Respond to this Article April 2004

Doctors Without Borders

Why you can't trust medical journals anymore.

By Shannon Brownlee

With financial ties to nearly two dozen drug and biotech companies, Dr. Charles B. Nemeroff may hold some sort of record among academic clinicians for the most conflicts of interest. A psychiatrist, a prominent researcher, and chairman of the department of psychiatry and behavioral science at Emory University in Atlanta, Nemeroff receives funding for his academic research from Eli Lilly, AstraZeneca, Pfizer, Wyeth-Ayerst--indeed from virtually every pharmaceutical house that manufactures a drug to treat mental illness. He also serves as a consultant to drug and biotech companies, owns their stocks, and is a member of several speakers' bureaus, delivering talks--for a fee--to other physicians on behalf of the companies' products.

But it was just three of Nemeroff's many financial entanglements that caught the eye of Dr. Bernard J. Carroll last spring while reading a paper by the Emory doctor in the prominent scientific journal, Nature Neuroscience. In that article, Nemeroff and a co-author reviewed roughly two dozen experimental treatments for psychiatric disorders, opining that some of the new treatments were disappointing, while others showed great promise in relieving symptoms. What struck Carroll, a psychiatrist in Carmel, Calif., was that three of the experimental treatments praised in the article were ones that Nemeroff stood to profit from--including a transdermal patch for the drug lithium, for which Nemeroff holds the patent.

Carroll and a colleague, Dr. Robert T. Rubin, wrote to the editor of Nature Neuroscience, which is just one of a family of journals owned by the British firm, Nature Publishing Group, pointing out the journal's failure to disclose Nemeroff's interests in the products he praised. They asked the editor to publish their letter, so that readers could decide for themselves whether or not the author's financial relationships might have tainted his opinion. After waiting five months for their letter to appear, the doctors went to The New York Times with their story--a move that sparked a furor in academic circles, and offered the public yet another glimpse into conflict of interest, one of the most contentious and bitter debates in medicine.

In his defense, Nemeroff told the Times he would have been happy to list his (many) relationships with private industry--if only the journal had asked. "If there is a fault here," he said, "it is with the journal's policy," which did not require authors of review articles to disclose their conflicts of interest.

And that is pretty much where the debate over conflict of interest in medical journals stands: Should research scientists who have financial stakes in the products they are writing about be forced to disclose those ties? To which the average person might reasonably respond, of course they should. But the more pertinent question is why scientists with financial stakes in the outcome of scientific studies are allowed anywhere near those studies, much less reviewing them in elite journals.

The answer to that question is at once both predictable and shocking: For the past two decades, medical research has been quietly corrupted by cash from private industry. Most doctors and academic researchers aren't corrupt in the sense of intending to defraud the public or harm patients, but rather, more insidiously, guilty of allowing the pharmaceutical and biotech industries to manipulate medical science through financial relationships, in effect tainting the system that is supposed to further the understanding of disease and protect patients from ineffective or dangerous drugs. More than 60 percent of clinical studies--those involving human subjects--are now funded not by the federal government, but by the pharmaceutical and biotech industries. That means that the studies published in scientific journals like Nature and The New England Journal of Medicine--those critical reference points for thousands of clinicians deciding what drugs to prescribe patients, as well as for individuals trying to educate themselves about conditions and science reporters from the popular media who will publicize the findings--are increasingly likely to be designed, controlled, and sometimes even ghost-written by marketing departments, rather than academic scientists. Companies routinely delay or prevent the publication of data that show their drugs are ineffective. The majority of studies that found such popular antidepressants as Prozac and Zoloft to be no better than placebos, for instance, never saw print in medical journals, a fact that is coming to light only now that the Food and Drug Administration has launched a reexamination of those drugs.

Today, private industry has unprecedented leverage to dictate what doctors and patients know--and don't know--about the $160 billion worth of pharmaceuticals Americans consume each year. This is an unsettling charge that many (if not a majority) of doctors and academic researchers don't want to acknowledge. Once grasped, however, the full scope and consequences of medical conflict of interest beget grave doubts about the veracity of wide swaths of medical science. As Dr. Drummond Rennie, deputy editor of The Journal of the American Medical Association (JAMA), puts it, "This is all about bypassing science. Medicine is becoming a sort of Cloud Cuckoo Land, where doctors don't know what papers they can trust in the journals, and the public doesn't know what to believe."

