Leaked documents show Merck knew of Vioxx dangers, yet hid them for years

Saturday, August 06, 2005 by: Dani Veracity
Tags: Merck, Vioxx, bad medicine

"What are the long-term benefits of your being able to bring value to the relationship with our customers?" Merck asked sales trainees in a PowerPoint slide captioned "The Payoff." "Bonus," appeared on the next slide, showing a sales representative holding a glowing bag of money. This is from a company that is "really putting patient safety first," according to Merck Chief Executive Raymond Gilmartin's statement in September 2004, upon finally pulling Vioxx of the market. As the thousands of wrongful death and injury lawsuits against Merck go to trial one by one, internal company documents like this training slide show are beginning to reach the public eye. These leaked documents began with previously undisclosed emails discussing safety risk, but the clamor has now reached crescendo with the most potentially damaging document yet: A leaked communication between Merck researchers and the company's patent department.

An application for a patent seems harmless enough, except when the product in question is a correcting reformulation of the now-withdrawn prescription drug Vioxx. In this leaked document, the authors specifically stated that Vioxx increases the risk of potentially fatal cardiovascular disease by reducing the body's production of a substance called prostacyclin, which prevents platelet coagulation. This reduction may alter the ratio of prostacyclin to thromboxane, a substance which can constrict blood vessels, resulting in excessive blood clotting, and, consequently, heart attacks and strokes -- the very disorders that Merck denies Vioxx promotes.

In other words, based on this evidence, Merck has apparently been feigning ignorance of Vioxx's disastrous complications for the last five years. Their knowledge of the risk wasn't cursory, either. In fact, as early as March 30, 2000, Edward Scolnick, the former head of Merck's research labs, realized the risk was high enough to suggest that Vioxx be combined with an anti-clotting agent. Then, in 2001, Merck filed an application with the U.S. Patent Office for a new-and-improved Vioxx that was to be combined with a thromboxane inhibitor, but Merck eventually dropped the project and the patent. In response to the leaked document concerning the proposed patent, Merck's law firm released a statement saying that the application had nothing to do with Merck's firm belief that Vioxx was safe; however, the statement seems illogical: Why would Merck wish to fix what wasn't broken?

How to bury scientific truth

On Nov. 1, 2004, the eastern edition of The Wall Street Journal broke the story: "Warning Signs: Emails Suggest Merck Knew Vioxx's Dangers at Early Stage," discrediting Merck's feigned ignorance of Vioxx's cardiovascular risks. According to a memo dated Nov. 21, 1996, Merck officials first "wrestled" with the issue of Vioxx's dangerous effects in 1996 when they considered running a trial to demonstrate that Vioxx is gentler on the digestive system than other painkillers, like aspirin. Officials feared that the study would also reveal Vioxx's cardiovascular risk because the subjects of course would not be able to avoid the risk by taking aspirin. The controversy continued into 1997, when Merck official Briggs Morrison sent an email dated Feb. 25, 1997, arguing that, unless test subjects received aspirin, the revealed cardiovascular risks would "kill [the] drug."

Now, let's examine Merck's concerns for a moment: Based on leaked ducuments, Merck officials knew that Vioxx posed cardiovascular risk as early as 1996 and, yes, they were worried about it, because if it were revealed, the risk might decrease sales. In response to Morrison's email, Alise Reicin, who is now Merck's vice president for clinical research, emailed that the company was in a "no-win situation" and proposed that people with high risk of cardiovascular problems be excluded from the story, so that the difference between the rate of cardiovascular problems associated with Vioxx and other drugs "would not be evident."

(In other words, it's not okay for people with increased cardiovascular risk to take Vioxx in a research study that will have publicized results, but it seemed perfectly alright for them to take Vioxx by prescription and suffer or die in private.)

