When drug companies are paying the bills, what happens to researchers’ objectivity and independence? The stakes are sickness or health, life or death

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TWENTY-EIGHT MEN and women were already dead.

In the ballroom of a Maryland hotel, an expert panel was huddling to decide what government regulators should do about Warner-Lambert’s controversial diabetes drug Rezulin. They heard warnings that day that the risk of liver failure associated with the drug was perilously high.

But they also heard from a procession of nine prominent university researchers who downplayed concerns that the drug was killing patients. The scientists, from Harvard, UCLA and other schools, all urged the Food and Drug Administration to keep Rezulin on the market.

And they all had financial ties to the drug’s manufacturer.

Another year would pass-and 33 more deaths would be reported-before Rezulin was finally pulled from the market March 21. But while the incident focused public attention on internal squabbles at the FDA, the financial links between Warner-Lambert and the researchers illuminate a deeper, far-reaching problem.

A growing reliance of university scientists on corporate cash is threatening the tenets of openness, honesty and objectivity in academic medical research.

From $1,000-a-day consulting fees to hefty research grants to big-payoff stock deals, industry money has become a pervasive force in academia. And as government grants have tightened, corporate money has produced a profound cultural shift that has introduced the bottom-line values of the marketplace to university science.

The scientific community has responded for the most part with modest concern, saying that industry cash fuels discovery and, moreover, that no amount of money can corrupt a researcher who is trained to seek the truth. The complex nature of scientific inquiry makes it difficult to draw a straight line between financial ties and questionable conclusions in any given case.

But a Courant review of recently developed drugs, as well as interviews with dozens of researchers across the nation, has found that scientists are asking questions-and getting answers-that neatly fit the agenda of their corporate sponsors.

The implications are profound. In biomedical research-where the stakes are sickness or health, life or death-objectivity and independence are crucial tools. They assure the public that a researcher is guided by the truth rather than a potential payoff for the “right” answer.

Dr. Marcia Angell, until last spring editor in chief of the New England Journal of Medicine, is troubled by the attitude of her fellow scientists.

“The best analogy is with a judge,” Angell said. “Imagine a judge who has before him a case involving two companies suing each other-and he owns one of the companies. And he says, ‘Not to worry. I’m a judge and I learned how to evaluate things in a dispassionate way.’ He’d be laughed out of court.

“But that’s exactly what you hear.” .

It wasn’t always this way. For decades after World War II, bright scientists planted themselves in university labs and enjoyed a reliable stream of government support. But as federal money tightened in the 1970s, scientists hungry for research dollars turned to the private sector.

Although the federal government remains the primary source of funding for academic medical research, the amount-and influence-of corporate cash has grown dramatically over the past 20 years.

The exact dollar figure is difficult to quantify because of the variety of ways researchers get industry money. But at the Duke University Medical Center, for example, corporate-sponsored biomedical research increased nearly 70 percent in the last two years, jumping from $63 million in 1997 to $107 million in 1999.

Nationally, pharmaceutical-industry spending for research outside the drug companies’ own labs-a sum that includes not only academic sites but also private research companies-increased in the 1990s at a rate six times faster than the growth in federal grants. Many in academia see this as a positive development. Corporate money, proponents say, has helped fuel a golden age in biomedical research. It has led to discoveries that have helped lengthen the average life span and put cures for dreaded diseases within reach. The basic honesty of good scientists, they say, is an adequate antidote for any possible conflicts of interest.

“You may think I’m a Pollyanna or something, but most people are honest,” said Niels Reimers, an early pioneer of the movement that forged closer ties between the worlds of science and commerce. “It’s sort of the ethos of academic research – the search for truth.” But others say corporate money corrupts that search.

“The drug companies, really, they make it very clear what the results had better be if you want any more money from them,” said Dr. Allen Arieff of the University of California at San Francisco.

Arieff had been hired to test a popular diabetes drug. But when he publicly presented research results showing the drug had dangerous side effects, he said, his five-year grant was summarily pulled after only two years.

“There are always strings,” Arieff said.

Jeff Trewhitt, a spokesman for the Pharmaceutical Research and Manufacturers of America, counters that drug companies are too dependent on maintaining the trust of doctors and the FDA to play games with scientific facts.

“This allegation is one of the more popular myths about pharmaceutical companies,” Trewhitt said. “But malfeasance and fudging the facts, they occur as rare exceptions to the rule. And they occur at the risk of hurting your credibility, and bringing on an avalanche of lawsuits.” But the case of Betty Dong illustrates how the clash between the values of scientists looking for answers and corporations looking for sales can hurt consumers.

