The safety of

Merck's

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Vioxx has been questioned again with the posting of an internal Food and Drug Administration study on the agency's Web site.

The study, posted Tuesday, says the recently withdrawn Vioxx increased by 3.7-fold the risk of "serious coronary heart disease" when compared to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

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Celebrex.

The study also says a standard dose of Vioxx increased the cardiovascular risk by 1.5 times over Celebrex.

The study was conducted by Dr. David J. Graham, associate director for science in the FDA's office of drug safety. It builds upon research that he presented at a medical conference in France in late August, which generated headlines and spooked investors at the time.

Merck withdrew Vioxx on Sept. 30, saying it acted because a company-sponsored study that showed long-term use of the drug -- more than 18 months -- increased cardiovascular risk among patients who took Vioxx vs. those who took a placebo. Using Vioxx for less than 18 months, Merck said, posed no statistically significant risk compared to taking a placebo.

Since Merck pulled Vioxx, Pfizer has been releasing results of several tests to show that its drug Celebrex doesn't cause the same problems. However, Pfizer announced recently that it is sponsoring long-term tests to assess cardiovascular safety of Celebrex and a similar drug, Bextra. Both are COX-2 inhibitor drugs, just like Vioxx.

The latest FDA report, however, came with a host of qualifications, saying that the report "was prepared for internal FDA use." The qualifying note said that this report "may differ from any subsequent manuscript publications of the study results."

The agency emphasized that Graham's study "has not been fully evaluated by the FDA and may not reflect the official views of the agency." However, because Merck pulled Vioxx from the market, the FDA said it decided to release the report.

Making a Comparison

"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.

"Prior to today, my conclusions regarding rofecoxib were that high-dose usage of the drug should be ended and that lower-dose rofecoxib should not be used by physicians or patients," Graham said. "If lower dose rofecoxib remained on the market, physicians and patients needed to understand that the risk of

heart attack or sudden cardiac death was substantially increased and that there were safer alternatives."

Graham criticized Merck's previous assertion that it could not conclusively prove Vioxx's cardiovascular risk based on a trial called VIGOR. This study tried to determine if Vioxx had fewer gastrointestinal side effects than a common pain reliever, naproxen.

Preliminary results of the VIGOR study became available in March 2000, showing "a difference in the cardiovascular event rate" between Vioxx patients and naproxen patients, Merck said in a press conference last month. The data didn't match test data that Merck had submitted to the FDA in November 1998 showing no difference between Vioxx and placebo or between Vioxx and other non-naproxen pain relievers. (The FDA approved Vioxx in May 1999.)

A top Merck executive said the company couldn't ascertain cardiovascular risk in the VIGOR trial because the study didn't include a placebo as a comparison. When the VIGOR results became known, Merck checked safety data in two ongoing studies comparing Vioxx and placebo in patients with Alzheimer's disease. Merck found no difference in cardiovascular problems between patients taking Vioxx and those taking a placebo.

Based on these tests and because naproxen has an anti-clotting effect, Merck concluded that naproxen had a beneficial heart effect in the VIGOR study. Merck submitted the new data to the FDA . The Vioxx label was changed by the FDA in 2002, referring to the cardiovascular data in the VIGOR and Alzheimer's disease studies.

Graham argued that Merck should have acted after its saw the results of the VIGOR trial. "The manufacturer attributed this difference

in cardiovascular risk to a never-before recognized protective effect of naproxen," Graham said. He added that four studies "found no evidence" that naproxen provides any heart-protection improvement. Three other studies "that reported a protective effect were misleading," he added.

Continuing Controversy

The Nov. 2 report from Graham expands upon a presentation he made at a medical conference in France in late August, using three years of prescription and medical data compiled by the Kaiser Permanente health maintenance organization. Merck criticized Graham's original study, saying that this retrospective data analysis had more limitations than carefully controlled clinical trials. (Merck pulled Vioxx from the market based on a controlled clinical trial.)

Last month, Sen. Charles Grassley, R-Iowa, accused the FDA of trying to block Graham's presentation of his findings, an allegation the FDA rejected. Grassley, chairman of the Senate Finance Committee, has been examining how the FDA deals with drug safety issues.

On Monday,

The Wall Street Journal

said Merck executives were reportedly aware of -- and tried to play down -- Vioxx's potential risk for causing cardiovascular problems such as heart attack and stroke before the drug was approved by the FDA and afterward. Citing internal emails, marketing documents and interviews with "outside scientists," the

Journal

said that Merck "fought forcefully for years to keep safety concerns from destroying the drug's commercial prospects."

The article says the prospect of cardiovascular risk emerged in the mid- to late 1990s, adding that internal emails say company officials discussed how to design clinical studies that, the newspaper says, would "minimize the unflattering comparison" that showed Vioxx had a greater heart risk than cheaper pain relievers. The article said internal marketing materials showed, in part, that sales representatives were told to "dodge" questions from doctors about heart risks.

Before the article was published, Merck said on Friday: "These documents are pulled from the millions of documents Merck has produced to date during these legal proceedings. Past experience of other companies in such situations suggests that documents will be deliberately presented out of context to advance the interest of the parties who have started Vioxx. As such, the documents, the surrounding events and the business practices of Merck may well be misinterpreted in any reporting."