Vioxx, Celebrex, Bextra: COX2 Inhibitors Unsafe Warns FDA Panel

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Pharma

The three-day deliberations of experts called by the FDA to recommend on the fate of the "Vioxx class" pain drugs have led to recommendations of severe warnings to be put in black boxes on the drugs' packaging, but stopped short of recommending that they be removed from the market altogether.

After some days of stunned silence and media reporting that the drugs have been found safe enough to remain on the market, as well as an announcement by Dr Peter Kim, the president of Merck Research Laboratories, that the company was considering to bring Vioxx back to the market, we now hear that there were at least ten members of the expert committee that had ties to the very industries whose drugs they were considering.

Jeanne Lenzer puts the matter in perspective, when she titles her article in the British Medical Journal: FDA advisers warn: COX 2 inhibitors increase risk of heart attack and stroke.

Lenzer quotes Dr Alastair Wood, the panel's chairman and associate dean at Vanderbilt University School of Medicine, Nashville, who criticised US media coverage of the panel's findings. Wood said that the coverage was distorted because it focused on the fact that the panel had not recommended the drugs' withdrawal rather than on its finding of an increased risk of heart attack and stroke. He said,

"The general outcome [of the hearings] was greatly overrated in the US press. Two drugs were recommended for removal from the market by almost 50% of the committee. The press took this [the fact that a majority did not vote for withdrawal] as an endorsement [of their safety] by the committee. But it clearly was not. This is like assembling a group of pilots at the end of a jet way and half of the pilots tell you the plane is unsafe to fly. Would you get on it?"

FDA advisers warn: COX 2 inhibitors increase risk of heart attack and stroke

(see original)

Jeanne Lenzer
New York

After three days of deliberation an advisory panel to the US Food and Drug Administration decided that the widely used cyclo-oxygenase-2 (COX 2) inhibitors rofecoxib (Vioxx), celecoxib (Celebrex), and valdecoxib (Bextra) all carry serious risks of heart attack and stroke and recommended that the FDA demand that the drugs carry "black box" warnings. But the panel did not recommend that the drugs be withdrawn from the market.
The panel was convened after Merck voluntarily withdrew rofecoxib (Vioxx) from the market on 30 September, when it was found that the drug doubles the risk of heart attacks and strokes in patients who take it for 18 months or longer.

US media coverage of the panel's findings has been criticised by Dr Alastair Wood, the panel's chairman and associate dean at Vanderbilt University School of Medicine, Nashville. He said that the coverage was distorted because it focused on the fact that the panel had not recommended the drugs' withdrawal rather than on its finding of an increased risk of heart attack and stroke.

He said, "The general outcome [of the hearings] was greatly overrated in the US press. Two drugs were recommended for removal from the market by almost 50% of the committee. The press took this [the fact that a majority did not vote for withdrawal] as an endorsement [of their safety] by the committee. But it clearly was not. This is like assembling a group of pilots at the end of a jet way and half of the pilots tell you the plane is unsafe to fly. Would you get on it?"

The US findings came after similar findings by Australian and European authorities. On 10 February Australia's Therapeutic Goods Administration instituted a requirement that all COX 2 drugs carry a black box warning highlighting the risk of serious cardiovascular events and strongly urged doctors and patients to adhere to lower dose ranges.

After four days of deliberations the European Medicines Agency issued a statement on 17 February contraindicating COX 2 drugs for patients with ischaemic heart disease or stroke and urging caution for patients with risk factors such as high blood pressure, hyperlipidaemia, diabetes, heart disease, smoking, or peripheral vascular disease (www.emea.eu.int/pdfs/human/press/pr/6275705en.pdf).

The FDA advisory panel, a joint meeting of the agency's Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee, also recommended that the FDA require strongly worded black box warnings for each of the three COX 2 inhibitors currently approved in the United States - celecoxib, valdecoxib, and rofecoxib. The decision about rofecoxib was needed, according to FDA officials, because the drug was not ordered off the market but was withdrawn voluntarily.

The panel's finding of a class effect led to an unexpected announcement - which one committee member called a "cliff hanger" - by Dr Peter Kim, president of Merck Research Laboratories, who told the committee, "When we withdrew rofecoxib we thought there were safe alternatives." But he said that in light of "new scientific information" Merck would consider returning rofecoxib to the market.

