ALLIANCE FOR HUMAN RESEARCH PROTECTION
Promoting Openness, Full Disclosure, and Accountability
http://www.ahrp.org and http://ahrp.blogspot.com

FYI

This week further documented evidence demonstrates that reports in "peer
reviewed" journals about the safety and efficacy of prescription drugs are
no more credible than marketing hype. Journal reports are merely encased in
a thin veneer that passes for "science" when those reports are in fact,
fraudulent.

The Wall Street Journal reports: Just as the pharmaceutical industry seemed
on the verge of moving past a series of scandals that battered its
reputation earlier in the decade, a skein of new revelations could again
taint the drug makers in patients' eyes and renew pressure for tighter
regulation.
Indeed, the evidence underscores that companies that engage in corrupt
practices tend to be recidivist-repeat offenders--much like serial
criminals.

An analysis of  74 antidepressant trials reviewed by the FDA, 38 were judged
to be positive. Most of the studies found to have negative or questionable
results were not published. Yet, the published literature would have doctors
believe that 94% of the trials conducted were positive. By contrast, the FDA
analysis showed that 51% were positive. Separate meta-analyses of the FDA
and journal data sets showed that the increase in effect size ranged from 11
to 69% for individual drugs and was 32% overall.

According to the findings the worst exaggerations in antidepressant
published reports about the efficacy were made about Bistol Meyers-Squibb's
drug, Serzone (69%) ,  Pfizer's Zoloft (64%), Schering Plough's Remron
(61%), and GlaxoSmithKline's Paxil (55%). Eli Lilly's published reports
about Cymbalta exaggerated efficacy by 33%.

The authors CONCLUSIONS:
We cannot determine whether the bias observed resulted from a failure to
submit manuscripts on the part of authors and sponsors, from decisions by
journal editors
and reviewers not to publish, or both. Selective reporting of clinical trial
results may have adverse consequences for researchers, study participants,
health care professionals, and patients.

The lead author, Dr. Erick Turner, is a former FDA safety reviewer. The
analysis was published in today's New England Journal of Medicine, whose
editor acknowledged the dual crime of data concealment:

One thing is certain--pharmaceutical companies conceal the truth while
inflating the claims of safety and efficacy of their drugs.  And the worst
of it is that FDA officials sit idly by and allow the Big Lies to be
disseminated resulting in harm to consumers. Of note is the comment made by
Dr. Thomas P. Laughren, director of the division of psychiatry products at
the F.D.A., who told The New York Times that the agency had long been aware
that favorable studies of drugs were more likely to be published. "It's a
problem we've been struggling with for years," he said in an interview. "I
have no problem with full access to all trial data; the question for us is
how do you fit it all on a package insert," the information that accompanies
many drugs.

Clinicians, consumers, third party payers are barraged with false claims
about the safety and value of patented drugs.  Instead of scientifically
credible information the entire enterprise of medical research has been
corrupted not just by the prescription drug industry, but by their complicit
army of contracted physicians who conduct the trials and agree to keep the
findings secret. It has become common practice in this corrupt enterprise
for academicians to pen their name to ghostwritten reports for
cash--violating both their professional integrity and their moral
responsibility to patients. Medical journals who turn a blind eye by
regularly publishing fraudulent reports whose favorable conclusions are
based on partial data.

The response by Dr. Donald F. Klein, an emeritus professor of psychiatry at
Columbia, who had been a major industry-paid antidepressant researcher,
underscores the pervasive cynicism of influential academics who attempt to
whitewash the fraud perpetrated against science and the public:
"If it's your private data, and you don't like how it came out, well, we
shouldn't be surprised that some doctors don't submit those studies," he
said.

That said, it is clear that neither industry nor the academic establishment
is inclined to clean up their act by renouncing the culture of greed.

Thus, it is up to Congress to take action by criminalizing fraudulent
medical claims about drugs, vaccines and medical devices. Unless mandatory
penalties for violators are established--including jail time for fraudulent
claims that result in patient deaths--the public will increasingly be at
high risk of being seriously harmed or killed.

