The recent abrupt withdrawal of Vioxx, after a clinical trial linked the drug to heart attacks and stroke, will, more than likely, open the floodgate to lawsuits against the manufacturer, Merck. Over 20 million people have taken Vioxx since it was released to the public in 1999. The recently released clinical trial found that people taking a low dose of Vioxx, were twice as likely to have a heart attack or stroke as patients taking a placebo.

Researchers have warned about a connection between Vioxx and increased risk of heart attack and stroke for many years. But until last week, Merck ignored the presumptive data. Now that Merck has acknowledged the safety risks of its anti inflammatory medication, the result could be a flood of successful lawsuits.

Vioxx lawsuits could total over 30 Billion dollars over the course of the next few years. This number may seem astronomical, though when compared to the revenue generated from Vioxx, it's not. Vioxx sales exceeded 2.5 billion last year. After studies suggested serious side-effects, Vioxx was recalled on September 30, 2004. Consumer activists have argued dangers associated with Vioxx were clear from earlier studies and that company officials downplayed the heart risks. At the time of the Vioxx recall about 2 million people were using it. If you or a loved one have taken Vioxx, you may want to contact a Vioxx attorney to see how to proceed.

Merck Documents Shed Light on Vioxx Legal Battles Records Show Safety Panel Had Early Data Indicating Higher Heart-Problems Risk

By BARBARA MARTINEZ
Staff Reporter of THE WALL STREET JOURNAL
February 7, 2005; Page A1

When Merck & Co. pulled its painkiller Vioxx from the market in September, it said it was acting because a clinical trial had shown that users were at increased risk of heart attacks or strokes after 18 months.

That conclusion, and how it was reached, are the central issues for Merck in defending itself against a wave of lawsuits -- 575 as of the company's latest count, representing about 1,400 Vioxx users -- accusing the company of negligence. The suits could start being heard in courtrooms as soon as May. Previously undisclosed company records, which were reviewed by The Wall Street Journal, are casting light on the coming legal battles.

The records, which plaintiffs' attorneys have, show that the external committee charged with monitoring the drug's safety in the clinical trial had early data suggesting that users could be at increased risk of certain heart problems after as little as four months. Notes from committee meetings show that members were watching the "concerning nature of the trends" about Vioxx's possible effects on heart attacks and strokes from their first meeting. The records also show that the committee of five included one Merck employee and two doctors who had done consulting work for the company. One of the consultants was the lead author on a paper written with Merck scientists that defended Vioxx's safety and criticized a study raising safety concerns about the drug. All those issues are expected to be probed by plaintiffs' attorneys.

The records also show that the committee kept the trial going despite its concerns because it hoped to find whether Vioxx might prove effective in reducing colon polyps, a potential precursor to cancer. The records indicate that members did see some evidence of beneficial effects, while keeping an eye on numbers suggesting a possible increased risk of heart attacks, strokes and other cardiovascular problems among the Vioxx users in the trial, compared with those taking a placebo (see related article).

It was when those numbers met the test of statistical significance that the trial was halted, prompting Merck to yank the drug. Merck said that during the trial, 45 of the 1,287 patients who took Vioxx experienced heart attacks or strokes, compared with 25 patients out of 1,299 taking placebos.

In response to questions from this newspaper, Joan Wainwright, Merck's vice president of public affairs, provided a written statement. She said the committee "provided the exact kind of oversight and monitoring of patient safety that is needed in a clinical trial and met its professional and ethical responsibilities in raising safety concerns when it did." Any suggestion that committee members "lacked independence and acted inappropriately" is "wrong and not supported by the facts," she writes.

Merck, based in Whitehouse Station, N.J., started battling criticism of Vioxx soon after its release in 1999, as a series of researchers argued that the drug raised the risk of heart attacks and strokes. Until it pulled the drug last September, Merck defended Vioxx as safe. It says the clinical trial that prompted the drug's withdrawal was the only study to conclusively show a risk to users -- and only in those who had taken the drug daily for more than 18 months.

If Merck persuades jurors that the committee's timing and standards were appropriate, it could limit its potential liability substantially. More than 20 million people took Vioxx sometime between its release and withdrawal; many of those either didn't take the painkiller daily for more than 18 months or lack documentation showing that they took it at least that long. Wall Street analysts estimate its liability costs could range from $4 billion to more than $20 billion.

Plaintiffs' attorneys will seek to counteract Merck's claims in part by trying to pick apart how the committee overseeing the clinical trial was assembled and came to its conclusions.

The trial, which began in January 2000, was known as Approve and was aimed at studying the drug's effect on colon polyps. Merck appointed the external safety committee to monitor the drug's safety in late 2001.

Such panels are common in the drug industry, though manufacturers aren't required to set them up to monitor their clinical trials and there are no rules or regulations governing such bodies. It isn't uncommon for such panels to include members with ties to drug companies.

Before the Approve clinical trial began, Merck considered monitoring the safety data in-house, but later decided to set up an external panel. One senior Merck official wrote in a Sept. 13, 1999, internal e-mail that the clinical trial's lead researcher had told him the purpose of an external safety panel is "50% scientific need and 50% for appearances."

The trial's lead researcher, John Baron, a professor of medicine at Dartmouth Medical School, says, "I don't recall the conversation." But he says he thinks that if someone from Merck had asked him if an external safety board was necessary, "I would have said it's important because they would arguably do a better job helping us with the study. It would have more credibility if there was this independent body."

