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Testimony of Sidney Wolfe M.D., Elizabeth Barbehenn Ph.D. and Ben Wolpaw

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

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Testimony of Sidney Wolfe M.D., Elizabeth Barbehenn Ph.D. and Ben Wolpaw

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  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 (>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.” 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

  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 < 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.

  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.

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