Most Recent Vioxx Study Shows Merck Will Need More Than Courtroom Theatrics to Win Once the More Difficult Trials Start
Litigation Experts See Mass of Evidence against Merck as Virtually Insurmountable When the Company Defends Long-Use and Death Cases
Another day, another negative study involving COX-2 inhibitors; the class of drugs that includes Vioxx, Celebrex, Bextra, and other NSAIDs. All along, critics of these drugs saw them as dangerous, unnecessary, overpriced, “super aspirins” that would ultimately wind up injuring and killing people.
Merck and Pfizer, however, saw the drugs as potential blockbusters and, in what has been called the ultimate triumph of marketing over science, turned Vioxx, Celebrex, and Bextra into multi-billion dollar cash cows.
The latest study from Bispebjerg University Hospital in Copenhagen, which was funded by the Danish Heart Foundation and the Danish Pharmaceutical Association, has found that COX-2 inhibitors increase the risk of death among patients who have already survived a previous heart attack, especially when taken in high doses. The data was released yesterday at the American Heart Association conference in Dallas, Texas.
The study of 58,000 Danish patients showed that heat disease patients taking 25 mg of Vioxx per day were five times as likely to die as patients not taking the drug. The figure for Celebrex was 4.2 times for patients taking a 200 mg daily dose.
While this latest study is “a cause for concern” according to lead researcher Dr. Gunnar Gislason, it really isn’t any different in theme than all of the negative evidence that sits right now in litigation files involving the most serious of the 7,000 or so remaining cases against Merck.
This is significant because Judge Carol Higbee, who controls the progress of some 3,500 Vioxx cases pending in New Jersey, has now ordered that the next 10 trials involve plaintiffs who took Vioxx for at least 18 months.
Merck has already acknowledged the existence of an increased risk of heart attacks in long-term Vioxx users and even pulled the drug from the market for that very reason. Thus, legal analysts see Judge Higbee’s ruling as one that will make it virtually impossible for Merck to duplicate its recent victory where there were many factors in Merck’s favor.
Thus, a number of litigation attorneys we spoke with late last evening were of the opinion that this latest study merely confirms, yet again, the fact that Vioxx was always a dangerous drug regardless of what Merck wanted the public to believe and despite its approval by the FDA. In fact, each attorney said basically the same thing – “the second trial was a lucky break for Merck because it had a number of weaknesses in it as far as the plaintiff’s case was concerned.” The cases Judge Higbee now wants tried will have none of those weaknesses and that will only accentuate the overwhelming nature of the negative evidence.
In the recent New Jersey case that Merck won, there were a number of factors which favored Merck including: the plaintiff only took Vioxx for two months before his heart attack; he survived his injuries and actually appeared to be in surprisingly good health at trial despite the injuries he claimed to have suffered; plaintiff had a number of serious (non-Vioxx) risk factors that could have caused his heart attack; and Merck’s attorney made every effort to make it appear as if the trial judge was being unfair to the drugmaker with her rulings. The jury also was not enthralled by plaintiff’s trial attorney.
The negative evidence being referred to by those familiar with the Vioxx litigation is voluminous and quite damaging to say the least. It dates back to 1996 and never indicated a single reason why Vioxx or any of the COX-2 inhibitors should have been approved or allowed to be marketed in so cavalier a fashion as they were.
The Unbroken Chain of Damaging Evidence
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.
Nov. 21, 1996 – Memo by a Merck official shows the company wrestling with the issue of Vioxx's (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.
February 25, 1997 – Internal Merck e-mail warns 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."
The FDA approved Vioxx on May 20, 1999 for the use for the management of acute pain in adults and for relief of the signs and symptoms of osteoarthritis. (The original safety database included approximately 5,000 patients on Vioxx and did not, according to Merck, show an increased risk of heart attack or stroke).
November 18, 1999 – Meeting of the Data and Safety Monitoring Board (DSMB) discusses concerns over the "excess deaths and cardiovascular adverse experiences" that was observed in the group using Vioxx as compared to the patients taking Naproxen.
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.
March 17, 2000 – Merck updated the label by adding reported in the "adverse events" section of the label certain "cardiovascular" reports.
June of 2000 – Information presented at the European United League against Rheumatism, (Merck is a member and a corporate sponsor of this organization) demonstrated a statistically significant increase in hypertension and myocardial infarction.
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.
February 1, 2001 – 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.
February 8, 2001 – 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.
February 2001 – Letter by Dr. James Fries, senior professor and medical doctor from Stamford University Medical School to Merck complaining 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.
2001 – The concerns arising out of the VIGOR study were crystallized by Debabrata Mukherjee, Steven Nissen, and Eric Topol in JAMA in their review paper specifically highlighting the cardiovascular side-effect profile of COX-2 inhibitors.
May 22, 2001 – Despite the mounting evidence of the strong association of Vioxx to strokes and heart attacks, Merck issued a press release entitled "Merck Confirms Favorable Cardiovascular Safety Profile of Vioxx", claiming Vioxx has a "… favorable cardiovascular safety profile"
June 16, 2001 – Merck issued another press release (released in Europe), entitled "Vioxx Similar to Placebo and Three (3) Widely Prescribed NSAID's Regarding Cardiovascular Events".
July 11, 2001 , Merck modified the package insert for Vioxx.
August 22, 2001 – Study published in Journal of the American Medical Association by Drs. Mukherjee, Nissen, and Topol, researchers from the Cleveland Clinic, indicated that Vioxx was linked to a 200% increase in blood clots, heart attacks and strokes based on their review of previous clinical trials.
September 2001, the American Heart Association, the National Stroke Association and the Arthritis Foundation asked Merck to test whether Vioxx increased the risk of heart attack and stroke.
After it reviewed all of its Vioxx studies, Merck claimed there was no evidence that, in comparison with other NSAIDs, the drug increased the risk of heart problems. Merck (erroneously as it turned out) attributed the difference to a heart-protective effect it said the other drug had.
During this time period, Merck published training materials to be used by their sales rep's, one was entitled "Dodge Ball Vioxx". Each of the 1st 12 pages lists a scenario that maybe posed by a physicians questions or concerns. Each of the last four pages contain a single word in capital letters "DODGE!" clearly indicating that Merck was training its sales reps to "dodge" the tough questions and concerns of the physicians regarding the cardiovascular risks that had started to make its way into publications.
September 17, 2001 – FDA sends Merck a strongly worded "Warning Letter" regarding Merck’s minimizing the potentially serious cardiovascular risks of Vioxx disclosed by the VIGOR trial and promoting Vioxx for unapproved uses. The letter demanding that Merck discontinue promoting Vioxx to doctors for unofficial uses, found after a review of several of Merck's promotional conference calls and sales pitches, that the promotions by Merck "are false, lacking in fair balance, or otherwise in misleading in violation of the Federal Food, Drug, and Cosmetic Act (the Act) and applicable regulations." It also required Merck to send letters about the deception to the medical community.
