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Celebrex & Vioxx Backlash on FDA
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Lancet Editorial questions & raises doubts of FDA review for new drugs. Backlash over Vioxx recall & expected article in NEJM question Celebrex and entire class of cox-2 inhibitors.
Vioxx: an unequal partnership between safety and efficacy
Lancet EDITORIAL, Oct 9, 2004
"...drug regulators must now reassess the safety and efficacy thresholds required for the licensing of a new pharmaceutical product... blindly aggressive marketing by Merck mixed with repeated episodes of complacency by drug regulators... We need clear statements from all parties in this sorry tale about the lessons to be learned. Without more vigilant drug regulation in the future, doctors will continue to be misled and patients' lives will continue to be endangered..."
Rofecoxib (Vioxx) is, or was, Merck and Co's leading drug for control of acute pain, and pain associated with osteoarthritis, rheumatoid arthritis, and menstruation. Last year worldwide sales of rofecoxib reached US$2·5 billion following the most impressive global sales growth for any drug in 2001. Last week, after urgent discussions with the US Food and Drug Administration (FDA), Merck felt compelled to withdraw rofecoxib after its most recent trial, APPROVe (Adenomatous Polyp Prevention On Vioxx), showed an adverse cardiovascular side-effect profile. For Merck to act so promptly in the face of these most recent safety concerns is commendable and should serve as an example of responsible pharmaceutical industry practice. However, the short history of cyclooxygenase (COX)-2 inhibitors has been plagued by persistent safety concerns. The question that must now be answered is why has it taken so long for Merck and government drug regulators to address these signals properly?
The story of COX-2 inhibitors began for clinicians and their patients in 1999 with the licensing of two first generation drugs, rofecoxib and celecoxib, by the FDA. Their primary indications were for the control of pain associated with several different conditions and their debut was announced in 2000 in the medical literature with two landmark trials: VIGOR for rofecoxib, and CLASS for celecoxib. Subsequently, a number of second generation COX-2 inhibitors have been developed. These include valdecoxib, parecoxib, etoricoxib, and lumiracoxib. The indications for their use have remained largely unchanged and more "me-too" COX-2 inhibitors are on the horizon.
From the outset, questions have been raised about the safety profile of these drugs. Although the CLASS trial did not find a difference in the incidence of cardiovascular side-effects between celecoxib and ibuprofen or diclofenac, the VIGOR trial revealed a significant increase in the number of myocardial infarctions in patients taking rofecoxib compared with those receiving naproxen. These concerns were crystallised the following year by Debabrata Mukherjee, Steven Nissen, and Eric Topol in JAMA in their review paper specifically highlighting the cardiovascular side-effect profile of COX-2 inhibitors. Concerns were shared by the FDA, who implemented labelling changes in 2002 to reflect the findings from the VIGOR trial. However, even following these warnings, and in the face of mounting evidence for the cardiovascular side-effects of rofecoxib, aggressive direct-to-consumer marketing of this questionable drug continued unabated.
What then finally tipped the balance in the risk-benefit equation leading to last week's dramatic global withdrawal of rofecoxib? APPROVe was a multi-centre, randomised, placebo-controlled, double-blind study investigating the effects of rofecoxib on the recurrence of neoplastic large bowel polyps in 2600 patients with a previous history of colorectal adenoma. It was stopped prematurely on the instruction of the data and safety monitoring board after the investigators found that after 18 months treatment, patients taking rofecoxib had twice the risk of a myocardial infarction compared with those receiving placebo. Advice is now being issued to pharmacists and doctors in each of the 80 countries where rofecoxib is marketed to stop prescribing the drug with immediate effect. 2 million patients already taking rofecoxib will be contacting their physicians to discuss discontinuing treatment--a busy and anxious time for doctors around the world.
A key question remains as to why it took this risk to be identified from a relatively small trial investigating a novel use for rofecoxib, after it had been licensed for several years and prescribed to so many patients? Although Peter Kim, president of Merck Research Laboratories, recently said "Merck has always believed that prospective, randomized, controlled clinical trials are the best way to evaluate the safety of medicines. APPROVe is precisely this type of study . . . ", it is unlikely that APPROVe was designed and executed with a general safety assessment as its primary goal. A further question relates to the safety of the other COX-2 inhibitors being actively marketed today. Although the TARGET trial published in The Lancet in August this year, and the largest COX-2 trial to date, failed to demonstrate a statistically significant difference in cardiovascular side-effects between lumiracoxib and naproxen or ibuprofen, more people taking lumiracoxib had a myocardial infarction.
