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Context of 'October 13, 2000: Merck Informs FDA of Last Three Deaths in Vioxx Clinical Study'

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Merck begins the Vioxx Gastrointestinal Outcomes Research (VIGOR) study, involving more than 8,076 subjects. The study is being carried out by a data and safety monitoring board (DSMB) that has been appointed by Merck. The Food and Drug Administration recommends the use of DSMBs but does not require them, nor does it require that the panels are put together by an independent party. Merck appoints Michael Weinblatt of Brigham & Women’s Hospital in Boston to lead the study. Weinblatt’s wife owns $73,000 in Merck stock, which according to doctors consulted by an NPR investigation, is enough to potentially influence Weinblatt’s judgment. Furthermore, during the course of the study, all the panel’s meetings will be attended by Merck employee Deborah Shapiro, who is present even during the panel’s private deliberations. She is also the notetaker for the meetings. (National Public Radio 6/8/2006) The VIGOR study is the largest clinical trial ever performed for the drug. Half the participants is given Vioxx, while the other half is given naproxen. The study is designed to determine whether Vioxx causes fewer digestive problems than naproxen, an older painkiller. The outcome of this study is important to Merck because Vioxx’s expected characteristic of being gentler on the stomach would be the drug’s only selling point since there is no evidence that it is a better painkiller than other drugs. The FDA currently requires Vioxx to have the same warning about gastrointestinal bleeding that is carried on the Naproxen label. (Rubin 10/12/2004; Bradley 4/28/2005; Prakash and Valentine 6/8/2006)

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.” (Prakash and Valentine 6/8/2006)

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. (Prakash and Valentine 6/8/2006; National Public Radio 6/8/2006)

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). (Prakash and Valentine 6/8/2006; National Public Radio 6/8/2006)

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. (Prakash and Valentine 6/8/2006; National Public Radio 6/8/2006)

The VIGOR study, a clinical trial for the drug Vioxx, comes to an end (see also January 1999). The goal of the study was to determine whether patients taking Vioxx experienced fewer gastrointestinal problems than subjects taking naproxen, another painkiller. The study’s results back Merck’s claim that Vioxx is gentler on the stomach. But it also seems to confirm the suspicions of some Merck scientists that it causes cardiovascular problems (see November 18, 1999 and December 22, 1999). During the course of the 12-month study, 20 of the patients taking Vioxx died, far more than the number of deaths among the group taking naproxen. (Prakash and Valentine 6/8/2006; National Public Radio 6/8/2006) Later analyses of the data from the study find that subjects taking Vioxx were five times more likely to suffer a heart attack. (Bradley 4/28/2005)

Merck issues a press release announcing the results of the VIGOR study (see March 2000) and saying that the study showed patients taking Vioxx experienced fewer gastrointestinal problems than patients on naproxen. Merck also says that “significantly fewer thromboembolic events were observed in patients taking naproxen.” Merck asserts that this was due to “naproxen’s ability to block platelet aggregation,” (Merck 3/27/2000) a theory for which there is no conclusive evidence. (Peterson 5/22/2001)

Merck submits the results of the VIGOR clinical trial for its drug Vioxx to the New England Journal of Medicine (NEJM) for publication. The data include only 17 of the 20 deaths that occurred among patients taking Vioxx (see March 2000). (Prakash and Valentine 6/8/2006) Data concerning the last three deaths were deleted two days before, according to Dr. Gregory Curfman, executive editor of the journal, who does not discover the missing data until December 2004. “When you hover the cursor over the editing changes, the identity of the editor pops up, and it just says ‘Merck,’” Curfman later tells Forbes magazine. (Langreth and Herper 12/8/2005)

The authors of a paper on VIGOR, a clinical study on the drug Vioxx, submit two sets of corrections to the New England Journal of Science for the manuscript they submitted in May (see May 18, 2000). They do not correct the omission of three fatal heart attacks that occurred toward the end of the study (see March 2000) after a February 10 “cut-off” date (see Early February 2000). (Prakash and Valentine 6/8/2006)

In a memo to Merck scientist Alise Reicin, Merck statistician Deborah Shapiro includes a reference to the three Vioxx deaths that occurred during the last month of the VIGOR study (see March 2000). Those three deaths—numbers 18, 19, and 20—were not included in a paper submitted to the New England Journal of Medicine in which Reicin and Shapiro are listed as authors (see May 18, 2000). (Prakash and Valentine 6/8/2006)

Merck informs the FDA about three fatal heart attacks (deaths 18, 19, and 20) that occurred toward the end of VIGOR, the clinical trial for its drug Vioxx that ended last March (see March 2000). These three deaths were initially left out because they had taken place after a February 10 “cut-off” that had been set at the company’s insistence (see Early February 2000) (Prakash and Valentine 6/8/2006)

The New England Journal of Medicine publishes the VIGOR paper (see May 18, 2000) summarizing the results of a clinical trial for the drug Vioxx. The paper’s main conclusion is that patients taking the drug experienced fewer gastrointestinal complications than patients taking naproxen, another painkiller. This conclusion is important to Merck, the maker of the drug, because this is Vioxx’s only selling point. There is no evidence that Vioxx is a more effective painkiller than any other drug available on the market. But the paper’s section on “General Safety” is misleading because the authors leave out the deaths of three Vioxx patients (see March 2000). The authors were aware of the fatal heart attacks and had at least two opportunities to correct these omissions (see July 2000-November 2000). Notwithstanding their knowledge of these deaths, the authors say there is no causal relationship between Vioxx and heart problems. (Bombardier et al. 2000; Prakash and Valentine 6/8/2006) When the Journal learns about the missing deaths, executive editor Dr. Gregory Curfman, demands a correction. He tells Forbes magazine, “I was somewhere between surprised and stunned. They allowed us to publish an article that was just incomplete and inaccurate in some respects and was misleading and may have contributed to the detriment to the public health.” (Langreth and Herper 12/8/2005)

