"When the CLASS and VIGOR trials were started, the cardiovascular adverse events were not foreseen. However, when these clinical trials showed an increased risk of myocardial infarction, rather than consider this finding a major danger signal, the manufacturers designed trials to show efficacy for other indications and enhanced the cardiovascular safety monitoring in these subsequent trials. It is a sobering thought that although the number of deaths and cardiovascular events attributable to COX-2 inhibitors remains in dispute, had trials designed to test the question of cardiovascular toxicity directly been launched in 1999 and executed with urgency, substantial morbidity and perhaps a substantial number of deaths could have been prevented. As we apply new science to develop new medicines, we must not forget that our first job is to do no harm."
--Drazen, NEJM Volume 352:1131-1132 March 17, 2005 Number 11
By the time of rofecoxib's withdrawal from the market in September 2004, after a placebo-controlled study confirmed its cardiovascular risk, more than 100 million prescriptions had been filled in the United States. Tens of millions of these prescriptions were written for persons who had a low or very low risk of gastrointestinal problems. (hence, these prescriptions were written because of clever advertising not a true indication, as typical nsaids work as well as cox-2s in those who didn't need the lower GI risk from the class --ij) ... The pharmaceutical industry spends more than $5.5 billion to promote drugs to doctors each year — more than what all U.S. medical schools spend to educate medical students. Major drug companies employ about 90,000 sales representatives — one for every 4.7 doctors in the United States, according to the American Medical Association... May 5 hearing of the Government Reform Committee focused on Merck, the manufacturer of Vioxx, which has an excellent reputation within the drug industry and supports many products, such as vaccines, that are medically essential but not very profitable. The company funded VIGOR and appropriately sought to publish its results in a prestigious medical journal. In advance of the committee's hearing, Merck cooperated voluntarily with our request for information, providing more than 20,000 pages of internal company documents. Merck also voluntarily sent a senior executive to testify at the hearing and answer the committee's questions. Yet as we learned, even a company like Merck can direct its sales force to provide clinicians with a distorted picture of the relevant scientific evidence.
On February 7, 2001, the Arthritis Drugs Advisory Committee of the Food and Drug Administration (FDA) met to discuss the VIGOR study. At this meeting, Merck argued that the significant increase in the rate of myocardial infarction (which further analysis had determined to be a fivefold increase) was explained by a protective effect of naproxen, not by any inherent risk posed by its drug. After the FDA's medical reviewer and others expressed concern about this explanation, the advisory committee voted unanimously that physicians should be made aware of VIGOR's cardiovascular results.
The next day, Merck sent a bulletin to its rofecoxib sales force of more than 3000 representatives. The bulletin ordered, "DO NOT INITIATE DISCUSSIONS ON THE FDA ARTHRITIS ADVISORY COMMITTEE . . . OR THE RESULTS OF THE . . . VIGOR STUDY." It advised that if a physician inquired about VIGOR, the sales representative should indicate that the study showed a gastrointestinal benefit and then say, "I cannot discuss the study with you."
Merck further instructed its representatives to show those doctors who asked whether rofecoxib caused myocardial infarction a pamphlet called "The Cardiovascular Card." This pamphlet, prepared by Merck's marketing department, indicated that rofecoxib was associated with 1/8 the mortality from cardiovascular causes of that found with other antiinflammatory drugs.
The Cardiovascular Card provided a misleading picture of the evidence on rofecoxib. The card did not include any data from the VIGOR study. Instead, it presented a pooled analysis of preapproval studies, in most of which low doses of rofecoxib were used for a short time. None of these studies were designed to assess cardiovascular safety, and none included adjudication of cardiovascular events. In fact, FDA experts had publicly expressed "serious concerns" to the agency's advisory committee about using the preapproval studies as evidence of the drug's cardiovascular safety.4
Persistent physicians who sought additional information about the cardiovascular effects of rofecoxib were directed to send inquiries to the company's headquarters. Merck's response to these physicians highlighted the misleading information from the Cardiovascular Card.
Beyond these specific communications to physicians, our committee also heard evidence of a broad disparity between the evidence-based perspective provided by scientific journals and expert committees, on the one hand, and the sales pitch used by the company's field staff, on the other. Merck instructed its sales representatives, for example, to provide only certain approved study results to doctors. Approved scientific studies were defined as those that provide "solid evidence as to why [doctors] should prescribe Merck products for their appropriate patients." By contrast, those studies that raised safety questions about drugs were considered background studies. Distributing the results of a background study was "a clear violation of Company Policy."
Merck also trained its representatives to identify speakers for educational events who were "opinion leaders" who could provide "favorable" views of the company's products to other doctors. Underlining the promotional nature of these events, Merck instructed its sales representatives to track whether the physicians who attended them subsequently prescribed more Merck drugs.
In addition to providing selective evidence and biased presentations, Merck counseled its representatives to use an array of subliminal selling techniques to affect prescribing — potentially undermining the ability of physicians to choose drugs strictly on the basis of the risks, benefits, and costs for a particular patient. For example, in a training course on selling skills, Merck taught representatives to mimic the words and body language of doctors during sales calls. The curriculum explained that "mirroring is the matching of patterns, verbal and non-verbal, with the intention of helping you enter the customer's world. It is positioning yourself to match the person talking. It subconsciously raises his/her level of trust by building a bridge of similarity.