Doctors need to be more aware of the very preliminary nature of data, both for safety and efficacy, provided with newly licensed drugs. For rofecoxib the original safety data were based on results from approximately 5000 patients. In comparison with the 2 million people receiving the drug until last week, this is a very small number and helps to explain how an important side-effect could have been missed, and subsequent confidence in the drug misplaced. For all newly licensed drugs, confidence about safety can only be provisional.
Pharmaceutical companies also have lessons to learn. Merck responded well to this latest piece of the rofecoxib jigsaw puzzle. However, the real picture of cardiovascular risk has been apparent for some time and Merck's vigorous defence of this drug in the past was clearly an error. If the dangers associated with rofecoxib were not proven, they were certainly possible, even probable, given the available data, and it should not have been left to a small trial in a novel application to reveal them. In the end it is patients, now understandably confused by the implications of rofecoxib's withdrawal, who will lose the most. Which drugs, they will ask, should they trust?
Finally, drug regulators must now reassess the safety and efficacy thresholds required for the licensing of a new pharmaceutical product. Clearly, this is an immensely complicated equation involving, among other factors, the nature of the condition being treated, the therapeutic strategies already available, and the perceived benefit-to-hazard ratio of the new treatment. The Vioxx story is one of blindly aggressive marketing by Merck mixed with repeated episodes of complacency by drug regulators. We need clear statements from all parties in this sorry tale about the lessons to be learned. Without more vigilant drug regulation in the future, doctors will continue to be misled and patients' lives will continue to be endangered. * The Lancet
Drugs Similar To Vioxx May Raise Heart-Attack Risks
AP, Wall St Jnl, DOW JONES NEWSWIRES
October 6, 2004
NEW YORK (AP)--Scientists and European regulators are now questioning the safety of other pain relievers like Vioxx, saying these medications also might raise the risk of heart attack and stroke.
Vioxx, heavily marketed as an arthritis drug, was pulled from the market last week after its maker announced that a study showed it doubled the risk of heart problems. But the U.S. Food and Drug Administration said similar prescription drugs were safe.
On Wednesday, the European Medicines Agency in London announced it would review drugs similar to Vioxx. And researchers writing in the New England Journal of Medicine voiced their concerns as well with such drugs as Pfizer Inc.'s (PFE) popular Celebrex .
The medical journal published two reports on the issue Wednesday on the Internet, ahead of their planned publication, because of their public health importance.
Studies done five years ago when Celebrex and Merck & Co.'s (MRK) Vioxx were approved suggest that the same mechanism that inhibits inflammation and makes the drugs easier on the stomach than traditional painkillers also blocks a substance that prevents heart problems, according to Dr. Garret FitzGerald, a University of Pennsylvania cardiologist who led the studies, which were designed by him but funded by the drug companies.
"I believe this is a class effect," meaning that the problem also applies to Celebrex and Pfizer's newer, similar drug, Bextra, which remain on the market.
He called on the FDA to change its advice to patients and doctors to reflect the new safety concerns. In a separate report also released by the medical journal, Dr. Eric Topol of the Cleveland Clinic chastises the FDA for not requiring Merck to do studies investigating heart problems with Vioxx when hints of them first appeared years ago.
Pfizer's medical director, Dr. Gail Cawkwell, insisted that its drugs are safe.
"The data for Celebrex is robust and exceeds, in the length of patients in studies and in the size of studies, the data Vioxx has," she said.
She called FitzGerald's contention "an interesting theory," but said, "there is no evidence" of increased risk of heart problems among the 75 million Americans who have taken Celebrex . Long-term studies are not yet available on Bextra, which was approved in 2001.
FDA officials did not immediately return phone calls seeking comment.
When Merck voluntarily withdrew Vioxx, FDA officials said heart problems were unique to that drug and that the mechanism underlying them wasn't known.
But FitzGerald and colleagues published two studies in 1999 and another in 2001 suggesting that by selectively blocking one of the two substances called prostaglandins that lead to inflammation, these so-called cox-2 inhibitors were sparing the stomach at the expense of the heart.
"There's a good prostaglandin and a bad prostaglandin as far as the heart is concerned," he explained.
