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BOSTON - Three years into one of history's largest trials of a new AIDS treatment, Steve Lagakos realized that it wasn't working and ordered a halt. Lagakos' verdict disappointed tens of thousands who suffer from the deadly disease, more than 2,500 patients who had volunteered for the study and the Harvard scientist himself, who has dedicated his career to the fight against the illness.
When Lagakos delivered the news to the trial sponsors at a Chicago hotel, Immune Response Corp. executives seemed to take it in stride. But as the months passed, they first suggested, then insisted, that Lagakos and his collaborator, Dr. James O. Kahn of the University of California, San Francisco, report that its therapeutic vaccine had some effect.
Lagakos and Kahn refused and published their unflinching findings last November. That might have been the end of it. But the company took the extraordinary step of filing an arbitration claim seeking up to $10 million, alleging that the scientists had defamed its product.
"Just put yourself in my position," says Dennis J. Carlo, president and chief executive of the biotech company. "I spent over $30 million. I would think I have certain rights."
The company's actions may have been unusual, but efforts by industry to manipulate, delay or suppress the findings of university-based research are not, scientists say. That's because the difference between favorable and unfavorable results in a drug study can be measured in the billions of dollars. Many academic researchers, unlike Kahn and Lagakos, keep quiet to avoid angering corporate sponsors, according to Drummond Rennie, a medical journal editor who has studied the issue.
As pharmaceutical and biotech companies pour money into universities, there is growing concern over their clout on campuses. Marcia Angell, the former editor of the New England Journal of Medicine, says industry influence has so distorted medical literature that she calls this the "misinformation age" of medical research.
Increasingly, scientists working with companies are blocked from providing information to other researchers. In some corporate-sponsored studies, journal editors say, key data are omitted. A cancer researcher at the National Institutes of Health said a medical company would let him use a biological substance only if he kept the results of his work secret for a decade. As companies fund more medical research, scientists say, those sorts of demands are more common.
Some worry that corporate money will skew the research agenda, inspiring academic scientists to conduct research that promises quick results or profits, rather than pursue work that could save lives but make less money.
"The mission of academic medicine should not be confused with the mission of investor-owned businesses," says Angell.
One pharmaceutical company nearly abandoned a new cancer drug in the mid-1990s that an oncologist at Oregon Health Sciences University helped develop. Novartis, a leading drug manufacturer, thought the drug, Gleevec, might work only against rare cancers, making it unprofitable. Novartis pursued the drug - hailed as a breakthrough when it won FDA approval last month - only after cancer patients mounted a campaign.
Industry-sponsored research has helped spur the discovery of exciting new drugs. But some scientists worry that corporate money will subvert the centuries-old traditions of science, the free exchange of information that has allowed researchers to build on others' successes and learn from others' failures. This isn't just a philosophical question, some dry academic debate. For the public, medical research can be a matter of life and death.
"To me, as a doctor who takes care of patients every day, it boils down to a pretty simple issue: If you don't share information, then you potentially delay the time to find effective treatments for patients," says Dr. Steven Rosenberg, chief of surgery at the National Cancer Institute. "If you delay effective treatments, then people die."
Pharmaceutical companies, engaged in one of the world's most profitable businesses, lavish gifts and goodies on private physicians, giving them everything from pizzas to weekends at golf resorts. In the Baltimore area, doctors can pick up a free turkey from Graul's supermarket at Thanksgiving or dinner at the elegant Charleston restaurant, compliments of the industry. The aim is simple: to influence what drugs doctors prescribe.
Increasingly, drug companies try to enlist the help of the researchers who conduct drug studies and write about them in journals. Drugmakers regularly sponsor all-expense-paid educational conferences at luxurious resorts and posh hotels, where academics give talks. A 1998 survey in the Journal of the American Medical Association found that 43 percent of scientists at major universities had accepted gifts, including lab equipment and trips to meetings, from industry. Many recipients said donors expected something in return, including previewing articles for publication or patent ownership of any products.