Clinical trial and error

How did we get to this point? What effect is industry influence having on the treatment of patients? And why are the medical journals not more vigilant to weed out papers that have been distorted by conflict of interest? The answers to these questions begin, oddly enough, with an amendment to U.S. patent law called the Bayh-Dole Act. Passed in 1980, Bayh-Dole for the first time permitted universities to commercialize products and inventions without losing their federal research funding, the seed money for innovative research. The brainchild of George Keyworth II, President Reagan's science advisor, who was watching the United States get beaten in world markets by the Japanese, Bayh-Dole was intended to stimulate advanced technological invention and speed its transfer from university labs into private industry, where it could be put to work spurring U.S. productivity.

It seemed like a win-win proposition. Indeed, Bayh-Dole has helped launch the biotech industry and has propelled several life-saving products to market. The basic research behind Gleevec, for instance, an incredibly effective new anti-cancer drug, was done by a university scientist. The drug's manufacturer, Novartis, stepped in and provided additional funding for development. In 1984, private companies contributed a mere $26 million to university research budgets. By 2000, they were ponying up $2.3 billion, an increase of 9,000 percent that provided much needed funds to universities at a time when the cost of doing medical research was skyrocketing.

That's the upside. The downside is that Bayh-Dole has also fostered increasingly cozy relationships between the academics upon whom the nation depends for unbiased medical information and Big Pharma, private companies whose main goal, let's face it, is making a profit. And we're talking serious money here. In addition to the salaries built into company-sponsored research grants, academic clinicians at medical schools can pad their already decent incomes with $1,000-a-day consulting contracts with pharmaceutical companies, patent royalties, licensing fees, and big-payoff stock options. Nemeroff stood to reap as much as $1 million in stock from a company that manufactured one of the products in his Nature Neuroscience paper. At many of the top research universities and medical schools around the country, a substantial percentage of the faculty enjoys the perks of industry relationships. At MIT, 31 percent of the science and engineering faculty has outside income; at Stanford Medical School, it's 20 percent.

What's in it for the pharmaceutical companies? Simple economics. It's Marketing 101. By penetrating the wall that once existed around academic researchers, drug companies have gained access to the "thought leaders" in medicine, the big names whose good opinion of an idea or a product carries enormous weight with other physicians. Companies target academic KOLs, or Key Opinion Leaders, in the lexicon of marketing, and woo them with invitations to sit on scientific advisory committees, or to serve as members of speakers' bureaus, which offer hefty fees for lending their prestige to a company and touting its products at scientific meetings and continuing medical education conferences. Of course, KOLs must be convinced of their own impartiality, says Carl Elliott, a moral philosopher at the University of Minnesota and author of Better Than Well: American Medicine Meets the American Dream. "If they understood that they were being used as industry mouthpieces, they would probably pull the plug on the whole enterprise." Drug companies encourage their KOLs to consult for multiple companies so the appearance of objectivity can be maintained. But the drug industry's most powerful means of boosting the bottom line is funding research, which allows companies to control, or at least influence, a great deal of what gets published in the medical journals, effectively turning supposedly objective science into a marketing tool.

"These are not benign people who are interested in helping people with their new wonder drugs," says Drummond Rennie. "The drug companies are run by hard-nosed marketers, not by the physicians and the scientists. They use what works, and money works." Rennie, who has a thatch of unkempt white hair and remnants of the accent of his native Leeds, England, got a clear picture of the extent to which drug companies will go to control the results of studies they fund in 1993, when a colleague at University of California San Francisco tried to publish a paper in JAMA in 1993 on the metabolic activity of four different forms of thyroid hormone. Betty J. Dong, a pharmacologist, had been contracted in 1987 by Flint Laboratories to run a clinical trial comparing Synthroid, Flint's synthetic version of thyroid hormone, to that of three competing formulations. At the time, Synthroid was the market leader and the most expensive drug in its class. Dong and Flint signed a lengthy agreement detailing the design of the study, and both sides fully expected the results would show that Synthroid was superior.

