Avandia
Hearing Exposes FDA
As Negligent Watchdog
By Evelyn Pringle
15 June, 2007
Countercurrents.org
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.
Persons seeking legal advice
regarding Avandia can contact Baum Hedlund Law Firm at: (800) 827-0087;
http://www.baumhedlundlaw.com/
http://www.avandia-heart-lawyers.com/
[email protected]
(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 America)
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