Contact: Vera Hassner Sharav
verac...@ahrp.org
212-595-8974

http://content.nejm.org/cgi/content/short/358/3/252
   New England  Journal of Medicine; NY Times
Volume 358:252-260      January 17, 2008  Number 3

Selective Publication of Antidepressant Trials and Its Influence on Apparent
Efficacy
Erick H. Turner, M.D., Annette M. Matthews, M.D., Eftihia Linardatos, B.S.,
Robert A. Tell, L.C.S.W., and Robert Rosenthal, Ph.D.

ABSTRACT

Background Evidence-based medicine is valuable to the extent that the
evidence base is complete and unbiased. Selective publication of clinical
trials - and the outcomes within those trials - can lead to unrealistic
estimates of drug effectiveness and alter the apparent risk-benefit ratio.

Methods We obtained reviews from the Food and Drug Administration (FDA) for
studies of 12 antidepressant agents involving 12,564 patients. We conducted
a systematic literature search to identify matching publications. For trials
that were reported in the literature, we compared the published outcomes
with the FDA outcomes. We also compared the effect size derived from the
published reports with the effect size derived from the entire FDA data set.

Results Among 74 FDA-registered studies, 31%, accounting for 3449 study
participants, were not published. Whether and how the studies were published
were associated with the study outcome. A total of 37 studies viewed by the
FDA as having positive results were published; 1 study viewed as positive
was not published. Studies viewed by the FDA as having negative or
questionable results were, with 3 exceptions, either not published (22
studies) or published in a way that, in our opinion, conveyed a positive
outcome (11 studies). According to the published literature, it appeared
that 94% of the trials conducted were positive. By contrast, the FDA
analysis showed that 51% were positive. Separate meta-analyses of the FDA
and journal data sets showed that the increase in effect size ranged from 11
to 69% for individual drugs and was 32% overall.

Conclusions: We cannot determine whether the bias observed resulted from a
failure to submit manuscripts on the part of authors and sponsors, from
decisions by journal editors and reviewers not to publish, or both.
Selective reporting of clinical trial results may have adverse consequences
for researchers, study participants, health care professionals, and
patients.

