VIOXX & Public Health

In 1999, the U.S. Food and Drug Administration (FDA) approved Vioxx, a promising new prescription drug, for entrance onto the U.S. drug market. Although related to some familiar over-the-counter anti-inflammatory pain relievers, such as ibuprofen, Vioxx offered similar relief without causing ulcers, bleeding or other gastrointestinal problems.

However, on September 30, 2004, Merck Co., Inc. (Merck), the manufacturer of Vioxx, announced that it was voluntarily pulling Vioxx from the worldwide drug market. Although the emergence of Vioxx began with tremendous potential, Merck now faces an onslaught of legal battles related to the drug's link to cardiovascular problems.

How Vioxx Works

"Vioxx" is the trade name for the generic drug rofecoxib and it acts, in general, as a non-steroidal anti-inflammatory drug (NSAID). However, Vioxx specifically functions as a COX-2 inhibitor. Essentially, humans use two cyclo-oxygenase enzymes, COX-1 and COX-2, to produce what are known as prostaglandins, which are associated with pain and inflammation in the body. Vioxx acts to inhibit only COX-2 enzymes from producing prostaglandins.

Related traditional "non-selective" NSAIDS, such as ibuprofen and naproxen, inhibit both COX-1 and COX-2. However, COX-1 is used to monitor and maintain stomach tissue in the body. By inhibiting COX-1 enzymes, chronic use of non-selective NSAIDS is associated with ulcers and other gastrointestinal problems (or "GI events"). By selectively inhibiting only COX-2, Vioxx was hoped produce the same pain relieving result of other NSAIDS, but without the associated GI events.

What Went Wrong

The FDA approved the use of Vioxx to treat osteoarthritis, menstrual pain and management of acute pain in adults in 1999. Three years later, the treatment of rheumatoid arthritis was added to the FDA's list of approved uses. However, reports and studies began linking Vioxx to an increase in cardiovascular problems such as the risk of blood clots, heart attacks and strokes (or "CV events").

Merck had itself conducted two studies of Vioxx, focusing on discovering meaningful GI effects and exploring other potential beneficial uses of Vioxx. The studies were called VIGOR and APPROVe. Review and reanalysis of the results from Merck's studies alerted researchers to the alternative finding of CV events in the subjects.

Merck Studies of Vioxx: VIGOR and APPROVe

Shortly after Vioxx was approved in 1999, Merck continued testing the drug in a study called Vioxx Gastrointestinal Outcomes Research (VIGOR). This study was conducted with the purpose of examining "clinically meaningful" GI effects such as stomach ulcers and bleeding when compared to the non-selective NSAID, naproxen. The study was performed with 8,000 rheumatoid arthritis patients, who require a higher dose of the drugs (50mg). Some patients took Vioxx and others took naproxen. No placebo was used. Results showed a higher incidence of CV events in patients taking Vioxx than naproxen.

In early 2000, Merck began to enroll trials for another study called Adenomatous Poly Prevention on Vioxx (APPROVe). APPROVe trials were conducted with the purpose of discovering whether 25mg of Vioxx was effective to prevent the recurrence of colon polyps as compared with a placebo. CV events occurred almost twice as frequently in the Vioxx group.

Reaction to Merck's Studies

In February 2001, the FDA Arthritis Advisory Committee met to discuss concern about potential CV risks associated with Vioxx, but no further action was taken at that time. In May 2001, Merck issued a press release entitled "Merck Reconfirms Favorable Cardiovascular Safety of Vioxx." In August 2001, a closer analysis of VIGOR by the Cleveland Clinic prompted a Journal of the American Medical Association report linking Vioxx to an increase in CV events.

The American Medical Association, National Stroke Administration and Arthritis Foundation asked Merck to test Vioxx specifically for CV events. Merck declined and urged that the VIGOR results were not due to a problem with Vioxx, but rather, that they were due to the particularly "cardioprotective" effects of naproxen. However, in September 2001, the FDA sent Merck a Warning Letter which demanded that Merck cease promotion of Vioxx to doctors for unapproved uses and ordered Merck to send letters to the medical community regarding the deception.

Additional Studies and the Withdrawal of Vioxx from the Market

Over the next three years, more studies linked Vioxx to CV events. Results demonstrated that, especially taken chronically and in high doses, Vioxx and CV events may be linked. Despite these studies, Vioxx persisted on the market and the FDA even added an approved use of Vioxx, to treat rheumatoid arthritis, in 2002. However, the FDA did change the warning on Vioxx to include that those with a "history of heart disease" should take precaution when taking Vioxx.

In August of 2004, the FDA partially funded a study of Vioxx by examining the records of Kaiser Permanente patients taking Vioxx. The results of the Kaiser study showed heightened CV risks for Vioxx. On September 30, 2004, Merck voluntarily pulled Vioxx from the worldwide market. Merck cited the reason for the withdrawal as the unexpected CV results of the APPROVe study of which trials were stopped early. The same day, the FDA issued a Public Health Advisory on Vioxx.

Merck's Liability

Since problems with Vioxx were first discovered, finger pointing has ensued. Blame has been placed on the FDA, Merck and (to a lesser extent) Pfizer, the manufacturer of  Celebrex and Bextra, which are direct competitor drugs to Vioxx (but which remain on the market). However, currently, Merck is under the most fire. Merck faces federal investigations by the U.S. Senate Finance Committee, criminal investigation by the Justice Department and investigation by the SEC for misleading investors. In addition, there are thousands of federal products liability lawsuits that have been filed by injured plaintiffs and plaintiff classes. In December of 2005 a financial analyst for Bear Stearns estimated Merck's potential liability exposure for Vioxx-related claims at $10 billion.