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Context of 'March 9, 2000: Merck Scientist Notes that Anticipated Heart Problems Among Vioxx Users Are a ‘Shame’'

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A Merck official writes a memo on the question of whether the company should conduct a trial to demonstrate that Vioxx is gentler on the stomach than other painkillers. The memo notes that such a study would likely show that “there is a substantial chance that significantly higher rates” of cardiovascular problems will occur among the patients taking Vioxx. [Wall Street Journal, 11/1/2004; CBS News, 4/28/2005]

Entity Tags: Merck

Timeline Tags: US Health Care

Merck official Briggs Morrison sends an e-mail warning that if the company conducts a proposed trial of the drug Vioxx (see also November 21, 1996), and the subjects do not take aspirin, there will be “more thrombotic events [i.e., more blood clots] and kill [the] drug.” In response, Merck scientist Alise Reicin laments that the company is in a “no-win situation.” She suggests that people with a high risk of cardiovascular problems be excluded from the study so the association between Vioxx and thrombotic events “would not be evident.” [Wall Street Journal, 11/1/2004]

Entity Tags: Briggs Morrison, Alise Reicin

Timeline Tags: US Health Care

Research done by Dr. Garrett FitzGerald suggests that COX-2 inhibiting drugs, like Vioxx and Celebrex, increase the risk of cardiovascular problems. FitzGerald believes that COX-2 inhibitors block the production of a substance called prostacyclin, which leads to blood vessel constriction and clotting. His research is dismissed by Merck, the maker of Vioxx. Vioxx’s only selling point is that it causes fewer gastrointestinal problems than other pain killers on the market. But according to FitzGerald, the mechanism that makes the drug gentler on the stomach is also responsible for causing the cardiovascular problems. [MSNBC, 10/6/2004] FitzGerald’s research is later published in two studies, one in 1999 and another in 2001. [Associated Press, 6/22/2005]

Entity Tags: Merck, Garrett FitzGerald

Timeline Tags: US Health Care

At the VIGOR safety panel’s second meeting (see also January 1999 and October 3 or 4, 1999), panel members discuss concerns over the “excess deaths and cardiovascular adverse experiences” observed among patients taking Vioxx. [US Food and Drug Administration, 2/1/2001, pp. 5 pdf file] As of November 1, 1999, 79 patients out of the 4,000 taking the drug have experienced serious heart problems or have died, compared with 41 patients taking naproxen. Minutes of the meeting note that “while the trends are disconcerting, the numbers of events are small.” [National Public Radio, 6/8/2006]

Entity Tags: Merck

Timeline Tags: US Health Care

The VIGOR study’s safety panel meets for a third time and learns that as of December 1, 1999, the number of Vioxx patients who have experienced heart problems or have died is twice as high as those taking naproxen. The panelists are shown a chart with two lines—one showing the number of deaths in the Vioxx group; the other, deaths in the naproxen group. The chart shows that since the sixth week of the study, the line representing the Vioxx group has been going up at an increasingly brisk pace, while the naproxen group’s line rises slower and is relatively linear. [National Public Radio, 6/8/2006] Some members suggest that diverging lines could be “due to cardioprotective effects of Treatment B,” i.e., that naproxen is somehow reducing the risk of heart problems. [US Food and Drug Administration, 2/1/2001, pp. 6 pdf file] The panel’s chairman, Michael Weinblatt, and Merck statistician Deborah Shapiro write a letter to Merck’s Alise Reicin advising that the company develop a plan to study the cardiovascular results before the VIGOR study is completed. When an investigation by NPR learns about this meeting, it asks three experts to comment on the chart and the panel’s decision. All three say that the study should have been called off immediately because the chart clearly showed that the risk of heart problems among those taking Vioxx increased with time. The panel, in a statement to NPR, claims that it did not cancel the study noting that it was not clear to the panelists at the time whether the different rates of heart problems and deaths were a result of Vioxx causing the cardiovascular problems, or naproxen preventing them. But no study has ever proven that naproxen is cardioprotective. [National Public Radio, 6/8/2006; National Public Radio, 6/8/2006]

Entity Tags: Alise Reicin, Michael Weinblatt, Merck, Deborah Shapiro

Timeline Tags: US Health Care

Merck says it does not want to begin developing a plan to analyze the data on the large number of deaths from heart problems that has occurred during a clinical trial for its drug Vioxx (see December 22, 1999 and November 18, 1999). Michael Weinblatt, who is heading the study, sent a request to Merck the month before asking the company to develop such a plan (see December 22, 1999). Merck suggests that they wait and combine the cardiovascular results of this study with the results from other clinical studies for the drug. But Weinblatt is adamant that the company needs to begin analyzing the data immediately, and continues discussing the matter with Merck, which finally agrees to a plan the following month (see Early February 2000). [National Public Radio, 6/8/2006; National Public Radio, 6/8/2006]

Entity Tags: Merck

Timeline Tags: US Health Care

Merck finally agrees to analyze the data on deaths that have occurred during the clinical trials for its drug Vioxx (see December 22, 1999 and November 18, 1999). The analysis was requested by Michael Weinblatt, who is leading the Vioxx study (see December 22, 1999). But Merck says it will only analyze the deaths that take place before February 10, one month before the study ends. Any deaths that occur after this “cut-off” date will not be factored into the analysis. [National Public Radio, 6/8/2006; National Public Radio, 6/8/2006]

