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Senior Citizen Health & Medicine
Senate Committee Wants Answers About Avandia,
Company Defends Record
Committee leaders send letters to FDA and
GlaxoSmithKline
 May 22, 2007 – The Senate Finance Committee
leadership obviously had their guns loaded when the New England Journal
of Medicine published a study yesterday showing the type 2 diabetes drug
Avandia (rosiglitazone) significantly increases the risk of heart attack
and death. And, the drug-maker quickly responded to the senators.
Sens. Max Baucus and Chuck Grassley, Chairman and
Ranking Member of the Committee on Finance, yesterday issued comments
and and also sent letters regarding the contents of a study to the Food
and Drug Administration and the company, GlaxoSmithKline.
The senators are asking the Food and Drug
Administration to tell them about what the FDA knew about Avandia and
when they learned about it. The senators are asking the drug maker to
respond to allegations that company executives sought to silence
independent scientist(s) about risks with this particular drug. (Copies
of the letters are below.)
Sen. Baucus issued this comment:
“What we are learning about the handling of Avandia
by both GlaxoSmithKline and the FDA is appalling and unacceptable. Both
the drug company and the FDA 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 patients. The number one priority for drug
manufacturers and the FDA must be patient safety. Medicare and Medicaid
patients—and all Americans—must never be put at risk like this again.”
Sen. Grassley issued this comment:
“We need to know if this is another Vioxx, where
the FDA sat on its hands and endangered lives. The FDA 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 that claim. It’ll take more than
administrative reforms to fix the system within the FDA.
"Congress ought to take advantage of the
opportunity that we have right now with the FDA funding bill to make a
real difference for public safety. Study after respected study has said
that the FDA office responsible for postmarket review of drug safety
ought to have equal footing with the FDA’s drug approval office.
“It’s hard to understand how there’s any resistance
to this kind of reform if you care about public safety and public access
to the never ending flow of new information about pharmaceuticals. I
won’t stop making the case for giving the post-market review office real
clout.”
GlaxoSmithKline Responds
The following is GlaxoSmithKline's reponse, issued
Monday, to the press release from the US Senate Committee on Finance
about Avandia (rosiglitazone maleate):
The suggestion that GlaxoSmithKline has placed
patients at risk and attempted to silence independent investigation of
data is absolutely false. Any fair examination of the company's record
will show that GSK has been fully transparent in its efforts to
thoroughly study the safety and effectiveness of Avandia, and to widely
communicate that information to governments, scientists, physicians, and
the public in the best interests of both patients and scientific debate.
The statistical analysis on which the Committee
bases its concern is, by the author's own admission, limited, while the
editorial accompanying the paper states: "the possibility that the
findings were due to chance cannot be excluded."
In contrast, GSK has initiated the most
comprehensive and rigorous program of scientific analysis for any oral
anti-diabetic medicine on the market today, with experience in over
52,000 patients. The company has initiated:
● Extensive clinical trials, including long-term
clinical trials in diabetic patients;
● A prospective, long-term, clinical trial
specifically designed to address cardiovascular safety in diabetic
patients;
● A proactive, integrated clinical trial analysis
of the company's own collected data; and
● Rigorous monitoring of spontaneously reported
adverse events.
These data show that Avandia has a cardiovascular
safety profile comparable to other oral anti-diabetic medicines. In
addition, independent investigators performed a comprehensive analysis
of patients in a US managed care database of more than 33,000 people
with diabetes, and showed there was no difference in cardiovascular
events among patients taking Avandia- containing regimens versus other
oral anti-diabetic medicines.
Over time, the company has actively shared new data
on Avandia with the FDA and with regulators worldwide as quickly as
scientifically possible. GSK has a strong commitment to providing timely
access to its data, which is why the company was one of the first to
develop a Clinical Trials Register, on which Avandia data has been
posted, and where it is available to any scientific investigator
interested in doing their own analysis.
GSK stands firmly behind the safety of Avandia when
used appropriately, and will strongly defend its commitment to patient
safety and to full transparency of its scientific information. We
welcome the opportunity to meet with the Committee and its staff to
correct misunderstandings and to clarify the record.
GlaxoSmithKline -- one of the world's leading
research-based pharmaceutical and healthcare companies -- is committed
to improving the quality of human life by enabling people to do more,
feel better and live longer. For company information, visit
GlaxoSmithKline on the World Wide Web at www.gsk.com.