When the maker of a popular thyroid drug wanted to find out if the drug was better than the less expensive generics on the market, it turned to Dong, a prominent researcher at the University of California at San Francisco.

In what could have been a devastating blow for the company-and a consequent boost for consumers-Dong found that generic substitutes worked just as well in controlling people’s thyroid problems. The publication of Dong’s research would have hurt the very company that had paid for the study.

The drug maker, Knoll Pharmaceuticals, challenged the results, attacked Dong’s work and told her she couldn’t publish the study. A behind-the-scenes battle erupted, and, for more than five years, Dong’s findings about Synthroid remained hidden, surfacing in 1996 after details of the episode became public.

The Dong case put universities across the nation on notice that they had to be careful about what rights they signed away.

But protecting the right to publish the whole truth is no guarantee that researchers will.

When Dr. Stanley Malamed in 1997 touted a $1,000 dental device designed to deliver a painless dose of anesthesia, his online testimonial for “The Wand” assured readers that they were getting a cold, critical analysis.

“As Chairman of Anesthesia and Medicine at the University of Southern California School of Dentistry, I am first an educator and clinical researcher,” Malamed said on the company’s Web site. “As you might imagine, I deal with new products from a skeptic’s point of view.” But the skeptic was also a consultant, clinical evaluator and “special technology adviser to the president” of Milestone Scientific, the device’s manufacturer. Part of his compensation: an option to purchase a large block of stock at a discount price. The economics were simple: If The Wand was a hit, Malamed would get rich.

A study by Malamed, cited frequently by the company, showed the vast majority of test patients said the shot was painless. “Only a small percentage reported the minor post-operative awareness that an injection had even been administered,” Malamed said in company documents.

Later, dentists learned Malamed hadn’t told the whole story. While the patients in his study said the injection itself was indeed painless, many also said it failed to numb their gums. Malamed’s online testimonial cited the need for “more detailed information on product capabilities and applicable procedures” but did not specifically mention its shortcomings.

Milestone said it has since improved The Wand.

Malamed, in an interview, declined to say why he never published a detailed report on his study.

But he said he never intended to mislead dentists about the quality of The Wand. He said the company quoted him out of context and that he was unaware of it until months later, when questions were raised about his research.

“I try very, very hard, and I’ve done a good job in my career, of being non-biased-which this, definitely, took away,” Malamed said. “I came across as a person who is out there on the bandwagon pushing this device. That was not my intent, ever.” Malamed’s paper fortune never materialized, as Milestone’s share price fell dramatically. But does he believe the prospects for a huge payout affected his research or his opinion of The Wand? “I would like to believe, honestly, that the answer is no.” .

As the ties between academia and industry grow, researchers are increasingly wearing two hats: as both objective evaluator and paid company spokesman. If understating the liabilities or dangers of a drug or a device is one side of the coin, the other is overstating the advantages.

Jacob Lalezari, an assistant clinical professor at the University of California at San Francisco, was enthusiastic last summer when the FDA approved the flu drug Relenza. Lalezari, who is also chief executive officer of a private clinical research firm, was the principal investigator for Relenza and is paid as both a consultant and member of the speakers’ bureau for the drug’s maker, Glaxo Wellcome.

“For the first time in human history,” Lalezari proclaimed to ABC News after the drug’s approval, “we are now prepared to treat whatever Mother Nature throws at us.” It was, he told USA Today, a “historic” moment.

FDA scientists had not been nearly so excited.

An advisory panel had recommended, 13-4, against approval of the drug.

Although two studies conducted overseas had showed modest benefit, an independent government review of a larger study in the United States concluded the drug had not been proven effective.

But Lalezari saw good news, saying in a Glaxo Wellcome press release that Relenza was “a valuable resource for doctors and patients in the battle against this ancient and dreaded illness.” Lalezari said he knows scientists and companies that have distorted research to serve commercial ends. But he said that doesn’t apply to him.

“I can’t tell you that money has no influence. Obviously I’m trying to make a living like anybody else,” Lalezari said. “But I’ve got to tell you that the single most important aspect of what I do is maintaining the integrity of what I say. I try and be very careful to be balanced and not say anything I don’t believe.” With Relenza, Lalezari said the FDA unfairly analyzed the U.S. study, and he said his enthusiastic comments were based on his belief that Relenza could help stem an influenza pandemic in the event of an unforeseen vaccine-resistant outbreak.

Dr. Michael Todd, editor in chief of the journal Anesthesiology, says he is convinced that money affects scientists. But he said there is a clear line between a researcher’s hype and outright lies.

“For people who say, ‘Oh, I can take that speaker’s engagement or I can take this money, and it will have absolutely no influence on my way of thinking’-come on, give me a break. But it isn’t the same as saying you’ve been bought,” Todd said.

