Merck conducts clinical trial (unpublished) called Study "090" which finds that among 978 patients, serious cardiovascular problems occurred six times more often in those taking Voixx than those not taking Vioxx (Merck said study not large enough to draw conclusions).

Vioxx is introduced with U.S. Food and Drug Administration (FDA) approval and no warning regarding cardiovascular risks is required to be placed on the label.

Merck conducts VIGOR Study—then, the largest-ever clinical trial of Vioxx—a study of 8,000 people designed to see if Vioxx was safer on the stomach than other pain relievers.

VIGOR study is concluded; Vioxx was found safer on stomach, but those taking it had a five-fold increase in heart attacks.

Merck's research president writes internal email in which he stated that "heart problems 'are clearly there,' and 'It is a shame, but it is a low incidence and it is mechanism-based as we worried it was.'"¹

Dr. Eric Topol, chief of cardiovascular medicine at the Cleveland Clinic, concludes based on the combination of both Study 090 and VIGOR that there is strong evidence that Vioxx is unsafe.

FDA sends a warning letter to Merck saying that sales representatives "have engaged in false or misleading promotional activities" and that its advertising "minimizes the potentially serious cardiovascular findings." They required Merck "to correct false or misleading impressions and information."²

FDA asks Merck to change the Vioxx label in order to make the warnings about cardiovascular risks more prominent on the packaging, but does not require the language to be placed in the "warnings" section on the label (Merck complies a year later).

Dr. Eric Topol conducts study (published in the journal of the American Medical Association) of available Vioxx data which finds "a very substantial worrying risk of heat attacks and strokes—across the board—from the VIGOR trial and about Vioxx."³

Merck makes the FDA-mandated labeling change to the packaging of Vioxx, but does not put the information in the "warnings" section on the package.

Large epidemiologic study reported a two-fold increase in risk of heart attack with high-dose Vioxx.

2004:

Merck spends over $1.7 million to oppose bills such as the Pharmaceutical Market and Drug Safety Act.⁴

Dr. Graham, Associate Director for Science and Medicine in FDA's Office of Drug Safety, reports his Vioxx study which said that Vioxx "increased the risk of heart attack and sudden death by 3.7 fold for high-dose and 1.5 fold for low-dose, compared to Celebrex."

FDA announces its approval for Vioxx use in children with rheumatoid arthritis.

September, 2004: Merck receives results of its APPROVe study which indicated that patients taking Vioxx for longer than 18 months were twice as likely to suffer a heart attack or stroke than those taking a placebo.

Merck "voluntarily withdraws" Vioxx from the market.

The FDA puts a report describing Dr. Graham's study on its website on election day.

The Lancet (British medical journal) publishes study that concludes that Vioxx should have been taken off the market several years ago.