Grassly and Baucus Letter to FDA Commissioner
Andrew C. von Eschenbach
The United States Senate Committee on Finance
(Committee) has jurisdiction over the Medicare and Medicaid programs
and, accordingly, a responsibility to the more than 80 million Americans
who receive health care coverage under those programs to ensure that
beneficiaries receive drugs that are both safe and effective.
Today, the New England Journal of Medicine
published a study on adverse effects of rosiglitazone (Avandia), a
pharmaceutical manufactured by GlaxoSmithKline (GSK) to treat type II
diabetes. The study reported a 43% increase in the risk of myocardial
infarctions/heart attacks in people taking Avandia and potentially a 64%
increase in the risk of cardiovascular deaths. Since the Food and Drug
Administration (FDA/Agency) approved Avandia in 1999, physicians have
written tens of millions of prescriptions for the drug. This could mean
tens of thousands of cardiovascular adverse events attributable to this
drug.
Diabetics take Avandia to improve their overall
health as well as avoid one of the major causes of death among
diabetics, heart attacks. 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, American taxpayers have spent hundreds of
millions of dollars on this drug through the Medicare and Medicaid
programs.
In addition, the Committee has received reports
that executives with GSK met with FDA officials in October 2005 and
later in August 2006 after further exploring these cardiovascular
problems. We understand that during the same time period, other concerns
were raised by FDA employees.
Ironically, on May 9, 2007, Dr. Steven Galson,
Director of the Center for Drug Evaluation and Research, testified
before Congress that FDA guidance approved in March should protect the
public against problems with pharmaceuticals such as what we are now
seeing with Avandia. Dr. Galson testified, "The guidance affirms the
Agency's commitment to communicate important drug safety information in
a timely manner including in some situations when the Agency is still
evaluating whether to take any regulatory action." Dr. Galson's
testimony flies in the face of FDA's leisurely reaction to GSK's
briefing over a year ago on cardiovascular problems attributed to
Avandia.
It appears that the new guidance on communicating
drug safety information has not improved the FDA's ability to protect
the American people in a timely manner. We are greatly concerned about
these alleged missteps and would like to further understand why FDA has
not taken any action.
In light of the serious concerns raised in this
letter, we would like to have you personally brief us on Avandia. We
request that Dr. Galson and the lead safety official in Office of
Surveillance and Epidemiology who has been monitoring Avandia join you
for the briefing.
Additionally, we would also appreciate responses to
the following questions and requests for documents and records in
advance of the briefing. Please respond by repeating the enumerated
question, followed by the accompanying response.
1. When did you first become aware that Avandia may
cause a higher incidence of myocardial infarctions, cardiovascular
disease, and/or cardiovascular death?
2. How did the FDA first become aware of this
problem?
Describe in detail FDA's actions to address this
problem.
3. Given the effects of Avandia on blood glucose
levels and other cardiovascular risk factors like cholesterol levels and
body weight, did the FDA consider requiring GSK to conduct a long-term
randomized trial to demonstrate risks and/or benefits such as how
Avandia affects heart attack risk?
What were the discussions, if any, around this
issue at the FDA?
Did the FDA make the suggestion to GSK?
If so, what was GSK's response?
Please provide a complete account of the evolution
of these discussions, including related communications, documents, and
records.
4. Please provide a formal, detailed timeline of
your agency's actions regarding Avandia beginning with the date on which
FDA staff first became aware of this higher incidence of cardiovascular
problems related to Avandia and/or were notified by GSK of these
problems. This timeline should identify, among other things, any
internal or external communications and/or meetings, including meetings
with GSK. Please provide relevant documents and/or records.
5. Describe in detail actions that FDA has taken to
investigate the potential for Avandia to cause cardiovascular problems
since FDA was first advised or became aware of such risks.
6. Please provide all documents and/or records
regarding Avandia since your agency first began examining whether
patients taking the drug might be at a higher risk for myocardial
infarctions, cardiovascular disease, or cardiovascular death.
7. Please identify all agency personnel (including
full name, title and contact information) who have examined the issue of
Avandia and myocardial infarctions, cardiovascular disease, and/or
cardiovascular death. Also, explain what role they played in
investigating and/or communicating that Avandia may cause these adverse
reactions. In responding to this question, please include internal and
external communications.
8. When did the FDA first learn of the study and/or
work of Dr. Steven Nissen, one of the authors of the New England Journal
of Medicine article, regarding Avandia and myocardial infarctions?
Please provide all communications, documents and
records, both internal and external, regarding Dr. Nissen's study and/or
work on Avandia.
