Throughout the scientific (and now legal) battle surrounding that has become little more than a debacle, Merck has used its enormous wealth and influence to fashion a defense for itself with respect to its ill-fated COX-2 inhibitor, Vioxx.
That defense has taken the form of treating a mountain of negative (and long-standing) evidence as if it was just the opposite. Scientific studies that clearly warned of the potentially serious cardiovascular risks Vioxx posed were either ignored by Merck or given imaginative interpretations so as to preserve an aura of safety around the drug.
Clever (and quite expensive) marketing campaigns downplayed or even ignored the significant risks Vioxx posed to the millions of consumers who trusted the drug to alleviate their pain while sales representatives were trained to dodge difficult questions and safety concerns raised by doctors.
Even when Merck could no longer keep Vioxx on the market, the company attempted to make the best out of a very bad situation by making it appear as if its voluntary withdrawal of Vioxx was motivated by concern for the public. The evidence does not support that position.
Most business experts regarded Merck’s decision as a purely financial consideration on the part of Merck which stood to lose $700 to $750 million in the fourth quarter of 2004 alone. The lawsuits were piling up and some of the cases were close to trial. No one analyzing the situation (except Merck itself) attributed the move to any sudden pangs of conscience on the part of Merck’s CEO or Board of Directors.
In fact, the evidence showed that Merck was still solely interested in widening the market for COX-2 inhibitors. The very study (APPROVe trial) which led to Merck’s decision to voluntarily withdraw VIOXX from the market was really aimed at gaining FDA approval for Vioxx as a treatment for preventing the recurrence of colon polyps. It had nothing to do with safety and everything to do with gaining approval from the FDA for even wider use of Vioxx.
In Merck’s open letter to “VIOXX Patients,” which appeared in newspapers across the country, Merck claimed that the study was “a clinical trial to better understand the safety profile of VIOXX.” It was actually no such thing. In fact, had the 3-year study not been halted abruptly on September 24, 2004 by the Data Safety Monitoring Board for safety reasons, Vioxx would probably still be on the market.
Finally, even though Vioxx was finally exposed for what it was; a dangerous drug, Merck stated in its press release that the drug was being withdrawn despite Merck’s belief that “it would have been possible to continue to market Vioxx with labeling that would incorporate these new data.” Thus, Merck would still have kept Vioxx on the market had it not met with the FDA on September 28 and been forced to confront the disastrous results of its own study.
We have set forth the years of negative evidence on a number of occasions over the past several months along with the detailed time-line that demonstrates Vioxx was known to have potentially serious cardiovascular side-effects from as far back as 1996.
All of this, however, is of little consequence unless it can be tied together in a coherent manner and presented to the juries that will ultimately decide the issue of Merck’s liability for the injuries and deaths allegedly caused by its drug.
This could only be done by an expert who has: (1) intimate knowledge of the scientific research involving Vioxx; (2) the expert qualifications needed to interpret that data; and (3) first-hand experience with Merck’s corporate mindset which was to preserve Vioxx’ as a billion-dollar blockbuster drug.
On Saturday, the jury in the current Vioxx trial in U.S. District Court in Houston heard precisely that kind of no-nonsense testimony from Dr. Eric Topol, one of the only experts with both the professional credentials and intimate knowledge of the applicable research.
From the beginning of the Vioxx saga the two constants that Merck has feared the most are (1) the paper trail of negative evidence, and (2) Dr. Eric Topol, chairman of cardiovascular medicine at the world-renowned Cleveland Clinic.
Until now, Dr. Topol has been silent, having not been asked to testify at either of the prior state court trials in Texas and New Jersey. As the first federal trial got under way, however, Judge Fallon ruled the jury will be allowed to see a videotaped deposition from Dr. Topol himself.
In that deposition (taken last week), Dr. Topol openly accused Merck of scientific misconduct, misrepresenting facts and endangering patients. He also testified that Merck’s former chief executive complained to a top Cleveland Clinic official about his activities.
In order to understand the significance of Dr. Topol’s entry into the litigation, one must consider the earliest evidence that Vioxx was a potentially dangerous drug and how Dr. Topol was immediately concerned about the cardiovascular risks posed by Vioxx and its COX-2 siblings.
