Vioxx hearing raises questions about what Merck knew and when

Janis Kelly

November 25, 2004

Nov 25, 2004

Washington, DC - A recent US Senate Finance Committee hearing, "FDA, Merck and Vioxx: Putting Patient Safety First," turned a harsh spotlight on nearly every aspect of the development, approval, marketing, and withdrawal of rofecoxib (Vioxx, Merck). Witnesses and committee members charged that Merck:

  • Knew about the potential for Vioxx cardiovascular (CV) risk quite early in the drug development process.

  • Tried to avoid, disguise, explain away, or stifle discussion of CV risk, even designing clinical trials in a way that would minimize that risk.

  • Was enabled by a "too-cozy" relationship with the FDA and delayed warning physicians and patients about the CV risk for nearly 2 years while continuing a multimillion dollar direct-to-consumer marketing campaign for Vioxx.

Merck believed wholeheartedly in Vioxx. I believed wholeheartedly in Vioxx. In fact, my wife was a user of Vioxx until the day we withdrew it from the marketplace.

Merck president, chair, and chief executive officer Raymond V Gilmartin disputed all of these charges and vigorously defended his company's actions with regard to Vioxx.

"Merck believed wholeheartedly in Vioxx. I believed wholeheartedly in Vioxx. In fact, my wife was a user of Vioxx until the day we withdrew it from the marketplace," Gilmartin told the committee.


What did Merck know?

Dr Bruce M Psaty (Cardiovascular Health Research Unit, University of Washington, Seattle) traced some of the path of Vioxx development, drawing on internal Merck communications.

"In November 1996, Merck scientists hypothesized that patients taking Vioxx would have higher rates of heart disease than those taking an aspirinlike comparison treatment [ 1 ].

"By April 1998, Merck scientists knew of evidence that COX-2 inhibitors such as Vioxx reduce the production of prostacyclin, which prevents platelet aggregation [ 2 - 4 ]. In other words, Vioxx not only lacks the antiplatelet effects of aspirin, but it also disables one of the blood vessel's main defenses against the clumping of platelets.

"On the basis of this biologic evidence, it would be reasonable to hypothesize that the treatment of patients with Vioxx might increase the risk of heart attack and stroke compared with either an aspirinlike treatment or with placebo (no active treatment)," Psaty said.




"Initially, Merck excluded [from clinical trials] patients with recently diagnosed cardiovascular disease and patients taking aspirin. This approach maximized the possibility of finding a GI benefit and, at the same time, minimized the possibility of uncovering convincing evidence about cardiovascular harm," Psaty explained to the committee.

Dr Gurkirpal Singh (Stanford University School of Medicine, CA) had similar concerns.

"At that time [1996], it was not known that Vioxx might itself cause heart attacks. Rather, the discussion focused on the issue that other painkillers, by inhibiting platelets, may protect against heart attacks. Vioxx has no such effect on platelets, and thus may seem to increase the risk of heart attacks in studies comparing it with other painkillers. This was a serious concern, because the entire reason for the development of Vioxx was safety--please note, once again, that it is no more effective than older NSAIDs," Singh said.

"If the improved stomach safety of the drug was negated by a risk of heart attacks, patients may not be willing to make this trade-off. Merck scientists, considered by many to be the best and brightest in the pharmaceutical industry, were among the first to recognize this," Singh said. "At this point in time, scientists should have started a public discussion about this potential trade-off and designed studies that would more carefully evaluate the risk/benefit ratio of the drug."

Singh pointed to an unpublished 1998 analysis by Merck scientist Dr Doug Watson, which concluded that men taking Vioxx had a 28% greater risk of serious heart problems and women had a 216% greater risk, the latter of which was statistically significant compared with patients not taking Vioxx. Singh also discussed an analysis by FDA medical officer Dr Maria Lourdes Villalba during the Vioxx new drug application (NDA) review that found a 3-fold higher rate of cardiovascular events in patients taking Vioxx vs placebo [ 5 ].

Many scientists would consider this 3-fold difference as an early warning sign. . . . It is my opinion that at this point in time, larger and more definitive studies should have been done before the drug was approved.

"This meant that not only did Vioxx not inhibit the platelets, but for some reason, it was likely to promote heart attacks directly. Many scientists would consider this 3-fold difference as an early warning sign. . . . It is my opinion that at this point in time, larger and more definitive studies should have been done before the drug was approved," Singh said.

