In the fall of 2001, the editors of 12 prominent medical journals collectively announced that they would refuse to publish research on new prescription drugs unless the authors provided assurances that they had had unimpeded access to the data and were fully responsible for the paper’s conclusions. The announcement was an extraordinary admission of just how extensive industry control over medical research had become. The editors noted that more and more, the authors of scientific papers – even authors based at prestigious universities – did not have access to the complete trial data. In some cases, the editors observed, authors were unable to publish without prior authorization from the corporate sponsor.
The journal editors pointed out that publication of clinical studies in respected peer-reviewed journals is the “ultimate basis for most treatment decisions,” so it is essential that the data be gathered and presented in “an objective and dispassionate manner.” Medicine is only as good as the science on which it is based, and if that science is not objective and honest, then patients can be seriously harmed. The editors noted “that the current intellectual environment … may threaten this precious objectivity.” Until recently, university medical centers contributed to the “quality, intellectual rigor and impact of such clinical trials,” they explained, “but as economic pressures mount, this may be a thing of the past.”
With the possible exception of business schools, industry’s penetration into the nation’s medical schools has been more sweeping than in any other sector of the university. Pharmaceutical companies sponsor daily lunches for medical students, during which they market their latest drugs; they ply professors with fancy dinners, gifts, luxurious trips and free prescriptions designed to influence their medical decisions and prescribing habits. These academic “opinion leaders” consult for, or hold equity in, the same firms that manufacture the drugs they are studying, while also often accepting generous fees to join their corporate advisory boards and speakers’ bureaus. Sometimes they even hold the patent to the drug or device being tested. In a study of 800 scientific papers published in leading journals of medicine and molecular biology, Sheldon Krimsky, a professor of public policy at Tufts University, found that slightly more than a third of the lead authors based at research institutions in Massachusetts had a significant financial interest in their own reports. These included owning related patents, or holding an executive, advisory or major equity position in a company with a stake in the research.
So pervasive are such ties that journal editors now frequently complain they can no longer find academic experts who do not have a financial interest in a drug or therapy they would like to review. This may be good news for corporations, but it is anything but good news for ordinary citizens. Indeed, the growing nexus between universities and the pharmaceutical industry could not come at a worse time. The cost of pharmaceutical drugs – and health care in general – in America continues to skyrocket. Expensive new drugs are aggressively marketed on TV and in doctors’ offices the moment they hit the market. Yet physicians warn that many of these hyped prescriptions are simply “me-too drugs” that vary only slightly from medications already on the market, despite being far more expensive. Research suggests that publicly funded science, most of it performed at universities, was a “critical contributor” to the discovery of nearly all of the 25 most important breakthrough drugs introduced between 1970 and 1995. If university scientists lose their independence, who will perform this pathbreaking research and objectively evaluate the safety and effectiveness of drugs already on the market?
Independence in jeopardy
Unfortunately, it is this scholarly independence that is now in jeopardy. “The boundaries between the academic medical colleges and the drug companies are becoming ever more porous,” says Marcia Angell, a senior lecturer at Harvard’s School of Public Health and former editor in chief of the New England Journal of Medicine (NEJM). “It used to be that academic medical colleges said, ‘OK, we will take this industry grant and do the study, but our researchers are going to retain the data; they are going to analyze the data.’ Now this arm’s-length relationship has broken down.”
Indeed, there are strong indications that university-based medicine is losing its hallowed objectivity. After conducting an extensive review of the medical literature for an article in the NEJM, Thomas Bodenheimer, an internist at University of California, San Francisco, found that academic investigators were rapidly ceding to industry the control over nearly every stage of the clinical research process.
In the past, for example, it was common for university scientists to initiate the research protocol. Now, however, studies are frequently conceived and designed in the company’s own pharmacological and marketing departments, thus removing this formative stage of the research from academic hands almost entirely. The company then shops the study around to various academic institutions (and a growing number of competing for-profit entities as well), in search of investigators to conduct the research. Should a professor choose to reject the study or insist on changes not agreeable to the sponsor, another university scientist will very likely be more solicitous.
In this way, industry is slowly changing the direction of academic research, causing it to be far more market-driven and less directed toward truly important science. Not surprisingly, wrote Bodenheimer, exercising control over trial design makes it far easier for companies to build biases into their research – some easier and some harder to detect. One analysis by Paula Rochon, published in the Archives of Internal Medicine, found that in 54 percent of corporate-sponsored arthritis drug trials, the dose of the funding company’s drug was higher than that of the comparison drug, so that the results were clearly skewed in the sponsor’s favor.
