As we've reported previously, doctors may prescribe Food & Drug Administration-approved medicines any way they see fit. But companies are legally barred from promoting unapproved, or so-called off-label, uses.
According to the Justice Department press release, Pharmacia & Upjohn Company will pay a criminal fine of $1.195 billion, the largest criminal fine ever imposed in the United States for any matter, for the Bextra promotions. Pharmacia & Upjohn will also forfeit $105 million, for a total criminal resolution of $1.3 billion. According to Reuters, Bextra had only been approved to treat two types of arthritis pain and uterine pain, but the government claims it was marketed as a treatment for all types of pain.
In addition, Pfizer has agreed to pay $1 billion to resolve allegations it illegally promoted Bextra; Geodon, an anti-psychotic drug; Zyvox, an antibiotic; and Lyrica, an anti-epileptic drug, causing false claims to be submitted to government health care programs for uses that were not medically accepted indications and therefore not covered by those programs.
The civil settlement also resolves allegations that Pfizer paid kickbacks to health care providers to induce them to prescribe these, as well as other, drugs. The federal share of the civil settlement is $668,514,830 and the state Medicaid share of the civil settlement is $331,485,170. This is the largest civil fraud settlement in history against a pharmaceutical company, the press release said.
Pfizer also has agreed to enter into an expansive corporate integrity agreement with the Office of Inspector General of the Department of Health and Human Services. That agreement provides for procedures and reviews to be put in place to avoid and promptly detect conduct similar to that which gave rise to this matter, the Justice Department said.
According to the Justice Department, the settlement is the result of the investigation instigated by six whistleblowers. As a result of the settlement, the whistleblowers will receive $102 million of the federal fines.
In 2005, FDA and European regulators formally asked Pfizer, Inc. to suspend sales of Bextra in the U.S. and Europe. As a result, Pfizer announced it would immediately halt Bextra sales in the U.S. and European Union countries. The FDA stated that the risks—a high rate of heart attacks, strokes, other cardiovascular injuries, and Stevens Johnson Syndrome—posed by Bextra outweighed its benefits.
Bextra was a Cox-II inhibitor approved in by the FDA in November 2001 for the signs and symptoms of osteoarthritis and adult rheumatoid arthritis at 10 mgs and for primary dysmennorhea at 20 mgs, twice daily, as needed. In 2001, the FDA specifically denied Pfizer’s request to approve Bextra for acute pain, including surgical pain, because the safety in these other uses had not been established and it was specifically concerned about the results of a study in which there was an excess of cardiovascular events in patients who underwent coronary artery bypass graft surgery and used Bextra.
Mary Holloway, 47, of Branchburg, New Jersey, has been sentenced by U.S. Magistrate Judge Judith Dein to pay a $75,000 fine and twenty-four months of probation after pleading guilty to a so-called “Information” charging her with distribution of a misbranded drug. According to prosecutors speaking to the Court at the plea hearing, had the case proceeded to trial, the Government’s evidence would have proven that:
From approximately November 2001, through April 2005, Holloway was employed as a Regional Manager at a pharmaceutical company and was responsible for Bextra sales in her region.
Holloway was aware of the FDA’s safety concerns, but had her sales staff of approximately 100 employees sell Bextra for precisely the uses that the FDA refused to approve. The U.S. DOJ cited, as an example, that Holloway trained and encouraged her sales teams to promote Bextra by obtaining protocols from doctors that instructed that Bextra be used for the pain of surgery, an unapproved use, and at 20 mgs, an unapproved dose.
Holloway also instructed her staff to market Bextra for use before, during, and after surgery to reduce the risk of deep vein thrombosis, which is a form of life-threatening blood clots, even though she knew there were no studies showing Bextra was safe and effective for this use.
Holloway encouraged her staff to make false safety claims about Bextra in order to sell the drug.
Acting United States Attorney Michael K. Loucks said, “We will continue to hold individuals responsible for their conduct in promoting pharmaceutical drugs outside of the uses for which they have been found to be safe and effective by the United States FDA. The conduct at issue here undermined the FDA’s regulatory scheme and put patients at risk for the purpose of pursing profits for the individual and the pharmaceutical company,” quoted the U.S. DOJ.
