Vioxx, Celebrex, Bextra: COX2 Inhibitors Unsafe Warns FDA Panel
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
Jeanne Lenzer
New YorkAfter 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 But the panel did not recommend that the drugs be withdrawn from the market.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.
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..."
See: Washington Post articleThis 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?
Contact: Vera Hassner Sharav
212-595-8974
veracare@ahrp.org
THE NEW YORK TIMES
February 25, 2005
10 Voters on Panel Backing Pain Pills Had Industry Ties
By GARDINER HARRIS and ALEX BERENSONTen 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 A01Most 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.
24 February 2005 - A comment by the ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP) on the recent FDA panel decision to not recommend withdrawal of Vioxx, Bextra, and Celebrex...
"Half of the drugs prescribed today are being used in situations where we don't have a good handle on whether they're either safe or effective, and that's a big problem."
But the problem is not being addressed in a forthright manner - neither by the medical community nor the FDA. Last week, FDA's advisory panel failed to meet the challenge before them: they did not recommend measures to prevent future, preventable, drug-induced catastrophes. That leaves drug safety issues to be resolved by Congressional action - and the courts. It is no coincidence that friends of the pharmaceutical industry are attempting to control the damage by lobbying to deprive citizens of just compensation for drug-induced harm.
The Washington Post reports that Dr. Alistair Wood, the Chair, advised the panel just before voting began that they were faced with "the biggest and most complicated drug safety issue to come before the FDA." He noted that "of the 16 drugs the FDA has taken off the market, none had affected nearly as many people because they involved relatively rare side effects and not a general cardiovascular threat."
The panel voted unanimously that all three COX-2 painkillers - Vioxx, Bextra, and Celebrex - "significantly increase" heart attacks and strokes, and agreed that the evidence for both safety and benefits was insufficiently documented. Despite agreement about the hazards, the panel was split on whether to allow these drugs to remain on the market.
            Â
The experts were unable to agree that a demonstrable increased risk of death outweighed any (admiteddly unproven) benefit greater than that provided by existing safer drugs. One wonders under what kind of cost / benefit analysis this decision would appear reasonable?
The rationale given by those who voted to allow drugs that induce fatalities to be marketed, is that the data from randomized controlled clinical trials is insufficient. But that rationale is contradicted by federal law which puts the burden of proof on drug manufacturers.
Federal law requires manufacturers to provide adequate scientific evidence of a drug's safety and effectiveness BEFORE obtaining an FDA license to market a new drug. But pharmaceutical companies are unwilling to conduct adequate controlled trials that are capable of detecting rare but lethal drug effects - they are not anxious to produce evidence that would jeopardize FDA approval. The FDA has betrayed its public responsibility of protecting the public from unsafe drugs by accommodating drug manufacturers. FDA officials have turned the law that was enacted to protect the public from unsafe drugs on its head: Â FDA policy ASSUMES a new drug is safe, until proven with absolute certainty, that it is unsafe.
Instead of requiring drug companies to demonstrate their products' safety by designing their tests to detect whether rare, but serious adverse effects exist, FDA officials demand that independent scientists who detect lethal drug effects demonstrate - in controlled clinical trials - with 95% accuracy - that the drugs pose a safety hazard.
FDA officials and their advisory panels disregard the human casualties linked to the drugs, arguing that documented evidence from the real world is not valid. The panel's split vote sends a mixed message to the public and physicians. Â The panel's failure to use the opportunity of uncontested drug induced cardiovascular fatalities to make recommendations that address the large safety issues - to prevent future drug induced catastrophes - demonstrates a colossal lack of political courage.
Critics view the panel's indecisiveness as a confirmation that drug safety is not a priority. How can physicians sworn to "do no harm" justify prescribing drugs with lethal side effects for conditions that are not life-threatening?
What assurance does anyone have that patients will be fully informed that chronic use of COX2 painkillers - as for arthritis pain - will likely be a trade off between future years of life in return for relief of pain that might well be had by using much safer and cheaper Aleve or aspirin?
The most stunning demonstration that commercial considerations, rather than safey, influence the drug approval and safety assessment process, is the panel's recommendation giving Merck the green light to market Vioxx. The advisory panel appeared to be less convinced by the evidence than Merck. The Washington Post reports that when it withdew the drug, "the company said it believed Vioxx could remain on the market with restrictions, but it decided not to do so because there were alternatives with fewer safety concerns." But safety concerns were clearly not a priority of a panel that voted to give Pfizer and Merck equal commercial opportunities even in the knowledge that lives would likely be sacrificed.
The Chicago Tribune reports that the panel's recommendation to ban direct-to-consumer advertising of painkillers that kill "could be the first step toward limiting a lucrative privilege the government granted the drug industry eight years ago." Â Restoring restrictions on drug advertising - say, for the first 10 years during which safety issues have not been resolved - will substantially reduce the number of people harmed by hazardous drug effects.An added benefit of advertising restrictions would be to free the major media from its dependence on drug advertising revenues. This unacknowledged conflict of interest has rendered many reporters and editors timid about reporting the scope of harm produced by hazardous drug effects.