The early in vitro warnings were supported by some early epidemiologic data, but, as Gilmartin pointed out, the results of epidemiologic studies require careful interpretation. "For example, years of epidemiological studies on hormone replacement therapy [HRT] appeared to indicate that HRT was heart and cancer protective. In fact, recent well-controlled clinical studies have proven the opposite," he said. He pointed out that not every heart attack in a patient taking Vioxx was due to the drug.

Study duration was also an issue. In the Adenomatous Polyp Prevention on Vioxx (APPROVE) trial, the cardiovascular event rate of patients taking Vioxx became significantly higher than that for placebo patients only after 18 months of treatment.

"We only found an increased risk of cardiovascular events because Merck continued to study Vioxx for such a long time period. In fact, Vioxx and aspirin are the only 2 NSAIDs for which there is significant, publicly available long-term safety data," Gilmartin said.

Vioxx and aspirin are the only 2 NSAIDs for which there is significant, publicly available long-term safety data.

Singh said that detecting the heart risk in the APPROVE study was largely a piece of luck. "It is important to note that the APPROVE study, which conclusively proved the increased risk of Vioxx was not a safety study—it was an efficacy study designed to add another indication for Vioxx treatment. It was not large enough to detect a heart attack risk. That it did find a risk was a lucky break for patients, but this is not what it was designed to do," he said.

In a letter to Merck, Sen Charles Grassley (R-IA) also raised questions about the decision to remove Merck researcher Dr Carolyn Cannuscio as a coauthor of a study of Vioxx and myocardial infarction risk. Cannuscio was listed as coauthor when the study was presented at the 2003 ACR meeting, but no Merck authors were listed on the published study [ 6 , 7 ].


What role did denial, discounting, and dodging play?

Hopes for the coxibs were high in the beginning, and to a great extent they were realized.

In May 2004, I presented data that showed a significant reduction in the number of stomach bleeds in the US after the launch of these drugs.

"It was hoped that these drugs would relieve pain but not have any stomach problems. Indeed, this seems to be the case. In May 2004, I presented data that showed a significant reduction in the number of stomach bleeds in the US after the launch of these drugs," Singh said [ 8 ].

Questions about the design and reporting of Vioxx clinical trials are many and troubling, however.

"It appears . . . that in early 1997 Merck scientists were exploring study designs that would exclude people who may have a weak heart so that the heart-attack problem would not be evident. . . . Clinical trials should not be designed to selectively favor one outcome over another by excluding people similar to those who would take the drug after its approval. Certainly, clinical trials should not be designed to put marketing needs in front of patient safety. We need to know how a drug behaves in people who are going to take it, even if it 'kills the drug.' It is better to kill a drug than to kill a patient," Singh said.

We need to know how a drug behaves in people who are going to take it, even if it 'kills the drug.' It is better to kill a drug than to kill a patient.

He noted that the VIOXX GI Outcomes Research (VIGOR) paper, published in November 2000, contained no indication that the data were incomplete but that Merck later said that the published VIGOR data were "preliminary" and that "final" data were presented to the FDA [ 9 ].

"In my view, it is inappropriate to publish 'preliminary' or incomplete data without clearly stating that the data are preliminary. This is especially true if the favorable data are complete but the unfavorable data are 'preliminary' and likely to get worse," Singh said.

He said that the VIGOR report minimized the significance of heart attacks, prominently discussed the reduction in stomach bleeds with Vioxx, and did not mention that patients on Vioxx had more serious adverse events and more hospitalizations than patients on naproxen.

"The true rates for cardiovascular thrombotic adverse events (a prespecified study end point in the protocol), hypertension, and congestive heart failure—which were all higher in the Vioxx group—were not shown in the paper at all," Singh said.

The New York Times had previously reported that Merck research and marketing executives decided in May of 2000 not to do a study directly testing the possibility that Vioxx might raise the risk of heart attacks and strokes. According to the Times, a slide prepared for that meeting said, "At present, there is no compelling marketing need for such a study. Data would not be available during the critical period. The implied message is not favorable" [ 10 ].

Psaty said that although complete cardiovascular data were not available when the VIGOR study was reported, FDA medical officer Dr Shari Targum included them in her Vioxx analysis, which was discussed at the February 2001 arthritis advisory committee meeting that recommended Vioxx label changes [ 11 ].

