Question: Merck and Vioxx On September 30, 2004, Merck voluntarily withdrew its $2.5 billion blockbuster drug Vioxx (rofecoxib) because new clinical research showed a significantly higher probability of cardiovascular events, such as heart attacks, for patients who took the drug for over 18 months. Merck's market capitalization fell by 27 percent on the day of the announcement and subsequently fell another 13 percent. The withdrawal met with instant praise for the quick decision, but soon the praise turned to questions as information became available about whether the company should have recalled the drug years earlier. Merck defended itself in a series of full-page advertisements in major newspapers. In three full-page ads on November 21, 2004, Merck defended its actions, restated its commitments to patients, and attempted to assure investors about its financial strength and its future. The first ad stated: We extensively studied VIOXX before seeking regulatory approval to market it. We promptly disclosed the clinical data about VIOXX. When questions arose, we took additional steps, including conducting further prospective, controlled studies to gain more clinical information about the medicine. When information from these additional prospective, controlled trials became available, we acted promptly and made the decision to voluntarily withdraw VIOXX.

Vioxx, along with Pfizer's Celebrex and Bextra, were Cox-2 inhibitors used to treat patients with chronic pain. Traditional painkillers, such as aspirin and ibuprofen, blocked the Cox-1 and Cox-2 enzymes that cause pain. Blocking Cox-1 enzymes had the benefit of reducing cardiovascular risks, such as blood clots and heart attacks, but it could contribute to intestinal and stomach problems including stomach bleeding and ulcers. Cox-2 inhibitors did not block Cox-1 enzymes, so relative to traditional painkillers they provide benefits to patients at risk from intestinal and stomach bleeding. Vioxx had sales of $2.5 billion in 2003, Celebrex had sales of $1.9 billion, and Bextra, a newer version of Celebrex, had sales of $687 million. The Initial Marketing Decision for Vioxx Early Merck memoranda suggested that the company recognized that sales would be limited if Vioxx were restricted to patients with stomach or intestinal bleeding. If the drug were marketed as a general-purpose painkiller for arthritis and other persistent ailments, sales could be much higher. If Merck were to market Vioxx as a general-purpose painkiller, it would use direct-to-consumer (DTC) advertising. In designing clinical trials for Vioxx in the mid-1990s Merck recognized that to show its effectiveness trial subjects could not take aspirin. Consequently, the trials could show increased blood clots and cardiovascular events. A Merck scientist proposed that patients with a high risk of cardiovascular problems be kept out of the clinical trials. Information on the final design of the clinical trials was not available.41 The Food and Drug Administration approved Vioxx for sale in 1999. The Phase III clinical trials required by the FDA for approval found "there was not an increased risk of cardiovascular events with VIOXX compared with placebo or VIOXX compared with other non-naproxen non-steroidal anti-inflammatory drugs (NSAIDS)."42

Preparation Questions

1. Should Merck seek to market Vioxx as a general-purpose painkiller with heavy DTC advertising or limit its marketing to those patients with gastrointestinal problems?

2. Should Merck conduct additional clinical trials to evaluate the risks of blood clots and cardiovascular events?

The Success of Vioxx Merck aggressively promoted Vioxx as a general-purpose pain reliever for arthritis and other conditions. In 2000 it spent $161 million on DTC advertising for Vioxx. Continued heavy advertising and traditional marketing to doctors resulted in 2003 sales of $2.5 billion worldwide. The VIGOR Clinical Trials In early 1999 Merck began a clinical study called VIGOR to demonstrate the effectiveness of Vioxx for patients with gastrointestinal problems. The control was naproxen, and participants were prohibited from taking aspirin. Patients with heart problems were not included in the trials. The results were released in March 2000 and showed that patients receiving Vioxx had fewer gastrointestinal problems than those receiving naproxen.43 The results also showed that of the 4,047 people taking Vioxx, 101 had cardiovascular adverse events, such as blood clotting, whereas 46 of the 4,029 taking naproxen had such events. Because earlier studies had shown no greater cardiovascular problems with Vioxx than with a placebo, Merck suspected that the difference in cardiovascular adverse events was due to the beneficial effects of naproxen rather than to problems with Vioxx.44 Merck and the FDA began discussions about what information from the VIGOR trial would be included in the new label for Vioxx.

1. In light of the results of the VIGOR trials, should Merck issue a warning to doctors and patients?

2. Should Merck reduce its DTC advertising of Vioxx?

3. Should Merck conduct new clinical trials designed to identify any cardiovascular adverse effects of Vioxx?

4. What information should Merck support for inclusion on the new Vioxx label?