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AVANDIA Liability, Science,

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Title: AVANDIA Liability, Science,


1
AVANDIALiability, Science, Studies
  • Vance Andrus
  • vandrus_at_yahoo.com
  • 1775 Sherman St., 31st Floor
  • Denver, CO 80203
  • (866) 795-9529
  • With Special Appreciation to
  • Richard Meadow Catherine Heacox
  • The Lanier Law Firm, PLLC
  • Neil Overholtz
  • Aylstock Witkin Kreis Overholtz, PLLC

2
AVANDIA
3
Avandia Overview
  • What Is Avandia?
  • Drug Class thiazolidinediones (glitazones)
  • Rosiglitazone
  • Avandia, Avandaryl, Avandamet (GSK)
  • Troglitizone
  • Rezulin (Warner-Lambert) - severe hepatatoxicity
  • Pioglitazone
  • Actos, ActosPlusMet (Eli Lilly Takeda)

4
Avandia Overview
  • What is Avandia?
  • GlaxoSmithKline (GSK) Prescription Drug
  • Indicated for treatment of Type 2 Diabetes
  • Active ingredient Rosiglitazone Maleate

5
Avandia Overview
  • How does Avandia work?
  • Rosiglitazone is agonist of peroxisome
    proliferator activated receptors (PPARs)
  • Avandia lowers blood glucose primarily by
    increasing insulin sensitivity in peripheral
    tissues

6
Avandia Overview
  • Manufactured by GlaxoSmithKline (GSK)
  • British Company with U.S. contacts in
    Pennsylvania and North Carolina
  • Pharmaceutical Operations headquarters in
    Philadelphia, Pennsylvania and Research Triangle
    Park, North Carolina
  • Major RD sites in Research Triangle Park, North
    Carolina and Upper Merion and Upper Providence,
    Pennsylvania
  • Major manufacturing sites for prescription
    products in King of Prussia, Pennsylvania and
    Zebulon, North Carolina

7
Avandia Overview
  • Three GSK Products with Rosiglitazone
  • Avandia
  • Avandamet
  • Avandaryl

8
Avandia Overview
  • Rosiglitazone only
  • FDA approved 5/25/99 for Type 2 diabetes
  • In 2006, GSKs 2nd largest product with more
    than 2 billion in sales
  • Used by an estimated six million people in the
    United States since approval

9
Avandia Overview
  • Rosiglitazone and metformin
  • FDA approved 10/10/2002
  • In 2005, the 154th best selling drug
  • 1.9 million prescriptions sold
  • 261 million in sales

10
Avandia Overview
  • Rosiglitazone and glimepiride
  • FDA approved 11/23/2005

11
Avandia Science
  • Major Completed Studies
  • NEJM Meta-analysis
  • GSK Meta-analysis
  • DREAM trial
  • ADOPT trial

12
Avandia Science
  • NEJM Study - Findings
  • People taking Avandia are 43 more likely to
    suffer a heart attack than control groups
  • Statistically significant increased risk
  • Odds Ratio for MI on Rosiglitazone is 1.43 (95
    CI, 1.03-1.98 P 0.03)

13
Avandia Science
  • NEJM Study

Nissen SE, Wolski K. Effect of rosiglitazone on
the risk of myocardial infarction and death from
cardiovascular causes. N Engl J Med 2007356
Epub ahead of print 1-15.
14
Avandia Science
  • NEJM Study - Findings
  • 64 increased risk of CV death on Avandia
  • Borderline statistical significance
  • Odds Ratio for CV Death on Rosiglitazone is 1.64
    (95 CI, 0.98 to 2.74 P 0.06)

15
Avandia Science
  • NEJM Study - Conclusion
  • Our data show that, as compared with placebo or
    with other antidiabetic regimens, treatment with
    rosiglitazone was associated with a significant
    increase in the risk of myocardial infarction and
    with an increase in the risk of death from
    cardiovascular causes that had borderline
    significance.

