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http://www.nytimes.com/2007/07/22/business/22nissen.html?

July 22, 2007

Drug Safety Critic Hurls His Darts From the Inside

By STEPHANIE SAUL

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.