Medicine Fueled by Marketing Intensified Trouble for Pain Pills

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.

•	Medicine Fueled by Marketing Intensified Trouble for Pain Pills The New York Times, Sunday, Dec. 19, 2004 Byline: Barry Meier

•	Celebrex inventor fears for drug's future Former Washington U. researcher says the painkiller may not be dangerous at low dosage levels. St. Louis Post-Dispach, Saturday, Dec. 18, 2004 Byline: Rachel Melcer

	Story also ran in 2 others:  Pittsburgh Post-Gazette and KTVI-TV St. Louis