16
Avandia Science
  • DREAM Trial
  • Diabetes Reduction Assessment with Ramipiril and
    Rosiglitazone Medication trial
  • Industry sponsored study
  • Avandia tested on 5,269 low CV risk, pre-diabetic
    patients over 3 years
  • Designed to evaluate whether Rosiglitizone could
    prevent Type 2 Diabetes

Gerstein HC, et al, DREAM (Diabetes Reduction
Assessment with Ramipril and Rosiglitazone
Medication) Effect of rosiglitazone on the
frequency of diabetes in patients with impaired
glucose tolerance or impaired fasting glucose a
randomized controlled trial, Lancet. 2006 Sep
23368(9541)1096-105.
17
Avandia Science
  • DREAM Trial Findings
  • 37 Increased risk of combined CV adverse events
    borderline statistical significance
  • HR of 1.37 (95 CI 0.97-1.94)
  • MI and CV Death risk increased not statistically
    significant
  • MI - HR of 1.66 (95 CI 0.73-3.80)
  • CV Death - HR of 1.20 (95 CI 0.52-2.77)

18
Avandia Science
  • Psaty, NEJM Editorial

The manufacturer did not make a serious effort
to verify the presumed health benefits of
rosiglitizone in a timely fashion. In ADOPT.
CV events were not identified or recorded in a
systemic fashion, and heart failure was the only
outcome that was reviewed and adjudicated at the
end of the trial. Nonethelessrosiglitizone in
ADOPT was associated with a higher risk of
cardiovascular events than the comparator drug.
Psaty B, Editorial The Record on Rosiglitizone
and the Risk of Myocardial Infarction, NEJM epub
10.1056/NEJMeo78116
19
Avandia Science
  • GSK Meta-analysis
  • Avandia Cardiovascular Event Modeling Project
  • Patient level data analyzed
  • Completed 10/2005, not reported to FDA for 11
    months
  • Findings consistent with Nissen NEJM Study
  • HR 1.31 95 CI, 1.01 to 1.70

GlaxoSmithKline. Study no. ZM2005/00181/01
Avandia Cardiovascular Event Modeling Project.
(Accessed June 4, 2007, at http//ctr.gsk.co.uk/Su
mmary/Rosiglitizone/III_CVmodeling.pdf.)
20
Avandia Science
  • Nissen, Lancet Letter to Editor re DREAM

"In DREAM, despite a substantial delay in onset
of diabetes, rosiglitazone resulted in a 37
increase in adverse cardiovascular events, a
finding that very nearly reached conventional
levels of significance. This trend virtually
precludes the possibility of an overall benefit
and suggests an unexpected mechanism for harm.
Nissen SE, The DREAM trial, Lancet. 2006 Dec
9368(9552)2049.
21
Avandia Science
  • Psaty, NEJM Editorial

"In the absence of evidence of actual health
benefits, the public health rationale for the use
of a drug to treat a precondition and thereby to
prevent the onset of a related condition that
would, normally and simply, mark the beginning of
drug treatment is not clear. The DREAM study
represents an effort to medicalize a predisease
state.
Psaty B, Editorial The Record on Rosiglitizone
and the Risk of Myocardial Infarction, NEJM epub
10.1056/NEJMeo78116
22
Avandia Science
  • ADOPT Study
  • A Diabetes Outcome Prevention Trial
  • Funded by GSK
  • Published December 2006 in NEJM
  • 4,360 patients studied over 4 years

Kahn SE, Haffner SM, Heise MA, Herman WH,
Holman RR, Jones NP, Kravitz BG, Lachin JM,
O'Neill MC, Zinman B, Viberti G ADOPT Study
Group. Glycemic durability of rosiglitazone,
metformin, or glyburide monotherapy. N Engl J
Med. 2006 355 2427-43.
23
Avandia Science
  • ADOPT Study - Findings
  • Assessed adverse reactions but did not calculate
    hazard ratio, relative risk or odds ratios
  • Numerical results indicated 23 of Rosiglitazone
    users suffered serious cardiovascular events as
    compared to 3.2 of Metformin users and 1.8 of
    Glyburide users