Going back as far as 1996, the evidence is clear and consistent when it comes to the potential risks posed by Vioxx and the other COX-2 inhibitors like Bextra and Celebrex. Many critics believe that included withholding critical and damaging data and other information from the FDA and the public.
On Nov. 21, 1996, a Memo by a Merck official shows the company wrestling with the issue of Vioxx’ (Rofecoxib) involvement in increased cardiovascular events. At this early date, Merck avoided a trial to prove Vioxx gentler on the stomach than older painkillers because in such a trial, "there is a substantial chance that significantly higher rates" of cardiovascular problems would be seen in the Vioxx group.
On February 25, 1997, an internal Merck e-mail warned that if a proposed Merck trial was carried out "you will get more thrombotic events" – more blood clots "and kill [the] drug."
In response, Alise Reicin, later a Merck vice president for clinical research said in an e-mail that the company was in a "no-win situation." She went on to propose that people with high risk of cardiovascular problems be kept out of the study so the difference in the rate of cardiovascular problems between the Vioxx patients and the others "would not be evident."
On November 18, 1999 a meeting of the Data and Safety Monitoring Board (DSMB) discussed concerns over the "excess deaths and cardiovascular adverse experiences" that was observed in the group using Vioxx as compared to the patients taking Naproxen.
On March 9, 2000, Merck’s research chief, Edward Scolnick, e-mailed colleagues that the cardiovascular events "are clearly there" and stated "it is a shame but it is a low incidence and it is mechanism based as we worried it was."
Worried about the affect on Vioxx, Dr. Scolnick wrote that he wanted other data available before the results were presented publicly, so "it is clear to the world that this" was an effect of the entire Cox-2 class, not just Vioxx.
That same month, however, the company’s public statements continued to reject the link between Vioxx and increased intrinsic risk. Merck made no mention that the study found a "mechanism based" connection between Vioxx and the statistically significant increase in cardiovascular events.
The VIGOR study (VIGOR – Vioxx® Gastrointestinal Outcomes Research) sponsored by Merck was submitted to the FDA in June 2000. The study was primarily designed to look at the effects of Vioxx on side effects such as stomach ulcers and bleeding.
While the study showed that patients taking Vioxx had fewer stomach ulcers and bleeding than patients taking another drug, Naproxen, it revealed a statistically significant increase in the number of cardiovascular events (over 100% increase), myocardial infarctions/heart attacks (approx. 400% increase) and strokes in patients who have taken Vioxx compared to those receiving Naproxen.
The VIGOR study was published in the November 2000 issue of the New England Journal of Medicine but did not provide detailed information about other serious cardiovascular complications such as strokes or blood clots.
In February, 2001, a letter by Dr. James Fries, senior professor and medical doctor from Stamford University Medical School to Merck complained about the intimidation by Merck’s investigators including the threatening of the loss of funding because of the school’s discussion of cardio-vascular events associated with Vioxx.
On February 1, 2001, a Memo by Dr. Shari L. Targum, Medical Officer, Division of Cardio-Renal Drug Products of the FDA documented the serious cardiac events and myocardial infarctions and related deaths for participants in the study who were using Vioxx.
She also discussed the November 18, 1999 meeting of the Data and Safety Monitoring Board (DSMB) where concern was raised over the "excess deaths and cardiovascular adverse experiences" in the group using Vioxx as compared to the patients taking Naproxen.
On February 8, 2001, the FDA Arthritis Advisory Committee Meeting discusses the VIGOR study expressed concern over the unexpected findings of cardiovascular risks and myocardial infarctions associated with the use of Vioxx that was disclosed in the VIGOR study. Merck eventually was required (April, 2002) to add some of the data as to cardiovascular events to their label.
On August 22, 2001, the concerns arising out of the VIGOR study were crystallized by Drs. Debabrata Mukherjee, Steven Nissen, and Eric Topol in Journal of the American Medical Association (JAMA) in their review paper specifically highlighting the cardiovascular side-effect profile of COX-2 inhibitors. The doctors indicated that Vioxx was linked to a 200% increase in blood clots, heart attacks and strokes based on their review of previous clinical trials.