--Waxman, NEJM Volume 352:2576-2578 June 23, 2005 Number 25
Obtain the full text at
www.content.nejm.org by searching "vioxx;" its free.
"In response to Drs. Kim and Reicin, I believe that many vital steps were not taken to evaluate the cardiovascular safety of rofecoxib properly. They assert that the clinical data for the initial FDA approval "did not suggest an adverse cardiovascular effect." In contrast, at the time of approval in May 1999, the FDA reviewer, Dr. Villalba, wrote, "The data seem to suggest thromboembolic events are more frequent in patients receiving rofecoxib than placebo."1 In 2000, along with the VIGOR trial,2 a second trial conducted by Merck, known as Study 090, also showed a significant excess of heart attacks and strokes among patients taking rofecoxib, as compared with controls (Table 1). 3 Together with the results of the VIGOR trial, there was indeed replication in an independent, randomized, controlled trial of an excess of the cardinal cardiovascular end point of death, heart attack, and stroke. The excess of these events occurred within six weeks in Study 090, and the event curves were divergent by 30 days in the VIGOR trial. Not only was Study 090 never published and available solely through a subsequent FDA memorandum,3 but the data presented in the VIGOR article also suffered from errors of omission, along with erroneous information and lack of completeness.2 In Table 1, the data from the FDA report3 for VIGOR are presented. In the VIGOR article, the actual deaths were not reported, but it is stated in the article in three places that the overall mortality rate was similar in the two groups. The heart-attack rate for rofecoxib was erroneous. More than half of the thrombotic events are not presented in the VIGOR article but appear in the FDA report.3
Unfortunately, although my colleagues and I called for dedicated cardiovascular trials in 2001,4 Merck never initiated one and maintains that its trials conducted to seek new medical indications were determining cardiovascular risk. There was ample evidence that COX-2 inhibitors improve endothelial function and lower inflammatory proteins, such as C-reactive protein,5 justifying the benefit-and-risk assessment of these drugs directly in patients with established cardiovascular disease.
We indeed acknowledged that naproxen may have a cardioprotective effect,5 but the magnitude of the effect would be unlikely to exceed that of aspirin, at a 25 percent reduction of heart attacks. Instead, in the VIGOR trial, there was a 500 percent increase in heart attacks. This makes any "naproxen hypothesis" of cardioprotection mathematically indefensible.
Drs. Villalba and Witter are incorrect in suggesting that the FDA cannot influence post-marketing clinical trials that a sponsor performs. Their claim that the "50 percent decreased risk of gastroduodenal perforations" outweighed the cardiovascular risk in the VIGOR trial is not substantiated by the data. There were no differences in the rate of perforation (0.1 percent in both the rofecoxib and naproxen groups).2 It is hard to imagine that the small protection from gastric or duodenal ulcers in the VIGOR trial is an acceptable trade-off as compared with twice the incidence of death, heart attacks, and strokes. Indeed, Dr. Targum, the FDA reviewer of the VIGOR, wrote in her report, in reference to the cardiovascular findings, "This analysis could lead one to conclude that naproxen, with a 51 percent reduction compared to rofecoxib, would be the preferred drug."3 It took 14 months after the expert FDA panel convened, from February 2001 to April 2002, to change minimally the cardiovascular safety information for rofecoxib in the package insert. After their cumulative meta-analysis, Juni et al. correctly stated, "Our findings indicate that rofecoxib should have been withdrawn several years earlier."
Topol, NEJM Volume 351:2875-2878 December 30, 2004 Number 27
(reply to letters)
"When Merck announced the voluntary withdrawal of its acute-pain medication, rofecoxib (Vioxx), on September 30, 2004, its stock price collapsed, wiping out more than a quarter of the company's market value in a single day. A second blow came on November 1, when an article in the Wall Street Journal suggested that Merck had known about elevated risks of heart attack and stroke for years and had tried to intimidate scientists who questioned the safety of rofecoxib. On that day, Merck's stock price fell by another 10 percent. The recall came as a shock not only to patients and their physicians; the debacle was also terrible news for those awaiting new medical therapies, because the dramatic financial consequences of withdrawing rofecoxib might well hamper the ability of a major pharmaceutical company to invest in new drugs that could help patients in the future"
--Oberholzer-Gee. NEJM Volume 351:2147-2149 November 18, 2004 Number 21, speaking to the disincentives to do the safest thing in a punitive stock market...
And I'm sad to say, that if merck had been forthcoming on the risks of their drugs, they would not have been dinged like this. They failed to prevent injuries and deaths due to their drugs, for profit. For the shareholders you're worried about, in fact. Lemme dig up some examples.... but as i said before, they are responsible for an increment of heart attacks. Across a nation of 260 million that's a big deal! In any lawsuit where a patient taking vioxx whose heart attack risk rse, say, 2%, merck is to blame for 2/102nds of that death. That's the fraction of lost wages they should pay, too....