24
Avandia Science
  • RECORD Trial Preliminary Conclusion
  • Statistical power limited by drop outs low
    event rate
  • Findings inconclusive regarding overall risk of
    hospitalization or CV death from drug
  • Data insufficient to determine whether the drug
    was associated with an increased risk of MI
  • Statistically significant increased risk of heart
    failure

25
Avandia Science
  • Ongoing Clinical Trials
  • RECORD trial
  • BARI 2D
  • ACCORD

26
Avandia Science
  • RECORD Trial Psaty, NEJM Conclusion
  • The responsibility for the limited availability
    of high-quality data resides primarily with GSK
    and also perhaps with FDA
  • Rosiglitizone was approved on the basis of its
    ability to improve glycemic control, a surrogate
    endpoint. Because high glucose levels increase
    the risk of vascular disease, a glucose lowering
    drug is presumed to reduce the risk of major
    adverse health outcomes such as MI.
    Rosiglitizone however, appears to be associated
    with an increase rather than a decrease in the
    risk of MI.

27
Avandia FDA
  • FDA Medical Reviewer 5/25/1999
  • FDA approves Avandia, but Medical Reviewer raises
    concerns about CV risks and calls for further
    studies
  • Whether Avandia favorably affects the natural
    history of Type 2 diabetes is open to question.
    Long term improvement in blood sugar should
    decrease the risk of complications of diabetes.
    However, the increase in body weight and
    undesirable effects on serum lipids cholesterol
    is cause for concern. Heart disease due to
    atherosclerosis 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.

28
Avandia Science
  • Avandia Mechanism
  • MI mechanism unknown possibilities include
  • Edema
  • Increased LDL (bad) cholesterol
  • Weight gain
  • Cardiotoxic metabolites

29
Avandia FDA Actions
  • FDA Black Box Warning - 2007

On May 23, 2007, 2 days after publication of
Nissen, NEJM Study, FDA asked GSK and Eli Lilly
to add black box warnings to address risk of CHF
(not MI or CV death) with use of Avandia and
Actos by certain patients
FDA Commissioner, Andrew von Eschenbach, MD
30
Avandia FDA
  • Dr. Buse Letter to FDA 3/15/2000
  • Dr. Buse, Director Diabetes Care Center, U. North
    Carolina informs FDA of concerns re Avandia CV
    risks, and GSK fraudulent marketing practices
  • I remain concerned about the safety of
    rosiglitizone in light of its consistent negative
    impact on lipids documented in the FDA
    registration data as well as a worrisome trend in
    CV death and severe adverse events in the
    subjects exposed to rosiglitizone
  • I think the FDA has to act forcefully to prevent
    the rampant abuse of clinical trial data by
    GSK.

31
Avandia FDA Actions
  • FDA Meta-analysis Confirms Risk
  • On 8/2006 GSK reports to FDA meta-analysis data
    showing increased CV risks
  • FDA conducts independent meta-analysis of more
    than 40 Avandia clinical studies
  • FDAs meta-analysis confirms GSK and NEJM Study
    data of about 40 CV risk on Avandia

32
Avandia FDA Actions
  • FDA Safety Alert - 5/21/2007
  • FDA is aware of a potential safety issue related
    to rosiglitazone maleate. Safety data from a
    pooled analysis of controlled clinical trials
    have shown a significant increase in the risk of
    heart attack and heart-related deaths in patients
    taking Avandia..

33
Liability Issues
  • Labeling
  • Was the warning present?
  • Was it adequate?
  • DTC advertising
  • Learned Intermediary
  • Efficacy
  • Did the drug do what GSK promised it would?

34
Diabetes Mellitus
  • Chronic progressively worsening disease
  • Microvascular and macrovascular complications
  • Cardiovascular disease (CVD) is the main cause
    of death
  • Numerous Agents- Improvement in Diabetic Outcomes?