April 11, 2002 – FDA instructed Merck to include in the package insert certain precautions based on results of the VIGOR studies regarding a higher cumulative rate of serious cardiovascular thromboembolic adverse events (such as heart attacks, angina pectoris, and peripheral vascular events).
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.
April 14, 2004 – Study sponsored and conducted by Merck and Harvard Medical School and published in the journal Circulation, found an elevated risk of acute myocardial infarction associated with Vioxx but not with Celebrex. The risk was statistically significant in persons taking greater than 25 mg of Vioxx, was elevated during the first 90 days of exposure but not thereafter. These results were observed consistently in relation to several reference groups studied. What was especially noteworthy was that the elevation of relative risk was similar when Vioxx was compared with patients not taking any NSAID (Non-steroidal anti-inflammatory drugs), naproxen (e.g. Naprosyn, Aleve) or ibuprofen (e.g. Advil, Nuprin, Motrin).
Merck asked the researchers to delete or tone down the part of the statement about this no-painkiller group, but the researchers refused, according to Daniel Solomon, a Brigham and Women's Hospital - Harvard professor who was the lead author. "We made a decision that we should let the science rule the day," he says (WSJ, 11/01/04, page A1).
Just before the paper was published in Circulation (the journal of the American Heart Association), dated May 4, 2004, Merck removed the name of a key researcher, Carolyn C. Cunnuscio, from the study. She was employed by Merck and had worked on the study. Upon learning that Merck had removed their employee's name from the Circulation article, the current JAMA editor, Catherine DeAngelis expressed her disappointment, and rounded-off her comments by saying "Aren't they seeking truth?"
May 14, 2002 – E-mail from Ann Trontell, FDA deputy drug safety director, warned colleagues that a Merck official had reminded her that "there had been an agreement that Merck would be informed prior to any FDA publication about one of their drug products".
August 12 2004 – Trontell wrote in an e-mail to another official that the study's recommendation was "unnecessary and particularly problematic" because FDA funded the study and Graham (David Graham, an Associate Director for Science in FDA Drug Center's Office of Drug Safety and the FDA officer in charge of the report) also might be asked to present "alternative FDA opinion" on the drug, She added that Merck should be notified about the study results before they became public "so they can be prepared for extensive media attention that this will likely provoke" .
August 13, 2004 – John Jenkins, director of FDA's office of new drugs, wrote that Graham's conclusion uses "pretty strong language since, to my knowledge, FDA is not contemplating such a warning or labeling." Jenkins suggested that the conclusion be changed to read, "[T]his and other studies suggest an increased risk of AMI (acute myocardial infarction, or heart attack) with Vioxx use and should be considered by prescribers when making individual treatment decisions"
Shortly thereafter, Graham responded in an e-mail response to supervisors, "I've gone about as far as I can without compromising my deeply held conclusions about this safety question. I've also shared with you the perspectives of my co-authors, and I think it's safe to say they share these same conclusions"
August 25, 2004 – At a medical/pharmaceutical conference in Bordeaux, France, at the annual meeting of The International Society for Pharmacoepidemiology, Graham presented new data from a trial sponsored by the Food and Drug Administration that indicated patients administered Vioxx 25 mg or more per day have a risk of experiencing an acute myocardial infarction (AMI) or sudden cardiac death that is more than three times that of remote non-steroidal anti-inflammatory drug users.
Researchers analyzed data from a subset of Kaiser Permanente patients, aged 18 to 84 years, who were treated with a COX-2-selective or NSAID (Non-steroidal anti-inflammatory drugs) between Jan. 1, 1999, and Dec. 31, 2001. In the trial, approximately 1.4 million patients contributed 2.3 million person-years of observation time. Results showed that treatment with Vioxx 25 mg/day or more conferred a 3.15-fold greater risk of AMI or sudden cardiac death compared with "remote use of any NSAID." Such a risk was also observed with lower doses of Vioxx (less than 25 mg/d), but did not achieve statistical significance.
September 8, 2004 – Vioxx received approval from the FDA for the relief of the signs and symptoms of Juvenile Rheumatoid Arthritis (JRA) in children two years and older and who weigh at least 22 pounds.
September 30th, 2004 – Sudden global withdrawal of Vioxx during the APPROVe study (Adenomatous Polyp Prevention Vioxx®) which was a multi-centre, randomized, placebo-controlled, double-blind study investigating the effects of Vioxx on the recurrence of neoplastic large bowel polyps in 2600 patients with a previous history of colorectal adenoma. The study participants were screened so that anyone with a history of heart disease was screened out.
On September 14, 2004, the Data and Safety Monitoring Board received the data that eventually lead to the September 30th withdrawal. The polyp study was stopped prematurely on the suggestion of the Data and Safety Monitoring Board and a Merck statistician (James Neaton) after the investigators, who had access to all of the data, found that after 18 months treatment, patients taking Vioxx had twice the risk of a myocardial infarction compared with those receiving placebo.
September 17, 2004 – Merck statistician and the four safety committee members had a conference call with John Baron who was the principal investigator of the polyp study and other Merck officials. After the Merck officials and Baron left the call, the four safety committee members agreed that the study had to be stopped. Neaton then called John Baron and explained to him the committee's decision. After reviewing the data that the decision was based on, Baron concurred.
Baron then took the next week to meet with the people at Merck including the steering committee, to explain to them the decision that both the committee and he arrived at, that is halting the polyp trial.
September 23, 2004 –The full steering committee agreed to the halting of the polyp trial. Baron then advised Merck that same day that Vioxx presented an unacceptable risk of a cardiovascular event.
Baron spent the next few days presenting the data and the conclusions to other experts in and outside of Merck. Merck also spent the next few days reviewing all of the data from the polyp study.
September 27, 2004 – Ranking officers at Merck decided that Vioxx needed to be withdrawn. However, the decision was made to take this decision to the board of directors.
Merck's board of directors met on September 28. About this time, Merck notified the FDA that they needed to have an emergency meeting with them that afternoon informing them of Merck's decision to withdraw the drug.
September 29, 2004 – Merck informed its international affiliates of the decision and asked them to withhold informing the regulators in their jurisdiction until the information was made public.
September 30, 2004 – Merck & Co., Inc. announced a voluntary withdrawal of the arthritis and pain relief drug from the worldwide drug market. Merck's action was not ordered by the U.S. Food and Drug Administration (FDA), but was initiated by Merck based on its own findings from the clinical trial.