Pfizer reached the $2.3 billion agreement with the Massachusetts U.S. Attorney to, it said, “resolve previously disclosed investigations" regarding Bextra and "other open investigations," reported Bloomberg, which added that while Pfizer disclosed no other details, its fourth-quarter earnings dropped a massive 90 percent over the charges and investigation. The Wall Street Journal blog (WSJ) noted that Pfizer’s fourth-quarter earnings dropped to $266 million from $2.72 billion the prior year.
According to Bloomberg News, the Pfizer settlement is the largest for allegations of off-label marketing practices, a topic of concern to consumers, the medical community, and patient advocates. The prior record had occurred earlier this month when Eli Lilly & Company paid out $1.42 billion over its antipsychotic Zyprexa, said Patrick Burns of Washington advocacy group Taxpayers Against Fraud, reported Bloomberg. Pfizer spokesman, Christopher Loder, explained that the $2.3 billion settlement represents an "agreement in principle to resolve government allegations of past off-label practices," said Bloomberg, noting that Loder refused to say what other investigations were covered.
The WSJ noted that Pfizer couched the settlement news around its Wyeth purchase, but noted that Pfizer also agreed to pay $745 million for agreements in principle to settle personal injury suits over painkillers Bextra and Celebrex, late last year. FT.com said that amid news of the Wyeth takeover, a “tiny reference” was made in Pfizer’s fourth-quarter results issued on Monday that mentioned the record-breaking $2.3 billion agreement in principle. Also, said WSJ, there was $60 million for attorneys general in 33 states and the District of Columbia, and $89 million to resolve class actions, which were not included in the “investigation by the Department of Justice of the marketing of the company’s Cox-2 medicines, particularly Bextra,” Pfizer said in a recent quarterly filing, reported the WSJ.
Pfizer has also beeh hit hard by a number of other factors, said the Journal, including competition with the generic version of allergy medication Zyrtec and reports about odd and controversial reactions to Chantix, its smoking cessation medication. Chantix sales dropped by $36 percent—to $180 million—when stories of bizarre reactions to the medication began surfacing and making the news. To make matters worse, said the WSJ, the combined Pfizer-Wyeth will be reducing staff by 10 percent, which is part of a larger 15 percent reduction. The workforce reduction translates into about 19,500 jobs.
Pfizer acquired Bextra in a takeover of Pharmacia, which was finalized in 2000, reported FT.com. Bextra, a Cox-2 painkiller is in the same class as Merck’s Vioxx, which was withdrawn in 2004 following reports that Vioxx was linked to an increased incidence of heart attacks. Meanwhile, Pfizer’s Celebrex, another Cox-2 painkiller, which was associated with skin infections and concerns over cardiac risk pushed the FDA to seek the drug’s withdrawal, said FT.com.
Zonie is reporting that the Arizona Attorney General filed a 15-page court complaint that alleges that Pfizer repeatedly conned consumers to increase Bextra sales; the lawsuit states that Pfizer misrepresented Bextra risks, enlisting doctors to promote the drug to increase sales. The FDA approved Bextra for “treatment of arthritis and menstrual pains.” According to Zonie, the lawsuit says that Pfizer: “Withheld studies that showed safety risks, deployed an enormous sales staff to promote Bextra’s “off-label” uses, and gave improper gifts to physicians in return for their help marketing the product.”
Lawyers for the Attorney General claim that the “deceptions began in 2001” following the FDA’s declination of Bextra approval for all of the “off-label” uses for which Pfizer was seeking approval, said Zonie, which added that Pfizer settled with the federal government for nearly $900 million. The state’s suit also alleges that Pfizer was looking to promote Bextra for treatment for “acute and perioperative pain” and also to help with “gastrointestinal side effects,” all without appropriate and complete research.
Zonie notes that the controversy involves COX-2 inhibitors, medications that block pain and inflammation and that the complaint states that three COX-2 inhibitors received FDA approval. Pfizer released Celebrex in early 1999; soon after Merck released Vioxx. In 2004, Merck removed Vioxx—known generically as Rofecoxib—after data from a clinical trial found an increased risk of heart attack and stroke, blood clots, and other cardiovascular complications. The complaint states that, in 2004, Bextra was withdrawn and Celebrex received a “black box” label warning, notes Zonie.
