Merrill Goozner argues that the danger runs deeper. “In many precincts of the scientific enterprise, the needs of industry have become paramount,” he says, turning science into “a contested terrain” where facts are increasingly contingent on who is funding the research. “The whole scientific revolution, which was a product of the Enlightenment, is threatened when you commercialize science,” he warns.
So is private funding a boon or a bane for American science? The answer, like good science itself, requires looking carefully at how the phenomenon is playing out in the real world.
Steven Nissen is perhaps the most prominent physician speaking out about the pharmaceutical industry’s growing influence over medical research. An esteemed cardiologist at the Cleveland Clinic, Nissen has written more than 300 articles and served as the immediate past president of the American College of Cardiology. Working in a bustling academia-affiliated medical center has given Nissen a unique perspective on the benefits and risks of privatization.
In the past, academic medical investigators strove to maintain “arm’s-length relationships with their corporate sponsors,” says Marcia Angell, a former editor in chief at The New England Journal of Medicine. That changed with the rise of biotechnology and the passage of landmark congressional legislation known as the Bayh-Dole Act. Passed in 1980, the act granted universities and their professors automatic rights to own and commercialize federally funded research. The goal was to unlock financial incentives that would speed the pace of American scientific innovation. Overnight, many of the cultural taboos associated with overt commercial profiteering on campus began to evaporate.
Nissen believes that interactions between academia and industry are crucial to the development of new treatments. He also accepts sponsored research grants from industry, both to test drugs and develop new treatments, although he tries to limit his personal financial conflicts of interest by requiring that any other consulting fees and honoraria be given directly to charity. Still, he is clearly troubled by the threat that privatization poses to academic autonomy—and to research objectivity. “We can only make good decisions in science when all of the information is available for physicians, scientists, and patients to review,” he says. But drug companies are increasingly keeping physicians and their patients in the dark.
Last year, Nissen grew suspicious about possible health risks associated with GlaxoSmithKline’s top-selling diabetes drug, Avandia. “We requested access to the original patient-level data,” he says, but “we were not afforded access.” Nissen wasn’t surprised; for years he has perceived a growing tendency by the drug industry to suppress negative research data.
Searching the Internet, Nissen stumbled upon a remarkable cache of data belonging to Glaxo. His search unearthed 42 Avandia clinical trials—only 15 of which had ever been published. Nissen didn’t know it at the time, but the reason Glaxo’s data were just sitting there on the Web was the outcome of a lawsuit filed by former New York attorney general (and current governor) Eliot Spitzer in 2004. The lawsuit alleged that Glaxo had concealed negative trial data associated with its popular antidepressant drug, Paxil. When the data were properly analyzed, they showed that children given Paxil were actually two times more likely to experience suicidal thinking and behavior than children given a placebo, or sugar pill. When Glaxo settled the suit, it denied having suppressed data and consented to posting results of all its clinical trials online—including its data on Avandia.
Nissen knew there were limitations to the public information he had. He lacked any original patient-level information, and a meta-analysis of prior drug studies is always less powerful than a large prospective, randomized clinical trial. This May, however, Nissen felt compelled to alert doctors and patients to what he had found.
Publishing in The New England Journal of Medicine, Nissen reported that Avandia raised the risk of heart attacks in patients by 43 percent. The news made front-page headlines. Two days later, the FDA, which had already been assessing the health risks of Avandia, imposed its toughest warning label, the “black box,” on the drug, as well as on Actos, another drug used to treat diabetes.
At a subsequent congressional hearing chaired by Representative Henry Waxman, it came to light that the FDA had known about Avandia’s risks for some time. Rosemary Johann-Liang, a former FDA drug safety supervisor, had recommended a black box warning label for Avandia due to its harmful effects on the heart one year prior to Nissen’s publication. Glaxo’s own meta-analysis, presented to the FDA in 2006, showed a 31 percent increased risk of heart attacks. Yet according to Johann-Liang, “my recommending a heart failure box warning was not well received by my superiors, and I was told that I would not be overseeing that project.” She was also told to obtain her supervisors’ approval before making any future black box recommendations. After the hearing, the FDA completed its own meta-analysis of the original patient data and found virtually the same heart risks Nissen had reported.
Nevertheless, Nissen found himself under attack, often by people with explicit financial ties to the drug industry. His challengers have included Valentin Fuster, who wrote a critique of Nissen’s work in Nature Clinical Practice Cardiovascular Medicine. Fuster receives Glaxo funding and serves as the chairman of Glaxo’s Research and Education Foundation. Peter Pitts wrote a stinging attack on Nissen in The Washington Times; he is a senior vice president at the PR firm Manning Selvage & Lee, which represents Big Pharma, including Glaxo. Douglas Arbesfeld, a senior communications consultant at the FDA, disparaged Nissen in a biting e-mail to the media. He formerly worked as a spokesman for Johnson & Johnson.
Press reports over the last 15 years detail how whistle-blowers inside academia and within the FDA who have attempted to expose drug-research and safety issues have been pressured. Some were threatened with legal action, others punished by their superiors and discredited. “Whenever we’ve raised safety questions about drugs,” Nissen says, “there’s always been a reaction like this. Exactly the same thing happened in 2001 when we published a manuscript that suggested that Vioxx might be causing excess heart attacks.” Nissen was coauthor of one of the first studies on the dangers of Vioxx. Three years later, Merck pulled the drug from the market. By that time, one FDA analyst estimates, the drug had contributed to up to 139,000 heart attacks. (A Merck representative states that the paper from which the estimate of 139,000 was derived had “serious limitations” and did not necessarily reflect the views of the FDA.)
Experiences like these have bolstered Nissen’s position that the independent research system needs to be protected and preserved. “I think having independent physicians leading the study and analyzing the data is the best way to protect against biases in the reporting of results.” But increasingly, he says, the pharmaceutical industry is farming out its clinical trials to for-profit entities, known as contract research organizations. Independent academic investigators are getting shut out.
The numbers bear Nissen out. Big Pharma now finances approximately 70 percent of the nation’s clinical drug research. In the past, most of this sponsored-research money went to academic medical centers; today an estimated 75 percent flows to for-profit contract research firms.
Even when academic physicians are involved, often they don’t enjoy anything close to true research independence, Nissen says: “Academic physicians are still involved in the leadership of the study, but not fundamentally in the design of the study, or in the key aspects of the execution of the study.” Often, he notes, the industry sponsor will prevent the academic investigator from performing any independent analysis of the complete raw data related to his or her research. “The physician gets a printout of the main results,” Nissen says, “but the actual analysis itself is done by statisticians within the companies.”