Another disturbing trend in university medicine today is the growing use of ghostwriters and “guest writers.” Readers may see a prominent academic’s name at the top of a research article or review, but that scholar may or may not be the person who actually wrote the paper. Frequently, a big-name professor or department chair is invited to appear as a “guest author,” even though she or he had no involvement in the research. Or in the case of company-initiated studies and reviews, the manuscript may have been ghostwritten by a medical communications company working for the drug maker, and its author may have been paid an honorarium to attach his or her name to it. The average reader thus thinks the study bears the stamp of approval of an independent academic scholar, when in fact this is nothing more than an illusion. The Lancet commented on this alarming phenomenon in an editorial, noting with some bitterness that “the pinnacle of success, presumably, is to sign up a prominent academic” to lend an aura of objectivity and prestige to the company’s research.
The practice of ghostwriting has become extremely prevalent, raising troubling questions about the trustworthiness of the science appearing in even the most prestigious medical journals. As Richard Horton, editor of The Lancet, caustically observed in 2004, “Journals have devolved into information-laundering operations for the pharmaceutical industry.”
Regulating access to the raw data from a large, multisite trial is yet another tactic the drug industry commonly deploys to skew medical research in its favor. Sometimes the principal investigators are given unimpeded access, but increasingly companies prefer to control the data themselves. Frequently, explained Bodenheimer, studies are designed with multiple end points (or measurable outcomes), so that it is relatively easy for the company to “publish those end points favorable to their product and bury data on less favorable end points.”
Recently, M. Michael Wolfe, a gastroenterologist at Boston University, publicly disclosed that Pharmacia Corporation, the manufacturer of the blockbuster arthritis drug Celebrex, had duped him in precisely this manner. In the summer of 2000, the Journal of the American Medical Association (JAMA) asked Wolfe to write a review of a Celebrex study showing that the drug was associated with lower rates of stomach and intestinal ulcers and other complications than two older arthritis medications (diclofenac and ibuprofen). Wolfe found the study, tracking eight thousand patients over a six-month period, persuasive and penned a favorable review, which helped to drive up Celebrex sales. But early the next year, when he had occasion to review the same study again – this time while serving on the Food and Drug Administration’s arthritis advisory committee – Wolfe was flabbergasted by what he saw. Pharmacia’s study had run for one year, not six months, as both Wolfe and JAMA had been led to believe. When the complete data set was considered, most of Celebrex’s advantages disappeared because the ulcer complications that occurred during the second half of the study were disproportionately found in patients taking Celebrex. “I am furious … I wrote the editorial,” Wolfe told the Washington Post. “I looked like a fool. But … all I had available to me was the data presented in the article.” None of the original study’s sixteen authors, including eight university professors, had spoken out publicly about the suppression of data. All the authors were either employees of Pharmacia or paid consultants of the company.
The sordid story of SSRIs
Industry also manipulates academic research by suppressing negative studies altogether. Consider the recent medical scandal surrounding the class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs), which have been linked to an increased risk of suicidal thinking and behavior in young people. Throughout the latter half of the ‘90s, the number of young Americans being given Prozac, Paxil, Zoloft and other antidepressants skyrocketed. By 2002, roughly 11 million prescriptions had been handed out. Boys under the age of 12 diagnosed with “conduct disorders” were the fastest-growing group. The bulk of the published academic literature strongly supported treating depressed children and adolescents with SSRIs. As it turns out, however, this recommendation was at odds with what the complete research record showed. In early 2004, an FDA scientist reviewed all 15 pediatric SSRI studies in the agency’s files, including many that had never been published. In all but three of those studies, young patients suffering from depression experienced no greater improvement taking an SSRI than they did with a placebo, or sugar pill. Given that scientists were very likely involved in a large portion of this research and duty-bound to publish, how did so much of this negative evidence drop from public view?
In June 2004, this question made its way into the headlines when New York attorney general Eliot Spitzer filed suit against GlaxoSmithKline (GSK), the manufacturer of Paxil, charging that the company had “engaged in repeated and persistent fraud by misrepresenting, concealing and otherwise failing to disclose” information showing that its drug was not only ineffective in treating child and adolescent depression but also linked to an increased risk of suicidal thoughts and self-injurious behavior. GSK had funded five studies on Paxil and childhood depression, only one of which ever got published. Taken together, however, the data clearly showed that those children who took Paxil were approximately two times more at risk of becoming suicidal than those taking a placebo. Parents of children who had committed suicide, along with a small minority of psychiatrists, had been suggesting for some time that there appeared to be a link between SSRIs and suicide, but until these revelations, their concerns had been largely discredited.
Unfortunately, GSK wasn’t the only company burying research in this way. When Andrew Mosholder, a senior FDA epidemiologist, examined 22 pediatric studies, he found that children taking a wide range of antidepressants were also nearly twice as likely as those given a placebo to show signs of becoming suicidal – a finding that his FDA supervisors initially sought to suppress but was later corroborated by an independent research team at Columbia University. What was perplexing was that nearly all of the published literature, authored by many of the leading lights of academic psychiatry, had arrived at the opposite conclusion: SSRIs were safe and effective in treating depression in youngsters.
Was this really what their academic studies showed?