Minutes from meetings show that committee members voiced concerns about safety at their first meeting in January 2002, two years after the clinical trial began. "There were some trends noted in serious adverse clinical events and in thromboembolic events," such as heart attacks, strokes and dangerous blood clots, according to the minutes.

The members would be "exercising diligence" to review the data "due to the concerning nature of the trends, even though the numbers are small," the minutes show.

Early on, the committee requested data looking at the combined rates of heart attacks, strokes, congestive heart failure, pulmonary edema and cardiac failure. That data showed that some Vioxx patients began to experience one or more of the problems much earlier than the 18-month mark.

Congestive heart failure is the inability of the heart to pump blood efficiently, causing someone with the condition to become short of breath and tired with minimal exertion. The heart's inability to pump efficiently as a result of congestive heart failure can lead to fluid buildup, particularly in the lungs, which is called pulmonary edema. Hypertension, or high blood pressure, can lead to congestive heart failure.

A chart tracking the rate of those combined problems showed a clear separation between the side effects reported by some Vioxx users and those taking placebos beginning at 120 days, or about four months.

In her statement, Ms. Wainwright writes that hypertension and fluid retention are "known side effects" of Vioxx, and "this was clearly stated in Vioxx's label. So it would be expected to see a higher rate relative to placebo of these and related side effects, including potentially congestive heart failure" among Vioxx takers. She writes, "These events are very different from heart attacks and strokes."

Noting the clinical trial's purpose of studying Vioxx's effects on polyps, Ms. Wainwright also writes that "the consistent trend" indicated a "rather dramatic beneficial effect." That meant the committee had to balance the drug's risk profile "so as not to prematurely (or inappropriately) end a trial that might show significant benefits," she writes.

Notes from committee meetings make it clear that members were studying a growing trend of heart attacks and strokes. At its last meeting, last Sept. 17, at which the committee decided to halt the trial, the notes show that "the trend for excess risk" for heart attacks and strokes "has continued to grow at each meeting over the last 1-2 years." The minutes note that in May 2003, committee data showed a 20% higher chance of heart attack or stroke in Vioxx patients than in those taking placebos. The risk grew steadily to a 40% higher rate in November 2003, 80% higher in February 2004 and finally 120% in September 2004.

Ms. Wainwright writes that the committee was monitoring the events carefully over time: "Those percentages are based on very small numbers of events," and that the safety board determined the difference between the drug and placebo wasn't statistically significant. The notes reviewed by the Journal don't indicate any dissension among board members.

Safety committees usually have wide latitude in deciding whether to recommend that a clinical trial be halted when concerns over patient safety emerge. Safety boards have shut down other clinical trials without waiting for serious problems to reach statistical significance. Generally, statistical significance means the results are only 5% or less due to chance.

For instance, in 2002, the government called an early halt to its Women's Health Initiative clinical trial testing the hormone estrogen after safety-board members found an increased risk of breast cancer, although the risk didn't reach statistical significance.

"We don't need to prove something is harmful without a shadow of a doubt," says Garnet Anderson, a co-investigator and biostatistician of the Women's Health Initiative studies. Some critics have said the Women's Health Initiative studies were halted prematurely.

Merck and safety-board members say that because there had been conflicting Vioxx studies in the past, a definitive conclusion on cardiovascular safety was needed for the company to act.

"If we were to terminate too early it wouldn't answer the question and it was a critical question to answer," says David Bjorkman, dean of the University of Utah School of Medicine, and one of the members of the safety board who had consulted for Merck previously. "To fail to do that would have been a disservice to all the patients on the drug."

Speaking generally, Jeremy Sugarman, professor of bioethics and medicine at Johns Hopkins University, says, "There are some great examples of situations" in clinical trials "where data look like it's going to be statistically significant and it goes away." Dr. Sugarman, who wasn't part of the Approve committee, has sat on several safety-monitoring boards of drug manufacturers as well as of the National Institutes of Health.

Ms. Wainwright confirms that two of the five safety board members have or have had consulting arrangements with Merck, but she writes that it would be wrong to suggest that "these respected scientists would sacrifice their integrity, subvert the scientific process, and jeopardize patients' health and lives for Merck consulting fees." A Merck spokesman says the company wouldn't disclose how much the researchers have been paid. Ms. Wainwright also writes that the committee member who worked for Merck was a statistician who had no committee vote.

Besides Dr. Bjorkman, who estimates he made less than $20,000 total as a Merck consultant and member of its speaker's bureau, the other physician with Merck ties on the panel was cardiologist Marvin Konstam, chief of cardiology at the Tufts-New England Medical Center. In October 2001, Dr. Konstam was the lead author on an article written with Merck employees and published in the journal Circulation. The article concluded that an analysis of Vioxx trials "provides no evidence for an excess of" cardiovascular events of Vioxx.

The article also took aim at an article published in the Journal of the American Medical Association a few months earlier that concluded that Vioxx posed heart attack and stroke risks. The authors called the JAMA article's methods "hazardous and considerably less reliable."

In a short e-mail response to the Journal, Dr. Konstam wrote, "I and the other members" of the safety panel took "our responsibilities to the patients in the Approve trial, and elsewhere, very, very seriously."
 

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