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http://www.nytimes.com/2002/06/01/health/01DRUG.html?tntemail0

Study Finding Celebrex Safer Was Flawed, Journal Says

By MELODY PETERSEN

n editorial in the June 1 issue of The British Medical Journal harshly criticizes a scientific study that the drug company Pharmacia used to promote Celebrex, the arthritis drug that is its best-selling product.

Its authors said the study, which concluded that Celebrex, which had $3 billion in sales last year, was safer than other widely used pain relievers because it caused fewer ulcers, had "serious irregularities."

They also said Pharmacia's previous explanation for discrepancies in the study was "inadequate." Doctors should be informed, they added, that the conclusion that Celebrex was safer than drugs like ibuprofen had been contradicted.

"The flawed findings published in the original article appear to be widely distributed and believed," wrote Dr. Peter Juni, a senior researcher at the University of Berne in Switzerland, and two other doctors. If Pharmacia is not required to inform doctors that the study's conclusion was invalid, they said, "the pharmaceutical industry will feel no need to put the record straight in this or any future instances."

Dr. Steve Geis, Pharmacia's vice president for clinical research, said yesterday that the company disagreed with the editorial. The Celebrex study used "appropriate scientific judgment," and the company stands by its conclusion, Dr. Geis said.

Celebrex and Vioxx, a similar medication sold by Merck & Company, are some of the most heavily advertised prescription medicines.

The drugs, known as Cox-2 inhibitors, have grown increasingly controversial because they have not been shown to reduce pain better than drugs like ibuprofen and naproxen, which are available in generic and over-the-counter versions, at a fraction of the cost.

The companies have said the new drugs are worth their high price because they are safer for the stomach and appear to cause fewer ulcers, a dangerous side effect of anti-inflammatory pain relievers like ibuprofen and aspirin.

The popularity of the two drugs has alarmed health insurers, as the cost of caring for arthritis patients has increased greatly. A month's prescription of either Celebrex or Vioxx costs about $80, many times the cost of generic pain relievers.

Many insurers and doctors say the new drugs should be prescribed only for people at risk for ulcers.

But Pharmacia is still struggling to convince the Food and Drug Administration that Celebrex is easier on the stomach. The agency and the company are discussing whether Celebrex's label should be changed to say the drug causes fewer ulcers and allow to advertise that claim. Much of the data that Pharmacia has presented to the agency to prove Celebrex is safer are those that the editorial's authors criticize.

The editorial focuses on a study reported in 2000 in The Journal of the American Medical Association. The study concluded that patients taking Celebrex suffered fewer serious ulcer complications than those taking ibuprofen or diclofenac.

About a year later, an article in The Washington Post disclosed that Pharmacia's published study included only the first six months of data in a study that had lasted a year. When all the data are analyzed, Dr. Juni and his colleagues said, much of Celebrex's safety advantage appears to disappear because almost all of the ulcer complications in the last six months occurred in Celebrex users.

Pharmacia and the doctors it hired to prepare the study, including professors from Harvard and Yale medical schools and six others, have said they omitted the last six months of data because many patients dropped out in that time, skewing the results. The high drop-out rate, they said, left more patients at risk of ulcers in the Celebrex group than in the groups taking the other drugs.

But Dr. Juni and his colleagues called that explanation "inadequate." The patients who dropped out, they said, did so gradually over the year of the study, without a sudden increase after six months.

Dr. Juni and the other authors said Pharmacia appeared to have widely distributed reprints of the Celebrex study. Thirty thousand reprints were purchased from the publisher, and the study was cited in 169 other medical articles, they said.

Dr. Geis said he did not know how many reprints the company distributed, but he said it regularly distributed copies of medical journal articles about its products if doctors requested them.

The doctors Pharmacia hired to help it perform the study are working on a more detailed explanation of why the study was appropriate, Dr. Geis said. Even as the study was being designed, he said, the company and the outside investigators believed that six months of data would provide the best answer about Celebrex's safety. The study continued, he said, to determine what happened over a year.

"The most meaningful answer," he said, "is in the first six months."

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