But all four drugs turned out to be essentially equivalent. In 1990, as Dong prepared a paper for JAMA, the company that was at first so eager to solicit her help, launched a vigorous campaign to discredit the study. Flint then rushed its own paper into press at a less prestigious journal, concluding--surprise!--that Synthroid was superior. After numerous attempts to address the company's criticisms, Dong finally submitted her paper to JAMA, only to withdraw it three months later when the firm threatened to sue for breach of contract. It took the FDA and U.S. Department of Health and Human Services to get the company to back down. Dong's paper did not see print in JAMA until 1997.

In this case, it might seem as if the only real harm to the public during the seven years that elapsed from the time Dong completed her study to its publication was higher prices to patients and insurers. To Rennie's way of thinking, the Dong imbroglio and others like it have a more insidious effect by sending a chilling message to scientists, namely, don't bite the hand that feeds you. In a recent survey of clinical researchers, nearly 20 percent of respondents admitted to delaying publication of their results by more than six months at least once in the last three years to allow for patent application, protect their scientific lead, or to slow the dissemination of results that would hurt sales of their sponsor's product--often without overt pressure from the company. "If you're getting a lot of money from a corporate sponsor, it's easy to get the impression that you'll get even more for future research if you don't write up the negative results," says Rennie--and that your funds will dry up if you do.

The bottom line is that articles appearing in medical journals contain a lot of happy talk about medical products. At least eight studies have shown that industry-sponsored research that gets published tends to produce pro-industry conclusions, according to a review by Yale University researchers that appeared last year in JAMA. By reanalyzing data from eight separate studies of the effect of conflict of interest on 1,140 published scientific papers, the researchers found that papers based on industry-sponsored research are significantly more likely to reflect favorably on a sponsoring company's drug or device than research that is supported by a non-profit entity or the federal government.

How can this be? Isn't science, well, scientific, an objective search for the truth? That's what many academic clinicians, especially those who are mixed up with corporate sponsors, would have the public believe. A typical comment comes from Niels Reimers, an early promoter of industry-university ties, who told the Hartford Courant, "You may think I'm a Pollyanna or something, but most people are honest. It's sort of the ethos of academic research." Here's Dr. Irwin Goldstein, a Boston University urologist who has consulted for at least seven companies developing impotence therapies: "Science is science. It comes down to the bottom line. What the data shows, the data shows."

Such statements reflect the ideal of science, not the reality, says Dr. Marcia Angell, former editor in chief of The New England Journal of Medicine. Public protestations aside, she says, "Clinicians know privately that results can be jiggered. You can design studies to come out the way you want them to. You can control what data you look at, control the analysis, and then shade your interpretation of the results." Even the most careful research can be fraught with murky results that require sifting and weighing, a measure of judgment that the researcher hopes will bring him closer to the truth. Was this patient's headache caused by the antibiotic you gave her, or does she have a history of migraines? Is that patient's depression lifting because of the drug you are testing, or because a kindly doctor is actually listening to him?

Sometimes there isn't much that journal editors can do to separate good science from that which has been weighed, sifted, and jiggered according to a corporate sponsor's needs. Increasing numbers of studies that get published are actually written by PR firms, "medical communications" specialists, who then go out and recruit an academic willing to put his name on the paper, for a fee. Other studies simply omit data that detract from the sponsor's message. In September 2000, for example, JAMA published a paper comparing the prescription painkiller Celebrex to over-the-counter ibuprofen. The manufacturer of the prescription drug, known as a selective Cox-2 inhibitor, launched the study in order to show that Cox-2 inhibitors, a class that also includes the prescription drug Vioxx and was already worth $3.5 billion a year, cause fewer instances of bleeding in the stomach and intestine than either aspirin or ibuprofen. The huge study, which looked at six months of data from more than 8,000 patients, produced unambiguous results: There were fewer side effects among patients on the Cox-2 drug.

