Mr. Chairman and members of the Committee, Introduction. 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.

By way of introduction, I graduated from the Johns Hopkins University School of Medicine, and trained in Internal Medicine at Yale and in adult Neurology at the University of Pennsylvania. After this, I completed a three-year fellowship in pharmacoepidemiology and a Masters in Public Health at Johns Hopkins, with a concentration in epidemiology and biostatistics.

Over my 20 year career in the field, all of it at FDA, I have served in a variety of capacities. I am currently the Associate Director for Science and Medicine in FDA's Office of Drug Safety.

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. The company said the drug was safe and that the comparison drug naproxen, was protective.

In 2002, a large epidemiologic study reported a 2-fold increase in heart attack risk with high-dose Vioxx and another study reported that naproxen did not affect heart attack risk. About 18 months after the VIGOR results were published, FDA made a labeling change about heart attack risk with high-dose Vioxx, but did not place this in the Warnings section. Also, it did not ban the high-dose formulation and its use.

I believe such a ban should have been implemented. Of note, FDA's label change had absolutely no effect on how often high-dose Vioxx was prescribed, so what good did it achieve?

In March of 2004, another epidemiologic study reported that both high-dose and low-dose Vioxx increased the risk of heart attacks compared to Vioxx's leading competitor, Celebrex. Our study, first reported in late August of this year found that Vioxx increased the risk of heart attack and sudden death by 3.7 fold for high-dose and 1.5 fold for low-dose, compared to Celebrex.

A study report describing this work was put on the FDA website on election day. 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. For the survivors, their lives were changed forever.

It's important to note that this range does not depend at all on the data from our Kaiser-FDA study. Indeed, Dr. Eric Topol at the Cleveland Clinic recently estimated up to 160,000 cases of heart attacks and strokes due to Vioxx, in an article published in the New England Journal of Medicine. This article lays out clearly the public health significance of what we're talking about today.

So, how many people is 100,000? The attached Tables 1 and 2 show the estimated percentage of the population in your home State and in selected cities from your State that would have been affected had all 100,000 excess cases of heart attack and sudden cardiac death due to Vioxx occurred only in your State or city. This is to help you understand how many lives we're talking about. We're not just talking numbers.

For example, if we were talking about Florida or Pennsylvania, 1% of the entire State population would have been affected. For Iowa, it would be 5%, for Maine, 10% and for Wyoming, 27%. If we look at selected cities, I m sorry to say, Senator Grassley, but 67% of the citizens of Des Moines would be affected, and what's worse, the entire population of every other city in the State of Iowa.

But there is another way to put this range of excess cases into perspective. Imagine that instead of a serious side-effect of a widely used prescription drug, we were talking about jetliners. Please ignore the obvious difference in fatality rates between a heart attack and a plane crash, and focus on the larger analogy I'm trying to draw.

If there were an average of 150 to 200 people on an aircraft, this range of 88,000 to 138,000 would be the rough equivalent of 500 to 900 aircraft dropping from the sky. This translates to 2-4 aircraft every week, week in and week out, for the past 5 years. If you were confronted by this situation, what would be your reaction, what would you want to know and what would you do about it?