In August of 2002, Dr. Topol and Dr. Falk, a Cleveland Clinic gastroenterologist, published an editorial in The Lancet, encouraging further warnings and labeling regarding the cardiovascular effects of Cox-2 drugs. Even following these warnings, and in the face of mounting evidence for the cardiovascular side-effects of Vioxx, aggressive direct-to-consumer marketing of Vioxx continued unabated.
Immediately after Vioxx was pulled from the market, Dr. Topol, Chief of Cardiovascular Medicine and Chief Academic Officer of the Cleveland Clinic, who was a co-author of the VIGOR Study discussed above told the Washington Post (10/1/04) that Merck’s action was “the right decision about three years too late. This is the sort of thing that Merck should have studied earlier, but they were too busy refuting the warning signs.”
In mid-October 2004, following his harsh criticisms of Merck in the New York Times and the New England Journal of Medicine, Dr. Topol was told by a colleague at the Cleveland Clinic, Richard Rudick, the director of clinical research, that Raymond Gilmartin, the former CEO and chairman of Merck, called a Cleveland Clinic board of trustees member to complain about him and his negative attitude toward Merck.
From courtroom accounts, Dr. Topol’s three-hour videotaped deposition was compelling, highly credible, and extremely damaging to Merck’s position.
Dr Topol testified that the drug maker of engaging in scientific misconduct, suppressing clinical evidence and stifling medical discourse as it promoted the painkiller. He stated that Vioxx could cause heart attacks anytime after a patient began taking it, and that its risks were apparent as early as 1999, when the drug was approved.
He accused Merck of engaging in scientific misconduct, suppressing clinical evidence and stifling medical discourse as it promoted the painkiller. He also called certain aspects of Merck’s behavior "repulsive" and "appalling."
Dr. Topol testified that Merck officials tried to pressure him into not publishing a critical article about Vioxx in 2001 by telling him he’d be "embarrassed" if he did so.
That article strongly cautioned against its use because it may cause heart attacks and strokes and urged Merck officials to conduct specific tests analyzing those risks.
When shown for the first time internal company documents suggesting that Merck officials sought to water down his article, Dr. Topol was clearly astonished by the company’s actions. "I’m actually appalled by this," said Topol.
Topol first became concerned about Vioxx in February 2001 when the FDA reviewed Merck’s VIGOR study that showed patients who took Vioxx had five times as many cardiac events as patients who took naproxen. Topol and two colleagues had serious doubts about Merck’s position that the reason for the disparity wasn’t that Vioxx caused heart trouble, but that naproxen protected against it.
For that to be true, one would have to believe that naproxen had many times the protective heart benefits as aspirin, but there was no data to support that. "I was significantly concerned that there was a medicine that was getting widespread use … and could something be wrong? That was a significant concern."
After Topol and his colleagues analyzed the VIGOR study and other data, they drafted their article and sent it to Merck expecting the company might be able to reconcile several major discrepancies between its data and that kept in the FDA database. It was then that Dr. Topol got a visit from Alise Reicin, a Merck researcher and chairman of its Vioxx Commercialization Committee.
It was at that meeting he was told we had gotten it wrong and would be embarrassed if we published the paper. "I thought it was harsh," he said.
Although Reicin said Merck was considering doing a heart risk study like the one Topol was urging, “I didn’t get the sense that Dr. Reicin was serious about it."
Dr. Topol is under subpoena and is not being compensated for his testimony.
Topol was shown copies of a draft of his article where he had noted that the VIGOR study revealed Vioxx patients had five times as many heart attacks and strokes. Merck officials wrote in parentheses, "we prefer to flip the data" to say naproxen patients had five times fewer.
Where Topol concluded patients should be cautious and a specific heart risk study be launched, Merck officials wrote: "Conclusion needs to be toned down." Elsewhere Merck wrote that the paper should be "neutralized" and reflect more of the "Merck perspective."
Many legal analysts believe it will be virtually impossible for Merck’s attorneys to “neutralize” Dr. Topol any longer. He has finally been given an opportunity to express his expert opinions in a forum where they will be weighed by members of the very public he has sought to protect all along. He appears to have made the most of that opportunity.