And Glaxo Share Blame
For Avandia Disaster
By Evelyn Pringle
04 June, 2007
On May 21, 2007, the New England
Journal of Medicine reported a study that found GlaxoSmithKline's diabetes
drug Avandia is associated with a 43% increase in heart attacks and
possibly a 64% increase in cardiovascular death. The NEJM said it posted
the article online ahead of its June 6, 2007 print edition because of
its medical importance.
Experts point out that the studies analyzed for the NEJM report were
not designed to look for heart risks, many were only 24 weeks long,
and it may be that higher risks will appear after a longer term of use.
Dr David Nathan, chief of diabetes care at Massachusetts General Hospital,
who reviewed the paper for the NEJM, told the Associated Press, "This
analysis is just scratching the surface of what may be there."
Avandia (rosiglitazone) was FDA approved in 1999 for the treatment of
type 2 diabetes, a disease that affects between 18 to 20 million Americans.
When approved, Glaxo promoted Avandia as being safer than Rezulin, a
diabetes drug removed from the market in 2000 after serious cases of
liver damage developed in patients taking the drug.
Avandia is currently the top selling diabetes drug with total US sales
of $2.2 billion in 2006, according to IMS Health, a healthcare tracking
information firm. A one-month supply sells for between $90 and $170,
the Associated Press reported on May 23, 2007.
"More than 6 million people worldwide," the Associated Press
reports, "have taken the drug to control blood sugar since it came
on the market eight years ago, and about 1 million Americans use it
The FDA is going to have an extremely tough time wiggling out from under
the rug of blame for this regulatory failure. The situation "reflects
very badly on the FDA and on Glaxo," Dr Nathan said. "It's
the FDA's responsibility to be monitoring this stuff."
In an editorial that accompanied the study in the NEJM, Dr Bruce Psaty
of the University of Washington and Dr Furberg of Wake Forest University
wrote: The drug "represents a major failure of the drug-use and
drug-approval processes in the United States."
They also state that "the rationale for prescribing rosiglitazone
at this time is unclear,” because when the drug was approved its
benefits were "at best mixed."
Documents dating back 7 years show the FDA knew about the risks associated
with Avandia and did nothing to protect consumers. The day after the
new study appeared online, on May 23, 2007, Dr Sidney Wolfe, director
of Public Citizen, a non-profit health research group, sent a letter
to FDA Commissioner Andrew von Eschenbach, which described a July 16,
2002 FDA memo that showed FDA scientists had recommended that the label
for Avandia be amended to include post-marketing reports of heart failure
among patients taking the drug.
"The failure of the FDA to act on the recommendations made almost
five years ago by its Division of Drug Risk Evaluation is yet another
case in which the conclusions of scientists who are engaged in post-market
drug safety review are not taken seriously enough or addressed soon
enough,” Dr Wolfe said in a press release.
"As a result," he stated further, "millions of people
– to the detriment of their health – are prescribed drugs
whose risks are dangerously understated, instead of being prescribed
safer, equally or more effective alternative drugs.”
According to the memo, in July 2002, the FDA had 25 adverse reaction
reports in which the use of Avandia resulted in hospitalization for
heart failure. By the fall of 2006, the number of cases had increased
to 415, Public Citizen reports.
Another memo dated May 22, 2002, submitted to the FDA by Dr. Wolfe and
Larry Sasich for an FDA Hearing on Risk Management of Prescription Drugs
informed the panel that a Glaxo-employed physician had contacted Public
Citizen to report that the company was concealing reports of serious
problems found with the drug.
"This week," they informed the FDA, "we received an anonymous
call from a GlaxoSmithKline physician who was alarmed at the failure
of his company to require a black box warning concerning heart failure
caused by Avandia."
"He maintained that the company currently has 450 reports of heart
failure associated with the use of the drug and over 1200 reports of
edema," the statement said.
Nearly two years earlier, on March 15, 2000, Dr. John Buse, an Associate
Professor of Medicine and Director of a Diabetes Care Center in Durham,
North Carolina, sent a letter to then FDA Commissioner, Dr Jane Henney,
warning the FDA about the risks of Avandia and describing the abuse
of clinical trial data by Glaxo.
"I remain concerned about the safety of rosiglitazone," Dr
Buse wrote, "in light of its consistent negative impact on lipids
documented in the FDA registration data as well as a worrisome trend
in cardiovascular deaths and severe adverse events in the subjects exposed
to rosiglitazone versus active comparators."
Dr Buse warned, "I think the FDA has to act forcefully to prevent
the rampant abuse of clinical trial data by SmithKline Beecham."
He warned Dr Henney that Glaxo was overstating the safety of Avandia
with respect to cardiovascular issues. "I have been shown glossy
materials claiming that rosiglitazone has been uniquely studied in patients
with preexisting cardiac disease," he wrote, "including patients
with a number of associated conditions (such as unstable angina)."
"I know for a fact," he noted, "that such patients are
excluded in clinical trials as I am a PI [Principal Investigator] in
one of their trials."