Senate Finance Committee Chair Charles Grassley (R-Iowa) started an investigation into the FDA. On October 7, Grassley compared Graham's experience to that of Andrew Mosholder, another FDA scientist whose research on the link between antidepressants and suicidality in children faced from superiors at the agency. "Dr. Graham described an environment where he was 'ostracized,' 'subjected to veiled threats' and 'intimidation,'" Grassley said in a statement after committee investigators interviewed the researcher. He added, "Merck knew it had trouble on its hands and took action. At the same time, instead of acting as a public watchdog, [FDA] was busy challenging its own expert and calling his work 'scientific rumor.'"
The Senate Finance Committee is one of three congressional committees examining FDA's actions. In addition, the Government Accountability Office has expanded its investigation of FDA's conduct in regard to Mosholder and the risks of antidepressants to include its handling of Vioxx studies.
November 2, 2004 – FDA posted an abridged version of study conducted by Dr. David J. Graham, associate director for science in the FDA's office of drug safety. The report, dated September 30, 2004 (the same day Merck withdrew Vioxx from the market) builds upon research that he presented at a medical conference in France in late August (referred to above). "Rofecoxib [Vioxx] increases the risk of serious coronary heart disease as defined by acute myocardial infarction [heart attack] and sudden cardiac death,"
Graham's report said. Rofecoxib is the scientific name for Vioxx. Graham defined a high dose of Vioxx as more than 25 milligrams; a standard dose is equal to or less than 25 milligrams. The study, posted Tuesday, says the recently withdrawn Vioxx increased by 3.7-fold the risk of "serious coronary heart disease" when compared to Pfizer's Celebrex. The study also says a standard dose of Vioxx increased the cardiovascular risk by 1.5 times over Celebrex. "The population impact of rofecoxib's increased risk is great because of the widespread exposure to the drug," said Graham.
November 5, 2004 , a major study, published in The Lancet, pooled data from more than 25,000 patients who participated in 18 clinical trials and 11 observational studies all conducted before 2001. The study demonstrated that patients taking Vioxx had 2.3 times the risk of heart attack as those prescribed placebos or other NSAIDs.
In addition, the researchers found an increased risk of myocardial infarction involving both short-term and long-term usage concluding that patients taking Vioxx for only a few months were also at risk.
The researchers specifically refuted Merck's position that there is no excess risk in the first 18 months of using Vioxx . In addition, the researchers also refuted Merck's contention that cardio-vascular involvement was dose-dependent. As to Merck's contention that in their VIGOR Study, Naproxen was cardio-protective and, therefore, influenced the outcome, these researchers found that if such evidence does exist, its effect is so small that it is not justified to claim Naproxen as a factor in the findings of the VIGOR Study.
In concluding their findings, the researchers stated that "If Merck's statement in their recent press release that 'given the availability of alternative therapies, and the questions raised by the data, we conclude that a voluntary withdrawal is the responsible course to take.' was appropriate in September, 2004, then the same statement could and should have been made several years earlier, when the data summarized here first became available. Instead, Merck continued to market the safety of Rofecoxib. This clearly demonstrated that Merck had, by the end of 2000, sufficient statistically significant information that required the immediate withdrawal of Vioxx from its world-wide market.”
Accompanying the study published in The Lancet on November 5, 2004 was an editorial that was even more damning than the study. Referring to the findings of the study, the editorial states "This discovery points to astonishing failures in Merck's internal systems of post marketing surveillance, as well as to lethal weaknesses in the Food and Drug Administration's Regulatory Oversight . . . The evidence showing that Vioxx caused significant adverse events was apparent well before data from the APPROVe trial triggered Merck's overdue intervention. This week's report by Peter Juni and colleagues will add significant weight to on-going litigation by patients who believe they were harmed by this drug."
The editorial went on to find ". . . the FDA tried to shore up its tarnished reputation by posting on its website an early version of a recently completed observational study into the safety of Vioxx. The report comes with a warning that it has 'not been fully evaluated by the FDA and may not reflect the official views of the agency'. The FDA investigation estimated that over 27,000 excess cases of acute myocardial infarction and sudden cardiac death occurred in the USA between 1999 and 2003. 'These cases' they write, 'would have been avoided had celecoxib been used instead of Rofecoxib'. . . It is unclear why the FDA could not have waited for the fully evaluated report to have been scrutinized, revised, and published according to the norms of scientific peer review. Bypassing independent peer review smacks of panic in the FDA, which is under intense reputational pressure. And, yet, its decision to try to undermine the integrity of its work shows, that the agency's senior management is more concerned with external appearance than rigorous science."
Finally, the editorial concludes "… with Vioxx, Merck and the FDA acted out of ruthless short-sighted and irresponsible self-interest." This is the most condemning editorial in a well-respected medical journal that most observers have ever seen.
It also turns out that Vioxx, despite the slick TV and magazine ads, has not been shown to be significantly more effective than the much less expensive non-prescription anti-inflammatories such as Tylenol and Advil.
Merck Withdrew Vioxx from the Market for Purely Economic Reasons
Although Merck 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 have little doubt that the removal of Vioxx from the market was anything but 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.
Corporate analysts who commented on Merck’s action saw it as a sound business move under the circumstances. They did not attribute it 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 deeply interested in widening the market for COX-2 inhibitors. That evidence included the following:
The 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 by the Data Safety Monitoring Board for safety reasons, Vioxx would probably still be on the market.
Merck had already developed a new COX-2 pain reliever called Arcoxia which was being marketed in 47 countries and for which Merck expected FDA approval in the near future. While Arcoxia was not yet the billion dollar drug Vioxx was, it is clear that Vioxx was well on the way to being replaced when it was pulled from 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.
Most experts who are familiar with the history of Vioxx from either a medical or business perspective were not surprised by Merck’s sudden withdrawal of the drug from the market. The only surprise any of these experts seems to have is why it took so long for it to happen.
Dr. Sidney Wolfe of Public Citizen was quoted in the San Francisco Chronicle ( 10/1/04). He stated: “This family of drugs, the COX-2 inhibitors, once referred to as ‘super aspirins,’ are turning out to be more like super disasters.”
Dr. Eric Topol, Chief of Cardiovascular Medicine and Chief Academic Officer of the Cleveland Clinic, was a co-author of the VIGOR Study discussed above. His comment to the Washington Post ( 10/1/04) was 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.”
The Wall Street Journal (10/1/04, page B1) noted that “Merck also may face more criticism for having strenuously denied for several years suggestions by outside researchers that use of Vioxx led to heart problems. The company even published its own studies suggesting the drug wasn’t causing harm.”
