Were there any warning flags that led to Merck's recall of Vioxx?

Ever since the FDA sent a warning letter to Merck in 1999 calling Merck's promotional materials “false and misleading,” and when the FDA directed Merck to send a letter to healthcare professionals with warnings involving the safety of its medication in 2002, Vioxx was headed for trouble. It's no surprise Merck finally decided to pull the plug, and on September 30, 2004, Merck withdrew Vioxx from the shelves. The timeline below shows the warning flag that led to the Vioxx drug recall:

• May 14, 1999. The Food and Drug Administration (FDA) approved the drug Vioxx manufactured by Merck, Inc., for relief of the signs and symptoms of osteoarthritis, the management of acute pain and the treatment of primary dysmenorrheal (menstrual cramping).
• December, 1999. The FDA sent warning letters to Merck regarding misrepresentation of safety information in promotional material, calling the material “false and misleading.”
•  November 23, 2000. An article in the New England Journal of Medicine reported the results of a randomized trial called the Vioxx Gastrointestinal Outcomes Research trial (VIGOR). The results of this trial, which was sponsored by Merck, revealed a 53 percent decrease in the risk of upper gastrointestinal toxicity, but a five-fold increase in the risk of myocardial infarction for Vioxx compared with Naproxen.
• September 17, 2001. Merck received a letter from the FDA, warning the manufacturer from engaging in a promotional campaign for Vioxx that minimized the potentially serious cardiovascular findings that were observed in the VIGOR study.
• April 1, 2002. Merck announced that it had won approval from the FDA to market Vioxx for the acute treatment of migraine with or without aura in adults.
•  April 11, 2002. The FDA approved a supplemental application for the use of Vioxx for the treatment of rheumatoid arthritis. It also approved a new label which added text regarding the new indication and precautions based on the results of the VIGOR trial.
•  April 11, 2002. Merck sent a “Dear Healthcare Professional” letter to physicians outlining the new label for Vioxx. The revised label recommended that physicians “use caution” in prescribing Vioxx for patients with ischemic heart disease and that 50 mg. a day is not recommended for chronic use. The April 2002 letter mentioned that the VIGOR study showed a higher incidence of serious cardiovascular thrombotic events including sudden death, myocardial infarction, unstable angina, transient ischemic attack (TIA) and peripheral venous and arterial thromboses. It also noted that in the phase III rheumatoid arthritis efficacy studies, the incidence of hypertension in rheumatoid arthritis patients receiving 25 mg. of Vioxx once daily was 10 percent, as compared to the incidence of hypertension in patients receiving 500 mg. of Naproxen twice daily at 4.7 percent.
• September 9, 2004. Merck announced that Vioxx had received approval from the FDA for the treatment of juvenile rheumatoid arthritis (JRA) in children 2 years and older and who weigh at least 22 pounds.
• September 27, 2004. The Data Safety Monitoring Board for an ongoing long-term study of Vioxx (APPROVe) recommended that the study be stopped for safety reasons. The study showed an increased risk of cardiovascular events (including heart attack and stroke) in patients on Vioxx compared to placebo, particularly those who had taken the drug for longer than 18 months.
• September 28, 2004. Merck and FDA officials met. At that meeting the FDA was informed that Merck was voluntarily withdrawing Vioxx from the marketplace.