Merck Research chief details background to Vioxx withdrawal

Merck Research chief details background to Vioxx withdrawal

(Remarks of Peter S. Kim, Ph.D., President, Merck Research Laboratories, Merck and Co., Inc. at a Press Availability in New York City, October 13, 2004)

NEW YORK, October 13, 2004 -- Since we announced the voluntary withdraw of Vioxx, there have been questions raised about what we knew before and after we obtained the results of the VIGOR study, and what actions we took before and after we knew those results. The purpose of today's briefing is to review the facts.

Almost three weeks ago, when we received the data from our APPROVe trial, in which there was an increased cardiovascular risk in patients using Vioxx beginning after 18 months of continuous use, Merck acted immediately and appropriately to voluntarily withdraw Vioxx from the market.

Over the past two weeks, questions have been raised regarding the results from an earlier study we conducted, known as the VIGOR trial. VIGOR evaluated the gastrointestinal safety profile of Vioxx versus naproxen. In this study, there was a higher incidence of cardiovascular events in patients receiving 50 mg of Vioxx and that difference was statistically significant.

Today, I would like to walk you through the key events in the Vioxx timeline.

In November 1998, Merck submitted a New Drug Application for Vioxx, containing data from about 5,000 patients who were exposed to Vioxx. The clinical trials compared the effects of Vioxx to other NSAIDs, as well as placebo, and included data covering patients who had been on Vioxx for longer than one year. These data showed no difference in cardiovascular risk between Vioxx and placebo or between Vioxx and NSAIDS. The FDA approved Vioxx in May of 1999.

Earlier that year, in January 1999, we had initiated a study known as VIGOR. VIGOR was designed to compare the gastrointestinal safety profile of Vioxx 50 mg with naproxen. The preliminary results from the VIGOR trial were available in March 2000. These results demonstrated a difference in the cardiovascular event rate between those patients taking Vioxx and those taking naproxen.

These data were of concern to us. All data from the previous studies demonstrated no difference in the cardiovascular event rate between Vioxx and placebo, or between Vioxx and non-naproxen NSAIDS. It is important to note that because the VIGOR study compared two drugs Vioxx and naproxen and did not contain a placebo arm, it was not possible to conclude based on this study alone whether naproxen was having a beneficial cardiovascular effect or whether Vioxx was having a detrimental cardiovascular effect.

The reason why it was not possible to distinguish between these two possibilities was there was not a placebo group, that is, a group that received an inactive "sugar" pill. When one compares a drug to a placebo, one can ascertain the effects of the drug because one has a neutral benchmark against which the drug effects can be measured. In this case, there was no placebo arm.

However, at that same time the initial results of VIGOR became available, we already had two long-term placebo-controlled studies ongoing, one for Alzheimer's prevention and one for Alzheimer's treatment. Both studies compared Vioxx to placebo - not another medicine. To help us evaluate the meaning of the VIGOR study, Merck unblinded the safety data from these two trials. What we found was consistent with all of our previous studies: no difference was observed between the cardiovascular event rates in patients receiving placebo or Vioxx in these two large Alzheimer's trials.

Because there was no difference between the CV event rates between Vioxx and placebo in these two Alzheimer's trials or between Vioxx and non-naproxen NSAIDS in our previous studies, and because naproxen is known to have anti-platelet aggregation effects similar to aspirin, Merck concluded that the most plausible explanation for the VIGOR results was that naproxen was exerting a cardioprotective effect.

To sum up, we became aware of the initial VIGOR results in March, 2000. Merck acted promptly to unblind key safety data from ongoing placebo-controlled studies that would inform the interpretation of the results in VIGOR and notified the medical community, the regulatory authorities, and the public though a press release of the VIGOR results all by the end of that same month.

Two months later, in May, 2000, we submitted the initial VIGOR results to the New England Journal of Medicine for publication and presented the data at a major scientific meeting. Later that same year, the data were published in the New England Journal of Medicine.

We submitted a supplemental New Drug Application to FDA in June 2000. The sNDA included extensive data on VIGOR and proposed prescribing information for Vioxx. We worked diligently with FDA to review these data and develop revised prescribing information.

As this review was underway, we continued our efforts to further characterize the cardiovascular safety profile of Vioxx. We developed a prospective plan to analyze the cardiovascular event rates in three large, placebo-controlled studies:

• The first was our APPROVe study, which was initiated in February 2000, one month before we learned of the VIGOR results. This study was designed to determine whether Vioxx could help prevent the recurrence of colon polyps;
• The second was a study to determine whether Vioxx could help prevent the recurrence of Colon Cancer;
• The third was a study to determine whether Vioxx could help prevent Prostate Cancer.

All three of these studies were overseen by a Steering Committee of external medical experts. In addition, each of these trials has an external Safety Monitoring Board which was responsible for monitoring patient safety in the trials, which were unblinded to the safety data during the trial. Importantly, the external Safety Monitoring Board was required to meet at least two times per year to evaluate the ongoing safety data from the studies. It was not until 3 weeks ago, 4.5 years after the APPROVe trial was initiated, that the Safety Monitoring Board determined that there was an issue and recommended that the APPROVe trial be stopped.

These three studies were all ongoing at the time the safety results from APPROVe became available to us. As we reported 2 weeks ago, in the APPROVe trial, during the first 18 months of therapy, there was no difference in the relative risk of confirmed cardiovascular events - primarily strokes and heart attacks - between those taking Vioxx and those taking placebo.

The study also found, however, that beginning after 18 months, there was a discernible and unexpected increased risk for confirmed cardiovascular events in patients taking Vioxx.

When we learned of these results 3 weeks ago, we moved quickly to answer the question of what is in the best interest of patients. We believe our decision to voluntary withdraw Vioxx from the market reflects Merck's commitment to patient safety.

Source: Merck

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