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Drug Safety Critic Hurls His Darts From the Inside

by Stephanie Saul

CLEVELAND - Back in the '60s, when University of Michigan students were holding protests over civil rights and the Vietnam War, an undergraduate named Steven E. Nissen was at the center of the political dissent. Four decades later, that former campus activist is now Dr. Nissen, who is shaking up the nation's pharmaceutical industry.

His questioning of the safety of the Avandia diabetes medication in late May, for example, prompted a federal safety alert and led to a sales decline of about 30 percent for the drug, which brought in $3.2 billion for GlaxoSmithKline last year. Now, with a federal panel soon to decide whether it can remain on the market, Avandia's future is uncertain.

The drug is the latest example of why Dr. Nissen, 58, whose day job is chairman of cardiovascular medicine at the Cleveland Clinic, has emerged as a Naderesque figure and the nation's unofficial arbiter of drug safety.

Admirers laud him not only for raising safety questions about Avandia, but also for sounding early warnings about the painkiller Vioxx, as well as other drugs. By digging deeply into companies' own clinical trial data - information that used to be available only to federal drug regulators who did not always mine it as aggressively - Dr. Nissen is among a new cadre of activist scientists demanding greater vigilance on drug safety.

But Dr. Nissen also has critics, who say he seeks the spotlight as much as the safety of medicine. Others see a conflict of interest in his self-appointed role as the drug industry watchdog while he also presides over industry-financed research worth millions of dollars. "I'm an insider and an outsider at the same time," Dr. Nissen says in an official Cleveland Clinic biography.

His crusading for drug safety, and his recent informal advisory role to members of Congress on legislation to strengthen drug safety enforcement, have fostered speculation that Dr. Nissen, a Democrat who has worked with members from both parties, covets an official public platform. Some see him angling to be the commissioner of the Food and Drug Administration, an agency whose decision-making he has frequently questioned.

Although Dr. Nissen denies that he is campaigning for the job, or even that he is really interested in it, he refuses to rule it out. "I want to fix the F.D.A.," Dr. Nissen said in a recent interview.

He also wants to influence health policy more generally. In one of his final acts this year as the president of the American College of Cardiology, a doctors' group, Dr. Nissen gave a speech calling for universal health insurance.

People listen to Dr. Nissen partly because of his unabashed self-confidence and outgoing personality. Friends from college remember his mischievous air, a demeanor that has endured alongside his willingness to raise tough questions.

Dr. Nissen also has a statistician's zeal for drilling deep into clinical data, seeking signs that some widely used drugs pose undisclosed risks to patients. In discussing his work, he describes sleepless nights poring over numbers.

Dr. Nissen's article in The New England Journal of Medicine, published in May, was based on his review of 42 clinical studies of Avandia involving nearly 28,000 patients. His conclusion, that the drug seems to raise the risk of heart attacks, was widely covered in the news media, including this newspaper.

After the Nissen article appeared on the journal's Web site on May 21, the F.D.A., which said it had been evaluating the drug's risks, issued a safety alert advising Avandia patients to consult their doctors.

The agency also scheduled a hearing on July 30, at which a panel of expert advisers could recommend restrictions, or even a ban, on Avandia's use. The F.D.A. has asked Dr. Nissen to attend to answer questions.

GlaxoSmithKline has challenged the significance of Dr. Nissen's findings and has defended the drug's safety. Avandia, which has been used by about seven million people, is merely the latest drug to become a target of Dr. Nissen, who describes himself as an advocate of patients.

In 2005, for example, Dr. Nissen attacked the experimental diabetes drug Pargluva, from Bristol-Myers Squibb, saying it posed serious heart risks. Although an F.D.A. advisory panel had overwhelmingly recommended its approval, Pargluva never made it to market.

Dr. Nissen, who had warned of the dangers of the painkiller Vioxx, from Merck, before it was withdrawn in 2004, challenged Merck's follow-on product, Arcoxia, which failed to win approval this year. He called Arcoxia the "son of Vioxx," telling a reporter, "This is a genie I don't want to see let out of the bottle."

In his article on Avandia, Dr. Nissen was careful to note the limitations of his analysis. In some media interviews, though, he was less guarded. On the ABC television program "Nightline," Dr. Nissen predicted that the deaths caused by Avandia could "dwarf" the carnage of Sept. 11, 2001.

