House of Paine

more snake oil science

 hey 

pass the medicine hat boyz ....



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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.
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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).