The Disturbing Senate Testimony of FDA Whistleblower David J. Graham, MD, MPH
Dr. David Graham, an Associate Director for Science and Medicine in the FDA’s Office of Drug Safety is a scientist with impeccable credentials as well as a man of unchallenged integrity. He has devoted his entire professional life to making a real difference in the cause of patient safety.
Although he fought long and hard against Vioxx based upon the overwhelming evidence of its serious cardiovascular risks, he was little more than “a voice crying in the wilderness” who received no support within the FDA. He was also the target of Merck’s scorn since he posed a threat to its corporate balance sheet.
Once Vioxx was pulled from the market, however, Dr. Graham could no longer be ignored nor could his medical opinions be marginalized by his detractors. Suddenly, those in authority wanted to hear from this public servant turned whistleblower.
On November 18, 2004, Dr. Graham appeared before the Senate Finance Committee Chaired by Sen. Charles Grassley (R-Iowa). Dr. Graham delivered compelling and often shocking testimony ( http://finance.senate.gov/hearings/testimony/2004test/111804dgtest.pdf) concerning the very real dangers of Vioxx and the unconscionable delay in pulling the drug from the market which has exposed the public to a degree of risk never before seen with respect to any prescription drug including sulfanilamide and thalidomide.
Dr. Graham presented the evidence against Vioxx in painstaking detail. He also set forth the disturbing facts surrounding the FDA’s efforts to suppress his research, censor and alter his scientific and medical findings and conclusions, and discredit his work.
Probably the most striking portion of Dr. Graham’s testimony involved his carefully formulated opinion that (even using Merck’s own VIGOR and APPROVe trials) some 88,000 to 139,000 Americans alone have already suffered heart attacks as a result of taking Vioxx and of that number, “30-40% probably died.” (Note that Dr. Eric Topol estimated the heart attack figure to be up to 160,000).
Dr. Graham put these astounding figures in perspective by using various examples. Most compelling, however, was the following statement:
“Imagine that instead of a serious side effect of a widely prescribed prescription drug, we were talking about jetliners…If there were an average of 150 to 200 people on an aircraft, this range of 88,000 to 138,000 would be the rough equivalent of 500 to 900 aircraft dropping from the sky. This translates to 2-4 aircraft every week, week in and week out, for the past 5 years. If you were confronted by this situation, what would be your reaction, what would you want to know and what would you do about it?”
“Even more revealing, a mere 6 weeks before Merck pulled Vioxx from the market, CDER, OND and ODS management did not believe there was an outstanding safety concern with Vioxx. At the same time, 2-4 jumbo jetliners were dropping from the sky every week and no one else at FDA was concerned.”
“At this meeting [Sept. 22, 2005], the reviewing office director asked why had I even thought to study Vioxx and heart attacks because FDA had made its labeling change and nothing more needed to be done. At this meeting a senior manager from ODS labeled our Vioxx study ‘a scientific rumor.’ Eight days later, Merck pulled Vioxx from the market, and jetliners stopped dropping from the sky.”
Merck’s Victory in the Most Recent Trial is of Little Significance
In terms of what Merck’s recent victory means litigation-wise, Merck’s defense team is experienced enough to know it means very little since it is somewhat like trying to stop a tidal wave with a sponge.
Merck would have to win virtually all of the remaining 7,000 (and growing) cases to stave off a financial catastrophe since each negative verdict has the potential of being in the millions of dollars. Even scattered losses for Merck can add up to a financial disaster.
Is such a possibility realistic? Not even Merck’s attorneys could believe that. Shortly after the verdict we spoke with several seasoned trial and appellate attorneys who were all of the same opinion; Merck’s victory means little, if anything, to the overall litigation situation the company faces. This is especially true since Merck has repeatedly stated that it intends to fight each case individually.
The reason for this is that each case Merck wins only serves as a victory on the particular facts of that case since every plaintiff’s claim is factually different and the law allows each injured party to have a chance to prove his or her case.
Each case that Merck loses, however, has a cumulatively negative effect since it has gotten another chance to prove its lack of culpability and has failed. As one attorney put it: “Each plaintiff has only one chance to prove he’s right in order to win, but Merck has to show it’s right another 7,000 times in order to walk away without being liable. The likelihood of that is zero.”
It is highly unlikely that there will be a confluence of all of the factors that favored Merck in any of the remaining cases. Many of the remaining cases involve factors which will make Merck’s job much harder.
These cases involve deaths, long-term use of Vioxx, plaintiffs without additional risk factors for heart attack, and different plaintiffs’ trial attorneys (a factor which cannot be underestimated).
In addition to the immediate problems Merck faces in New Jersey, Texas (the site of the $253 million verdict against Merck) is still not finished with the company since the state itself has brought charging Merck defrauded it out of hundreds of millions of dollars in Medicaid payments by misrepresenting the safety of Vioxx for several years. While Texas was the first state to do this, it probably will not be the last.
In addition to $168 million in damages, the state is seeking additional civil penalties. Texas Attorney General Greg Abbot believes the state can prove total damages in excess of $250 million including treble (triple) reimbursement of $56 million (or $168 million) for five years of filled Vioxx prescriptions.
It is estimated that 700,000 Vioxx prescriptions were filled through Medicaid during those five years in Texas alone. Abbot sees these prescriptions as part of a willful misrepresentation on Merck’s part as to the safety of the drug. To him, the entire affair represents nothing more than “a prime example of a company’s drive for profit steamrolling its duty to be safe.”
Clearly, as Merck’s legal problems mount, no one victory will mean very much while each loss will be extremely damaging indeed. Each loss will make manageable personal injury settlements impossible and virtually guarantee the success of the types of actions brought by Local 68 and the state of Texas. This could spell financial ruin for Merck.
Finally, if Merck is found to have knowingly, or even carelessly, engaged in conduct which forces the company into Chapter 11 or otherwise destroys its once enormous profitability or stock value, disgruntled and very angry shareholders will no doubt explore the possibility of commencing a stockholders derivative suit to recoup their investment losses.
Judge Higbee has scheduled a hearing with respect to her decision to proceed with the most serious cases next. That hearing is scheduled for Thursday at which time Merck’s attorneys hope to convince the judge to change her mind.
Plaintiffs’ attorneys welcome the judge’s plan as a way to move the litigation along. While no definite figure is available, estimates put the number of 18-month ( New Jersey) cases at somewhere between 1,400 and 2,100.
Merck’s lead outside attorney Ted Mayer has stated that: “We are confident in our defense of 18-month cases.” One has to wonder, however, if that is anything more than saber-rattling given the additional negative evidence that will directly impact Merck in those particular cases.
Since it is unlikely Judge Higbee will accede to Merck’s request that the court change its decision with respect to the order in which Vioxx cases will be tried, Merck must begin to accept the very real possibility that the next several months may significantly affect the financial future of the world’s fifth largest pharmaceutical company, and not in a positive way.
