My Life and Times

December 19, 2004
Medicine Fueled by Marketing Intensified Trouble for Pain PillsBy BARRY MEIER
his article was reported by Barry Meier, Gina Kolata and Andrew Pollack and written by Mr. Meier.
In the mid-1990's, the medical community reached an inescapable conclusion. Researchers at the Stanford University Medical School and elsewhere who had long been monitoring arthritis and rheumatism patient records had found that thousands of patients, perhaps as many as 16,500, were dying annually from bleeding ulcers and other problems caused by widely used painkillers like ibuprofen.
Within a few years, a new class of pain relievers, the so-called COX-2 inhibitors, burst onto the market with the promise they might reduce that toll. Sales of the best known products, Celebrex and Vioxx, quickly skyrocketed - thanks in part to changes in federal rules in 1997 that made it much easier for drug makers to advertise medications directly to consumers on television, in newspapers and in magazines.
Now, though, the flight path of these blockbuster drugs has been aborted. On Friday, Pfizer the maker of Celebrex, which is expected to end up with sales of $3.3 billion this year, disclosed that a patient trial by the National Cancer Institute had found significant risks of heart attacks. Vioxx, which was made by Merck and had sales of $2.5 billion last year, was pulled from the market in late September after similar findings.
In some ways, the story of the COX-2 drugs, a class that includes another troubled Pfizer medication, Bextra, is part of an age-old search for safer pain treatments. And some doctors say that they have helped. But it is also perhaps the clearest instance yet of how the confluence of medicine and marketing can turn hope into hype - and how difficult it is for the Food and Drug Administration to monitor the safety of drugs after they have been approved for the market. Celebrex and Vioxx, after fast-track approval from the F.D.A., hit the nation's pharmacies as revolutionary drugs that could not only treat arthritis patients' pain, but potentially save their lives.
But having spent hundreds of millions of dollars to develop their drugs, the makers of Celebrex and Vioxx, cheered on by Wall Street, had every motivation to expand their markets beyond the older people most at risk of ulcers to encourage the drugs' use by millions more people of all ages. That was so even as, at least in the case of Vioxx, there was evidence as early as 2000 that a COX-2 drug could cause heart problems.
"You have to realize that these medications, they are not candies, they are not placebos," said Dr. Gurkirpal Singh, a Stanford professor who has worked on the arthritis database project. A big problem with the COX-2 drugs, he said, has been the tendency of doctors to use them indiscriminately. "Like all medications, you have to identify which people will benefit the most, and which won't."
Since the drugs' release, the companies have spent hundreds of millions of dollars on television, newspaper and magazine advertising for them and, by some estimates, at least as much on marketing and promoting the drugs to doctors. As a result, many medical experts now say that Celebrex and Vioxx, selling for $2 or $3 a pill, have been too widely prescribed to patients who could safely obtain the same pain benefits from over-the-counter drugs costing pennies apiece.
Potentially wasted money, though, is not the main point about the sales push, now that there is clinical evidence that all the COX-2 drugs on the market can, in some circumstances, increase a user's likelihood of strokes or heart attacks.
On Friday, Pfizer characterized the cancer trial findings as an anomaly requiring further study and said it was not ready to withdraw the drug. But the news of the trial results was enough to send drug stocks plummeting and to cast grave doubts on the future of the entire COX-2 drug category. Only a few weeks ago, the F.D.A. ordered Pfizer to put a label warning on Bextra, noting that it could pose cardiac risks to patients recovering from heart surgery.
Pfizer and Merck have repeatedly said that their marketing has been accurate and responsible. "We market all of our medicines consistent with regulation," said a spokeswoman for Pfizer. "Doctors and patients are in the best position to say which drugs are most appropriate for them."
But the rapid rise and now shaky future of this class of drugs, some researchers say, is emblematic of the way drug companies' efforts to spur the use of costly new medicines can distort the medical realities of safety and effectiveness.
Too often, marketing can drown out medical science, said Dr. James F. Fries, the director for the Stanford arthritis database project, which receives funding from the National Institutes of Health. "Here, it was not a fair battle."
