Tainted to the Core
Why conflicts of interest are hazardous to your health
By Jennifer Washburn    June 7, 2005

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."
Buried data

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.

Jennifer Washburn is a freelance journalist and a fellow at the New
America Foundation. This article has been adapted from her book
University Inc: The Corporate Corruption of Higher Education (Basic
Books 2005).

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