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 bringing 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

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 But the panel did not recommend that the drugs be withdrawn from the market.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 September 30th, 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 (www.tga.gov.au/media/2005/050210_cox2.pdf).

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 affecting the safety of patients and the integrity of medicine. The new rules will bring NIH staff scientists in line with federal legislation prohibiting government employees from having conflicts of interest or using insider information for self-enrichment.

But the NIH scientists are furious about a requirement that they divest themselves of pharmaceutical company stocks. Incredibly, they seem to have found support from apologists at the Washington Post. Earlier this week, a front page article, accompanied by an editorial, supported the disgruntled NIH scientists who had used their position and insider knowledge. Scientists at NIH have a sense of entitlement to be free to strike stock option deals with companies for whom they conducted clinical trials, to engage in lucrative lecture and consultancy deals--while drawing the highest level government salaries.

The Post reported that an NIH investigation found that: "as much as 80 percent of the seeming improprieties were actually the result of errors by government investigators." However, as has been amply demonstrated, NIH self-investigations have no credibility. The editorial said the rules "went too far." "They threaten to harm the ability of the institutes to attract and retain top scientists..."

This is an astonishing about face, from a July 5, 2004, editorial, "Double Dipping at NIH" which raised doubts whether Dr. Zerhouni's announcement that he would impose "drastic changes" to curtail conflicts of interest would be enough:

"Dr. Zerhouni's prescription, which goes beyond his original recommendations, may turn out not to be strong enough medicine. It's a legitimate question whether any outside consulting at all should be allowed."

See: Washington Post's earlier article Whatever changed the editors' position?

Might this be a payoff for the few crumbs the Post receives from government officialdom?


THE NEW YORK TIMES
February 25, 2005
10 Voters on Panel Backing Pain Pills Had Industry Ties
By GARDINER HARRIS and ALEX BERENSON

Ten of the 32 government drug advisers who last week endorsed continued marketing of the huge-selling pain pills Celebrex, Bextra and Vioxx have consulted in recent years for the drugs' makers, according to disclosures in medical journals and other public records. 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 votes of the 10 did not substantially influence the committee's decision on Celebrex because only one committee member voted that Celebrex should be withdrawn.


Washington Post
NIH Clears Most Researchers In Conflict-of-Interest Probe
By Rick Weiss
Wednesday, February 23, 2005; Page A01

Most of the 100 or so National Institutes of Health researchers who the agency has said are under investigation for allegedly engaging in secret deals with pharmaceutical and biotechnology companies have been cleared by NIH investigators, according to agency officials. The unexpected finding that as much as 80 percent of the seeming improprieties were actually the result of errors by government investigators has undermined the rationale behind NIH Director Elias A. Zerhouni's recent decision to impose severe restrictions on the personal activities and finances of all of the agency's more than 5,000 employees, said scientists and NIH officials upset about the new rules.



The FDA's Pure Evil In Reapproving Vioxx

Drugs aren't commodities to be hustled like cars and cookies

By ANDRÉ PICARD - The Globe and Mail
Thursday, February 24, 2005

One of the most important and overlooked recommendations of the U.S. advisory committee that held public hearings on the safety of Vioxx and other cox-2 inhibitors is a call to ban all advertising of the popular painkillers. It is clear to the panel members that advertising played a central role in this debacle.

Vioxx and Celebrex were among the most heavily advertised drugs in history. Their main claim to fame, touted in slick ads, was that they were safer than cheaper painkillers such as ibuprofen when, in reality, they increased the risk of heart attack and stroke. Advertising, in no small measure, led to the gross overprescription of these drugs to people with arthritis and other painful conditions. And it is telling that, when questions began to be raised about the safety of Vioxx, its maker, Merck & Co., responded by bolstering the ad campaign for the drug, not by commissioning research to investigate scientists' concerns.