"In 1000 patients followed for 1 year, Vioxx treatment would likely be associated with 24 fewer GI events (about 8 of them complicated or severe) and 6 more heart attacks than naproxen treatment. Because VIGOR excluded high-risk patients taking aspirin, the balance of GI benefit and heart-disease risk in these patients is not known. . . . If these safety results had been available to the FDA 7 months earlier, it is possible that Vioxx might not have been approved in May 1999, at least not without additional studies," Psaty suggested.

Gilmartin defended the FDA, saying the agency accepted Vioxx "only after Merck had extensively studied the medicine and found it to be safe and effective." He maintained that over the 6 years since Merck first submitted a new drug application for Vioxx, "we have promptly disclosed the results of numerous Merck-sponsored studies to the FDA, physicians, the scientific community, and the media and have participated in a balanced, scientific discussion of its risks and benefits." He said that Merck supported "a healthy scientific discussion of the safety of Vioxx and other COX-2 inhibitors" but "sought to set the record straight" about Vioxx "when researchers published articles or gave speeches that presented misleading or inaccurate information."

Singh's early post-VIGOR experience somewhat belied these claims.

"The results of the VIGOR trial—a 500% increase in heart attacks with Vioxx—stunned me. Clearly, the trade off of 500% increase in heart attacks for a 50% reduction in stomach bleeds did not seem attractive—at least not without a further discussion of data. Merck's press release on this issue and a brief mention of the heart-attack data were not enough for me to continue to educate physicians in my lectures," said Singh, who gave some medical education lectures as a consultant for Merck.

"I asked Merck for more detailed data, including information on high blood pressure and heart-failure rates. When I was unable to obtain this data after multiple requests, I added a slide to my presentations that showed a man—representing the missing data—hiding under a blanket," Singh said.

I was told that Dr Louis Sherwood, a Merck senior vice president and a former chief of medicine at a medical school, had extensive contacts within the academy and could make life 'very difficult' for me at Stanford and outside.

When Singh persisted in asking questions, he was threatened. "I was told that Dr Louis Sherwood, a Merck senior vice president and a former chief of medicine at a medical school, had extensive contacts within the academy and could make life 'very difficult' for me at Stanford and outside. . . . Dr Sherwood called several of my superiors at Stanford to complain. Subsequently, I learned that this was a persistent pattern of intimidation by Dr Sherwood. Prof [ James] Fries, too, felt that this suppression of scientific discussion was unethical and complained to Mr Raymond Gilmartin. Mr Gilmartin and Mr David Anstice took immediate action, and the threats stopped immediately," Singh noted.

"From then onward till today, Merck scientists and officials have treated me and my colleagues with appropriate respect and have always shared scientific data promptly," he added.

Merck's attempt to put a favorable spin on the VIGOR data also drew a September 17, 2001 warning letter from the FDA.

"We have identified aMerck press release, entitled 'Merck confirms favorable cardiovascular safety profile of Vioxx,' dated May 22, 2001, that is also false or misleading," said the letter from Thomas W Abrams, director of the FDA's Division of Drug Marketing, Advertising, and Communications. "Your claim in the press release that Vioxx has a 'favorable cardiovascular safety profile' is simply incomprehensible given the rate of MI and serious cardiovascular events compared with naproxen. The implication that Vioxx's cardiovascular profile is superior to other NSAIDs is misleading. In fact, serious cardiovascular events were twice as frequent in the Vioxx treatment group (101 events, 2.5%) as in the naproxen treatment group (46 events, 1.1%) in the VIGOR study."


Why did the label change take so long?

The Senate Finance Committee's next concern was why, after Merck and the FDA had the VIGOR data, adding a cardiovascular risk warning to the label took so long.

Grassley said, "Merck completed the VIGOR trial in March 2000. It gave the findings to the FDA in June 2000. The trial was the subject of an advisory board meeting in February 2001. But it was April 11, 2002 before the Vioxx label was actually changed. During these 22 months, Merck aggressively marketed Vioxx knowing that consumers and doctors were largely unaware of the cardiovascular risks found in the VIGOR trial."

Merck aggressively marketed Vioxx knowing that consumers and doctors were largely unaware of the cardiovascular risks found in the VIGOR trial.

An editorial in Nature Medicine pointed out that in 2003, Vioxx accounted for 11% of Merck's revenues. "The Vioxx case highlights another consequence of direct-to-consumer marketing—it increases consumption of drugs prior to assessment of their long-term safety. In the context of the concerns about the cardiovascular effects of rofecoxib, it is remarkable that the FDA did not act to regulate the marketing of Vioxx," the editorial said [ 12 ]. Before Merck's withdrawal of Vioxx, about 20 million Americans had taken the drug.