A year later, news surfaced that patients had actually been followed for 12-15 months at the time the JAMA paper came out, not six, and that during the second half of the study, the group taking the Cox-2 drug suffered higher rates of gastrointestinal side-effects than patients on the over-the-counter painkiller. To make matters worse, patients on the Cox-2 developed serious heart problems three times more often than those on ibuprofen. The authors of the paper--all of them either consultants to the manufacturer or employees"defended their decision to report only the first, positive, half of their study, saying several patients who weren't taking the Cox-2 drugs dropped out after six months, making the statistics more difficult to analyze. But Dr. Catherine D. DeAngelis, JAMA's editor in chief, told The Washington Post: "I am disheartened. We are functioning on a level of trust that was, perhaps, broken."

Disheartened? Not furious? No, because DeAngelis could not know for certain whether or not the authors held back half the data in order to make their sponsor's drug look better"no matter how likely that explanation may seem. When researchers submit papers to a journal, the editor has little choice but to trust the authors have employed a ruthless skepticism when viewing their own results, that they have bent over backwards to minimize self-delusion. Editors and peer reviewers can ferret out sloppy reasoning, look at how an author has designed and executed a study, and correct faulty statistics, but as Angell remarked, "We don't put bamboo slivers under their nails. If they wanted to lie, they could lie."

Articles of faith

Dr. Arnold Relman began worrying about this problem way back in 1977, when he became editor-in-chief of The New England Journal. That year, Relman got a call from a reporter about a paper that was due to appear in the next issue, discussing serious side effects--including lowering a man's testosterone and sperm counts--of a popular antacid. The reporter wanted to know what Relman intended to do about the fact that Wall Street analysts had acquired early copies of the paper and now the stock of the company that made the drug was falling.

Relman, who began practicing medicine in the 1950s and calls himself a "relic," says before that reporter's call, it had never occurred to him that medical research could have financial consequences for industry. But the more he thought about it, he told me recently, "The more I became convinced that the commercialization of medical practice and medical research, and the use of the information for commercial purposes, was a major threat to the integrity of the whole system." He recognized that medical researchers, being only human, would have trouble applying that ruthless skepticism that was so necessary to good science when there was money at stake.

The obvious solution to Relman and Angell, who was by then a deputy editor at The New England Journal of Medicine, was disclosure. Forcing authors to tell the world they were taking industry money, the editors reasoned, would prompt a little soul-searching among researchers who might otherwise be inclined to turn a blind eye to negative results or shade conclusions in favor of a corporate sponsor. It would put them on notice that readers would be watching. The editors also figured that disclosure would help readers judge the validity of an author's conclusions. "They could evaluate the data for themselves," Relman told me recently. "But the discussion, the interpretation by the author can be slanted . . . it was still important for readers to know when articles were sponsored by industry." JAMA, largely at Rennie's urging, followed suit soon after.

Six years later, Relman upped the ante by barring researchers with conflicts of interest from writing editorials or review articles--like the one penned in Nature Neuroscience by Charles Nemeroff"because they carry great weight with doctors in private practice. Angell explains their decision like this: "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." She and Relman argued that just as judges must recuse themselves from cases in which they have financial ties to a litigant, editorialists and review authors with conflicts of interest should refrain from offering medical opinions.

Angell was still defending that decision a decade later, as editor in chief at the Journal, when she wrote in 2000 that disclosure was not sufficient to preserve the integrity of the science that appeared in her journal's pages: "We believe that a policy of caveat emptor is not enough for readers who depend on the opinion of editorialists." Why was it necessary to defend the Journal's policies? Partly because authors were ignoring them. In 1997, when Sheldon Krimsky, a professor of public policy at Tufts University, surveyed 61,134 articles in some 181 journals, he found that only 0.5 percent disclosed a conflict of interest related to the topic of the article, an impossibly low number given the fact that a quarter of biomedical researchers at the time were receiving funding from industry. The reason for this low rate of disclosure, as Krimsky notes dryly in his book, Science in the Private Interest, is that "author compliance is not especially high."

"Lots of eminent people took great offense at being accused of being influenced," Relman told me recently. "'What an insulting thing to say. I value my reputation; doctors and scientists know best. Trust us.' I spent the first 25 years of my career doing clinical research and being one of them, and I know the feeling." As Harvey Lodish, professor of biology at MIT, huffed to Technology Review in 1984, when Relman first required disclosure at the Journal, "Scientists have all kinds of private consulting arrangements with biotechnology companies and many own stock in these companies, but that's nobody's business. It has nothing to do with the quality of their research."