Dr. Michael A. Weber, a professor of medicine at SUNY Downstate Medical Center in Brooklyn, is among the doctors who worry that Dr. Nissen's Avandia rhetoric has been inflammatory. Dr. Weber cited Dr. Nissen's reference to the World Trade Center attack as "something that doesn't need to be part of a good clinical scientific discussion."

GlaxoSmithKline complained about the same thing. "In some of his comments to the media, Dr. Nissen has gone beyond discussing the scientific findings of his study to language that frightens patients," a company spokeswoman, Mary Anne Rhyne, said in an e-mail message.

Even Dr. Delos M. Cosgrove, Dr. Nissen's supervisor at the Cleveland Clinic, where his department of 90 cardiologists handled 234,000 patient visits last year, says he advised Dr. Nissen simply to talk about the science.

Among his contributions to the clinic is his pioneering work in using ultrasound images to measure fatty plaque inside the walls of coronary arteries, a procedure known as intravascular ultrasound.

While some other drug safety critics avoid all industry ties, Dr. Nissen actively seeks industry-financed research. To avoid undue influence, he says, he insists that charities be given any industry consulting and speaking fees that he would have personally received.

Beneficiaries of the money, hundreds of thousands of dollars over the years, have included the American College of Cardiology. Another recipient has been the Cleveland Museum of Art, one of the major museums and galleries that has shown the work of his wife, Linda Butler, an award-winning photographer.

Dr. Sidney M. Wolfe, the head of the consumer organization Public Citizen's Health Research Group, is generally supportive of Dr. Nissen's efforts on behalf of drug safety. "He's very smart and he's done a lot of good," Dr. Wolfe said.

But he says that Dr. Nissen's diverting drug company money to charity is not an adequate buffer from industry influence. "It's still a conflict of interest," Dr. Wolfe said.

Dr. Nissen's industry ties have enabled critics to question his analysis of Avandia, for example, because he has served as a consultant for Takeda and Eli Lilly, the companies that together market Avandia's main competitor, Actos.

Pointing out that he does not personally receive money from any company, Dr. Nissen said his work for Takeda, Eli Lilly or any other drug maker does not affect his scientific detachment.

"My involvement with any company does not bias my scientific perspective and I scrupulously avoid even the appearance of a conflict of interest," he said.

And Dr. Nissen says he believes his alarms about drug safety have sometimes caused the Cleveland Clinic to miss out when companies award contracts for clinical research trials.

But his adversarial reputation can also work the other way. Because of Dr. Nissen's reputation, companies may seek him out for research projects.

After the withdrawal of Merck's Vioxx, for example, Pfizer chose Dr. Nissen to lead a 20,000-patient study of whether its similar drug, Celebrex, carries heart risks.

"In the view of Pfizer, who is co-sponsoring the trial, they know that whatever we report will be believable," Dr. Nissen said. The study, which will cost millions of dollars, is expected to be completed in 2010.

A Pfizer spokesman, Raymond F. Kerins Jr., said the company picked Dr. Nissen because it seeks advice from leading experts. "These experts ask excellent - and often tough - questions," Mr. Kerins said.

Although he is the son of a doctor, Dr. Nissen initially rebelled against following that path.

In college in the late 1960s and early '70s, while working as an editor at his campus newspaper, The Michigan Daily, he became active in the antiwar movement, the civil rights movement, the women's movement and the Human Rights Party, a largely student-run group that elected two members to the Ann Arbor City Council.

One of those council members, Jerry DeGrieck, remembers the young Steve Nissen's work in leading a voter registration drive.

Those extracurricular activities left little time for classes, which is why Dr. Nissen likes to recall that he was on the "eight-year plan" at Michigan, and says he was lucky to have been accepted to the University of Michigan medical school after finally getting his bachelor's degree, in 1974.

Mr. DeGrieck, now a government public health policy adviser in Seattle, says he never imagined that his college friend would become one of the nation's most influential doctors. But he says he is not surprised at all by Dr. Nissen's activism.

"He's always questioned authority," Mr. DeGrieck said.

Copyright 2007 The New York Times Company