35
Background
  • Avandia was first approved for use in the United
    States in 1999 for the use in treatment of
    diabetes.
  • In 2002, Avandamet, a combination of Avandia
    and metformin, was approved in the United States
    for use in treatment of diabetes.
  • In 2005, Avandaryl, a combination of Avandia and
    Amaryl, likewise was approved in the United
    States for use in treatment of diabetes.

36
The 1999 Approval Letter from FDA to SK included
the following statement
We remind you of your Phase 4 commitment
specified in your submission dated May 25, 1999,
to conduct a long-term (4-year) safety and
efficacy study (titled ADOPT study) of Avandia
monotherapy compared to metformin or glipizide in
patients with drug-naïve, recent-onset (less than
2 years) type 2 diabetes mellitus. This study
will assess maintenance/restoration of pancreatic
beta-cell insulin secretion and long-term safety
(incidence of ALT elevatiosn, cardiovascular and
hematologic events, changes in body weight and
serum lipids.
37
Avandia Labels
  • March 25, 1999
  • February 8, 2001

38
AVANDIA March 25, 1999 Label
39
  • Animal Toxicology
  • Heart weights were increased in mice (3
    mg/kg/day), rate (5 mg/kg/day), and dogs (2
    mg/kg/day) with rosiglitazone treatments
    (approximately 5, 22, and 2 times human AUC at
    the maximum recommended human daily dose,
    respectively).
  • Morphometric measurement indicated that there
    was hypertrophy in cardiac ventricular tissues,
    which may be due to increase heart work as a
    result of plasma volume expansion.

40
Liability Issue
  • If its in the label, is it a warning?
  • Or could it be evidence of company knowledge
    which would require
  • A better warning
  • A better warning sooner
  • Are physicians supposed to sort through Animal
    Toxicology sections, and determine if the
    manufacturer is trying to convey a warning for
    their patients?

41
  • Edema Avandia should be used with caution
    in patients
  • with edema. In a clinical study in healthy
    volunteers who
  • received Avandia 8 mg once daily for 8 weeks,
    there was a
  • statistically significant increase in median
    plasma volume
  • (1.8L/kg) compared to placebo.
  • In controlled clinical trials of patients with
    type 2 diabetes,
  • mild to moderate edema was reported in patients
    treated with
  • Avandia (See ADVERSE REACTIONS).

42
Liability issues
  • Defense Perspective
  • See, look we told them!
  • Plaintiff Perspective
  • See, they misled them
  • Only said use in caution in patients with
    pre-existing edema
  • Not that the drug could cause edema.
  • And not what that might mean to the patient with
    respect to their diabetic outcomes or their
    overall health

43
  • Use in Patients with Heart Failure In
    preclinical studies,
  • thiazolidinediones, including rosiglitazone,
    cause plasma
  • volume expansion and pre-load-induced cardiac
    hypertrophy.
  • Two ongoing echocardiography studies in patients
    with type
  • 2 diabeteshave shown no deleterious alteration
    in cardiac structure or function. These studies
    were designed to detect a change in left
    ventricular mass of 10 or more.
  • Patients with New York Heart Association (NYHA)
    Class 3
  • and 4 cardiac status were not studied during the
    clinical
  • trials. Avandia is not recommended in patients
    with NYHA
  • Class 3 and 4 cardiac status unless the benefit
    is judged to
  • outweigh the potential risk.

44
Liability Issues
  • IF these patients werent studied, then
  • What benefit in those patients is GSK talking
    about?
  • Who does the judging? GSK? Physician?
  • How is the Dr. supposed to know the potential
    risk in those patients?
  • Statement implies that the benefits could
    outweigh the risk
  • Off-Label

45
AVANDIA 1999 Label Contd Avandia increases
LDL Levels
46
Liability Issues
  • Does this paragraph give any guidance to a
    physician?
  • Its labeled
  • but no consequences are discussed.