Entity Tags: Merck

Timeline Tags: US Health Care

Edward Scolnick, head of Merck’s research labs, sends an e-mail to his colleagues noting that Vioxx’s anticipated cardiovascular side effects “are clearly there… It is a shame but it is a low incidence and it is mechanism based as we worried that it was.” [Wall Street Journal, 11/1/2004; HeartWire, 11/1/2004]

Entity Tags: Merck, Edward Scolnick

Timeline Tags: US Health Care

According to an internal company document, Merck research chief Edward Scolnick discusses possible plans to reformulate Vioxx with the company’s in-house patent counsel. The new Vioxx would contain an anti-clotting agent to reduce the risk of cardiovascular problems. The document indicates that the company’s researchers believe the current Vioxx formula inhibits the production of a substance called prostacyclin which leads to blood vessel constriction and clotting. But Merck was alerted to this problem two years before by scientist Garrett FitzGerald, who had warned the company that all Cox-2 inhibitors would likely have this effect. Merck, eager to get its drug on the market, dismissed his research (see 1998). [Associated Press, 6/22/2005]

Entity Tags: Edward Scolnick, Merck

Timeline Tags: US Health Care

Merck sends all of its sales representatives a “Cardiovascular Card,” a tri-fold pamphlet on the safety of Vioxx, so they “are well prepared to respond to questions about the cardiovascular effects of Vioxx.” Since the announcement (see March 27, 2000) of the VIGOR study results, physicians have been asking the representatives whether Vioxx causes heart problems. The pamphlet contains a table of data appearing to indicate that patients on Vioxx are 11 times less likely to die than patients on standard anti-inflammatory drugs, and 8 times less likely to die from heart attacks and strokes. Another section displays data showing that Vioxx patients are half as likely to suffer heart attacks as patients who receive a placebo. The risk for patients on other anti-inflammatory drugs appears to be identical. [Merck, 4/28/2000 pdf file] But the pamphlet is based on the combined data of several disparate studies, conducted before the drug’s approval. None of the studies were designed to test the cardiovascular safety of the drug. An FDA medical reviewer later tells the staff of a congressional committee that the relevance of those studies to the question of Vioxx’s effects on the heart is “nonexistent.” Furthermore, the reviewer says it would be “ridiculous” and “scientifically inappropriate” to use the pamphlet as evidence of the drug’s safety. [Office of Representative Henry A. Waxman, 5/5/2005, pp. 16-19 pdf file]

Entity Tags: Merck, VIGOR

Timeline Tags: US Health Care

Merck files a patent application with the US Patent Office for a drug that would contain a combination of Vioxx and an anti-clotting agent, or thromboxane inhibitor. The new drug would hopefully reduce the risk of cardiovascular problems while preserving Vioxx’s gastrointestinal benefits. Merck never develops the drug. Critics later note that Merck’s interest in this new drug contradicted its assertions that Vioxx was safe for the heart. [Associated Press, 6/22/2005]

Entity Tags: Merck

Timeline Tags: US Health Care

The Food and Drug Administration holds an advisory meeting on the VIGOR study, a clinical trial for the drug Vioxx, to assess whether there is a connection between the drug and heart problems. Unlike the VIGOR study published in the New England Journal of Medicine (see November 23, 2000), this group includes heart attacks 18, 19, and 20 (see March 2000) in their analysis. The meeting’s members conclude that there is not enough data to draw a solid conclusion. [US Food and Drug Administration, 3/8/2001; National Public Radio, 6/8/2006] Notwithstanding, they do recommend that physicians be informed that the VIGOR study showed “an excess of cardiovascular events in comparison to naproxen.” [Office of Representative Henry A. Waxman, 5/5/2005, pp. 21 pdf file] On March 7, the agency publishes all of the VIGOR data on its website, as well as its analysis. [US Food and Drug Administration, 3/8/2001]

Entity Tags: US Food and Drug Administration

Timeline Tags: US Health Care

Fearing increased public concern over the safety of Vioxx, Merck sends its sales representatives a bulletin instructing them in all capital letters: “Do not initiate discussions on the FDA Arthritis Advisory Committee… or the results of the… VIGOR study.” The previous day, an FDA panel (see February 8, 2001) reviewed the results of the VIGOR study and said physicians need to be informed that Vioxx appears to cause “an excess of cardiovascular events in comparison to naproxen.” The Merck bulletin provides a list of responses that its representatives are authorized to use in addressing physicians’ concerns. It emphasizes that these are the only responses they are allowed to use. If doctors ask about Vioxx’s effects on the heart, sales persons should say, “Because the study is not in the label, I cannot discuss the study with you.” However, as a report by Henry A. Waxman notes, drug company representatives are permitted by FDA regulations to discuss safety concerns even when those concerns are not on the label. The sales persons are also advised to tell physicians to submit their questions in writing to Merck’s medical services department. Merck says reps can also show the physicians the Cardiovascular Card, a pamphlet consisting of data that appears to show that Vioxx is safe (see April 28, 2000). The bulletin indicates that sales reps are not supposed to leave the pamphlet with the doctor. [Merck, 2/9/2001 pdf file; Office of Representative Henry A. Waxman, 5/5/2005, pp. 22 pdf file]

Entity Tags: Merck

Timeline Tags: US Health Care

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