Then, on March 9, 2000, a year after the FDA's approval of Vioxx, Scolnick sent his colleagues an email in which he said that Vioxx's cardiovascular side effects "are clearly there" and are a "shame." However, four years later, Gilmartin still had the gall to say that the research findings that finally initiated Vioxx's ban were "unexpected." This apparent lie could have gone unnoticed, if it hadn't been for The Wall Street Journal's breaking story. It was noticed, however, and it has sparked a series of media coverage and stock market losses. "Can the news get any uglier for Merck?" asked the November 6, 2004 issue of Economist. Well, thanks to the latest leaked document, it just did.

Merck is going to have a difficult time backing out of this corner. In the New Jersey Vioxx lawsuit where the unscrupulous communication by Merck was first revealed, the judge called the document privileged information, so it was not used. Other judges might not consider it privileged, thus allowing it in their courtrooms. According to Associated Press reporter Theresa Agovino, analysts estimate that Merck's liability could reach as high as $18 billion. Based on current evidence, Merck ignored research findings in order to make more money; now, they may lose more than they ever imagined.

Sources on the recent Vioxx leak (in order of appearance in this article):

"The Payoff and the Company that 'Really Puts Patient Safety First'"

One slide was captioned, "The Payoff." "What are the long-term benefits of your being able to bring value to the relationship with our customers?" it asked. Pictured underneath was a sales rep holding a glowing bag of cash captioned "Bonus."
"For Our Eyes Only … Inside Merck's Mess" by Jim Edwards and Michael Applebaum, Brandweek 5/16/2005, page 52

When Merck & Co. pulled its big-selling painkiller Vioxx off the market in September, Chief Executive Raymond Gilmartin said the company was "really putting patient safety first."
"Warning Signs: E-Mails Suggest Merck Knew Vioxx's Dangers at Early Stage; As Heart-Risk Evidence Rose, Officials Played Hardball; Internal Message: 'Dodge!'; Company Says 'Out of Context'" by Anna Wilde Mathews and Barbara Martinez, Wall Street Journal (Eastern edition) 11/1/2004, page A1

"Leaked Communication Reveals Merck Tried to Reformulate Vioxx in 2000 and Patent It in 2001"

Merck & Co. researchers privately sought to reformulate Vioxx in 2000 to reduce its cardiovascular side effects, even as the drug maker was publicly playing down a study that highlighted the pain relief medication's potential heart attack risk, an internal company document shows.

The widely publicized study in March 2000 found that patients taking Vioxx were five times more likely to have heart attacks than individuals using the generic medicine naproxen. Merck insisted at the time that this was a result of naproxen's cardioprotective properties and not any defect in Vioxx.

But behind the scenes, company scientists were considering combining Vioxx with another agent to reduce the risk of heart attacks and strokes, according to a document that was mistakenly provided by Merck to plaintiff lawyers as part of the evidence-gathering process in one of the hundreds of Vioxx lawsuits around the country.

That document, a communication between Merck researchers and the company's patent department, stated that the way Vioxx works to reduce pain might also increase cardiovascular problems. They suggested a patent be sought for a combination drug mixing Vioxx with another agent to lessen the risk.

Merck filed an application with the U.S Patent Office in 2001 to combine Vioxx with what is called a thromboxane inhibitor, according to a statement released Wednesday by the company's counsel, Hughes, Hubbard & Reed. The statement said the hope was that Vioxx could provide cardioprotective protection while preserving its gastrointestinal benefits. But the project was later dropped, making the patent application moot.
"Merck Tried to Alter Vioxx in 2000" by Theresa Agovino, Associated Press

"Researchers Knew that Vioxx May Lead to Cardiovascular Problems"

According to the document, Edward Scolnick, the former head of Merck's research labs, was the first to suggest combining Vioxx with an agent that would block blood platelets from clotting. Such clots can lead to heart attacks and strokes. There are three dates on the document; the first is March 30, 2000.