Suppressing both, as older painkillers like aspirin and other nonsteroidal anti-inflammatory drugs, or NSAIDS do, helps the heart. But shutting down just the "good" one raises the risk of high blood pressure, hardening of the arteries and clotting, he reports.
The studies will be published in the Oct. 21 print edition of the medical journal.
European Regulators to Review Drug Class After Vioxx Recall
Other Arthritis Drugs May Raise Risk Of Heart Attack, According to Study
Associated Press
October 6, 2004 Wall St Jnl
LONDON -- European drug regulators said Wednesday they plan to investigate the safety of all brands of a popular type of arthritis pain reliever after one was withdrawn from world-wide markets last month because of heart attack and stroke worries.
The European Medicines Agency said it will review in the next two weeks all available long-term studies of licensed drugs belonging to a class known as Cox-2 inhibitors, named after the enzymes produced during inflammatory responses that cause arthritis joint pain.
The move follows the withdrawal of rofecoxib -- marketed under names such as Vioxx, Foldox or Meoroxx -- after its manufacturer, Merck & Co., discovered that it doubled the risk of heart attacks and strokes when taken long term.
Recall of Merck's Pain Drug Sparks Hunt for Alternatives Wall St Jnl
Rofecoxib, which is mainly prescribed for arthritis pain but also for acute pain and disorders such as carpal tunnel syndrome, was seen as a potential cancer-prevention medicine as well. The recall was prompted by a three-year study aimed at showing that the drug could prevent the recurrence of potentially cancerous polyps in the colon and rectum.
Participants taking the drug for more than 18 months were found to be twice as likely as those given dummy pills to suffer a heart attack, stroke or other heart complications. During the study, 10 patients died -- five who had been taking the treatment and five who took dummy pills.
Other Cox-2 inhibitors include celecoxib -- marketed in the U.S. as Celebrex -- and valdecoxib, which is called Bextra. Both are made by Pfizer Inc.
The medicines already contain warnings regarding heart problems.
Pfizer's medical director, Dr. Gail Cawkwell, insisted that its drugs are safe.
"The data for Celebrex is robust and exceeds, in the length of patients in studies and in the size of studies, the data Vioxx has," she said.
FDA officials did not immediately return phone calls seeking comment.
When Merck voluntarily withdrew Vioxx, FDA officials said heart problems were unique to that drug and that the mechanism underlying them wasn't known.
But Dr. FitzGerald and colleagues published two studies in 1999 and another in 2001 suggesting that by selectively blocking one of the two substances called prostaglandins that lead to inflammation, these so-called cox-2 inhibitors were sparing the stomach at the expense of the heart.
Merck Downplayed Risks of Its Vioxx
October 7, 2004, Wall St Jnl
In your Oct. 1 editorial "A Vioxx Elegy" you managed to make a success story out of Merck's decision to withdraw the arthritis drug Vioxx because it doubles the risk of heart attacks and strokes. Since I was a foil for the editorial, allow me to respond.
The fact that Vioxx probably increased the risk of heart attacks and strokes was known for three years, but Merck downplayed it and did not undertake studies to settle the matter, while the FDA sat on its hands. As you acknowledged, the risk was confirmed only serendipitously in a clinical trial for another purpose. Over the past three years, it is likely that many more people had heart attacks and strokes from Vioxx than were saved from bleeding ulcers, given the high prevalence of heart disease in the population that uses Vioxx and the deliberate exclusion of those people in the trial.
Since Cox-2 inhibitors like Vioxx are no better than over-the-counter drugs for relieving arthritis symptoms (they do not enable you to skate like Dorothy Hamill), far more expensive and of only limited effectiveness in preventing gastrointestinal complications, it's hard to share your enthusiasm for them except as cash cows for Pfizer and Merck.
As for Pfizer's Celebrex and Bextra, you are wrong to assume that they are in the clear, or that the Vioxx story somehow supports having me-too drugs on the market. What it supports is the need for Celebrex and Bextra to be studied in similarly large, long-term trials, and the FDA should insist on it. Since they are so much like Vioxx, I would not bet my ice-skates that they are not eventually shown to have similar risks.
Marcia Angell, M.D.
Senior Lecturer
Harvard Medical School
Cambridge, Mass.