Data from the APPROVE trial finally led to withdrawal of the drug. Gilmartin said that on the afternoon of September 24, 2004, he received a call from the head of Merck Research Laboratories, Dr Peter Kim, with the news that the APPROVE independent data safety monitoring board had discovered "an increased risk of confirmed cardiovascular events beginning after 18 months of continuous daily treatment in patients taking Vioxx compared with those taking placebo." Merck called the FDA and within 4 days pulled Vioxx off the market. Gilmartin stressed that until this point, the combined data from Vioxx randomized controlled clinical trials showed no difference in confirmed cardiovascular event rates between Vioxx and placebo or between Vioxx and NSAIDs other than naproxen.

"Given the availability of alternative therapies and the questions raised by the data, withdrawing Vioxx was consistent with an ethic that has driven Merck actions and decisions for more than 100 years. Merck puts patients first," Gilmartin said.

Withdrawing Vioxx was consistent with an ethic that has driven Merck actions and decisions for more than 100 years. Merck puts patients first.

Gilmartin described Merck's approach as "searching to find any issues with a drug, even negative to us, publishing the data, and encouraging discussion." However, a news report in the New York Times the day of the Senate hearing said that in November 2003, nearly a year before the APPROVE data were available, Merck received preliminary results from a company-sponsored (and still unpublished) analysis of patient records that "also apparently indicated that the drug posed cardiovascular risks" [ 12 ].

That study, final data from which were delivered to Merck 10 days before it pulled Vioxx from the market, used patient records from UnitedHealth Group to compare relative risks of heart attack and stroke in people taking Vioxx, celecoxib (Celebrex, Pfizer), and traditional over-the-counter analgesics.

According to the Times, "One person who was briefed on the data and who spoke on the condition of anonymity said that the results indicated that Vioxx posed an increased risk of cardiovascular problems, compared with the other drugs studied." The study was conducted by Merck researchers and Dr Alexander Walker (Harvard School of Public Health, Boston, MA and the Ingenix unit of UnitedHealth Group.) Data from this study were not presented at meetings, and, when asked about the study, Gilmartin told the Senate that he had not seen the results because they were "just submitted for publication."


Sources

  1. Muliner T. Anticipated consequences of NSAID antiplatelet effects on cardiovascular events and effects of excluding low-dose aspirin use in the COX-2 GI outcomes megatrial. Letter of November 21, 1996, to B Friedman, A Nies, and R Spector.

  2. McAdam BF, Catella-Lawson F, Mardini IA, et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2 the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci 1999; 96:272-277. Abstract.

  3. Buerkle MA, Lehrer S, Sohn HY, et al. Selective inhibition of cyclooxygenase-2 enhances platelet adhesion in hamster arterioles in vivo. Circulation 2004; 110:1053-1059. Abstract.

  4. FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004; 351:1709-1711. Abstract.

  5. Villalba ML. FDA medical officer review of VIOXX (rofecoxib). NDA 21-042 (capsules) and NDA 21-052 (oral solution). Available at : http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_03_med.pdf

  6. Solomon DH, Schneeweiss S, Glynn RJ, et al. The relationship between selective COX-2 inhibitors and acute myocardial infarction. American College of Rheumatology 2003 meeting; October 24-28, 2003; Orlando, FL; abstract 1823.

  7. Solomon DH, Schneeweiss S, Glynn RJ, et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 2004; 109:2068-2073. Abstract.

  8. Singh G, Mithal A, Triadafilopoulos G. Decreasing hospitalizations due to complicated gastric and duodenal ulcers in the United States: 1998-2001. Gastroenterology 2004; 126:A97-98.

  9. Bombardier C, Laine L, Reicin A, et al, for the VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343:1520-1528. Abstract.

  10. Berenson A, Harris G, Meier B, et al. Merck feared "unfavorable message" from Vioxx study. New York Times November 15, 2004.

  11. Targum SL. Consultation on NDA 21-042, S-007. Review of cardiovascular safety database [on Vioxx or rofecoxib]. FDA Memorandum, February 1, 2001. Available at: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.pdf

  12. [no authors listed]. Withdrawal syndrome [editorial]. Nature Medicine 2004; 10:1143. Abstract.

  13. Meier B. Earlier Merck study indicated risks of Vioxx. New York Times November 18, 2004.


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