“The honorarium, the consultancy fee, the speaker bureau, the trip to Boca Raton to give a talk; it doesn’t buy the company a mouthpiece. If anything, what it does is it brings the investigator into the corporate team. They become somebody who has a commitment to this product,” he said.

It’s a big problem for doctors like Henry W. Vaillant, a general practitioner in Acton, Mass., who’s been treating patients for 30 years.

When new medications make it past the FDA-and into prime-time television ads-Vaillant’s busy group practice faces an onslaught of calls from eager patients. But Vaillant said the growing links between researchers and pharmaceutical companies have made it tough for doctors to get an unbiased read on the safety and effectiveness of newly minted drugs.

“There have been several instances where as high as 90 percent of the published information on a medication is sponsored by the very industry that designed the medication,” Vaillant said. “That worries the hell out of me.” “There are cozy relationships that develop over the years that can partially blind an investigator,” he said. “It’s not fraud. But what I’m saying is: There get to be easy ways of doing things, and that can just slightly influence the way you set up [an experiment], even in ways you don’t fully appreciate.” So Vaillant, a Harvard-educated internist, has learned to troll the Internet for drug information, and he’s found a straight-shooting newsletter, The Medical Letter, that he’s convinced is free of industry influence.

But it doesn’t give him peace of mind.

“I just have a working rule that I don’t prescribe anything until it’s been out six months,” Vaillant said. “My own policy is to let somebody else’s patients check out the side effects.” Joy Kerr, a Manchester woman who was taking Rezulin before it was withdrawn from the market, wonders if consumers might be better served if the scientists testing drugs had no financial ties to the drug makers.

“Money will do anything. That’s the biggest corrupter in the world,” Kerr said. “You’re dealing with people’s lives.” .

A handful of studies has tried to determine whether scientific outcomes are influenced by financial ties, and several point to a problem.

In one of the most comprehensive, a team of Canadian researchers waded into a thorny question being hotly debated by specialists in heart disease: Are calcium-channel blockers a safe way to treat hypertension and angina? The team reached a troubling conclusion in a 1998 article published in the New England Journal of Medicine. After analyzing 70 studies, the researchers found that authors who backed the use of calcium-channel blockers were far more likely to have financial relationships with the companies that make them than scientists who were neutral or critical.

The study found that while 96 percent of authors who wrote favorably about calcium-channel blockers had links with manufacturers, only 37 percent of the critical scientists had relationships with the industry.

“The medical profession,” the study concluded, “needs to develop a more effective policy on conflict of interest.” Another survey, from 1996, looked at the increasingly popular practice of releasing new information at scientific gatherings, rather than in peer-reviewed journals. Mildred Cho, now of Stanford University, and Lisa Bero of the University of California at San Francisco found that studies financed by drug companies were more likely to support the drug in question than those without financial backing from the industry.

Finding a scientifically proven link between research money and research results has obvious implications for academic medical research. But there aren’t many such studies, and Sheldon Krimsky, a professor at Tufts University and a longtime critic of academic-industry ties, says the reason is no surprise.

“Truth is,” he said, “there aren’t a whole lot of studies like that, because no one wants to pay for them.” .

So who’s a consumer to trust? A tale of two drug companies trying to prove which makes the best medicine to stop the crippling effects of osteoporosis shows that can be a tough question.

In a Merck-financed study released in 1999, a university researcher compared Merck’s osteoporosis drug, Fosamax, to a popular product made by rival Novartis. At a symposium in Southern California, the scientist told fellow endocrinologists that Merck’s drug worked better, because it led to a greater improvement in bone density.

But an academic scientist with ties to Novartis trashed the research, saying bone density was the wrong measure of an osteoporosis drug’s effectiveness. The right measure, he said, was spinal fractures. And company-sponsored research had shown Novartis’ drug, Miacalcin, to be effective in reducing spinal fractures.

“Nobody wants to admit that science can be shaped,” Krimsky said. “But there are so many ways that bias comes into it.” Lynn McAfee, who heads an advocacy group for the obese, says she has watched as virtually all of the top obesity researchers at the nation’s universities have aligned themselves with drug companies. She says she’s seen the lure of industry money change the focus of obesity research and cast doubt on the integrity of the results.

And she is distressed that nobody seems to have a problem with it.

“What they say is: ‘I’m an honest person. You can’t buy me,'” said McAfee, director of the Council on Weight and Size Discrimination, based in Philadelphia. “But it’s not like that. We’re not meeting in Washington parking garages and exchanging a million dollars. It’s much more subtle, and much more damaging, because it’s enmeshed into the fabric of research.

“And that has changed the very nature of science.”