Reference no: EM131497768

Question: The Approve Study In August 2001 researchers at the Cleveland Clinic published an article in the Journal of the American Medical Association raising concerns about Vioxx's cardiovascular risks. In 2002 a researcher at the Catalan Institute of Pharmacology in Barcelona criticized Merck's handling of Vioxx. The same criticism had been published in the British medical journal The Lancet. The FDA was also concerned about the results of the VIGOR trial and particularly a Merck press release entitled "Merck Confirms Favorable Cardiovascular Safety Profile for Vioxx." In a September 17, 2001, letter to Merck the FDA called the press release "simply incomprehensible" and said that Merck had engaged "in a promotional campaign for Vioxx that minimizes the potentially serious cardiovascular findings that were observed."

The letter also stated that "patients on Vioxx were observed to have a four- to five-fold increase" in heart attacks.45 The new label for Vioxx mentioned both the gastrointestinal and cardiovascular results of the VIGOR trial. As a result of the VIGOR trial, Merck researchers began discussing the possible risks associated with Vioxx and the other Cox-2 inhibitors. In May 2000 Merck considered conducting a cardiovascular study on Vioxx but decided not to do so. Earlier in 2000 Merck had begun enrolling patients for a 156-week study named APPROVe to demonstrate the effect of Vioxx on "the recurrence of neoplastic polyps of the large bowel" in patients with colorectal adenoma. In the study Merck used a placebo as the control and decided to monitor patients carefully for cardiovascular events. Merck established an external safety review board for the study.

The board reviewed the interim results periodically. In May 2003 the panel noted a 20 percent higher risk of heart attack and stroke and by February 2004 the risk was 80 percent higher. Two of the five board members had consulting arrangements with Merck.46 An article published in Circulation in May 2004 found that Vioxx was "associated with an elevated relative risk" compared to Celebrex and to no pain reliever. Vioxx was also criticized at a medical conference in August by an FDA researcher. In September 2004 the cardiovascular results in the APPROVe study showed 15 heart attacks or strokes per 1,000 patients with Vioxx compared to 7.5 with the placebo. Merck decided to withdraw Vioxx from the market. Merck reported, "In this study, there was an increased relative risk for confirmed cardiovascular (CV) events, such as heart attack and stroke, beginning after 18 months of treatment in the patients taking VIOXX compared to those taking ­placebo. The results for the first 18 months of the APPROVe study did not show any increased risk of confirmed CV events on VIOXX, and in this respect are similar to the results of two placebo-controlled studies described in the current US labeling for VIOXX."47

1. In light of the criticism of Vioxx and the letter from the FDA, should Merck have withdrawn Vioxx or issued warnings to doctors and patients prior to learning the results of the APPROVe study?

2. Should Merck have conducted a specific cardiovascular study?