Lawmakers in both Houses of Congress reacted to the news of another
FDA regulatory failure immediately. On May 21, 2007 the US House of
Representatives Committee on Oversight and Government Reform announced
that a hearing would be held on June 6, 2007, at 10:00 am in Room 2154,
Rayburn House Office Building, to assess the FDA's role in the evaluation
of the safety of Avandia.
Committee chairman, Rep Henry Waxman (D-CA) extended an invitation to
the author of the NEJM article, cardiologist, Dr Steven Nissen of the
Cleveland Clinic, to testify at the hearing and discuss his article.
Dr Nissen and statistician Kathy Wolski, MPH, evaluated 42 studies involving
nearly 28,000 patients and compared the 15,560 patients who were using
Avandia to the patients who were not using the drug. The study found
there were 86 myocardial infarctions in the Avandia group and 72 in
the control group and there were 39 deaths from cardiovascular causes
in Avandia patients compared to 22 in the control group.
Rep Waxman also sent a letter to FDA Commissioner Andrew von Eschenbach
requesting his testimony at the hearing. In addition, he instructed
the Commissioner to provide the Committee with specific information
from August 1, 2005, to the present to include: (1) A chronology of
actions taken by FDA in relation to the cardiovascular safety of rosiglitazone;
(2) All communications between GlaxoSmithKline and the FDA relating
to cardiovascular safety of rosiglitazone; and (3) All internal FDA
analyses, slide presentations, and memoranda relating to the cardiovascular
safety of rosiglitazone.
"In complying with this request," Rep Waxman advised the Commissioner,
"you should produce all responsive documents in your possession,
custody, or control."
Rep Waxman also told the Commissioner, "you should submit a written
certification, signed by you or your counsel, stating that: (1) a diligent
search has been completed of all documents in your possession, custody,
or control which reasonably could contain responsive documents: and
(2) all documents located during the search that are responsive have
been produced to the Committee or identified in a privilege log."
And last but not least, Rep Waxman sent a letter to Glaxo CEO, Dr Jean-Pierre
Garnier, asking him to appear. "We request that you come prepared
to discuss your company's actions with regard to the cardiovascular
safety of Avandia," the letter states.
Over in the US Senate, Senators Max Baucus and Chuck Grassley, Chairman
and Ranking Member of the Senate Committee on Finance, which has jurisdiction
over the Medicare and Medicaid programs, issued a public statement and
sent letters to the FDA and Glaxo demanding they provide specific documents
and other information to the Committee.
“What we are learning about the handling of Avandia," Sen
Baucus said in the statement, "by both GlaxoSmithKline and the
FDA is appalling and unacceptable."
"Both the drug company and the FDA," he said, "have some
major explaining to do about what they knew about Avandia, when they
knew it, and why they didn’t take immediate action to protect
“We need to know if this is another Vioxx," Senator Grassley
stated, "where the FDA sat on its hands and endangered lives."
"The FDA," he continued, "has talked a good game about
how it’s beefed up post-market
surveillance over the last two years, but a case like this undermines
Experts say the new study findings are alarming because two-thirds of
the people with type 2 diabetes die of heart problems. In a May 21,
2007 letter to Christopher Viehbacher, President, US Pharmaceuticals,
GlaxoSmithKline, Senators Baucus and Grassley wrote, "It is troubling,
to say the least, that by taking Avandia, diabetics may be increasing
their risk of the very adverse event that they hope to prevent by controlling
their blood sugar."
"To make matters worse," they advised, "American taxpayers
have spent hundreds of millions of dollars on this drug through the
Medicare and Medicaid programs."
"One of the most immediate concerns to us," they told Mr Viehbacher,
"are reports that GSK employees silenced one or more medical professionals
who attempted to speak out about the potential for cardiovascular problems
"This allegation is very serious and warrants further investigation,"
the Senators wrote.
According to plaintiffs attorney, Karen Barth Menzies of Baum Hedlund,
a law firm that has been litigating drug related cases against Glaxo
since 2001, “"The relationship between FDA and the drug industry
is disturbing. We've seen internal correspondence between GSK and the
FDA that would cause anyone to question the objectivity and regulatory
effectiveness of the FDA. Apparently the FDA has failed yet again to
protect the public - to the benefit of pharmaceutical industry profits.
This failure, and FDA's derogatory attitude towards Dr. Nissen's study,
should sound an alarm to all healthcare providers, patients and legislators
that the problem is systemic. Patient safety commands serious change
in the agency and the industry."
Already, legal conferences are being scheduled to discuss the legal
implications of this latest drug safety scandal. Karen Barth Menzies
is an invited speaker at an upcoming legal conference regarding Avandia.
The conference will include Avandia’s background, the science
behind the drug, its side effects as well as the FDA’s role in
Persons seeking legal advice regarding Avandia can contact Baum, Hedlund,
Aristei, Goldman & Menzies at: (800) 827-0087; http://www.avandia-heart-lawyers.com/
(Written as part of a series on Avandia sponsored by Baum Hedlund's
Pharmaceutical Litigation Department)
(Evelyn Pringle is a regular columnist for OpEd News and investigative
journalist focused on exposing corruption in government and corporate
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