Another day, another negative study involving COX-2 inhibitors; the class of drugs that includes Vioxx, Celebrex, Bextra, and other NSAIDs. All along, critics of these drugs saw them as dangerous, unnecessary, overpriced, “super aspirins” that would ultimately wind up injuring and killing people.
Merck and Pfizer, however, saw the drugs as potential blockbusters and, in what has been called the ultimate triumph of marketing over science, turned Vioxx, Celebrex, and Bextra into multi-billion dollar cash cows.
The latest study from Bispebjerg University Hospital in Copenhagen, which was funded by the Danish Heart Foundation and the Danish Pharmaceutical Association, has found that COX-2 inhibitors increase the risk of death among patients who have already survived a previous heart attack, especially when taken in high doses. The data was released yesterday at the American Heart Association conference in Dallas, Texas.
The study of 58,000 Danish patients showed that heat disease patients taking 25 mg of Vioxx per day were five times as likely to die as patients not taking the drug. The figure for Celebrex was 4.2 times for patients taking a 200 mg daily dose.
While this latest study is “a cause for concern” according to lead researcher Dr. Gunnar Gislason, it really isn’t any different in theme than all of the negative evidence that sits right now in litigation files involving the most serious of the 7,000 or so remaining cases against Merck.
This is significant because Judge Carol Higbee, who controls the progress of some 3,500 Vioxx cases pending in New Jersey, has now ordered that the next 10 trials involve plaintiffs who took Vioxx for at least 18 months.
Merck has already acknowledged the existence of an increased risk of heart attacks in long-term Vioxx users and even pulled the drug from the market for that very reason. Thus, legal analysts see Judge Higbee’s ruling as one that will make it virtually impossible for Merck to duplicate its recent victory where there were many factors in Merck’s favor.
Thus, a number of litigation attorneys we spoke with late last evening were of the opinion that this latest study merely confirms, yet again, the fact that Vioxx was always a dangerous drug regardless of what Merck wanted the public to believe and despite its approval by the FDA. In fact, each attorney said basically the same thing – “the second trial was a lucky break for Merck because it had a number of weaknesses in it as far as the plaintiff’s case was concerned.” The cases Judge Higbee now wants tried will have none of those weaknesses and that will only accentuate the overwhelming nature of the negative evidence.
In the recent New Jersey case that Merck won, there were a number of factors which favored Merck including: the plaintiff only took Vioxx for two months before his heart attack; he survived his injuries and actually appeared to be in surprisingly good health at trial despite the injuries he claimed to have suffered; plaintiff had a number of serious (non-Vioxx) risk factors that could have caused his heart attack; and Merck’s attorney made every effort to make it appear as if the trial judge was being unfair to the drugmaker with her rulings. The jury also was not enthralled by plaintiff’s trial attorney.
The negative evidence being referred to by those familiar with the Vioxx litigation is voluminous and quite damaging to say the least. It dates back to 1996 and never indicated a single reason why Vioxx or any of the COX-2 inhibitors should have been approved or allowed to be marketed in so cavalier a fashion as they were.
The Unbroken Chain of Damaging Evidence
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.
Nov. 21, 1996 – Memo by a Merck official shows the company wrestling with the issue of Vioxx's (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.
February 25, 1997 – Internal Merck e-mail warns 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."
The FDA approved Vioxx on May 20, 1999 for the use for the management of acute pain in adults and for relief of the signs and symptoms of osteoarthritis. (The original safety database included approximately 5,000 patients on Vioxx and did not, according to Merck, show an increased risk of heart attack or stroke).
November 18, 1999 – Meeting of the Data and Safety Monitoring Board (DSMB) discusses concerns over the "excess deaths and cardiovascular adverse experiences" that was observed in the group using Vioxx as compared to the patients taking Naproxen.
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.
March 17, 2000 – Merck updated the label by adding reported in the "adverse events" section of the label certain "cardiovascular" reports.
June of 2000 – Information presented at the European United League against Rheumatism, (Merck is a member and a corporate sponsor of this organization) demonstrated a statistically significant increase in hypertension and myocardial infarction.
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.
February 1, 2001 – 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.
February 8, 2001 – 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.
February 2001 – Letter by Dr. James Fries, senior professor and medical doctor from Stamford University Medical School to Merck complaining 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.
2001 – The concerns arising out of the VIGOR study were crystallized by Debabrata Mukherjee, Steven Nissen, and Eric Topol in JAMA in their review paper specifically highlighting the cardiovascular side-effect profile of COX-2 inhibitors.
May 22, 2001 – Despite the mounting evidence of the strong association of Vioxx to strokes and heart attacks, Merck issued a press release entitled "Merck Confirms Favorable Cardiovascular Safety Profile of Vioxx", claiming Vioxx has a "… favorable cardiovascular safety profile"
June 16, 2001 – Merck issued another press release (released in Europe), entitled "Vioxx Similar to Placebo and Three (3) Widely Prescribed NSAID's Regarding Cardiovascular Events".
July 11, 2001 , Merck modified the package insert for Vioxx.
August 22, 2001 – Study published in Journal of the American Medical Association by Drs. Mukherjee, Nissen, and Topol, researchers from the Cleveland Clinic, indicated that Vioxx was linked to a 200% increase in blood clots, heart attacks and strokes based on their review of previous clinical trials.
September 2001, the American Heart Association, the National Stroke Association and the Arthritis Foundation asked Merck to test whether Vioxx increased the risk of heart attack and stroke.
After it reviewed all of its Vioxx studies, Merck claimed there was no evidence that, in comparison with other NSAIDs, the drug increased the risk of heart problems. Merck (erroneously as it turned out) attributed the difference to a heart-protective effect it said the other drug had.
During this time period, Merck published training materials to be used by their sales rep's, one was entitled "Dodge Ball Vioxx". Each of the 1st 12 pages lists a scenario that maybe posed by a physicians questions or concerns. Each of the last four pages contain a single word in capital letters "DODGE!" clearly indicating that Merck was training its sales reps to "dodge" the tough questions and concerns of the physicians regarding the cardiovascular risks that had started to make its way into publications.
September 17, 2001 – FDA sends Merck a strongly worded "Warning Letter" regarding Merck’s minimizing the potentially serious cardiovascular risks of Vioxx disclosed by the VIGOR trial and promoting Vioxx for unapproved uses. The letter demanding that Merck discontinue promoting Vioxx to doctors for unofficial uses, found after a review of several of Merck's promotional conference calls and sales pitches, that the promotions by Merck "are false, lacking in fair balance, or otherwise in misleading in violation of the Federal Food, Drug, and Cosmetic Act (the Act) and applicable regulations." It also required Merck to send letters about the deception to the medical community.
