As Vioxx-Gate Unfolds, Merck's Corporate Profits Over Safety Mind-Set May Finally Be Its UndoingDec 9, 2005 | www.Newsinferno.com
The Vioxx debacle is but the latest example of a corporation placing profits ahead of sound business judgment. Unfortunately, unlike other corporate catastrophes where the ultimate loss was one of money alone (as serious as that may be), this excursion into avoidance left a trail of injured and dead consumers whose only crime was to believe in the integrity of the pharmaceutical industry.
This sad episode, which is still a long way from being resolved, has seen a giant corporation place profits over safety in order to engineer what has been called the ultimate “triumph of marketing over science.” After all, what were a few thousand ruined lives compared to the opportunity to market a “blockbuster” drug capable of generating billons of dollars in annual sales?
Merck has been willing to say just about anything to have the public (and now, juries) believe that the entire Vioxx saga has been a sterling example of a drug company doing everything possible to look out for the public’s wellbeing while developing, testing, and marketing a prescription medication.
Of course, the public has gradually learned that a mountain of damaging evidence existed from 1996 to 2004 that repeated pointed to Vioxx (and the COX-2 inhibitor class of drugs) as nothing more than “super aspirins” with an unacceptable high risk of dangerous cardiovascular side-effects.
Merck’s insistence that its self-serving interpretation of the facts alone is correct and that everyone who chooses instead to believe the indisputable evidence is simply wrong call to mind that old country-western song, “Who are you gonna believe, me or your lying eyes?”
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.
In the end, it will be Merck’s corporate mind-set and not Vioxx that will bring the giant to its knees. Despite every indication that pursuing the “we did nothing wrong” path was not the way to go, the intoxicating effect produced by Vioxx’ multi-million dollar annual sales, lead Merck to ignore the warning signs that it was going about the whole process of marketing the drug in the wrong way.
Merck was apparently trying to “fool all of the people all of the time” when the pharmaceutical giant would have done a whole lot better following the maxim, “honesty is the best policy.”
How does a drug that wasn’t really as dangerous as many other medications that remain on the market reach the point of being:(1) pulled off the market by its manufacturer;(2) the subject of almost 8,000 personal injury lawsuits;(3) on the wrong end of a $253 million verdict;(4) investigated by Congress; and(5) compared to “Watergate”?
The story could have had a far different (and much more favorable) ending for both Merck and the patients who relied on Vioxx had the company’s approach been to level with the FDA and the public from the beginning. Everyone would have known the risks and intelligent decisions could have been made with respect to labeling and prescribing from day one.
The fault lies with Merck and the mind-set that has driven the pharmaceutical industry for the past several years. This includes: (1) rushing potential blockbuster drugs to market as quickly as possible under the “fast track” approval process; (2) minimizing the significance of negative clinical trial results; (3) avoiding longitudinal trials with large subject groups which are far more reliable but which tend to delay the approval process; (4) spending more money on slick direct-to-consumer (DTC) advertising campaigns than on research and development; and (5) training sales representatives to use pre-planned marketing tactics to convince doctors, skeptical of a drugs safety record, that they should prescribe it as often as possible; and (6) making advertising claims that are improper and run afoul of FDA guidelines.
Apparently, in the case of Vioxx, there may have been one more troublesome piece to the puzzle, however, and that was the alleged efforts to conceal negative clinical data supporting the widely-held belief that Vioxx was, indeed, a drug with significant cardiovascular risks associated with it.
The revelation that damaging information regarding deaths suffered by Vioxx test subjects was improperly excised from study data is both shocking and disturbing. The evidentiary “paper trail” left by Merck now seems minor when compared to the accusations leveled against the company today. In fact, today’s reports make Dr. Eric Topol’s testimony look all the more convincing and trustworthy.
In his 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.
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."
Now, a top editor of the New England Journal of Medicine (NEJM)claims that he was stunned to find out that data linking Vioxx to cardiovascular risk was actually deleted from the VIGOR study his journal published five years ago--and that it appears that Merck researchers may have deleted that data.
According to Dr. Gregory Curfman, executive editor of The Journal: "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."
Soon after Merck pulled Vioxx from the market, editors at the Journal discovered a diskette containing earlier versions of a manuscript for the VIGOR clinical trial that they had published in November 2000.