"They actually believe that they aren't influenced," says Angell. Aside from the fact that it's not in physicians' self-interest to acknowledge the effects of corporate money, they may have a hard time seeing the problem for the same reason fish don't know they're swimming in water: Doctors are surrounded by conflicts of interest almost from the moment they arrive at medical school. Pharmaceutical companies begin wooing young doctors with small tokens at first, pens and coffee mugs emblazoned with drug logos, then escalating to pizza night for medical residents, dinners at expensive restaurants and tickets to sporting events. Most schools offer a class in medical ethics, but there's no requirement that they discuss conflict of interest. Besides, a few lectures can't outweigh the message young doctors absorb every day, as they watch the icons in their profession--their professors, visiting lecturers, heads of departments--taking gifts, speaking on behalf of companies, flying first-class to medical meetings in Paris and Honolulu. By the time medical residents enter private practice or the lab, the gifts from industry no longer seem like gifts, but entitlements"just another way to be compensated for all those brutal, slogging years of lousy pay and long nights.

A journalist friend of mine recently told me about the day his then-girlfriend, who was a neurosurgeon, received a check for several hundred dollars in the mail, along with a note from a drug company representative. It seemed his girlfriend had made favorable mention of a particular drug during a lecture she delivered a few days earlier, and the money was just a little thank you from the manufacturer. When my friend told her she could not in good conscience cash the check--that it was a conflict of interest--she looked at him, he said, as if he were speaking in some unintelligible language.

This deafness to the power of money to corrupt medical science leads physicians and scientists to display an arrogance and a remarkable na´vete, both of which were very much in evidence in a snippy editorial entitled, "Avoid Financial 'Correctness,'" written in 1997 by the editors at Nature. They derided disclosure as a waste of time, writing, "This journal will persist in its stubborn belief that the research as we publish it is indeed research, not business." The Nemeroff case has not changed the editors' view substantially, although they did alter their policy after it broke. Nature Publishing now requires editorial and review writers, along with the authors of original research papers, to inform readers whether or not they have conflicts of interest, or to say they decline to declare. Charles Jennings, executive editor of Nature, says they have no intention of following the New England Journal in barring editorialists who have conflicts. "I flatly disagree with that policy," he told me. "That would exclude many of the leading experts. You don't want a policy that prevents Thomas Edison from writing about the future of electricity. Our position is for readers to decide for themselves about whether an author is biased."

Of course, most readers, especially practicing physicians, don't have the expertise or the resources to decide for themselves--to know how the studies might have been constructed differently, whether the conclusions have been shaded to favor the author's sponsor, or which data the author decided conveniently to leave out of the article. Knowing that an author might be biased doesn't aid in determining the extent and nature of the bias. It's not as though there will be two articles, one by a biased writer and one by an unbiased writer, published side by side to allow readers to identify the differences. Besides, conflicts of interest are now so pervasive, says Rennie, many readers scarcely take note, even when they're disclosed.

Race for the cure?

It's tempting to wonder what medical research would look like if universities and medical associations and editors of journals stopped talking about how to manage conflict of interest and started thinking about how to expunge it. Just say no. Proponents of Bayh-Dole will object, claiming the pace of medical advances will slow to a crawl, but bear with me for a moment and just imagine a different universe. Let's start with the medical schools"those temples of higher learning. They would be the first to cast out the drug merchants. Hospitals would pay their medical residents a decent wage so they can afford to buy their own beer and pizza. FDA advisory panelists who have a financial stake in the drug being considered would not be allowed to vote. And if the journals stopped publishing papers and editorials penned by academic clinicians with conflicts of interest, authors would be forced to choose between taking scientific credit and taking the money.

Of course, that's not going to happen unless academic clinicians somehow decide there's something wrong with the status quo. In Sheldon Krimsky's view, the only way to deter conflict of interest is for academics to feel shame. Maybe so, but as a journalist who has spent a decade and a half peering at medicine from the outside, nose pressed to the glass, I'm struck more than anything by the apparent lack of shame among clinicians when it comes to this issue.