April 11, 2002 – FDA instructed Merck to include in the package insert certain precautions based on results of the VIGOR studies regarding a higher cumulative rate of serious cardiovascular thromboembolic adverse events (such as heart attacks, angina pectoris, and peripheral vascular events).
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.
April 14, 2004 – Study sponsored and conducted by Merck and Harvard Medical School and published in the journal Circulation, found an elevated risk of acute myocardial infarction associated with Vioxx but not with Celebrex. The risk was statistically significant in persons taking greater than 25 mg of Vioxx, was elevated during the first 90 days of exposure but not thereafter. These results were observed consistently in relation to several reference groups studied. What was especially noteworthy was that the elevation of relative risk was similar when Vioxx was compared with patients not taking any NSAID (Non-steroidal anti-inflammatory drugs), naproxen (e.g. Naprosyn, Aleve) or ibuprofen (e.g. Advil, Nuprin, Motrin).
Merck asked the researchers to delete or tone down the part of the statement about this no-painkiller group, but the researchers refused, according to Daniel Solomon, a Brigham and Women's Hospital - Harvard professor who was the lead author. "We made a decision that we should let the science rule the day," he says (WSJ, 11/01/04, page A1).
Just before the paper was published in Circulation (the journal of the American Heart Association), dated May 4, 2004, Merck removed the name of a key researcher, Carolyn C. Cunnuscio, from the study. She was employed by Merck and had worked on the study. Upon learning that Merck had removed their employee's name from the Circulation article, the current JAMA editor, Catherine DeAngelis expressed her disappointment, and rounded-off her comments by saying "Aren't they seeking truth?"
May 14, 2002 – E-mail from Ann Trontell, FDA deputy drug safety director, warned colleagues that a Merck official had reminded her that "there had been an agreement that Merck would be informed prior to any FDA publication about one of their drug products".
August 12 2004 – Trontell wrote in an e-mail to another official that the study's recommendation was "unnecessary and particularly problematic" because FDA funded the study and Graham (David Graham, an Associate Director for Science in FDA Drug Center's Office of Drug Safety and the FDA officer in charge of the report) also might be asked to present "alternative FDA opinion" on the drug, She added that Merck should be notified about the study results before they became public "so they can be prepared for extensive media attention that this will likely provoke" .
August 13, 2004 – John Jenkins, director of FDA's office of new drugs, wrote that Graham's conclusion uses "pretty strong language since, to my knowledge, FDA is not contemplating such a warning or labeling." Jenkins suggested that the conclusion be changed to read, "[T]his and other studies suggest an increased risk of AMI (acute myocardial infarction, or heart attack) with Vioxx use and should be considered by prescribers when making individual treatment decisions"
Shortly thereafter, Graham responded in an e-mail response to supervisors, "I've gone about as far as I can without compromising my deeply held conclusions about this safety question. I've also shared with you the perspectives of my co-authors, and I think it's safe to say they share these same conclusions"
August 25, 2004 – At a medical/pharmaceutical conference in Bordeaux, France, at the annual meeting of The International Society for Pharmacoepidemiology, Graham presented new data from a trial sponsored by the Food and Drug Administration that indicated patients administered Vioxx 25 mg or more per day have a risk of experiencing an acute myocardial infarction (AMI) or sudden cardiac death that is more than three times that of remote non-steroidal anti-inflammatory drug users.
Researchers analyzed data from a subset of Kaiser Permanente patients, aged 18 to 84 years, who were treated with a COX-2-selective or NSAID (Non-steroidal anti-inflammatory drugs) between Jan. 1, 1999, and Dec. 31, 2001. In the trial, approximately 1.4 million patients contributed 2.3 million person-years of observation time. Results showed that treatment with Vioxx 25 mg/day or more conferred a 3.15-fold greater risk of AMI or sudden cardiac death compared with "remote use of any NSAID." Such a risk was also observed with lower doses of Vioxx (less than 25 mg/d), but did not achieve statistical significance.
September 8, 2004 – Vioxx received approval from the FDA for the relief of the signs and symptoms of Juvenile Rheumatoid Arthritis (JRA) in children two years and older and who weigh at least 22 pounds.
September 30th, 2004 – Sudden global withdrawal of Vioxx during the APPROVe study (Adenomatous Polyp Prevention Vioxx®) which was a multi-centre, randomized, placebo-controlled, double-blind study investigating the effects of Vioxx on the recurrence of neoplastic large bowel polyps in 2600 patients with a previous history of colorectal adenoma. The study participants were screened so that anyone with a history of heart disease was screened out.
On September 14, 2004, the Data and Safety Monitoring Board received the data that eventually lead to the September 30th withdrawal. The polyp study was stopped prematurely on the suggestion of the Data and Safety Monitoring Board and a Merck statistician (James Neaton) after the investigators, who had access to all of the data, found that after 18 months treatment, patients taking Vioxx had twice the risk of a myocardial infarction compared with those receiving placebo.
September 17, 2004 – Merck statistician and the four safety committee members had a conference call with John Baron who was the principal investigator of the polyp study and other Merck officials. After the Merck officials and Baron left the call, the four safety committee members agreed that the study had to be stopped. Neaton then called John Baron and explained to him the committee's decision. After reviewing the data that the decision was based on, Baron concurred.
Baron then took the next week to meet with the people at Merck including the steering committee, to explain to them the decision that both the committee and he arrived at, that is halting the polyp trial.
September 23, 2004 –The full steering committee agreed to the halting of the polyp trial. Baron then advised Merck that same day that Vioxx presented an unacceptable risk of a cardiovascular event.
Baron spent the next few days presenting the data and the conclusions to other experts in and outside of Merck. Merck also spent the next few days reviewing all of the data from the polyp study.
September 27, 2004 – Ranking officers at Merck decided that Vioxx needed to be withdrawn. However, the decision was made to take this decision to the board of directors.
Merck's board of directors met on September 28. About this time, Merck notified the FDA that they needed to have an emergency meeting with them that afternoon informing them of Merck's decision to withdraw the drug.
September 29, 2004 – Merck informed its international affiliates of the decision and asked them to withhold informing the regulators in their jurisdiction until the information was made public.
September 30, 2004 – Merck & Co., Inc. announced a voluntary withdrawal of the arthritis and pain relief drug from the worldwide drug market. Merck's action was not ordered by the U.S. Food and Drug Administration (FDA), but was initiated by Merck based on its own findings from the clinical trial.