Despite looming lawsuits, Pfizer apparently continued to sell Bextra as a pain killer and—according to the Zonie report regarding the contents of the complaint—minimized the findings of a negative study, bought research from advertising agencies with which it contracted, and arranged for the publication of positive studies publish in a major medical journal before editors were able to retract the piece. Also, according to the Zonie piece, Pfizer also only disclosed “favorable” Bextra data, running ad campaigns promoting Bextra as the “ideal pain-killer” for the “weekend warrior”; and “also sought out and developed physician speakers who were high prescribers of Bextra and supported its off-label use,” according to the complaint. “These health care providers were then paid to give lunch or dinner talks relating to off-label use of Bextra,” Zonie quoted from the complaint.
Zonie noted that the complaint detailed how sales staff would join doctors on their presentations, with the most successful doctors “rewarded with ‘preceptorships’ in which they received up to $500 to allow Bextra sales reps to accompany them on their rounds or in the operating room,” said Zonie. The state Attorney General is seeking a permanent injunction barring Pfizer from continuing these alleged practices in Arizona.
Celebrex and Bextra are COX-2 inhibitors, a class of drugs that also includes Merck’s recalled Vioxx. Such medications are linked to an increased risk of blood clots, heart attacks and strokes. Pfizer withdrew Bextra from the market in 2005, and Celebrex is the only COX-2 inhibitor still on the market in the United States.
Celebrex carries the Food and Drug Administration’s (FDA) strictest “black-box” warning on its drug label, stating that it may cause an increased risk of serious cardiovascular events such as heart attacks and strokes. Despite its apparent risk, Celebrex continued to generate $2.3 billion in sales in 2007, a 12 percent increase from the previous year.
According to The New York Times, $760 million of the Bextra and Celebrex settlement would go to settle roughly 7,000 personal injury cases, $60 million will cover settlements with attorneys general in the 33 states and the District of Columbia, and $89 million will cover consumer fraud class action cases over reimbursement for money spent on the two drugs.
Pfizer said it hopes to finalize the settlement by the end of the year. A spokesperson for the company said that Pfizer would also like to include many of the remaining personal injury lawsuits the settlement. The company will fight those not settled with court motions or at trial.
COX-2 inhibitors have been the subject of safety worries since 2004, when Merck pulled Vioxx from the market. The FDA ordered the painkiller off the market after an analysis of patients using Vioxx linked the defective drug to more than 27,000 heart attacks or sudden cardiac deaths in the U.S. from 1999 through 2003. The Vioxx recall led to thousands of lawsuits.
Last November, Merck announced a $4.85 billion settlement with the thousands of people who had filed Vioxx injury lawsuits. Under the terms of the settlement, Merck set up a $4 billion fund for people who claim they suffered heart attacks as a result of Vioxx, and another $850 million fund for those who suffered ischemic strokes. Partial settlement payments started going out to some Vioxx plaintiffs last month.
This latest study, which looked at the stroke risk of COX2 inhibitors like Vioxx and Bextra, as well as the risk of other NSAIDs like ibuprofen, was conducted by researchers at Vanderbilt University in Tennessee. The study focused on the seven most common NSAIDs, including Celebrex, Vioxx, Bextra, ibuprofen, naproxen, indomethacin, and diclofenac.
Among the participants, 78,036 were current users of one of the seven study NSAIDs, 16,420 were current users of other NSAIDs or NSAID combinations, and 242,450 were nonusers.
The study found that the risk of stroke was 28 percent higher among Vioxx users and 41 percent higher among Bextra users. The risk of stroke was not significantly increased with Celebrex or with other NSAIDs
In an interview with Reuters news service, lead researcher Dr. Christianne Roumie said the decisions to take Vioxx and Bextra off the market were justified. "This study suggests that rofecoxib (Vioxx) and valdecoxib (Bextra) were associated with higher stoke risk than other NSAIDs," Roumie said in the interview.
"Because of this and other studies, their withdrawal from the market is appropriate and these medications should not be re-introduced, especially since safer alternatives are available," she explained.
