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A TIMES INVESTIGATION

Drug Trials With a Dose of Doubt

A National Institutes of Health researcher with ties to pharmaceutical firms helped test their new medications. Some scientists questioned the results of the studies.

July 16, 2006|David Willman | Times Staff Writer

BETHESDA, Md. — On Jan. 10, 2001, pharmaceutical giant Merck & Co. gathered its forces in a hotel conference room here with a clear-cut mission: Win a favorable vote for a new antifungal drug from a federal advisory committee -- a victory that would position the product for swift government approval and for hundreds of millions of dollars in sales.

But after hours of speeches and slides, the committee members, appointed by the U.S. Food and Drug Administration, had yet to vote. The members were focused on the quality of Merck's case for the new drug, which rested on the treatment of only 69 patients.

Merck summoned to the microphone one of its announced consultants, a man whose government job was nearby, at the National Institutes of Health. Dr. Thomas J. Walsh assured the committee that Merck's data describing the patients was "extremely robust and very, very rigorous." He said his government staff had assisted in vetting the company's data. About 30% of the patients were helped by the drug, he said.

The advisory committee voted unanimously to endorse the drug, called Cancidas. Sixteen days later, the FDA approved it. Doctors would later prescribe it for patients whose immune systems had been ravaged by chemotherapy and who were presumed to have a potentially deadly, invasive fungal infection. In its first five years on the U.S. market, Cancidas would generate $859 million in sales for Merck.

U.S. law generally prohibits a federal employee from representing an outside party before a government agency.

In building a career as an influential government scientist, Walsh has served as both a paid and unpaid advisor to pharmaceutical companies and has helped lead clinical trials that tested the effectiveness of their products. With his help, the companies have brought new antifungal drugs to market, but controversy has flared over whether results from two of the studies were misleading and whether some of the participating patients received adequate treatment.

In written comments for this article, Walsh said his advice to industry did not conflict with his position at the NIH's National Cancer Institute, or affect his scientific judgment.

"I am not and have never been a representative of, or advocate for, any pharmaceutical company," Walsh said.

Two drug makers involved with his federal research, Merck and Pfizer Inc., said they have paid fees to Walsh. Merck and another company, Fujisawa USA Inc., have made financial or other donations to support Walsh's federal research with the approval of his NIH superiors, interviews and government records show.

From 1997 to 2003, Walsh appeared at meetings with FDA committees or staff alongside representatives of Pfizer, Fujisawa and Merck, according to videotapes, transcripts and other government records. He also helped design, oversee and interpret the results of major clinical studies of four antifungal drugs made by those companies. The studies helped win FDA approvals for three of the drugs.

In separate letters to a leading medical journal, other researchers criticized two of those studies. They questioned whether the studies artificially boosted the new products by comparing them to drugs that were given at doses that were too low.

More patients died who took the "comparator" drugs than those who got the new products.

Walsh, in journal articles and in remarks to medical leaders, noted the disparities in deaths while describing the advantages of the newer drugs. In published responses to the scientific critics, he said the doses of the comparator drugs reflected the general standard of care at the participating hospitals.

What led to the higher death rates of the control-group patients in the two major studies may never be known: A limited number of autopsies were performed, and factors other than fungal infections, such as the patients' cancer, could have caused the deaths.

No published study has established that a higher dose of an antifungal drug is more effective in treating suspected infection, and some studies have suggested that lower dosing may provide similar benefits. But the possibility that patients did not receive adequate doses, combined with Walsh's advisory role with the drug companies, adds a new dimension to the furor over NIH scientists' ties to industry.

Earlier revelations of the agency scientists' outside arrangements called into question their impartiality and the independence of the NIH, the nation's largest agency for experimental medical research, prompting congressional hearings, policy reforms and ethics investigations.

However, even as the NIH moved recently to ban some of the activities with industry, the agency's director said the arrangements had apparently not jeopardized patients in clinical studies.

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