During the three days of hearings the 32 member panel heard emotional testimony from a number of patients who said that only a certain COX 2 drug helped their pain and who begged the panel not to withdraw their treatment.

The challenge of making decisions in the face of imperfect science was a topic of much discussion. Panel members repeatedly cited examples of findings from observational studies that were later discredited by randomised controlled trials. One panellist said, "The road to hell is paved with biological plausibility."

Dr David Graham, the FDA's associate director for science in the Office of Drug Safety, presented unpublished data confirming the risks of rofecoxib and the risks of heart attack and stroke associated with non-selective non-steroidal anti-inflammatory drugs, such as the top selling drug meloxicam (Mobic).

A few panellists raised questions about Dr Graham's data, but others defended both his findings and the nature of the study.

Questions were also raised during the hearings about whether cardiovascular risks were dealt with in a timely and appropriate manner after the Vioxx gastrointestinal outcomes research (VIGOR) study in 2000 that first showed excess cardiovascular deaths in patients taking the drug.

Dr Richard Platt, a member of the Drug Safety and Risk Management Advisory Committee and chairman of the Department of Ambulatory Care and Prevention at Harvard Medical School and Harvard Pilgrim Health Care, said, "My concern is that the VIGOR study did not result in a prompt change in practice." Part of the problem in realising there was a genuine signal, said Dr Platt, was that common disorders are harder than rare problems to confirm as side effects of a drug.

Some panel members urged caution about placing warnings on COX 2 drugs, saying they didn't want to "scare" patients by issuing warnings without definitive proof of harm. But other members said that the standards of scientific proof for efficacy should not be the same as the standards used to warn of harm.

"One of the particular problems with COX 2 inhibitors," said Dr Platt, "is that they were very widely used almost as soon as they were released, and they were used by many more people than just those at high risk for gastrointestinal problems." That problem, he said, was greatly aggravated by advertising directly to consumers.

Dr Curt Furberg, another member of the Drug Safety and Risk Management Advisory Committee, said that he was pleased with the black box warning, as it would make it very hard for manufacturers to advertise.

Dr Garret FitzGerald, a cardiologist at the University of Pennsylvania and a guest speaker at the hearing, said, "For those who wanted to pretend this is just a Vioxx problem... I'm glad to say those ghosts were exorcised."

"We need to figure out how we can do a better job in the future," said Dr Platt. "I think it would be very worthwhile for the FDA to enhance its capacity to identify important adverse events more quickly."

February 2005:

A communication from the ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

The latest example of the corrupting influence of the pharmaceutical industry on health care policy is the composition of FDA's advisory panel that last week endorsed the marketing of lethal COX-2 pain killers. A front page article in today's New York Times (below) reports that 10 of the 32 panelists on FDA's advisory committee swung the votes last week in favor of allowing the continued marketing of painkillers that induce fatal heart attacks and strokes had ties with those drugs' manufacturers - Pfizer and Merck.

"If the 10 advisers had not cast their votes, the committee would have voted 12 to 8 that Bextra should be withdrawn and 14 to 8 that Vioxx should not return to the market. The 10 advisers with company ties voted 9 to 1 to keep Bextra on the market and 9 to 1 for Vioxx's return."

The 10 panelists were identified by Merril Goozner of The Center for Science in the Public Interest from disclosures in medical journals and other public documents. Other panelists may have similar conflicts that have not yet been identified.

Major, pervasive conflicts of interest among senior scientists at the National Institutes of Health were documented by the Los Angeles Times beginning with a major expose on December 7, 2003. The scope and severity of NIH scientists' conflicts of interest is staggering ... 94% of the top paid NIH scientists failed to report their financial deals with pharmaceutical companies. Several Congressional hearings were held in 2004, and a request by Congressional staff sent to just 20--out of several hundred pharmaceutical companies-yielded 100 names of NIH scientists with whom the companies had financial deals. These 100 represent the tip of an iceberg.

The scientists who receive the highest government salaries, continue to deny all and have embarked on a battle against restrictions on their supplemental income. Multiple investigations confirmed the evidence uncovered by the LA Times, leading Dr. Elias Zerhouni, director of NIH, to finally issue new conflict of interest regulations, effective Feb. 3, 2005. But as Dr. Zerhouni predicted, the hardest part is to change the culture at NIH:

"It's easy to come up with regulations. It's not easy to change a culture."

The new rules are meant to root out conflicts of interest and prevent major ethical abuses aff