Bextra, made by Pfizer, was removed from the market in 2005. In May, The Wall Street Journal reported that Pfizer had reached settlements with three law firms representing patients who sued over the drug. Pfizer was reportedly offering such patients as much as $200,000 to settle their Bextra cases.
Vioxx was recalled in 2004. Last November, Merck announced a $4.85 billion settlement with the thousands of people who had filed Vioxx injury lawsuits. Under the terms of the settlement, Merck set up a $4 billion fund for people who claim they suffered heart attacks as a result of Vioxx, and another $850 million fund for those who suffered ischemic strokes. Partial settlement payments are expected to start going out this month.
Celebrex and Bextra are COX-2 inhibitors, a class of drugs that also includes Merck's recalled Vioxx. Such medications are linked to an increased risk of blood clots, heart attacks and strokes. Pfizer withdrew Bextra from the market in 2005, and Celebrex is the only COX-2 inhibitor still on the market in the United States.
According to The Wall Street Journal, Pfizer has reached settlements with three law firms representing more than 200 of the thousands who sued over the drugs. Firms have been offered $40,000 to $50,000 a client to resolve Celebrex cases and as much as $200,000 a client for Bextra. The Wall Street Journal reported that unlike Merck's recent mass settlement of litigation involving Vioxx, Pfizer is attempting to resolve its Bextra and Celebrex lawsuits on a firm-by-firm basis.
Celebrex carries the Food and Drug Administration’s strictest “black-box” warning on its drug label, stating that it may cause an increased risk of serious cardiovascular events such as heart attacks and strokes. Despite its apparent risk, Celebrex continued to generate $2.3 billion in sales in 2007, a 12 percent increase from the previous year.
Last month, the National Cancer Institute released an analysis of six Celebrex studies that included 7,950 patients. According to The Wall Street Journal, the analysis showed Celebrex was associated with an increased risk of cardiovascular death, heart attack, stroke, heart failure or thromboembolic event, or events related to blood clots, compared to patients not taking the drug. The researchers found that patients receiving the highest dose of Celebrex of 400 milligrams twice daily had a nearly three times higher risk of heart attacks and strokes than patients not taking the drug. Patients taking a lower dose of Celebrex, 400 milligrams once daily, had a 10% higher risk of a cardiovascular event. The study did not look at patients taking a once-daily, 200-milligram dose of Celebrex, which represents the way the drug is most commonly prescribed.
The first Bextra trial was due to begin today in federal court in San Francisco. But a lawyer involved in the case told The Wall Street Journal that the parties agreed to adjourn the case so Pfizer could attempt to settle Celebrex and Bextra cases across the country.
The suspension of Bextra sales was due to safety concerns related to rare but serious skin reactions and cardiovascular problems. At that time, Health Canada issued a stop-sale order which ensured that Bextra (valdecoxib) would not be permitted to return to the Canadian market without further consultation with Health Canada.
The Canadian agency, which is the equivalent of the U.S. FDA, studied all of the available data on COX-2 inhibitors in general and concerning Bextra, specifically. Based on that review Health Canada has determined that “there is an increased risk of heart attack and stroke when these drugs are used for long-term treatment. Studies also showed that these side-effects can occur when Bextra is used for short-term pain relief following high-risk heart surgery. Bextra is also associated with a risk of rare but severe and potentially fatal skin reactions.”
The official announcement on the agency’s Web site (http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2005/2005_134_e.html) states: “The decision to stop the sale of Bextra is based on information submitted by the manufacturer, Pfizer Canada Inc., and consultations with external experts and the public. Health Canada concluded that there is insufficient evidence to establish the safety of the drug for its recommended use.”
“As a result of this regulatory action, the manufacturer will not be able to bring Bextra back onto the Canadian market under its present conditions of use. Health Canada has sent a letter to inform Pfizer Canada Inc. of the status of Bextra.”
The advisory concludes by stating that: “Health Canada has completed the review and agrees with the panel that available evidence indicates that COX-2 selective inhibitors and all other non-steroidal anti-inflammatory drugs are associated with an increased risk of cardiovascular events when high doses are used for long periods. However, the exact nature of that increased risk may differ from one product to another. The panel also found that the overall risk versus benefit profile for Bextra does not support the marketing of this drug in Canada under its current conditions of use.”
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.
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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.