The early versions of the manuscript contained a blank table entitled "CV events" (cardiovascular). Software time stamps show that the table was deleted two days before the manuscript was submitted to the Journal on May 18, 2000.
Curfman confirmed that: "When you hover the cursor over the editing changes, the identity of the editor pops up, and it just says 'Merck.'"
The editors made no mention of their discovery since they did not know what significance it had at the time. It wasn't clear if the deleted information would have changed the conclusions of the study. The published version of the study did note a slightly higher heart attack rate in patients who took Vioxx compared with those who took naproxen.
On Nov. 21, 2005, however, Curfman was deposed in Boston by lawyers for plaintiffs in one of the Vioxx suits. During the deposition, which also included attorneys for the drugmaker, they showed Curfman an internal Merck document dated July 5, 2000 after the VIGOR manuscript was submitted to the Journal, but well before the study went to press.
That internal document clearly indicated that two Merck authors on the VIGOR study knew of three additional heart attacks among Vioxx patients in the study, which had not been disclosed to the NEJM. The heart attacks occurred in the final five weeks of the trial and in patients at low risk for heart problems.
The lawyers also showed him versions of the manuscript containing the deleted information. This version also revealed more cardiovascular problems potentially connected to Vioxx than those had been discussed in the published study.
The editors of the NEJM had assumed that the VIGOR manuscript they were given only contained limited cardiovascular data since that was all that was available. "It turns out that they had quite a bit more already worked up," Curfman stated. Curfman then spent the next few weeks analyzing all the VIGOR drafts, raw data, and correspondence.
The journal contends that "at least two" of the study's three authors knew of the additional heart attacks for some 4 1/2 months prior to publication. "There was ample time to include the data on these three additional infarctions in the article."
Yesterday, Curfman and two other editors released an editorial on the NEJM’s Web site entitled "Expression of Concern," which calls on the VIGOR authors to submit a correction of the 2000 manuscript. The statement has now challenged the study findings since: "Taken together, these inaccuracies and deletions call into question the integrity of the data on adverse cardiovascular events in this article."
Curfman contacted the study’s lead author, Claire Bombardier of the University of Toronto, to indicate the statement would be published. She told Curfman she would begin working on a correction. Bombardier, however, apparently e-mailed Forbes.com and said that the VIGOR paper appropriately disclosed the data.
Despite Bombardier’s response, Catharine Whiteside, dean of medicine at the University of Toronto, stated that she has yet to talk to Dr. Bombardier and; "In the event that information is brought to light in which we would need to investigate Dr. Bombardier, we would initiate due process."
In an effort at damage control as the first federal Vioxx case has gone into jury deliberations in Houston, Merck disputed the NEJM analysis. "The VIGOR publication, which was peer-reviewed, fairly and accurately described the results of the study as of the prespecified cutoff for analysis. The additional events referred to in the editorial were events that were reported after the prespecified cutoff date and, therefore, these were not included in the primary analysis reported in the article.
"Nevertheless, the additional events were disclosed to the FDA in 2000, presented publicly to the FDA's Advisory Committee in February 2001 and included in numerous press releases subsequently issued by Merck. We also note that these additional events did not materially change any of the conclusions in the article."
Curfman, however, responded; "We're not buying into that."
The accusation by the NEJM that Merck knowingly withheld data on three heart attacks, if true, significantly undermines the VIGOR study results as well as the entire premise upon which Merck has built its defense.
Attorneys involved in the ongoing litigation on behalf of a number of plaintiffs whose cases are still pending believe that this latest revelation must be brought to the court’s attention if Merck prevails since it could clearly change the result by greatly enhancing the plaintiffs’ position and seriously undermining Merck’s defense that has been forthcoming at all times with respect to Vioxx-related data.
It would certainly call into question the study’s findings, which have been a central element in the three trials, as well as the testimony of one of the study's authors, Dr. Alise Reicin, Merck's vice president for clinical research, who claimed the company never misled doctors or the public about Vioxx studies.
FDA researcher and whistleblower David Graham, who last year accused his agency of trying to block publication of a critical study he did on the drug, called Merck's argument "a fig leaf to hide behind. What other pieces of information might have been withheld?" What other information, indeed.