In cooperating with the Committee's review, no
documents, records, data or information related to these matters shall
be destroyed, modified, removed or otherwise made inaccessible to the
Committee.
We look forward to hearing from you regarding the
concerns and questions set forth in this letter by no later than June 4,
2007 in accordance with the attached definitions and general
instructions.
Main Portions of Baucus, Grassley Letter to
GlaxoSmithKline
…Since GSK began selling Avandia in 1999,
physicians have written tens of millions of prescriptions for it. This
could mean tens of thousands of cardiovascular adverse events
attributable to Avandia.
Diabetics take Avandia to improve their overall
health as well as avoid one of the major causes of death among
diabetics, heart attacks. 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, 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 are
reports that GSK employees silenced one or more medical professionals
who attempted to speak out about the potential for cardiovascular
problems with Avandia. This allegation is very serious and warrants
further investigation.
In addition, the Committee received reports that
GSK executives met with FDA officials in October 2005 and later in
August 2006.
In light of these allegations and concerns, we
request a briefing for our Committee staff, focusing in particular on:
(1) allegations that GSK executives sought to silence medical
professional(s) regarding possible serious adverse events related to
Avandia, and (2) the reports and any other information that GSK provided
to the FDA regarding adverse events related to Avandia.
We also request that GSK provide responses to the
following questions and requests for documents and records. Please
respond by repeating the enumerated question, followed by the
accompanying response.
1. When did GSK first become aware that Avandia may
cause a higher incidence of myocardial infarctions, cardiovascular
disease, and/or cardiovascular deaths?
How did GSK first become aware of this problem?
2. Describe in detail what actions GSK took to
address this problem. Please include copies of all responsive documents.
In responding to this inquiry, please be specific as to what raised
GSK's suspicion that people taking Avandia might be at a higher risk for
cardiovascular problems.
3. When it was approved or soon after, there was
evidence that Avandia improved the control of blood glucose but had
adverse effects on other risk factors like weight and cholesterol. An
important scientific question is whether Avandia thus reduces or
increases the risk of heart attack in diabetics. Answering this question
would require a large long-term randomized trial with heart attack as
one potential outcome. Please provide all communications, documents, and
records relevant to a discussion on conducting such a trial, from the
time that the New Drug Application was first submitted to the FDA. Did
GSK conduct such a trial?
If not, why not?
What were the arguments for and against conducting
such a trial?
What was the decision-making process regarding
such a trial?
4. Please provide a detailed timeline of GSK's
actions regarding Avandia beginning with the date on which your company
first became aware of the potential for a higher incidence of
cardiovascular problems related to the use of Avandia and the time GSK
notified the FDA of such potential. This timeline should identify
specifically, among other things, any internal or external
communications and/or meetings, including meetings with the FDA. Please
provider relevant documents and/or records.
5. Please identify all GSK personnel (including
full name, title and contact information) who have examined the issue of
Avandia and myocardial infarctions, cardiovascular disease, and/or
cardiovascular death. Also, explain what role they played in
investigating and/or communicating that Avandia may increase the risk of
these adverse reactions. In responding to this question, please include
internal and external communications.
6. Please provide any and all contracts or similar
instruments between GSK and any outside scientists/medical professionals
regarding Avandia and efforts to either directly or indirectly limit
that individual's ability to discuss adverse events related to Avandia.
For each contract or similar instrument, please provide all related
documents, records and/or communications.
7. Please identify any and all third parties (e.g.,
corporations, individuals, universities, etc.) engaged by GSK to
examine, review, evaluate or analyze Avandia and/or the effects of its
use. Please be sure to include the nature of the work performed and
provide a copy of any and all draft and final products provided to GSK.
8. When did your company first learn about the
study and/or work of Dr. Steven Nissen on Avandia and cardiovascular
problems?
Please provide all communications, documents and
records, both internal and external, regarding Dr. Nissen's study and/or
work on Avandia, including any consultants who may have been hired to
examine/discuss Dr.
Nissen's work.
In cooperating with the Committee's review, no
documents, records, data or information related to these matters shall
be destroyed, modified, removed or otherwise made inaccessible to the
Committee. In addition, we would appreciate your identifying a GSK
representative with whom we can discuss matters relating to Avandia as
soon as possible.
We look forward to hearing from you regarding the
allegations, concerns and questions set forth in this letter by no later
than June 11, 2007, in accordance with the attached definitions and
general instructions.
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