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; Prakash and Valentine 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)

The New York Times reports the results of the VIGOR study (see March 2000), which showed that Vioxx, marketed by Merck, increases the risk of heart attacks four-fold (later studies increase this to five-fold). The Times also reports Merck’s interpretation of the results—that the different number of heart attacks suffered by patients taking Vioxx compared to those using naproxen was due to the heart-protective properties of naproxen. But no studies have been done showing that naproxen prevents heart attacks, says Dr. Maria Lourdes Villalba, an FDA scientist who was interviewed by the newspaper. Another scientist, Dr. M. Michael Wolfe, chief of the gastroenterology section at the Boston University School of Medicine, says people need to know about these risks. “The marketing of these drugs is unbelievable. I’m sure there are many people out there who are taking these drugs that should not be,” he says. Another concern noted is that the very same people who are likely to take the drug—elderly people with arthritis—are the ones with the highest risk of having heart problems. (Peterson 5/22/2001)

Merck issues a press release titled “Merck Confirms Favorable Cardiovascular Safety Profile of Vioxx” asserting that there is no evidence that patients taking the prescribed dosage levels of Vioxx have an increased risk of having heart problems. It says that the higher number of heart troubles experienced by patients taking Vioxx compared to naproxen during the VIGOR study (see March 2000) was likely because naproxen has similar properties to aspirin, which is known to prevent heart attacks. (Merck 5/22/2001) The FDA later issues a warning to Merck calling this press release “simply incomprehensible, given the rate of MI and serious cardiovascular events compared to naproxen” (see September 17, 2001). (US Food and Drug Administration 9/17/2001, pp. 1-2 pdf file)

The Food and Drug Administration faxes a warning letter to Raymond Gilmartin, the CEO of Merck, accusing the company of conducting a deceptive promotional campaign for its drug Vioxx. The eight-page letter, referring mostly to events that took place between June 2000 and June 2001, states: “You have engaged in a promotional campaign for Vioxx that minimizes the potentially serious cardiovascular findings that were observed in the VIOXX Gastrointestinal Outcomes Research (VIGOR) study (see March 2000), and thus, misrepresents the safety profile for VIOXX. Specifically, your promotional campaign discounts the fact that in the VIGOR study, patients on VIOXX were observed to have a four to five fold increase in myocardial infarctions (MIs) compared to patients on the comparator non-steroidal anti-inflammatory drug (NSAID), Naprosyn (naproxen).… You assert that Vioxx does not increase the risk of MIs and that the VIGOR finding is consistent with naproxen’s ability to block platelet aggregation like aspirin. That is a possible explanation, but you fail to disclose that your explanation is hypothetical, has not been demonstrated by substantial evidence, and that there is another reasonable explanation, that Vioxx may have pro-thrombotic properties [i.e., cause heart attacks]. You have also engaged in promotional activities that minimize the Vioxx/Coumadin (warfarin) drug interaction, omit important risk information, make unsubstantiated superiority claims against other NSAIDS, and promote Vioxx for unapproved uses and an unapproved dosing regimen.… Your minimizing these potential risks and misrepresenting the safety profile for Vioxx raise significant public health and safety concerns.” The letter also warns the company about a May 2001 press release (see May 22, 2001), which claimed the drug has a “favorable cardiovascular safety profile.” (US Food and Drug Administration 9/17/2001, pp. 1-2 pdf file)

After six months of negotiations, Merck and the FDA finally agree on the text for a warning about Vioxx’s cardiovascular side effects that will be added to the drug’s label. The FDA had wanted to include a clear message that Vioxx increases the risk of heart problems since the current version of the label includes no information about such risks. An excerpt from the FDA’s originally proposed text reads: “VIOXX should be used with caution in patients at risk of developing cardiovascular thrombotic events… . The risk of developing myocardial infarction in the VIGOR study was five-fold higher in patients treated with VIOXX 50 mg (0.5 percent) as compared to patients treated with naproxen (0.1 percent).…” The FDA also wanted to include a graph showing that the risk of heart problems increases with continued exposure to the drug. Merck objected to the FDA’s proposals. It insisted that a description of the cardiovascular risks be included in the “Precaution” section of the label, instead of the more severe “Warning” section, as proposed by the FDA. The company also wanted to include results from several disparate clinical studies that had been conducted prior to the drug’s release. These are the same tests that are cited in the “Cardiovascular Card” that Merck sales people show to doctors (see April 28, 2000). But the FDA objected, telling the company that the studies were “trials of different design, size, and duration, using different doses of VIOXX and different comparators” and therefore did not provide useful data for determining the drug’s cardiovascular risk. The FDA eventually concedes to several of Merck’s requests. The final text of the warning is included in the “Precaution” section of the label, as Merck wanted, and does not include the graph that had been requested by the FDA. The text of the cautionary statement is also watered down. The section summarizing the results of the VIGOR study (see March 2000) and two other studies states: “The significance of the cardiovascular findings from these 3 studies (VIGOR and 2 placebo-controlled studies) is unknown.” (Merck 2001; US Food and Drug Administration 1/30/2002 pdf file; US Food and Drug Administration 2005; Office of Representative Henry A. Waxman 5/5/2005, pp. 16-19 pdf file)

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