Bad FDA: Part 3 Good morning. My name is David

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Good morning. My name is David Graham, and I am pleased to come before you today to speak about Vioxx, heart attacks and the FDA.

During my career, I believe I have made a real difference for the cause of patient safety. My research and efforts within FDA led to the withdrawal from the US market of Omniflox, an antibiotic that caused hemolytic anemia; Rezulin, a diabetes drug that caused acute liver failure; Fen-Phen and Redux, weight loss drugs that caused heart valve injury; and PPA (phenylpropanolamine), an over-the-counter
decongestant and weight loss product that caused hemorrhagic stroke in young women. My research also led to the withdrawal from outpatient use of Trovan, an antibiotic that caused acute liver failure and death. I also contributed to the team effort that led to the withdrawal of Lotronex, a drug for irritable bowel syndrome that causes ischemic colitis; Baycol, a cholesterol-lowering drug that caused severe muscle injury, kidney failure and death; Seldane, an antihistamine that caused heart arrhythmias and death; and Propulsid, a drug for night-time heartburn that caused heart arrythmias and death. I have done extensive work concerning the issue of pregnancy exposure to Accutane, a drug that is used to treat acne but can cause birth defects in some children who are exposed in-utero if their mothers take the drug during the first trimester. During my career, I have recommended the market withdrawal of 12 drugs. Only 2 of these remain on the market today-Accutane and Arava, a drug for the treatment of rheumatoid arthritis that I and a co-worker believe causes an unacceptably high risk of acute liver failure and death.

Vioxx and heart attacks. Let me begin by describing what we found in our study, what others have found, and what this means for the American people. Prior to approval of Vioxx, a study was performed by Merck named 090. This study found nearly a 7-fold increase in heart attack risk with low dose Vioxx. The labeling at approval said nothing about heart attack risks. In November 2000, another Merck clinical trial named VIGOR found a 5-fold increase in heart attack risk with high-dose Vioxx.

Among many things, this report estimated that nearly 28,000 excess cases of heart attack or sudden cardiac death were caused by Vioxx. I emphasize to the Committee that this is an extremely conservative estimate. FDA always claims that randomized clinical trials provide the best data. If you apply the risk-levels seen in the 2 Merck trials, VIGOR and APPROVe, you obtain a more realistic and likely range of estimates for the number of excess cases in the US. This estimate ranges from 88,000 to 139,000 Americans. Of these, 30-40% probably died.

We concluded that high-dose Vioxx significantly increased the risk of heart attacks and sudden death and that the high doses of the drug
should not be prescribed or used by patients. This conclusion triggered an explosive response from the Office of New Drugs, which approved Vioxx in the first place and was responsible for regulating it postmarketing. The response from senior management in my Office, the Office of Drug Safety, was equally stressful. I was pressured to change my conclusions and recommendations, and basically threatened that if I did not change them, I would not be permitted to present the paper at the conference. One Drug Safety manager recommended that I should be barred from presenting the poster at the meeting, and also noted that Merck needed to know our study results.

An email from the Director for the entire Office of New Drugs, was revealing. He suggested that since FDA was “not contemplating” a warning against the use of high-dose Vioxx, my conclusions should be changed. CDER and the Office of New Drugs have repeatedly expressed the view that ODS should not reach any conclusions or make any recommendations that would contradict what the Office of
New Drugs wants to do or is doing. Even more revealing, a mere 6 weeks before Merck pulled Vioxx from the market, CDER, OND and ODS management did not believe there was an outstanding safety concern with Vioxx.
https://www.finance.senate.gov/imo/media/doc/...dgtest.pdf

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