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(MRK) - Get Merck & Co., Inc. Report

decision to withdraw its popular arthritis drug Vioxx from the market in late September has raised questions about the process leading up to its regulatory approval in 1999 as well as the importance of subsequent medical studies.

Here are some key dates in the Vioxx saga:

November 1998: Merck submits application to Food and Drug Administration seeking approval for the COX-2 inhibitor drug, Vioxx, as a treatment for osteoarthritis, on the basis of clinical trials involving 5,400 patients. Merck says rates of cardiovascular risk were "similar" among patients taking Vioxx, placebo or other pain relievers.

January 1999: Merck begins the VIGOR trial designed to test gastrointestinal impact of Vioxx. A month later, Merck begins the first of two tests to determine if Vioxx has a beneficial effect on Alzheimer's disease patients.

May 1999: FDA approves Vioxx.

February 2000: Merck starts the APPROVE trial, which is designed to ascertain if Vioxx reduces certain colon polyps.

March 2000:Merck receives preliminary results of VIGOR trial, suggesting higher risk of cardiovascular problems among patients taking Vioxx vs. patients taking the pain reliever naproxen. Merck later speculates that the difference is caused by the heart-protective effect of naproxen rather than the heart-risk effect of Vioxx.

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March 2000: Merck announces preliminary results of VIGOR trial and submits data to the FDA. Later in the year, VIGOR trial results are published in the New England Journal of Medicine.

February 2001: FDA Advisory committee holds hearing on VIGOR trials.

April 2002: Vioxx receives a revised label that includes precautions about cardiovascular risk cited in the VIGOR trial.

August 25, 2004: Preliminary data from an FDA-financed study, using patient data compiled by the Kaiser Permanente health maintenance organization, says patients who took Vioxx had a higher cardiovascular risk than patients who took Celebrex. Merck disputes the study's methodology. FDA posts a more detailed version of the study on its Web site in November, but says the article hasn't been subject to standard peer review.

September 23, 2004: The independent safety monitoring board for the APPROVE trial recommends to Merck that it end the trial because of results showing that long-term use of Vioxx -- more than 18 months -- increases risk of heart attacks and strokes compared with patients who took a placebo. However, there is no difference in risk among patients taking Vioxx or placebo for less than 18 months.

September 30, 2004: Merck withdraws Vioxx from the U.S. and worldwide markets.

October 29, 2004: Merck receives conditional approval from FDA for Arcoxia, a cousin of Vioxx. However, this approval is contingent upon Merck completing more long-term safety and efficacy tests. Arcoxia is sold in 48 countries; Merck says it will work with regulators "to assess whether changes to the prescribing information for this class of drugs, including Arcoxia, are warranted."

November 8, 2004: Merck reveals that its handling of Vioxx is being investigated by the Justice Department and by the Securities and Exchange Commission.

November 9-17, 2004: Three credit rating firms -- Moody's Investor Service, Fitch Ratings and Standard & Poor's cut Merck's credit ratings, citing, among other things, the litigation uncertainty involving Vioxx. As of Oct. 31, Merck says it knows of 375 personal injury suits relating to Vioxx.