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 

4. Does the overall risk-benefit profile of Avandia support its continued marketing in the US ?

Preclinical (pre-approval) and Post-Approval Evidence of

Cardiac Toxicity

“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. ”

FDA Pharmacology Review: April 26, 1999

FDA Pharmacology Review: April 26, 1999

Comparison of lowest effective dose (LED) in dogs to the human dose

“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 (>6 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.”

PPAR Gamma-Mediated Cardiac Toxicity Dr. Jeri El-Hage, Former FDA Endocrine Metabolic Pharmacologist

Jeri El-Hage talk: Peroxisome proliferator-activated receptor (PPAR) agonists: Preclinical and clinical cardiac safety considerations http://www.fda.gov/cder/present/DIA2006/El-Hage_Safety.pdf

Singh, Loke, Furberg. Diabetes Care; May 2007

2.10

Adverse event

Avandia

Glucotrol

Increased rate: Avandia glucotrol*

Edema 1,782 61 24.8 x

Weight increased

1,441 61 20.1

Cardiac failure

698 39 15.2

FDA AERS Reports: 5/25/99 – 12/31/06

* Reporting ratios adjusted for prescriptions filled

Preclinical (pre-approval) and Post-Approval Evidence of

Liver Toxicity

FDA Pharmacology Review: April 26, 1999

Published Case Reports of Hepatic Toxicity From Rosiglitazone

Reference Age/Gender

RSG Dosage

Time to Injury

ALT (U/L)

AST (U/L) Total Bilirubin (mg/dL)

ALK PH (U/L)

Time to ALT Normalization

Forman et al. (2000)

69/M 4 mg 21 days 1905 11096 3.8 204 NR

Al-Salaman et al. (2000)

61/M 4 mg 2 weeks 1706 1370 13.8 519 ≤ 68 days

Hachey et al. (2000)

47/F 4 mg 4 months NR NR NR 656 2 weeks

Ravinuthala et al. (2000)

58/F 4 mg 2 weeks 314 251 2.4 NR 4 weeks

Gouda et al. (2001)

82/M NR > 1 year 6168 7872 5.9 NR patient died

Dhawan et al. (2002)

37/M 8 mg 15 months

84 49 5.9 162 2 months

Menees et al. (2005)

52/M NR ≥ 30 days 78 111 19.1 202 patient died

Su et al. (2006)

60/F 4 mg 11 months

1152 1518 22.3 NR ≤ 4 months

FDA AERS Liver Toxicity: 5/25/99 – 12/31/06

Adverse event

Avandia Glucotrol Increased rate:

Avandia Glucotrol*

Hepatic AEs

594 53 9.5

Hepatic failure

122 7 14.8

* Reporting ratios adjusted for prescriptions filled

Actos

Avandia

Glucotrol

Increased rateAv/gluc *

Cardiac failure

54 87 10 7.4 x higher

Hepatic failure

30 46 6 6.5 x higher

FDA AERS Death Reports: 5/25/99 – 12/31/06

* Reporting ratios adjusted for prescriptions filled

0

2

4

6

8

10

Total LowerLimb

UpperLimb

Fracture Type

Inci

denc

e (%

)

RosiglitazoneMetforminGlyburide

Fractures in Women(Data From ADOPT Trial)

Fractures in WomenData from ADOPT Trial

Fractures in WomenData from ADOPT Trial

Pre-approval and Post-Approval Clinical Evidence of

Anemia

• Anemia reported in 1.9% of patients receiving Avandia as monotherapy compared to 0.7% on placebo.[1]

• Severe anemia (M Hct < 31; F < 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.

ANEMIA

Adverse event Avandia Glucotrol Increased rate: Av/gluc*

Edema 1,782 61 24.8 x

Weight increased

1,441 61 20.1

Cardiac failure 698 39 15.2

Anemia 407 26 13.3

Hepatic AEs 594 53 9.5

Hepatic failure 122 7 14.8

Macular edema

83 2 35.3

Fracture 26 19 1.2

Bladder cancer

3 1 2.6

FDA AERS Reports: 5/25/99 – 12/31/06

* Reporting ratios adjusted for prescriptions filled

Adverse event Avandia Glucotrol Increased rate:Av/gluc*

Edema 1,782 61 24.8 x

Weight increased

1,441 61 20.1

Cardiac failure 698 39 15.2

Anemia 407 26 13.3

Hepatic AEs 594 53 9.5

Hepatic failure 122 7 14.8

Macular edema

83 2 35.3

FDA AERS Reports: 5/25/99 – 12/31/06

* Reporting ratios adjusted for prescriptions filled

“In theory, newer classes of antidiabetes medicationsmight 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?

“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

Labeling Changes are Not Enough

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

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.