When the FDA and other independent scientists took a closer look, they found a striking discrepancy between what these esteemed academic psychiatrists had written in their papers – and what the data actually revealed. In a surprising number of cases, the benefits of these drugs were overstated, and the problems were downplayed or buried. The only GSK study of Paxil that ever got published, for example, concluded that the data “provides evidence of the safety and efficacy of [Paxil] in the treatment of adolescent depression.” (On the basis of this one study, GSK launched a massive promotional campaign telling its sales representatives going out to doctors’ offices that Paxil had “REMARKABLE Efficacy and Safety in the treatment of adolescent depression.”) But when an FDA examiner studied the data more closely, he found the authors’ claims highly exaggerated, as the drug actually failed on the protocol’s two primary measured outcomes. The study also concluded that “most adverse events were not serious,” when, in fact, seven of the children who took Paxil had to be hospitalized after suffering severe adverse effects from the drug.
Eighteen of the Paxil study’s 22 authors were university scholars. Its lead author, Martin B. Keller, is a highly acclaimed psychiatrist and chair of the psychiatry department at Brown University who has extensive ties to the drug industry. In 1998, when the Rhode Island attorney-general’s office forced Keller to forfeit hundreds of thousands of dollars in state grant money to settle a financial fraud inquiry, it came to light that Keller had received more than half a million dollars from drug companies that year, most of it from the same firms whose drugs he had touted in journals and at medical conferences. According to the Boston Globe, Keller’s financial ties were so numerous that they prompted the National Institute of Mental Health to review its conflict-of-interest rules. The most recent publicly available data shows that as of June 2003, Keller had been consulting for at least 17 major drug firms, including Merck, Bristol-Myers, Eli Lilly and Pfizer, while also working under a $25 million research grant from Wyeth-Ayerst.
It is impossible to prove a direct causal relationship between Keller’s funding sources and the distortions found in his research. But at least three other studies authored by prominent academic psychiatrists on the pediatric use of SSRIs evidenced similar distortions – and all the authors had financial ties to the manufacturers. One of these was a 2003 study published in JAMA led by Karen Wagner, a renowned psychiatrist and director of the Division of Child and Adolescent Psychiatry at the University of Texas Medical Branch. The study claimed that the antidepressant Zoloft was “effective and well tolerated for children and adolescents.” But when the FDA and other outside experts examined the data from the two pooled studies more closely, they again found that the drug had failed to demonstrate positive outcomes. In fact, according to one analysis, when data left out of the published study were included, Zoloft had “an unfavorable risk-benefit balance.” In other words, the risks associated with taking the drug were greater than the anticipated benefits. At the time of this study, Wagner reported receiving research money from numerous pharmaceutical companies, consulting for 10 drug firms, and participating in speakers’ bureaus for Abbott Laboratories, Eli Lilly, GlaxoSmithKline, Forest Laboratories, Pfizer and Novartis. The study itself had been funded by Pfizer, the maker of Zoloft, and the “study supervisor” held stock options in the company. Finally, the FDA criticized two Prozac studies (1997, 2002) for overstating the drug’s efficacy in treating childhood depression. Both studies had been led by Graham Emslie, a professor at the University of Texas Southwestern Medical Center, and financed by Eli Lilly, the maker of Prozac. Emslie receives research support from industry; he also consults and serves on speakers’ bureaus of numerous drug companies, including Bristol-Myers, Eli Lilly and Wyeth-Ayerst.
In December 2003, when the faulty nature of this research finally came to light, it prompted a quick response from the British Drug Authority, which recommended that doctors not prescribe SSRI antidepressant drugs to children under 18, citing a two- to threefold increase in the risk of suicidal behavior and insufficient evidence of benefit. Nearly one year later, in October 2004, the FDA announced that all such antidepressants must carry a “black box” warning label linking the drugs to an increased risk of suicidal thoughts and behavior in children and teenagers.
Where’s the media?
Sadly these government warnings and restrictions have done little to address the underlying problem: The growing influence of pharmaceutical companies on academic medicine and research. When the American media tried to sort out the implications of the FDA’s new warning label on the SSRI drugs, the first experts they turned to were often the same academics who had been implicated in overlooking the SSRI drugs’ problems. In one story, the Chicago Tribune asserted that “a number of mental health experts cautioned that the strict warning label could discourage the use of antidepressants by adolescents who need them.” It went on to quote Graham Emslie, one of the doctors who had overstated the drugs’ benefits relative to his research data. None of Emslie’s financial ties to the drugs’ manufacturers were ever mentioned in the story. Emslie was simply identified as “the chief of child and adolescent psychiatry at the University of Texas Southwestern Medical Center.” Could anything sound more credible than that?
Thus far, neither the federal government nor the universities themselves have been willing to adopt strict conflict-of-interest guidelines. Unless the media and medical journals vigorously investigate these commercial ties – and bring them to the public’s attention – the drug industry will continue to exploit the aura of objectivity and independence that our universities command, eroding the academic mission and causing great harm to the medical enterprise and public health.
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