47
Dateline June 1999
  • John Buse, a professor at the University of
    North Carolina who is president-elect of the
    American Diabetes Association, told the FDA seven
    years ago that he was concerned about a
    "worrisome trend in cardiovascular deaths and
    severe adverse events" in the data submitted to
    win FDA approval for Avandia. He also warned of
    "rampant abuse of clinical-trial data" by
    then-maker SmithKline Beecham, saying the company
    had "overstated the safety of the drug with
    respect to cardiovascular issues."

48
March 15, 2000 Letter from Dr. Buse to FDA
I remain concerned about the safety of
rosiglitazone 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.
The above named petition is a prime example
of rampant half-truths regarding the issues at
hand.
49
Rosiglitazone is clearly a very different actor.
I do not believe rosiglitazone will be proven
safer than troglitazone in clinical use under
current 1abeling of the two products. In fact,
rosiglitazone may be associated with less
beneficial cardiac effects or even adverse
cardiac outcomes. I do not object to more
stringent labeling of the class.
50
  • I think the FDA has to act forcefully to prevent
    the rampant abuse of clinical trial data by
    SmithKline Beecham.
  • I believe they have overstated the safety of the
    drug with respect to cardiovascular issues.
    (emphasis added)

I am sure there have been abuses by
representatives of all companies that market
drugs, but there is something pervasive and
systematic that I detect in my travels regarding
the marketing of rosiglitazone. I have to admit
that now when I give CME lectures, I spend about
half my time discussing these issues. It seems to
me that blatant selective manipulation of data
has obfuscated relatively straightforward
conclusions evident from the FDA data sets.
(emphasis added).
51
GlaxoSmithKline Tries to Silence the Whistleblower
  • SB characterized Dr. Buse as a "liar" and
    challenged his integrity by saying he was "for
    sale."
  • SB threatened Dr. Buse with a lawsuit "The
    market capitalization of the company had declined
    by 4 billion and there were people in the
    company who felt I might be liable for that."

52
Excerpts from June 6, 2007 Congressional Hearing
In 1999 John Buse, MD, PhD had warned GSK and
the FDA about the cardiovascular risks. GSK
threatened him.
My impression was that Avandia had a potentially
negative effect on LDL, so called bad
cholesterol. There was a trend toward increases
in serious cardiovascular events and
cardiovascular deaths with Avandia as compared to
active comparators.
I presented the issue outlined at least twice in
June of 1999. In the week that ensued, there
were a number of phone calls in this regard from
SKB. During these calls, 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.
53
Excerpt from 1999 Letter from Dr. Buse to Dr.
Yamada, SmithKline Beecham
Please call off the dogs. I cannot remain
civilized much longer under this kind of heat.
Fortunately, I will be out of the country for
three weeks on vacation starting on Friday.
54
Dateline February 8, 2001
  • Revision to AVANDIA label approved

55
2/08/2001 Labeling Revision
Avandia, like other thiazolidediones, alone or in
combination with other antidiabetic agents, can
cause fluid retention, which may exacerbate or
lead to heart failure. Patients should be
observed for signs and symptoms of heart failure.
Avandia should be discontinued if any
deterioration in cardiac status occurs.
56
Liability Issue
  • Other TZDs class effect
  • No conclusions drawn or guidance given