Lancet Calls For Review Of Drug Safety Criteria
By ANITA GREIL, Dow Jones Newswire, Wall St Jnl
October 7, 2004
ZURICH -- Joining a growing chorus, a leading medical journal Friday called on drug regulators to reassess the safety and efficacy thresholds required to allow new medicines to the market.
In its editorial, British medical journal The Lancet also urged doctors and pharmaceutical companies to draw lessons from the "sorry tale" that led to the sudden withdrawal of Merck Co.'s (MRK) painkiller Vioxx last week.
The U.S.-based pharmaceutical company recalled Vioxx after five years on the market when a study found new risks. The study, sponsored by Merck, found that patients who've been taking Vioxx for 18 months or longer were facing a higher risk of heart attacks and strokes than those taking a placebo, or sugar pill.
The drug had generated $2.5 billion in sales in 2003.
But Vioxx and other drugs it its class, called Cox-2 inhibitors, have been surrounded by safety concerns long before. Evidence of an increase in the risk of myocardial infarctions in patients taking Vioxx emerged soon after the painkiller was launched. In 2002, the U.S. Food and Drug Administration added a warning about possible cardiovascular side-effects of Vioxx to the drug's label.
"The key question that must now be answered is why has it taken so long for Merck and government drug regulators to address these signals properly," the Lancet editorial said.
When reviewing required standards for new medicines' safety and efficacy, regulators should account for the nature of the condition being treated, whether treatments are already available and what perceived benefit the new treatment offers compared with risks from side effects.
So-called me-too drugs, or drugs very similar to medicines already on the market, have for years brought criticism on the industry and regulators. But following the largest drug recall in the history of the industry, they may now be getting more support for their cause.
The drug industry argues that each slight variation in a new drug could be helpful to patients not responding to current therapy. Critics say me-too drugs are often simply replacing older and cheaper therapies without proven benefits because pharmaceutical companies must only show that a drug works, not that it works better than existing therapies, to get permission to sell it.
In a first sign of regulatory action, the European Medicines Agency said Wednesday it would review all drugs of the same type as Vioxx. Also on Wednesday, researchers writing in the New England Journal of Medicine voiced their concerns over pills of the same type as Vioxx, including Pfizer Inc.'s (PFE) popular Celebrex.
The Lancet also said it is a lingering question for doctors and patients whether other Cox-2 medicines also increase the risk of heart attack and stroke.
A big trial that ended this year on another such drug, called Prexige and made by Novartis AG (NVS) of Switzerland, failed to show a statistically significant rise of cardiovascular side-effects when compared with older treatments. But the Lancet, which published the study in August, stresses that nonetheless "more people taking lumiracoxib had a myocardial infarction" than did those taking a placebo. Lumiracoxib is the generic name of Prexige.
Novartis has the U.K. regulator's approval but isn't selling Prexige yet. The company previously said it expects to launch Prexige in the U.S. in 2006.
Meanwhile, the Lancet also harshly criticized Merck for unabatedly continuing aggressive direct-to-consumer marketing of Vioxx even after early warnings and "in the face of mounting evidence for the cardiovascular side-effects of rofexocib." Rofexocib is the chemical name of Vioxx.
Researchers have been warning about a connection between Vioxx and increased risk of heart attack and stroke for years. But Merck has rejected such criticism saying earlier studies were inconclusive because they lacked the rigor of a placebo-controlled clinical trial.
However, the journal did also say that Merck responded well by recalling the drug immediately after its most recent trial showed cardiovascular safety risks.
Doctors also have lessons to learn. They need to be more aware of the very preliminary data provided with newly licensed drugs, the Lancet said.
Vioxx's approval was based on safety data on results from around 5,000 patients. A far cry from the millions of people who received the drug until last week, and a partial explanation of how an important side-effect could have been missed.
Pfizer Down; Report Raises Questions On COX-2s
DOW JONES NEWSWIRES, Wall St Jnl
October 7, 2004 1:28 p.m.
By Hollister H. Hovey Of DOW JONES NEWSWIRES
NEW YORK -- Pfizer Inc. (PFE) shares fell nearly 5% Thursday after a medical journal's editorial hypothesized that the same cardiovascular side effects that led to Merck & Co.'s (MRK) Vioxx being pulled off the market could affect all drugs in the class.
Pfizer makes Celebrex and Bextra, the other pain-relieving COX-2 inhibitor drugs, or coxibs.