Many researchers also collect consulting fees. The chief of psychiatry at Brown University's medical school, for example, received more than $500,000 in fees from drug companies in 1998, much of it from the makers of antidepressants he praised in journals. And so many prominent academic researchers serve as paid industry consultants that the Food and Drug Administration, needing their expertise, allows them to sit on drug approval advisory committees. Sometimes, half the panelists have a financial stake in the outcome, through ties to the drug manufacturer or a competitor.
Researchers generally say their alliances with industry help in the hunt for important treatments and don't threaten their independence. Companies, they say, want to buy their expertise, not their integrity.
But based on his experience, Dr. William B. Applegate, now chairman of the department of internal medicine at Wake Forest University School of Medicine, is not convinced.
Applegate helped lead a nationwide study in the late 1980s and early 1990s sponsored by Sandoz Pharmaceuticals Corp., (now part of Novartis), comparing the company's new calcium channel blocker with an older, less expensive medication for lowering blood pressure and preventing hardening of the arteries. Shortly before scientists met to learn the results, a Sandoz official called to offer Applegate a $30,000-a- year consulting job.
"Gosh," he thought, "this will help pay for the kids' education."
But the more Applegate considered it, the more it seemed an attempt to influence his judgment. He turned it down. When the scientists gathered, he discovered that the Sandoz drug did no better than the older medication at preventing hardening of the arteries. Worse, the company's drug was linked to higher rates of angina and stroke.
"When I saw the data, I thought the company was trying to buy my favor and my opinion," Applegate says.
As the researchers tried to draft a paper on the study - known by the acronym MIDAS - Sandoz scientists twice visited Applegate at the University of Tennessee at Memphis, where he was director of a clinical research center. Both times, Applegate says, they discussed giving the school research grants. Both times, over dinner, a company scientist casually asked Applegate: "Have you changed your mind over the MIDAS results?"
He hadn't. Feeling pressured, Applegate quit the study. The three other leaders of the MIDAS study quit, too. Then all four did something unusual: They made their concerns public, writing a letter published in the Journal of the American Medical Association in 1997, saying that "the sponsor of the study was attempting to wield undue influence" on the paper.
A Novartis spokeswoman says Sandoz's actions were "appropriate in all respects." Eventually, other scientists involved with the study published what Applegate views as an accurate paper.
Universities still receive most of their money for research from the National Institutes of Health. But drug companies spend about $30 billion a year on drug research and development, and some of that flows to academic labs. Some large drug companies spend one-fifth of their research dollars at universities; some small biotech companies do half of their research on campus. At many schools, corporate grants are growing faster than federal support.
Academic medical centers, pressured by insurers to control the patient care fees that help support research, are hungry for that industry money. While federal subsidies of research are at record levels, competition for NIH grants is fierce. At the same time, the cost of research is soaring.
For pharmaceutical companies, academic labs offer innovative ideas and relatively cheap, prestigious labor. They are staffed with graduate and postdoctoral students who may earn as little as $15,000 a year. Work in a university lab typically costs about half what it would at a drug company. And opinion polls show that the public has greater faith in research at universities than in private labs.
But a pharmaceutical company takes a risk when it has a university scientist test its drug. The results might not be favorable.
Academic researchers say that it is important to publish negative results, so physicians know what doesn't work and other scientists don't waste precious time and resources going down a dead end. Drug companies, though, sometimes balk at announcing their failures.
Betty Dong, a professor of clinical pharmacology at the University of California, San Francisco, has worked on a number of drug studies for industry. "If you do get information that's very favorable, they love you," she says.
But in the 1990s, Dong and a team of scientists conducting a major study found that a brand-name thyroid drug was no better than generics. The manufacturer blocked publication for years, invoking a confidentiality agreement. Americans were paying about $356 million more a year for the drug in higher prescription costs. Eventually, pressure from the Food and Drug Administration forced Knoll Pharmaceutical Co., to permit publication.