57
2/08/2001 Labeling Revision
Avandia, like other thiazolidediones, alone or in
combination with other antidiabetic agents, can
cause fluid retention, which may exacerbate or
lead to heart failure. Patients should be
observed for signs and symptoms of heart failure.
Avandia should be discontinued if any
deterioration in cardiac status occurs. In two
26-week U.S. trials involving 611 patients with
type 2 diabetes, Avandia plus insulin therapy was
compared with insulin therapy alone. These
trials included patients with long-standing
diabetes and high prevalence of pre-existing
medical conditionsIn these clinical studies an
increased incidence of cardiac failure and other
cardiovascular adverse events were seen in
patients on Avandia and insulin combination
therapy compared to insulin and placeboIn this
population, however, it was not possible to
determine specific risk factors that could be
used to identify all patients at risk of heart
failure on combination therapy.
58
2/08/2001 Labeling Revision
Avandia, like other thiazolidediones, alone or in
combination with other antidiabetic agents, can
cause fluid retention, which may exacerbate or
lead to heart failure. Patients should be
observed for signs and symptoms of heart failure.
Avandia should be discontinued if any
deterioration in cardiac status occurs. In two
26-week U.S. trials involving 611 patients with
type 2 diabetes, Avandia plus insulin therapy was
compared with insulin therapy alone. These
trials included patients with long-standing
diabetes and high prevalence of pre-existing
medical conditionsIn these clinical studies an
increased incidence of cardiac failure and other
cardiovascular adverse events were seen in
patients on Avandia and insulin combination
therapy compared to insulin and placeboIn this
population, however, it was not possible to
determine specific risk factors that could be
used to identify all patients at risk of heart
failure on combination therapy.
59
Dateline July 21, 2001 
  • In a Warning Letter dated July 21, 2001, the FDA
    accused GSK of making fraudulent and misleading
    representations about safety of Avandia.
    Specifically, the sales representatives denied
    the existence of cardiovascular risks associated
    with Avandia at GSKs promotional exhibit booth.
    Additionally, GSK displayed Exhibit panels
    (AV013G) at the meeting that minimized these new
    risks. 1
  • 1 Letter from Thomas Abrams, R.Ph., MBA,
    Director of the FDAs Division of Drug Marketing,
    Advertising and Communications to JP Garnier,
    Chief Executive Officer, GlaxoSmithKline (July
    17, 2001) (on file with the FDA).

60
DDMAC has concluded that GSK has promoted Avandia
in violation of the Federal Food, Drug, and
Cosmetic Act (Act) and its implementing
regulations. See 21 U.S.C. 331(a), (b), and
352(a), (n).
Your promotional activities that minimize serious
new risks are particularly troublesome because we
have previously objected, in two untitled
letters.
61
GSKs sales representatives have engaged in false
or misleading promotional activities with respect
to the new risk information in Avandias PL.
Specifically, two GSK sales representatives made
false or misleading statements about Avandia to a
DDMAC review at GSKs AACE promotional exhibit
booth. On May 3, 2001, a GSK sales
representative stated that there had been no
changes to the PL concerning the risk of
congestive heart failure. On May 4, 2001, a GSK
sales representative stated that there had been
no changes to the Avandia PL. He further stated
that he was unaware of any new risk information
concerning congestive heart failure or
postmarketing hepatic events associated with
Avandia.
62

Additionally, your exhibit panels 9AV013G fail
to present the warning from the PI that, in
clinical trials, there was an increased incidence
of CHF and other cardiovascular adverse events in
patients on Avandia and insulin combination
therapy compared to insulin plus placebo.
Due to the seriousness of your violations and
the fact that violative promotion of Avandia has
continued despite your written assurances to the
contrary, we request that you provide a detailed
response to the issues raised in this Warning
Letter.
63
Dateline July 16, 2002
  • FDA Interoffice Memorandum
  • As early as 2002, GSK had additional knowledge
    that TZD causes CHF and that, upon
    discontinuation of TZD, a high percentage
    (61) of cases was observed with symptomatic
    improvement of CHF when TZDs were discontinued
    and diuretic therapy initiated.
  • Postmarketing reports of TZD-associated CHF
    resulted in hospitalization