The roots of Celebrex and Vioxx reach back to the early 1990's. At the time, Harvey R. Herschman and colleagues at the University of California, Los Angeles were screening large numbers of genes trying to find ones that might be involved in cancer. The screen turned up a gene that was in many ways similar to a known gene for an enzyme called cyclooxygenase or COX.
It had long been understood that COX spurred the production in the body of chemicals called prostaglandins that contributed to pain, inflammation and fever. But it had always been thought that there was only one COX enzyme. Now in Dr. Herschman's laboratory emerged evidence of a new one, which came to be called COX-2. Similar discoveries were made about the same time in the laboratories of Donald A. Young at the University of Rochester and Daniel L. Simmons at Brigham Young University.
"It was totally unexpected, completely serendipitous," Dr. Herschman said of his own discovery, adding that he believed that to be true of the other labs as well.
But the implications were immediately clear to Philip Needleman, who had already hypothesized the existence of a second COX enzyme and had begun to characterize its role in the body. The original COX, now called COX-1, seemed to be present everywhere in the body and contributed to vital functions like protecting the stomach lining. COX-2 seemed to be present mostly during times of inflammation. So if a drug could be made to block COX-2 but not COX-1, the thinking went, it could relieve pain without causing ulcers.
Convinced of the importance of the discovery, Dr. Needleman had moved from Washington University in St. Louis to Monsanto in 1989 to lead an all-out effort to develop a COX-2 inhibitor. The result of Dr. Needleman's effort was celecoxib, or Celebrex. Monsanto's drug division, Searle, eventually was acquired by Pharmacia, which in turn was gobbled up by Pfizer, in a rush of mergers that swept the drug industry over the past decade to satisfy Wall Street's desire for rapid growth.
Thinking that Celebrex and Vioxx would help cut the rate of gastrointestinal bleeding, the F.D.A. took only six months to review the applications for both drugs, an accelerated process used only for drugs deemed medically important. But in both cases, the F.D.A. decided that the drugs had not sufficiently demonstrated that they reduced the rate of serious gastrointestinal problems compared with existing painkillers like aspirin and ibuprofen. So the drugs' labels contained the same warnings as the older drugs about such side effects.
Merck later conducted studies that persuaded the F.D.A. to change the label, but Pfizer's results were never convincing enough for the agency to remove the warning from Celebrex's labeling. In other words, the world's best-selling COX-2 has never been proven to the F.D.A.'s satisfaction to have the stomach-protecting benefits that originally were supposed to be the point of that category of drugs.
By the time they reached the market, the COX-2 drugs were marketed by makers as not simply improved versions of older treatments but as entirely new drugs.
"They wanted to use this as a discontinuity with the past," said Dr. Fries, the Stanford professor.
The audience also went beyond those at the highest risk of stomach bleeding - principally people over 65 years who have suffered from gastrointestinal problems or might be at risk for them.
Dorothy Hamill, the 1976 Olympic figure skating gold medalist, was the middle-aged celebrity face of Vioxx. Television commercials for Celebrex presented actors engaged in activities like riding bicycles and performing tai chi to the strains of the song "Celebrate" by the 1970's band Three Dog Night. The song's choice echoed more than the drug's name; it was also selected to appeal to a critical audience, baby boomers beginning to suffer from arthritis.
Celebrex has been one of the most heavily promoted prescription drugs in advertising aimed at consumers. For the first nine months of this year, Pfizer spent almost $71.2 million on Celebrex, up about 55 percent from almost $46.1 million spent in the same period a year ago, according to data from the research firm TNS Media Intelligence/CMR. The effect of such advertising, many doctors say, was to drive to consumer demand for COX-2 drugs far beyond the bulk of those patients who really benefit from them.
Dr. Elizabeth Tindall, the president of the American College of Rheumatology, a professional group, said her group believed that COX-2's are an appropriate treatment for patients at high risk of stomach problems. But "we weren't saying to anyone if you have a 23-year-old with ankle pain put them on this drug," said Dr. Tindall, who practices in Portland, Ore. "That was the impression that the TV advertising was giving."
Within little more than a year, the drugs had grabbed about 40 percent of the market from traditional anti-inflammatory drugs like ibuprofen. Some efforts were made to determine who would most benefit from the drugs. Researchers at Stanford developed a scoring tool that physicians could use to determine, based on a patient's age and medical history, whether they were at high risk for stomach bleeding and, as a result, candidates for drugs like Celebrex and Vioxx.