Merck pulled Vioxx from the market last week after a study showed the drug doubled the risk of heart problems when used for longer than 18 months.
Pfizer initially benefited from the withdrawal as patients scrambled for alternatives to Vioxx, which had made Merck billions of dollars. Pfizer's drugs haven't been linked to the same side effects but data from long-term studies currently haven't been released.
"It is essential to determine whether the cardiovascular risk is or is not a class effect," Dr. Garret FitzGerald, a University of Pennsylvania cardiologist, wrote in an editorial in the New England Journal of Medicine. "The burden of proof now rests with those who claim that this is a problem for (Vioxx) alone and does not extend to other coxibs. We must remember that the absence of evidence is not the evidence of absence."
Pfizer officials countered the claims against its drugs.
"We do feel that the market has overreacted to this," Dr. Joe Feczko, president of worldwide development at Pfizer, told Dow Jones Newswires. "The data accumulated on Celebrex is much more extensive than on Vioxx. We believe they do behave differently."
While Feczko said more data need to be made public, he noted that three long-term studies of Celebrex are ongoing, and their outside safety monitoring boards have not raised safety concerns.
He said the industry may be dealing with a situation similar to the Baycol withdrawal in 2001. Baycol, a cholesterol-cutting statin drug, was linked to muscle problems. But other drugs in the class like Pfizer's Lipitor and Merck's Zocor weren't.
Dr. Gail Cawkwell, the Celebrex worldwide medical director for Pfizer, said Merck has 2,600 patients in the study which led to the withdrawal. Pfizer has three studies with 6,500 patients enrolled longer than patients were in the Merck study. Three independent medical groups have reviewed the ongoing studies and haven't voiced safety concerns, she said.
FitzGerald designed studies done five years ago for Merck and Pfizer that suggested that the same mechanism that inhibits inflammation and makes the drugs easier on the stomach than traditional painkillers also blocks a substance that prevents heart problems.
"Whether ultimately true or not, because the piece shows up in the most widely-read medical journal, this could end up hurting the entire coxib class, above and beyond the damage that has already occurred," Prudential Equity Group analyst Tim Anderson wrote in a Thursday research note. He thinks that Pfizer will be the net gainer of new revenue on the back of Merck's problems, but "the more the notion of 'class effect' gets discussed in public forums, the less certain this becomes," he said.
Either Anderson or a member of his team owns Pfizer shares, but the firm is unaware of other conflicts of interest.
The drugs all use different molecules but work in the same way. All these drugs are used to block the COX-2 enzyme and fall into the same wide group as non-steroidal anti-inflammatory drugs, or NSAIDs.
However, traditional "nonselective" NSAIDs such as ibuprofen and naproxen target two kinds of enzymes - COX-1 and COX-2 - whereas the COX-2 inhibitors target just COX-2. The enzyme that the COX-2s leave alone - COX-1 - helps protect the lining of the stomach. It also aids in blood clotting.
That effect is usually counterweighted by the COX-2 enzyme, which makes platelets in the blood slippery. So patients taking the COX-2 inhibitors have the clotting effect of the COX-1 inhibitor. Older drugs like ibuprofen and naproxen block both enyzmes.
Field research done by William Blair & Co. analyst Winton Gibbons indicates that both Celebrex and Bextra have two-thirds of the half-life as Vioxx, meaning that they don't stay in the body as long, he said. Also, Celebrex appears to be one-tenth less specific in blocking COX-2 than Vioxx, so it allows more of the de-clotting effects of the enzyme to work, he said.
Meanwhile, Pfizer went to court Thursday morning to stop two generic drug companies from launching generic versions of its blockbuster epilepsy drug Neurontin. Alpharma Inc. (ALO) and Teva Pharmaceutical Industries Inc. (TEVA) have threatened to launch their versions of the drug imminently.
Pfizer spokesman Paul Fitzhenry declined to comment on the movement of the company's stock. Shares recently traded down 4.7%, or $1.47, to $29.71 on volume of 67.5 million. Average daily volume is 17.7 million.
Earlier Thursday, shares reached a new low $28.60, surpassing the previous los of $29.50 reached Oct. 16, 2003. The decline erased more than $13 billion in market capitalization for Pfizer.
-By Hollister H. Hovey, Dow Jones Newswires; 201-938-5287; hollister.hovey@dowjones.com
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