64
Forty-seven reports of TZD-associated CHF were
analyzed (table 1). Half of the reports
represented older females (N16/Total28 gt 65
years). Fifty-five percent (N26/Total47_ of the
reports describe New Onset CHF. New Onset
includes both reports specifically noting in the
narrative that the CHF was new onset as well as
those reports not describing existing CHF in the
narrative or past medical history. The remaining
45 (N21/Total47) of reports describe
exacerbation of stable CHF due to edema or
excessive weight gain. The average daily dose
was within the ranges recommended in the product
labels (piolitazone 29 mg (SD 12.0) and
rosiglitazone 6.7 mg (SD2.9).
65
(No Transcript)
66
The development of symptoms leading to
hospitalization nearly three months after
initiation of drug therapy may suggest an
insidious pathophysiological process that could
be consistent with insidious pathological process
that could be consistent with fluid retention as
opposed to a more direct cardiac effect. A high
percentage (61) of cases was observed with
symptomatic improvement of CHF when TZDs were
discontinued and diuretic therapy initiated. It
is plausible that cases still on TZD therapy
(29) would benefit from improvement of CHF
symptoms if TZDs were discontinued. (emphasis
added)
67
(No Transcript)
68
Despite this 2002 recommendation to mention
post-marketing cases of heart failure and the
fact that there are now a total of 689 cases
reported to the FDA with 415 hospitalizations the
2007 labeling for the Avandia still starts with
the identical 2001 warning with no mention of
heart attack or cardiac death. (See FDA AERS
Data base 9/30/06)
69
Dateline May 21, 2007
  • Nissen and Wolski meta-analysis is published by
    NEJM demonstrate an increased risk in myocardial
    infarction (MI) and cardiac death.

70
Nissen and Wolski found during the meta-analysis
that out of 158 myocardial infarctions, 86 of
those patients had been taking rosiglitazone and
out of 51 cardiovascular-related deaths, 37
patients were taking rosiglitazone
71
Dateline May 21, 2001
  • The NEJM article from 5-21-07 included a chart
    of every study conducted on Avandia,. It
    included the 49653/211 Protocol which was a study
    of DM2 patients with CHF. This study was
    concluded in November 2003.

72
Nissen and Wolski meta-analysis showed that in a
study coded 211, there were 5 MIs in the Avandia
group, and 2 in the placebo group.
5 MIs in Avandia group compared to 2 MIs in the
placebo group
73
Amazingly, this information was not put in the
Avandia label, in any way, including ever even
using the words MI or heart attack, until April
2007.
5 MIs in Avandia group compared to 2 MIs in the
placebo group
74
It took GSK 3.5 years to add information about MI
risk from Avandia to its label.
75
The New York Times
the handling of the case bears disturbing
resemblances to the Vioxx debacle, in which early
warning signs were ignored by its manufacturer
until the evidence of serious harm became
inescapable and the drug was pulled from the
market.
The New England Journal of Medicine suggests
that Avandia may instead increase the risk of
heart attack by 43 percent and perhaps the risk
of cardiovascular deaths as well.
Seven years ago a leading diabetes doctor warned
the F.D.A. of a worrisome trend in
cardiovascular deaths, two years later a safety
monitoring group within the agency expressed
concerns over cases of heart failure in patients
taking the drug.
76
DatelineMay 21, 2007 FDA Alerts Consumers
AVANDIA
  • In light of recent post-marketing safety
    information, Patients are being warned about
    possible cardiovascular risks and death, but are
    also being cautioned about the importance of
    consulting their healthcare providers before
    discontinuing treatment.

77
Safety data from a pooled analysis of controlled
clinical trials have shown a significant increase
in the risk of heart attack and heart-related
deaths in patient taking Avandia.
78
Dateline June 6, 2007
  • Committee on Oversight and Government Reform
    probes the FDA and GSK about Avandia serious
    cardiovascular risks.
  • During the hearing, the FDA announcing Avandia
    will be getting a boxed warning regarding CHF.
  • Hearing testimony that GSK tried to silence Dr.
    Buse, Committee on Finance releases a letter

79
June 6, 2007U.S. SenateCommittee on Finance
If pharmaceutical executives tried to silence a
researcher who found safety issues with Avandia,
then weve found a whole new level of culpability
here. If credible research exposes the risk of
death for patients taking a drug, then any drug
company attempt to squelch that information would
be morally reprehensible, said Chairman Baucus.
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