Brief History of Drug Disasters in the US

Another way to fully comprehend the enormity of the Vioxx debacle is to look briefly at recent US and FDA history. The attached figure shows a graph depicting 3 historical time-points of importance to the development of drug safety in the US.

In 1938, Congress enacted the Food, Drug and Cosmetic Act, basically creating the FDA, in response to an unfortunate incident in which about 100 children were killed by elixir of sulfanilamide, a medication that was formulated using anti-freeze. This Act required that animal toxicity testing be performed and safety information be submitted to FDA prior to approval of a drug.

In 1962, Congress enacted the Kefauver-Harris Amendments to the FD&C Act, in response to the thalidomide disaster in Europe. Overseas, between 1957 and 1961, an estimated 5,000 to 10,000 children were born with thalidomide-related birth defects.

These Amendments increased the requirements for toxicity testing and safety information preapproval, and added the requirement that substantial evidence of efficacy be submitted. Today, in 2004, you, we, are faced with what may be the single greatest drug safety catastrophe in the history of this country or the history of the world. We are talking about a catastrophe that I strongly believe could have, should have been largely or completely avoided. But it wasn't, and over 100,000 Americans have paid dearly for this failure.

In my opinion, the FDA has let the American people down, and sadly, betrayed a public trust. I believe there are at least 3 broad categories of systemic problems that contributed to the Vioxx catastrophe and to a long line of other drug safety failures in the past 10 years. Briefly, these categories are 1) organizational/structural, 2) cultural, and 3) scientific. I will describe these in greater detail in a few moments.

My Vioxx Experience at FDA.

To begin, after publication of the VIGOR study in November 2000, I became concerned about the potential public health risk that might exist with Vioxx. VIGOR suggested that the risk of heart attack was increased 5-fold in patients who used the high-dose strength of this drug.

Why was the Vioxx safety question important? 1) Vioxx would undoubtedly be used by millions of patients. That's a very large number to expose to a serious drug risk. 2) heart attack is a fairly common event, and 3) given the above, even a relatively small increase in heart attack risk due to Vioxx could mean that tens of thousands of Americans might be seriously harmed or killed by use of this drug. If these three factors were present, I knew that we would have all the ingredients necessary to guarantee a national disaster.

The first two factors were established realities. It came down to the third factor, that is, what was the level of risk with Vioxx at low- and high-dose. To get answers to this urgent issue, I worked with Kaiser Permanente in California to perform a large epidemiologic study. This study was carefully done and took nearly 3 years to complete.

In early August of this year, we completed our main analyses and assembled a poster presentation describing some of our more important findings. We had planned to present these data at the International Conference on Pharmacoepidemiology, in Bordeaux, France. 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 its 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.

At the same time, 2-4 jumbo jetliners were dropping from the sky every week and no one else at FDA was concerned.

There were 2 other revelatory milestones. In mid-August, despite our study results showing an increased risk of heart attack with Vioxx, and despite the results of other studies published in the literature, FDA announced it had approved Vioxx for use in children with rheumatoid arthritis.

Also, on September 22, at a meeting attended by the director of the reviewing office that approved Vioxx, the director and deputy director of the reviewing division within that office and senior managers from the Office of Drug Safety, no one thought there was a Vioxx safety issue to be dealt with. At this meeting, the reviewing office director asked why had I even thought to study Vioxx and heart attacks because FDA had made its labeling change and nothing more needed to be done.

At this meeting a senior manager from ODS labeled our Vioxx study "a scientific rumor." Eight days later, Merck pulled Vioxx from the market, and jetliners stopped dropping from the sky.

Finally, we wrote a manuscript for publication in a peer-reviewed medical journal. Senior managers in the Office of Drug Safety have not granted clearance for its publication, even though it was accepted for publication in a very prestigious journal after rigorous peer review by that journal. Until it is cleared, our data and conclusions will not see the light of day in the scientific forum they deserve and have earned, and serious students of drug safety and drug regulation will be denied the opportunity to consider and openly debate the issues we raise in that paper.