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At a time when drugmakers are under fire for selling risky products, Dr. Steven E. Nissen occupies a unique position. A cardiologist at the Cleveland Clinic Foundation, Nissen is both a gadfly and a leader of clinical trials determining the effectiveness and safety of new drugs.
The story of how Nissen came to play this critical yet controversial role goes back to 2001, when he began serving on a Food & Drug Administration panel reviewing new drug applications. He initially believed that the review process was sound. But four years working on the inside turned him into a radical. "Companies don't always do the right thing," he declares, "and the FDA misses some signals."
In the course of his conversion, Nissen has lobbed some powerful grenades. He and his boss, Dr. Eric J. Topol, were among the first to raise alarms about Cox-2 inhibitors -- a class of painkillers that includes Merck's () Vioxx and Pfizer's Celebrex. The former has been pulled from the market amid evidence that it may trigger heart attacks. And Pfizer Inc. says it is now planning a long-term study on the cardiovascular profile of Celebrex -- after constant prodding from Nissen and others. Nissen was also an early critic of Johnson & Johnson's () controversial heart failure drug, Natrecor. And he published a paper in late October warning of potential safety problems with a diabetes drug from Bristol-Myers Squibb Co. () and Merck & Co.
Nissen isn't all rebel, however. The 57-year-old physician has deep ties to several drugmakers, including those whose products he has publicly criticized. In fact, Nissen's detractors point out that he often urges companies to do trials to answer safety questions -- trials that his institution could clearly be a candidate to lead. And he helped device companies create and test an imaging technology, intravascular ultrasound (IVUS), that drugmakers use to study cardiovascular therapies. Thanks to the network he has built of 300 hospitals that will participate in his IVUS studies, Nissen has a big head start in applying that technology to heart drug studies. Among the cardiovascular drug trials he is leading is a massive study of the Pfizer drug torcetrapib, which raises "good" cholesterol. Nissen promoted the ultrasound technology aggressively to Pfizer executives in the late 1990s. Now Pfizer is hoping Nissen's studies will show that torcetrapib is actually causing a reduction in plaque that clogs heart vessels.
Drug companies may get agitated when Nissen raises a stir about safety, but there's not much they can do. "Who else is going to do the IVUS trials for them?" Nissen asks. "I have some advantages, and I use [them] when I can."
Nissen knows that consulting for drug companies could compromise his credibility. To insulate himself from potential conflicts of interest, he stopped accepting fees from the industry several years ago. Instead, he tells companies to make donations to the American College of Cardiology and other charities.
Meanwhile, his critiques continue to draw attention. In early September an FDA advisory panel recommended approval of Bristol's diabetes drug, Pargluva -- a potential blockbuster. But Nissen and a colleague did an analysis based on the limited data that were available on the FDA Web site and in late October, they dropped a bomb: Writing in the Journal of the American Medical Association (JAMA), they showed that the drug might be linked to a high rate of heart attack, stroke, and death. By then, the FDA was also requesting more data on the drug's cardiovascular safety. Bristol now confronts a tough decision: run a new, expensive trial or give up on the drug, which it still believes to be effective.LIMITED ACCESS
The FDA says Nissen's paper didn't influence its decision-making. Dr. Brian L. Strom, a professor at the University of Pennsylvania School of Medicine who has consulted for Bristol on Pargluva, agrees that Nissen's paper wasn't significant. Strom says the FDA was well aware of cardiovascular safety questions, and he argues that Nissen's analysis, based on limited access to data on the drug, contributed little to the debate. "What does an analysis of incomplete data add to that?" he asks. "And why would you publish it in JAMA except [to garner] press attention?"
Nissen says he takes no pleasure in clashing with the industry and only wrote the Pargluva paper because he thought no one was going to speak up about a possible "patient catastrophe."
Medicine wasn't initially in Nissen's stars. As the son of a gynecologist growing up in Southern California, he initially bucked his father's insistence that he become a doctor. Nissen took eight years to get his undergraduate degree at the University of Michigan, a period in which he actively protested the Vietnam War.
Later, Nissen grew increasingly ambitious. As a young cardiologist at the University of Kentucky Chandler Medical Center, he started a medical helicopter service to fetch very sick heart attack patients from rural areas, making hundreds of rides on the aircraft. In the early days of developing the IVUS technology in Kentucky, Nissen and colleagues would wait until late at night, then sneak lab dogs into the hospital rooms used to perform human cardiology procedures. They would work until 1 or 2 a.m. testing the new equipment on the dogs, then furiously clean up any errant canine hair so hospital officials would remain in the dark. "He's a swashbuckler," says Dr. Anthony N. DeMaria, a top cardiologist at the University of California at San Diego School of Medicine and Nissen's former boss in Kentucky.
Even though Nissen no longer accepts consulting fees, he benefits indirectly from the clinical trials that flow through his lab, gaining influence and prestige. But that never deters him from taking a critical stance, he says. After all, he was raising questions about Cox-2 drugs even as he was doing work for Pfizer, one of the biggest Cox-2 promoters. As Nissen puts it: "I'm an insider and an outsider at the same time." By Amy Barrett, with John Carey in Washington