Testimony of Sidney Wolfe M'D',

1
Testimony of Sidney Wolfe M.D., Elizabeth
Barbehenn Ph.D. and Ben Wolpaw Health
Research Group of Public Citizen FDA Endocrine
Metabolic Drugs Advisory Committee Meeting on
Rosiglitazone July 30, 2007  
2
4. Does the overall risk-benefit profile of
Avandia support its continued marketing in
the US ?
3
Preclinical (pre-approval) and Post-Approval
Evidence of Cardiac Toxicity
4
FDA Pharmacology Review April 26, 1999
At the high dose, rosiglitazone produced various
toxicities such as left atrial thrombosis,
hydrothorax, cardiohypertrophy and elevations of
hepatic enzymes .the various toxicities that
were manifest by the top dose of rosiglitazone
appear as long term clinical concern..
insufficient evidence to predict long- term
effects of rosiglitazone in human, based on
existing animal toxicological data. Pharmacology
recommends not to approve rosiglitazone for the
proposed indication for long-term human use.
5
FDA Pharmacology Review April 26, 1999
Comparison of lowest effective dose (LED) in dogs
to the human dose
6
PPAR Gamma-Mediated Cardiac Toxicity Dr. Jeri
El-Hage, Former FDA Endocrine Metabolic
Pharmacologist

• Fluid accumulation in all species
• (mouse, rat, dog, rabbit, monkey, human).
• Fluid accumulation leads to weight gain,
• edema, cardiac hypertrophy with resultant
• heart failure in all species.
• Drug-induced heart failure and death observed
• with chronic treatment (gt6 months in animals and
  man).
• The lowest adverse event level was only 1X that
  of humans
• (rat and monkey) and 2X (mouse) in chronic (one
  to two year) studies. In people, the longer
  a patient was on a PPAR gamma,
  the lower the dose needed to produce edema or
  CHF.

Jeri El-Hage talk Peroxisome proliferator-activat
ed receptor (PPAR) agonists Preclinical and
clinical cardiac safety considerations
http//www.fda.gov/cder/present/DIA2006/El-Hage_Sa
fety.pdf
7
2.10
Singh, Loke, Furberg. Diabetes Care May 2007
8
FDA AERS Reports 5/25/99 12/31/06
Reporting ratios adjusted for prescriptions
filled
9
Preclinical (pre-approval) and Post-Approval
Evidence of Liver Toxicity
10
FDA Pharmacology Review April 26, 1999
11
Published Case Reports of Hepatic Toxicity From
Rosiglitazone
12
FDA AERS Liver Toxicity 5/25/99 12/31/06
Reporting ratios adjusted for prescriptions
filled
13
FDA AERS Death Reports 5/25/99 12/31/06
Reporting ratios adjusted for prescriptions
filled
14
Fractures in WomenData from ADOPT Trial
Fractures in Women(Data From ADOPT Trial)
15
Fractures in WomenData from ADOPT Trial
16
Pre-approval and Post-Approval Clinical Evidence
of Anemia
17
ANEMIA

• Anemia reported in 1.9 of patients receiving
  Avandia as monotherapy compared to 0.7 on
  placebo.1
• Severe anemia (M Hct lt 31 F lt 28) in clinical
  trials 9/2121 patients on rosiglitazone, 0/485
  patients given placebo 2
• Seen most commonly in combination therapy with
  rosiglitazone plus metformin (7.1) compared to
  those receiving placebo plus metformin (2.2).3

1 Avandia (Rosiglitazone Maleate) Prescribing
Information. GlaxoSmithKline, 2007. pp. 24 2
FDA Medical Officer Review April 2, 1999 3
Wagstaff, Antona J., and Karen L. Goa. "Adis Drug
Evaluation Rosiglitazone a Review of Its
Use in the Management of Type 2 Diabetes
Mellitus." Drugs 62 (2002) 1826.
18
FDA AERS Reports 5/25/99 12/31/06
Reporting ratios adjusted for prescriptions
filled
19
FDA AERS Reports 5/25/99 12/31/06
Reporting ratios adjusted for prescriptions
filled
20
In theory, newer classes of antidiabetes
medications might be welcome additions to the
existing armamentarium however, those that have
been developed recently are generally no more
potent, and often less effective in lowering
glycemia, than the three oldest classes
(insulin, the sulfonylureas, and the
biguanides), all of which are more than 50 years
old. Moreover, the newer classes are
uniformly more expensive and are associated with
adverse effects some that are shared by the
older drugs, but others that are new.
Nathan. D. NEJM, Feb. 1 2007 Finding New
Treatments for Diabetes How Many, How Fast
. . . How Good?
21
The failure of clinicians and their patients
with diabetes to implement currently available
interventions aggressively and effectively is,
I suspect, the major barrier to good care. This
problem will not be fixed by making more
medications available.
Nathan. D. NEJM, Feb. 1 2007
22
Labeling Changes are Not Enough

• Even when labels are changed doctors continue
  to prescribe unsafe drugs. (Rezulin an excellent,
  unfortunate example of this)

23
4. Does the overall risk-benefit profile of
Avandia support its continued marketing in
the US ? The answer is clearly NO. There is no
evidence of any uniquely beneficial clinical
outcome for Avandia and growing evidence in
multiple organ systems (cardiac, liver, bone,
bone marrow) of unique risks. Public Citizen is
currently preparing a petition to the FDA to ban
Avandia.