Senate Finance Committee Chair Charles Grassley (R-Iowa) started an investigation into the FDA. On October 7, Grassley compared Graham's experience to that of Andrew Mosholder, another FDA scientist whose research on the link between antidepressants and suicidality in children faced from superiors at the agency. "Dr. Graham described an environment where he was 'ostracized,' 'subjected to veiled threats' and 'intimidation,'" Grassley said in a statement after committee investigators interviewed the researcher. He added, "Merck knew it had trouble on its hands and took action. At the same time, instead of acting as a public watchdog, [FDA] was busy challenging its own expert and calling his work 'scientific rumor.'"
The Senate Finance Committee is one of three congressional committees examining FDA's actions. In addition, the Government Accountability Office has expanded its investigation of FDA's conduct in regard to Mosholder and the risks of antidepressants to include its handling of Vioxx studies.
November 2, 2004 – FDA posted an abridged version of study conducted by Dr. David J. Graham, associate director for science in the FDA's office of drug safety. The report, dated September 30, 2004 (the same day Merck withdrew Vioxx from the market) builds upon research that he presented at a medical conference in France in late August (referred to above). "Rofecoxib [Vioxx] increases the risk of serious coronary heart disease as defined by acute myocardial infarction [heart attack] and sudden cardiac death,"
Graham's report said. Rofecoxib is the scientific name for Vioxx. Graham defined a high dose of Vioxx as more than 25 milligrams; a standard dose is equal to or less than 25 milligrams. The study, posted Tuesday, says the recently withdrawn Vioxx increased by 3.7-fold the risk of "serious coronary heart disease" when compared to Pfizer's Celebrex. The study also says a standard dose of Vioxx increased the cardiovascular risk by 1.5 times over Celebrex. "The population impact of rofecoxib's increased risk is great because of the widespread exposure to the drug," said Graham.
November 5, 2004 , a major study, published in The Lancet, pooled data from more than 25,000 patients who participated in 18 clinical trials and 11 observational studies all conducted before 2001. The study demonstrated that patients taking Vioxx had 2.3 times the risk of heart attack as those prescribed placebos or other NSAIDs.
In addition, the researchers found an increased risk of myocardial infarction involving both short-term and long-term usage concluding that patients taking Vioxx for only a few months were also at risk.
The researchers specifically refuted Merck's position that there is no excess risk in the first 18 months of using Vioxx . In addition, the researchers also refuted Merck's contention that cardio-vascular involvement was dose-dependent. As to Merck's contention that in their VIGOR Study, Naproxen was cardio-protective and, therefore, influenced the outcome, these researchers found that if such evidence does exist, its effect is so small that it is not justified to claim Naproxen as a factor in the findings of the VIGOR Study.
In concluding their findings, the researchers stated that "If Merck's statement in their recent press release that 'given the availability of alternative therapies, and the questions raised by the data, we conclude that a voluntary withdrawal is the responsible course to take.' was appropriate in September, 2004, then the same statement could and should have been made several years earlier, when the data summarized here first became available. Instead, Merck continued to market the safety of Rofecoxib. This clearly demonstrated that Merck had, by the end of 2000, sufficient statistically significant information that required the immediate withdrawal of Vioxx from its world-wide market.”
Accompanying the study published in The Lancet on November 5, 2004 was an editorial that was even more damning than the study. Referring to the findings of the study, the editorial states "This discovery points to astonishing failures in Merck's internal systems of post marketing surveillance, as well as to lethal weaknesses in the Food and Drug Administration's Regulatory Oversight . . . The evidence showing that Vioxx caused significant adverse events was apparent well before data from the APPROVe trial triggered Merck's overdue intervention. This week's report by Peter Juni and colleagues will add significant weight to on-going litigation by patients who believe they were harmed by this drug."
The editorial went on to find ". . . the FDA tried to shore up its tarnished reputation by posting on its website an early version of a recently completed observational study into the safety of Vioxx. The report comes with a warning that it has 'not been fully evaluated by the FDA and may not reflect the official views of the agency'. The FDA investigation estimated that over 27,000 excess cases of acute myocardial infarction and sudden cardiac death occurred in the USA between 1999 and 2003. 'These cases' they write, 'would have been avoided had celecoxib been used instead of Rofecoxib'. . . It is unclear why the FDA could not have waited for the fully evaluated report to have been scrutinized, revised, and published according to the norms of scientific peer review. Bypassing independent peer review smacks of panic in the FDA, which is under intense reputational pressure. And, yet, its decision to try to undermine the integrity of its work shows, that the agency's senior management is more concerned with external appearance than rigorous science."
Finally, the editorial concludes "… with Vioxx, Merck and the FDA acted out of ruthless short-sighted and irresponsible self-interest." This is the most condemning editorial in a well-respected medical journal that most observers have ever seen.
It also turns out that Vioxx, despite the slick TV and magazine ads, has not been shown to be significantly more effective than the much less expensive non-prescription anti-inflammatories such as Tylenol and Advil.
Merck Withdrew Vioxx from the Market for Purely Economic Reasons
Although Merck 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 have little doubt that the removal of Vioxx from the market was anything but 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.
Corporate analysts who commented on Merck’s action saw it as a sound business move under the circumstances. They did not attribute it 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 deeply interested in widening the market for COX-2 inhibitors. That evidence included the following:
The 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 by the Data Safety Monitoring Board for safety reasons, Vioxx would probably still be on the market.
Merck had already developed a new COX-2 pain reliever called Arcoxia which was being marketed in 47 countries and for which Merck expected FDA approval in the near future. While Arcoxia was not yet the billion dollar drug Vioxx was, it is clear that Vioxx was well on the way to being replaced when it was pulled from 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.
Most experts who are familiar with the history of Vioxx from either a medical or business perspective were not surprised by Merck’s sudden withdrawal of the drug from the market. The only surprise any of these experts seems to have is why it took so long for it to happen.
Dr. Sidney Wolfe of Public Citizen was quoted in the San Francisco Chronicle ( 10/1/04). He stated: “This family of drugs, the COX-2 inhibitors, once referred to as ‘super aspirins,’ are turning out to be more like super disasters.”
Dr. Eric Topol, Chief of Cardiovascular Medicine and Chief Academic Officer of the Cleveland Clinic, was a co-author of the VIGOR Study discussed above. His comment to the Washington Post ( 10/1/04) was 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.”
The Wall Street Journal (10/1/04, page B1) noted that “Merck also may face more criticism for having strenuously denied for several years suggestions by outside researchers that use of Vioxx led to heart problems. The company even published its own studies suggesting the drug wasn’t causing harm.”
The Disturbing Senate Testimony of FDA Whistleblower David J. Graham, MD, MPH
Dr. David Graham, an Associate Director for Science and Medicine in the FDA’s Office of Drug Safety is a scientist with impeccable credentials as well as a man of unchallenged integrity. He has devoted his entire professional life to making a real difference in the cause of patient safety.
