universityof Pennsylvania
GlaxoSmithKline said that it “does not condone any effort to silence” scientific debate, and that it disagrees with allegations that it tried to silence Dr. Buse. Still, it said the situation “could have been handled differently.”
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