Eager for industry alliances and wary of legal battles, universities sometimes fail to support researchers who come into conflict with a corporate sponsor. "You would hope that universities would stand up for academic freedom," says Dr. Kenneth Kendler at the Medical College of Virginia. "That is not always true. Universities are very interested in the income from industry collaborations."
Dr. David Kern, a former researcher at Brown University medical school, says he has learned that painful lesson. After a Rhode Island textile company hired his occupational health program, he found that some workers suffered from a previously unknown lung illness caused by airborne nylon fibers.
When Kern told Microfibres Inc. of Pawtucket, R.I., that he planned to present his research at a May 1997 scientific conference, the company objected. A Brown administrator and officials at the university-affiliated hospital where he worked urged him to cancel the talk, citing a document Kern had signed pledging not to reveal Microfibres' trade secrets.
To Kern, no trade secrets were involved; his research had identified a public health threat. After he went ahead and announced his results, his post was eliminated. "I felt infuriated," Kern says. "This was an opportunity to better understand a disease."
Later that year, the Centers for Disease Control and Prevention recognized flock lung as a new disease. Other public health physicians said Kern's work could save lives around the world. Still, Kern was unable to win back his job.
A Brown spokesman, Mark Nickel, said the university had little influence over the hospital's actions. The lesson for the university? "Even standard, routine forms need to be looked at carefully," he said.
Kern moved with his family to the Maine coast, where he has a general practice and rides his bicycle to work. His keenest disappointment, he says, was the reaction of colleagues.
"It was very dispiriting to see people who I thought were friends turn the other way. 'Of course,' they would whisper, 'I'm right behind you.' Then they wouldn't do anything."
Buying broad access
Where they once underwrote the work of individual scientists, corporations now buy access to the research of entire departments or institutions.
The Swiss drug giant Novartis is paying $24 million over six years to the University of Maryland's Psychiatric Research Center for access to its bank of brain tissue and one of its labs. The company pays $20 million a year for first look at some research at the Scripps Research Institute in California and over the past decade has paid up to $100 million for research at the Harvard-affiliated Dana Farber Cancer Institute.
The trick in negotiating those deals, which come with strings attached, is to make sure that institutions don't cede their independence, some scientists and university officials say.
Novartis is among the most aggressive corporations in tapping into academic labs. Sandoz, a Novartis predecessor, rattled the scientific world in 1993 when it bought exclusive access to the Scripps Institute's research, much of it paid for by NIH grants. The NIH objected, and Sandoz could only get rights to about one-half of the institute's work.
At the University of California at Berkeley, Novartis agreed in 1998 to pay $25 million for the first right to patents on some of its basic plant research. Students and some faculty protested, fearing an erosion of academic freedom, suspicious of efforts to genetically manipulate crops and uneasy about the increasing influence of corporate money on campus.
The drug company came to the University of Maryland at the invitation of Dr. William T. Carpenter Jr., director of the Psychiatric Research Center. Facing stagnating budgets and an important mission - the battle against schizophrenia - Carpenter approached Novartis researchers several years ago at a New Orleans scientific meeting.
The University of Maryland, like many other schools, has in recent years become more entrepreneurial and more interested in collaborations with industry. Though its medical school has produced far fewer patents, licensing income and start-up companies than Johns Hopkins across town, it too is undergoing a transformation.
"The focus now is to cooperate and achieve shared scientific goals," says Joann A. Boughman, director of research and development for Maryland's Baltimore campus.
The Novartis deal now provides one-third of the psychiatric center's budget. In effect, the company receives exclusive commercial access to 700 brains stored in freezers on the Spring Grove campus. In addition, the company gets first rights on licensing patents and can demand that researchers delay publication for three months. It also gets four seats on the eight-member panel that decides how the Novartis money is spent.