Although he fought long and hard against Vioxx based upon the overwhelming evidence of its serious cardiovascular risks, he was little more than “a voice crying in the wilderness” who received no support within the FDA. He was also the target of Merck’s scorn since he posed a threat to its corporate balance sheet.
Once Vioxx was pulled from the market, however, Dr. Graham could no longer be ignored nor could his medical opinions be marginalized by his detractors. Suddenly, those in authority wanted to hear from this public servant turned whistleblower.
On November 18, 2004, Dr. Graham appeared before the Senate Finance Committee Chaired by Sen. Charles Grassley (R-Iowa). Dr. Graham delivered compelling and often shocking testimony ( http://finance.senate.gov/hearings/testimony/2004test/111804dgtest.pdf) concerning the very real dangers of Vioxx and the unconscionable delay in pulling the drug from the market which has exposed the public to a degree of risk never before seen with respect to any prescription drug including sulfanilamide and thalidomide.
Dr. Graham presented the evidence against Vioxx in painstaking detail. He also set forth the disturbing facts surrounding the FDA’s efforts to suppress his research, censor and alter his scientific and medical findings and conclusions, and discredit his work.
Probably the most striking portion of Dr. Graham’s testimony involved his carefully formulated opinion that (even using Merck’s own VIGOR and APPROVe trials) some 88,000 to 139,000 Americans alone have already suffered heart attacks as a result of taking Vioxx and of that number, “30-40% probably died.” (Note that Dr. Eric Topol estimated the heart attack figure to be up to 160,000).
Dr. Graham put these astounding figures in perspective by using various examples. Most compelling, however, was the following statement:
“Imagine that instead of a serious side effect of a widely prescribed prescription drug, we were talking about jetliners…If there were an average of 150 to 200 people on an aircraft, this range of 88,000 to 138,000 would be the rough equivalent of 500 to 900 aircraft dropping from the sky. This translates to 2-4 aircraft every week, week in and week out, for the past 5 years. If you were confronted by this situation, what would be your reaction, what would you want to know and what would you do about it?”
“Even more revealing, a mere 6 weeks before Merck pulled Vioxx from the market, CDER, OND and ODS management did not believe there was an outstanding safety concern with Vioxx. At the same time, 2-4 jumbo jetliners were dropping from the sky every week and no one else at FDA was concerned.”
“At this meeting [Sept. 22, 2005], the reviewing office director asked why had I even thought to study Vioxx and heart attacks because FDA had made its labeling change and nothing more needed to be done. At this meeting a senior manager from ODS labeled our Vioxx study ‘a scientific rumor.’ Eight days later, Merck pulled Vioxx from the market, and jetliners stopped dropping from the sky.”
Merck’s Victory in the Most Recent Trial is of Little Significance
In terms of what Merck’s recent victory means litigation-wise, Merck’s defense team is experienced enough to know it means very little since it is somewhat like trying to stop a tidal wave with a sponge.
Merck would have to win virtually all of the remaining 7,000 (and growing) cases to stave off a financial catastrophe since each negative verdict has the potential of being in the millions of dollars. Even scattered losses for Merck can add up to a financial disaster.
Is such a possibility realistic? Not even Merck’s attorneys could believe that. Shortly after the verdict we spoke with several seasoned trial and appellate attorneys who were all of the same opinion; Merck’s victory means little, if anything, to the overall litigation situation the company faces. This is especially true since Merck has repeatedly stated that it intends to fight each case individually.
The reason for this is that each case Merck wins only serves as a victory on the particular facts of that case since every plaintiff’s claim is factually different and the law allows each injured party to have a chance to prove his or her case.
Each case that Merck loses, however, has a cumulatively negative effect since it has gotten another chance to prove its lack of culpability and has failed. As one attorney put it: “Each plaintiff has only one chance to prove he’s right in order to win, but Merck has to show it’s right another 7,000 times in order to walk away without being liable. The likelihood of that is zero.”
It is highly unlikely that there will be a confluence of all of the factors that favored Merck in any of the remaining cases. Many of the remaining cases involve factors which will make Merck’s job much harder.
These cases involve deaths, long-term use of Vioxx, plaintiffs without additional risk factors for heart attack, and different plaintiffs’ trial attorneys (a factor which cannot be underestimated).
In addition to the immediate problems Merck faces in New Jersey, Texas (the site of the $253 million verdict against Merck) is still not finished with the company since the state itself has brought charging Merck defrauded it out of hundreds of millions of dollars in Medicaid payments by misrepresenting the safety of Vioxx for several years. While Texas was the first state to do this, it probably will not be the last.
In addition to $168 million in damages, the state is seeking additional civil penalties. Texas Attorney General Greg Abbot believes the state can prove total damages in excess of $250 million including treble (triple) reimbursement of $56 million (or $168 million) for five years of filled Vioxx prescriptions.
It is estimated that 700,000 Vioxx prescriptions were filled through Medicaid during those five years in Texas alone. Abbot sees these prescriptions as part of a willful misrepresentation on Merck’s part as to the safety of the drug. To him, the entire affair represents nothing more than “a prime example of a company’s drive for profit steamrolling its duty to be safe.”
Clearly, as Merck’s legal problems mount, no one victory will mean very much while each loss will be extremely damaging indeed. Each loss will make manageable personal injury settlements impossible and virtually guarantee the success of the types of actions brought by Local 68 and the state of Texas. This could spell financial ruin for Merck.
Finally, if Merck is found to have knowingly, or even carelessly, engaged in conduct which forces the company into Chapter 11 or otherwise destroys its once enormous profitability or stock value, disgruntled and very angry shareholders will no doubt explore the possibility of commencing a stockholders derivative suit to recoup their investment losses.
Judge Higbee has scheduled a hearing with respect to her decision to proceed with the most serious cases next. That hearing is scheduled for Thursday at which time Merck’s attorneys hope to convince the judge to change her mind.
Plaintiffs’ attorneys welcome the judge’s plan as a way to move the litigation along. While no definite figure is available, estimates put the number of 18-month ( New Jersey) cases at somewhere between 1,400 and 2,100.
Merck’s lead outside attorney Ted Mayer has stated that: “We are confident in our defense of 18-month cases.” One has to wonder, however, if that is anything more than saber-rattling given the additional negative evidence that will directly impact Merck in those particular cases.
Since it is unlikely Judge Higbee will accede to Merck’s request that the court change its decision with respect to the order in which Vioxx cases will be tried, Merck must begin to accept the very real possibility that the next several months may significantly affect the financial future of the world’s fifth largest pharmaceutical company, and not in a positive way.
posted by Chris Placitella at 7:58 AM
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