Dr. Singh, the Stanford professor, said that most patients did not fall in the high-risk category.
Few groups or individuals, however, used the scoring tool. One organization that did was Kaiser Permanente, one of the nation's largest health care systems. Dr. David Campen, a medical director at Kaiser, said that because of the scoring system only about 5 percent of Kaiser's patients received a COX-2.
Beyond their heavily promoted use as prescription-strength painkillers, COX-2's have been extensively studied for other potential uses, like fighting or even preventing cancer. And, perhaps ironically for the drug companies, it was cancer prevention studies that ultimately provided clinical evidence that Vioxx and Celebrex posed cardiac risks.
For years scientists have pursued evidence that aspirin-like drugs may help control the occurrence of polyps in people at risk of colon cancer. But there was a problem with testing such drugs as cancer preventatives in healthy people: the drugs could cause ulcers and bleeding.
So when Vioxx and Celebrex were developed as drugs that might act like aspirin, without the risks of bleeding, cancer researchers saw their chance. In fact, based on tests Searle had conducted with the National Cancer Institute, the F.D.A. approved Celebrex for patients at high-risk of getting colon cancer.
By last year, more than a dozen studies of Vioxx and Celebrex were under way with people at high risk for cancers of the lung, breast, skin, prostate, colon, mouth, bladder or esophagus. They were being studied along with standard treatments in patients who already had cancer.
The trials that disclosed the dangers involved healthy people who had already had polyps removed from their colons and who were randomly assigned to take a placebo or a COX-2 inhibitor. Each study sought to learn if taking a COX-2 inhibitor prevented the subsequent formation of polyps.
That answer is not yet known and the researchers have not released those data. But in both studies, the participants taking the COX-2 inhibitor had more heart attacks and strokes than those taking a placebo. The problem was seen in the Vioxx trial after 18 months and after a longer period in the Celebrex trial among patients taking high doses.
For all their early promise, the future of COX-2's is uncertain.
Dr. Lester Crawford, the F.D.A.'s acting commissioner, said Friday that doctors should consider switching their Celebrex patients to other drugs. He said the F.D.A. had "great concerns" about Celebrex and Pfizer's Bextra and was considering regulatory measures that could include forcing Celebrex's withdrawal or placing severe warnings on its label.
Merck has a successor to Vioxx, called Arcoxia, pending approval at the F.D.A. But the agency, which has a panel planning to hold hearings on the entire class of drugs early next year, has tabled that application for now.
Some physicians, like Dr. Tindall, the rheumatologist in Portland, said they were concerned that if Celebrex or Bextra, or perhaps both, were withdrawn from the market that some patients who need such drugs will not get them. Indeed, many former Vioxx patients have complained about the withdrawal of that drug, saying it was the only pain medication that worked for them.
As it turns out, deaths and hospitalizations from stomach problems related to the use of ibuprofen and aspirin peaked in 1992 and had already dropped significantly before the appearance of Celebrex and Vioxx, according to data collected by Stanford University. In 1999, the year of the two drugs introductions, those problems also had another sharp decline.
Dr. Fries of Stanford said the drop-off over the past decade reflected, among other things, the use of lower doses of various painkillers. There has also been growing use of less toxic ones, not only COX-2's but other medications, like Mobic, that other drug makers began to sell in response to concerns about stomach bleeding. Many doctors also have patients taking medications like Prilosec to offset the stomach irritation of some painkillers.
In terms of stomach bleeding, the relative risks of some other less irritating painkillers like Mobic appear indistinguishable from COX-2's, Dr. Fries said. But because of the expense and difficulty of conducting broad-based clinical trials, there have been no studies comparing those drugs with one another and with the COX-2's.
Dr. Fries said the story of the COX-2's was emblematic of the consumer marketing forces that now propel the drug industry.
It is a market, he said, in which the lure of the new can run ahead of science.
"You have to have a new generation of drugs," said Dr. Fries. And under that model, "the old ones are dangerous, and the new ones are safe." Or until proven otherwise.
Stuart Elliott contributed reporting for this article.
Copyright 2004 The New York Times Company Home Privacy Policy Search Corrections RSS Help Back to Top