When the recall occurred, it came about because of a major clinical study sponsored by Merck that tracked 2,600 patients for almost three years to find out if Vioxx helped prevent colon polyps. Merck launched the effort hoping to create new markets for Vioxx, while also laying to rest questions about the drug's connection to heart attacks and strokes.
Far from it, the trial confirmed the predictions of Merck's harshest critics, who had long complained that the New Jersey manufacturer was closing its eyes to Vioxx's problems and improperly pushing a dangerous drug onto consumers with aggressive ads. Vioxx and other Cox-2 inhibitors like Celebrex had been promoted as wonder drugs, since they provided pain relief to arthritis sufferers without causing stomach problems, but now Vioxx is off the market and the others are under a cloud.
Cleveland Clinic cardiologist Eric J. Topol, an early critic of the drug, estimates Vioxx may have caused 30,000 to 100,000 heart attacks and strokes, many of them "preventable" because patients could have taken other drugs. "Why didn't they stop the DTC [direct to consumer] marketing?" that was a major factor in increasing sales, he said. "That's the tragedy here."
Data and a Decision to Make
The last days of Vioxx began with FedEx deliveries on Sept. 14. That was when the four members of the colon polyp trial's Data and Safety Monitoring Board, an independent panel of specialists hired to catch harmful developments in the trial, received heart attack and stroke data for the previous six months.
Most clinical trials include independent safety monitors, and their role is little understood but crucial. The four monitors, along with a Merck statistician were the only ones with full access to information about the trial, including which patients were getting Vioxx and which were getting the placebo. As a result, they alone were in a position to conclude the drug had proven too dangerous for the trial to continue.
The same team also was monitoring another Merck trial to see if Vioxx might help protect against prostate cancer. A third trial was studying the drug's effect on colon cancer was also underway. All three trials were placebo-controlled and "blinded" to investigators, making them the most trusted kind of drug research. These studies also were designed to answer questions about cardiovascular risk raised by earlier less conclusive research.
From the beginning of the colon polyp study, the safety monitors had noted an increased rate of hypertension among the Vioxx group. In addition, in 2003 and earlier this year, they found that more people in the Vioxx group were having cardiovascular events than in the placebo group. The numbers were small, in part because people with heart disease had been screened out of the trial, but the trend had been worrisome and the latest data were striking: After 18 months on the drug, the Vioxx group was clearly having more heart problems than the placebo group and the rate of difference was accelerating.
"When I saw the last set of data, I knew we had a tough decision to make," said James Neaton, a University of Minnesota biostatistician, who had monitored a dozen other studies but seldom had seen such troubling data. "There was so much at stake for everyone involved. . . . You have to have data that the scientific community will accept."
Neaton and the three safety committee members spent several days studying the data, then held their regularly scheduled phone conference Sept. 17. They talked first with Merck representatives and the principal investigator for the colon polyp trial, John Baron of Dartmouth Medical School.
Then Baron and the Merck people left the call, freeing the four safety panel members to talk openly about the latest unsettling data. Disturbing on its own, it also echoed less conclusive data from other trials.