Contact: Vera Hassner Sharav
212-595-8974
veracare@ahrp.orgSee also:
Pfizer takes painkiller Bextra off market, FDA wants warnings on others
Thursday, April 7, 2005 - BY CONNIE CASS - ASSOCIATED PRESS
WASHINGTON - The painkiller Bextra was taken off the market Thursday, and the government wants other drugs in the same class to carry the strongest possible warnings about increased risk of heart attack and stroke among the millions of people who rely on them.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.Side Effects Of The Drug Scares
New fears give rise to a more honest look at the risks for a pill-popping nation
It's enough to make your head spin. In September, Merck & Co. pulled its blockbuster painkiller Vioxx from the market because a study linked it to heart attacks and strokes. Another study fingered Celebrex, a similar drug made by rival Pfizer Inc.. The Food & Drug Administration quickly came under attack for failing to protect the public from these dangerous drugs. At a three-day FDA advisory committee hearing in late February, 32 outside experts agreed that these relatively new nonsteroidal anti-inflammatory drugs (NSAIDs) do pose serious risks.FDA Chooses Drug Industry Health Over Public Health
by Ritt Goldstein - Commondreams.org
The U.S. Food and Drug Administration (FDA) is supposed to ensure the safety and quality of drugs reaching the public, acting on the taxpayers' behalf. As of Friday (February 18), an extraordinary three-day FDA Advisory Committee meeting is finishing, but investigation suggests business interests have superseded public health at the agency.Deaths linked to heart drugs
Lois Rogers, Medical Editor - The Times
EXPERTS are calling for a complete safety review of heart drugs taken by millions of Britons. Government figures released last week show that 92 deaths have been linked to the statin drugs developed to lower cholesterol.Boston Globe: What ails the FDA? Payola
By Marcia Angell  - March 10, 2005
LET'S FACE it. The FDA is doing a poor job of ensuring that prescription drugs are safe and effective. It approves drugs that offer only minimal benefit, and then sometimes leaves them on the market long after they've been shown to be dangerous.Cox-2 drugs may suppress immune function
Study finds painkillers affect antibodies that attack germsNew York Times: April 24, 2005
Evidence in Vioxx Suits Shows Intervention by Merck OfficialsIn 2000, amid rising concerns that its painkiller Vioxx posed heart risks, Merck overruled one of its own scientists after he suggested that a patient in a clinical trial had probably died of a heart attack.
In an e-mail exchange about Vioxx, the company's most important new drug at the time, a senior Merck scientist repeatedly urged the researcher to change his views about the death "so that we don't raise concerns." In later reports to the Food and Drug Administration and in a paper published in 2003, Merck listed the cause of death as "unknown" for the patient, a 73-year-old woman.
The discussion of the death is contained in several previously undisclosed Merck records, including e-mail messages from Dr. Edward M. Scolnick, Merck's top scientist from 1985 until 2002, and from Dr. Alise S. Reicin, a vice president for clinical research, that indicate Merck's concerns about data contradicting its view that Vioxx was safe.
In one e-mail message, Dr. Scolnick said the drug trial that included the woman's death had "put us in a terrible situation." In others, he fiercely criticized the F.D.A. and said he would personally pressure senior officials at the agency if it took action unfavorable to Vioxx. As lawsuits against Merck over Vioxx move toward trial, the documents could help plaintiffs paint a picture of the company that is at odds with Merck's public statements that it had no evidence of Vioxx's cardiac risks until last fall.
The FDA, Vioxx, and crimes against humanity
No Cardiovascular Studies Done on Vioxx Before Launching It
August 2005: First Vioxx Verdict A Big Defeat For Merck
Merck faces huge bill after widow wins $250m Vioxx claim
Investigation: Victims of drug that took a hidden toll
Bextra - What Did Pfizer Know? - Everything
by Evelyn Pringle
Critics say millions of people were needlessly exposed to the risks of Bextra due to intense off-label promotion and advertising that boosted the painkiller to a position near the top of the list of the most widely prescribed drugs in US history. Although a drug can only be marketed for specific indications approved by the FDA, doctors are allowed to prescribe a drug for any use regardless of whether its approved for a diagnosis and Pfizer spent a fortune on convincing physicians to prescribe Bextra for unapproved uses.Study: Vioxx poses even short-term risks
A Montreal study raises questions about even short-term use of the pain drug Vioxx and may harm Merck & Co.'s defense against 11,500 lawsuits, a report said. The study, published Tuesday in the Canadian Medical Association Journal, said people 65 and older are at the greatest risk of suffering a heart attack within 6-13 days of their first ingestion of Vioxx. The McGill University study also found elderly patients' heart attack risk did not increase the longer they took the drug, which Merck pulled off the world market in 2004. A key element of Merck's defense has been that it took 18 months or longer for the heart attack risk to increase...
posted by Sepp Hasslberger on Monday February 28 2005
updated on Friday December 10 2010URL of this article:
http://www.newmediaexplorer.org/sepp/2005/02/28/vioxx_celebrex_bextra_cox2_inhibitors_unsafe_warns_fda_panel.htm
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October 29, 2003 - Sepp Hasslberger