Scientists at other institutions are leery of such tight links to industry. Dr. E. Fuller Torrey, director of the Stanley Foundation Research Programs in Rockville, says his group shares its collection of about 400 brains with researchers around the world. There's only one requirement: that all research be freely published.
He worries about deals like the one at the psychiatric center. "Does the arrangement between Novartis and the University of Maryland either slant or constrict research?" he asks.
Dr. Paul Herrling, director of research for Novartis, said the company has no intention of trying to hijack Maryland's research program or of blocking publication for longer than it needs to file patents. "Our goals are congruent and there is no conflict," he says.
After two years, center scientists say the collaboration works smoothly. But Carpenter concedes that the company, which can pull out of its contract with Maryland at two-year intervals, has enormous leverage.
"The thing that I worry about is, they could walk away from this," he says.
Patenting the sun
Newsman Edward R. Murrow once asked Dr. Jonas E. Salk who owned his polio vaccine, which spared millions from the crippling illness. "Well, the people, I would say," Salk replied. "There is no patent. Could you patent the sun?"
But when Salk came out of retirement in the late 1980s to tackle AIDS, it was the age of biotechnology. Salk applied for seven patents on his vaccine, called Remune. He also helped found a biotech company, Immune Response Corp., in Carlsbad, Calif., to develop it.
Unlike Salk's polio vaccine, Remune is a so-called therapeutic vaccine. It would not stop people from being infected with the virus that causes AIDS. It was supposed to keep people already infected from developing full-blown AIDS.
Salk used an approach to AIDS similar to the one he had used with polio, even though many AIDS experts were skeptical. By the mid-1990s, his vaccine had undergone preliminary tests, but members of an FDA panel accused the company of exaggerating the results.
To shore up credibility, executives at Immune Response Corp. hired Kahn and Lagakos, two widely known experts, to study the vaccine. "They felt that if an independent group did it, the results would be believed," Lagakos says.
He and Kahn say they insisted on absolute freedom to publish the data and their analysis. "We made it very clear to them we had to have complete control," Lagakos says.
But well into the trial, Lagakos realized that the data flowing to Harvard from 77 medical centers across the nation showed that the vaccine wasn't slowing progress of the disease. He halted the trial in May 1999. The financial fallout was immediate: The company's stock lost one-third of its value in a single day. A month later, the company laid off 43 people, about 30 percent of its staff. Senior management took pay cuts.
As Kahn and Lagakos began writing their paper concluding that the vaccine had failed, the company urged them to consider evidence that it said showed that the vaccine had had a limited effect in some patients. The scientists replied that the data wasn't meaningful and said the company was grasping at statistical straws.
The dispute - and the $10 million arbitration proceeding - became public when the study was published last fall in the Journal of the American Medical Association.
"Once it was clear that our data was different from their analysis, they acted like bullies in a sandbox," Kahn said.
Company officials argued that the article should have been more balanced and that it ought to have included what they viewed as encouraging results. The researchers "wanted it black and white, absolutely no effect," said Dr. Ronald Moss, the medical director for Immune Response Corp.
This month, a Remune trial in Spain backed up the conclusions of Kahn and Lagakos. It showed that the vaccine failed to benefit patients. While other studies continue, the vaccine's future is in question.
Suppression and spin
Drummond Rennie, deputy editor of the Journal of the American Medical Association, said the conflict between Kahn and Lagakos and their corporate sponsor has ramifications for science, patients and doctors all over the world.
"Why should we care about corporations trying to manipulate or suppress studies by academic scientists?" Rennie asks. "When I go to my doctor, I'm putting my health and my life in his hands. But how can my doctor know the real facts, the best evidence, when sponsors of research suppress, twist and spin the evidence?
"Every time a corporate sponsor messes with the data, the sponsor tricks my doctor," he says. "Every time that happens, my treatment, and the treatment of everyone else, suffers."