The document's authors said Vioxx might reduce the production of a substance called prostacyclin, which prevents platelet aggregation. That reduction may alter the ratio of prostacyclin to thromboxane, a substance which can constrict blood vessels and cause clotting. The change may cause increased risk of cardiac and cerebral adverse events, the document said.
"Merck Tried to Alter Vioxx in 2000" by Theresa Agovino, Associated Press

A Nov. 21, 1996, memo by a Merck official shows the company wrestling with this issue. It wanted to conduct a trial to prove Vioxx was gentler on the stomach than older painkillers. But to show the difference most clearly, the Vioxx patients couldn't take any aspirin. In such a trial, "there is a substantial chance that significantly higher rates" of cardiovascular problems would be seen in the Vioxx group, the memo said.

A similar view was expressed in a Feb. 25, 1997, e-mail by a Merck official, Briggs Morrison. He argued that unless patients in the Vioxx group also got aspirin, "you will get more thrombotic events" -- that is, blood clots -- "and kill [the] drug."

In response, Alise Reicin, now a Merck vice president for clinical research, said in an e-mail that the company was in a "no-win situation." Giving study subjects both Vioxx and aspirin, she wrote, could increase the "relative risk," apparently referring to gastrointestinal problems. But, she added, "the possibility of increased CV [cardiovascular] events is of great concern." From the context, it seems Dr. Reicin meant "increased" relative to older drugs.

She added in parentheses: "I just can't wait to be the one to present those results to senior management!" She proposed 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."
"Warning Signs: E-Mails Suggest Merck Knew Vioxx's Dangers at Early Stage; As Heart-Risk Evidence Rose, Officials Played Hardball; Internal Message: 'Dodge!'; Company Says 'Out of Context'" by Anna Wilde Mathews and Barbara Martinez, Wall Street Journal (Eastern edition) 11/1/2004, page A1

By 2000, one email suggests Merck recognized that Vioxx didn't merely lack the protective features of old painkillers but that something about the drug itself was linked to an increased heart risk. On March 9, 2000, the company's powerful research chief, Edward Scolnick, e-mailed colleagues that the cardiovascular events "are clearly there" and called it a "shame." He compared Vioxx to other drugs with known side effects and wrote, "there is always a hazard." But the company's public statements after Dr. Scolnick's email continued to reject the link between Vioxx and increased intrinsic risk.
"Warning Signs: E-Mails Suggest Merck Knew Vioxx's Dangers at Early Stage; As Heart-Risk Evidence Rose, Officials Played Hardball; Internal Message: 'Dodge!'; Company Says 'Out of Context'" by Anna Wilde Mathews and Barbara Martinez, Wall Street Journal (Eastern edition), 11/1/2004, page A1

"Can the News Get Any Uglier for Merck?"

Can the news get any uglier for Merck? Barely a month after Ray Gilmartin pulled Vioxx, a hitherto blockbuster arthritis drug, from the market, Merck's boss suddenly finds himself fighting for his job. Since he broke the news about Vioxx, citing new evidence that the drug raises the risk of heart attacks and strokes, the firm's share price has nearly halved, knocking over $30 billion off the value of the world's fourth-biggest drug company. This week, plaintiff lawyers leaked to the press an apparently damning e-mail and internal company documents (which were supposedly sealed under court order pending lawsuits involving Vioxx), calling into question Merck's reputation for probity. As the lawsuits pile up, the proud, insular giant is giving every appearance it has no idea what it is dealing with. The firm is "bewildered", says one well-placed source.
"Big trouble for Merck," Economist 11/6/1004, page 61

"Can the Leaked Documents be Used in Court?"

The document became an issue in a New Jersey Vioxx lawsuit when Merck objected to its use on the grounds that it was an attorney-client communication between company scientists and in-house patent counsel.
New Jersey Superior Court Judge Carol E. Higbee ruled May 27 that the document was privileged and could not be used at trial. She also ordered that all copies of the privileged document be returned to Merck or destroyed, but she required Merck to turn over other documents related to the reformulation, including e-mails and memos, within 30 days.
Benjamin Zipursky, a professor at Fordham Law School in New York, said it's conceivable that other judges could rule differently and allow the document to be used in Vioxx cases. Lawyers in the Texas case said they have the document and will attempt to make it part of their evidence.
"Merck Tried to Alter Vioxx in 2000" by Theresa Agovino, Associated Press