Here's a little thought experiment. Imagine that a medical journalist"me, for instance"makes a tidy sum writing press releases for, say Pfizer, the manufacturer of Viagra. I don't make a fortune, maybe just enough to cover a year's tuition for my son's private high school. And let's say for the sake of argument I also buy a few dozen Pfizer shares. Then I turn around and write a story for The New York Times about several new drugs for treating erectile dysfunction.

What would you think, dear reader, should my financial relationship with the pharmaceutical company that makes one of the drugs featured in my story come to light? Would you have reason to doubt its objectivity and accuracy? Of course you would. Not only that, I would be ashamed to show my face in any newsroom, and I would not be writing for the Times again. I'm not trying to claim that journalists are paragons of virtue, but we have no illusions about our ability to withstand temptation and avoid shading what we say when faced with a wad of cash.

Not so in medical research. In that world, the author of a review article can have direct financial relationships with the manufacturers of drugs he is critiquing and still argue he has done nothing unsavory. What that suggests is a sense of fiduciary responsibility is not built into the professional code of medicine, a doctor's internal compass of right and wrong.

And of course there are also pecuniary reasons not to acknowledge the power of money. The fact is, universities and doctors have become so dependent on industry largesse they can't even imagine disentangling themselves. Repeal the Bayh-Dole Act? Not on your life. Kick the drug representatives who wheel their little carts filled with sample packets of drugs out of your office? Who would pay for all those trips to medical meetings in exotic locales?

Company line

And so they try to manage it. About half of universities require that faculty disclose their conflicts of interest. A scant 19 percent set limits on the outside financial interests faculty may hold. Harvard University, long considered a paragon of scientific virtue, is now considering relaxing its rules governing industry collaborations. Now that Angell is gone, even the once-starchy New England Journal has loosened its restrictions on editorialists and review writers, who are now free to enjoy some corporate largesse, just not too much. "They think it's possible to be virtuous and rich at the same time, to take money from companies and then manage it," says Angell. "They come up with rules that are so complicated in order to give the appearance of worrying about this, when what they are really worried about is the money might go away."

All their managing doesn't seem to be working, and we are the ones who will suffer the consequences. In March 2000, the FDA yanked a diabetes drug called Rezulin off the market after it had been linked to at least 90 cases of liver failure and 63 deaths. The withdrawal came three years after the agency had approved the drug to great fanfare. Articles in the popular media quoted diabetes experts who praised Rezulin, calling it "a truly novel approach," and the manufacturer, Warner-Lambert, enjoyed a spectacular 144 percent rise in its stock price.

By the fall of 1997, however, the FDA had already begun to receive reports of patients on Rezulin suffering liver failure, a side-effect that the agency's advisory panel glossed over during its deliberations. A paper published in the New England Journal also made scant reference to liver toxicity, saying the drug was "well tolerated, and most adverse events were considered to be related to the underlying diabetes." Several clinicians with ties to the company subsequently urged the FDA not to withdraw the drug, even as the body count was rising. According to a Los Angeles Times investigation, at least 12 of 22 scientists who played a central role in the federally-funded study of Rezulin received research funding or other compensation from Warner Lambert, while four of the 12 voting members of the FDA advisory panel that approved Rezulin, and kept it on the market an extra 30 months, had financial ties to the company.

When industry has penetrated every level of medicine from the lab bench to the FDA advisory panels, from the pages of the medical journals to your doctor's prescription pad, how are physicians to make decisions about treating their patients? How are they to know whether or not expensive calcium channel blockers are really better than over-the-counter diuretics for high blood pressure? (They're not.) Should you take a mildly depressed teenager to a psychotherapist, or put him on an antidepressant and risk sending him into a suicidal tailspin? Maybe a cholesterol-lowering statin drug will prevent this patient from suffering a heart attack, as the studies claim. Then again, maybe it will simply cause her muscles to break down and destroy her kidneys, one of the drug's side effects.

And what about us patients? What are we to do with the knowledge that much of what passes as science in medicine is little more than gussied-up marketing? There isn't much we can do. And so, I say if you're ill, if you are ailing, or just sick at heart, go find a doctor who listens, who holds your hand. Just make sure you find a doctor who looks at evidence, not opinion, and when she pulls out the prescription pad, start asking a lot of questions.

Shannon Brownlee is a fellow at the New America Foundation.


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