Address reprint requests to Dr. Turner at Portland VA Medical Center,
P3MHDC, 3710 SW US Veterans Hospital Rd., Portland, OR 97239, or at
turn...@ohsu.edu.
~~~~~~

 THE WALL STREET JOURNAL
 THE MORNING BRIEF
 January 17, 2008
 New Suspicions  For Big Pharma
 By JOSEPH SCHUMAN

Just as the pharmaceutical industry seemed on the verge of moving past a
series of scandals that battered its reputation earlier in the decade, a
skein of new revelations could again taint the drug makers in patients' eyes
and renew pressure for tighter regulation.

 In the latest potential hit to the industry, researchers in this week's New
England Journal of Medicine say they were suspicious about the choices being
made on which drug studies to publish in peer-review journals and decided to
pour through the raw reviews given to the Food and Drug Administration. They
found that among 74 trials testing the effectiveness of 12 antidepressant
drugs, only 31% were published. And a systematic review of these selections
shows a link between the studies' outcome and whether and where they were
published. Nearly all studies with positive outcomes were published, while
most with negative or questionable outcomes were either not published or
published in a way that conveyed a positive outcome, the researchers say.

 "We cannot determine whether the bias observed resulted from a failure to
submit manuscripts on the part of authors and sponsors, from decisions by
journal editors and reviewers not to publish, or both," the researchers say.
But Dr. Jeffrey M. Drazen, editor in chief of the New England Journal,
explains to the New York Times why the study is so alarming for doctors and
patients. "When you prescribe drugs, you want to make sure you're working
with best data possible; you wouldn't buy a stock if you only knew a third
of the truth about it," he says. Moreover, patients who agree to be guinea
pigs "take some risk to be in the trial, and then the drug company hides the
data?" he asks. "That kind of thing gets us pretty passionate about this
issue." Lead researcher and psychiatrist Erick Turner points out to The Wall
Street Journal that doctors unaware of the unpublished studies can make
inappropriate prescribing decisions for their patients.

 Antidepressant sales in the U.S. come to about $21 billion a year, the
Journal says, citing IMS Health, and the drug makers were quick to defend
their blockbuster products. While Wyeth and Pfizer declined to comment on
the NEJM study, they expressed a commitment to disclose all trial results --
if not necessarily in the medical journals where doctors are looking.
GlaxoSmithKline said it has posted the results of more than 3,000 drug
trials on its Web site, and Schering-Plough and Eli Lilly said all their
study results are published, though sometimes as part of larger medical
articles rather than pieces on an individual drug, the Journal reports.

The NEJM study comes just two months after Merck announced a settlement that
potentially includes thousands of plaintiffs who claimed to suffer
cardiovascular problems as a result of taking one-time blockbuster
painkiller Vioxx -- which Merck pulled from the market in 2004 amid a run of
disturbing news about drugs that were harming patients despite their FDA
approvals. Under pressure from Congress and public opinion, the agency
tightened its controls on clinical-trial data before and after approval, and
the pharmaceutical firms promised to release more data to the public. The
new NEJM study raises new questions about whether profit concerns continue
to override patients', and comes on the heels of yet another finding that
renewed doubts about the industry's publishing veracity.

 Congress is now looking into whether Schering-Plough and Merck improperly
delayed publishing the results of studies that unfavorably compared
cholesterol medications Vytorin and Zetia -- Schering's most profitable
drugs, which the two companies jointly sell -- to cheaper generic
alternatives, as the Journal reports. Moreover, researchers studying the
drugs had even considered changing their study's principal goals in what
would have been a violation of scientific protocol. Worry about generic
competition -- Big Pharma's perpetual nemesis -- is apparently responsible
for the industry's other nascent scandal, which began to unfold yesterday in
Europe. European Commission regulators raided the offices of Pfizer,
GlaxoSmithKline, AstraZeneca and Sanofi-Aventis, among others, in search of
evidence that they conspired to keep generic competition off the market
after the patents of their own drugs expired. As the Financial Times notes,
European antitrust authorities are focusing on whether the companies abused
their patent rights to fight off lower-cost competition, and whether they
even made a deal with one manufacturer of generics in a way that excluded
others.
* *

http://online.wsj.com/article/SB120051950205895415.html?mod=googlenew...
Antidepressants Under Scrutiny Over Efficacy Sweeping Overview Suggests
Suppression of Negative Data Has Distorted View of Drugs
By DAVID ARMSTRONG and KEITH J. WINSTEIN January 17, 2008; Page D1

The effectiveness of a dozen popular antidepressants has been exaggerated by
selective publication of favorable results, according to a review of
unpublished data submitted to the Food and Drug Administration.

ACCENTUATE THE POSITIVE
 A review of research submitted to the FDA:
. Of 74 studies reviewed, 38 were judged to be positive by the FDA. All but
one were published, researchers said.
. Most of the studies found to have negative or questionable results were
not published, researchers found.
Source: The New England Journal of Medicine As a result, doctors and
patients are getting a distorted view of how well blockbuster
antidepressants like Wyeth's Effexor and Pfizer Inc.'s Zoloft really work,
researchers asserted in this week's New England Journal of Medicine.

Since the overwhelming amount of published data on the drugs show they are
effective, doctors unaware of the unpublished data are making inappropriate
prescribing decisions that aren't in the best interest of their patients,
according to researchers led by Erick Turner, a psychiatrist at Oregon
Health & Science University. Sales of antidepressants total about $21
billion a year, according to IMS Health.

Wyeth and Pfizer declined to comment on the study results. Both companies
said they had committed to disclose all study results, although not
necessarily in medical journals. GlaxoSmithKline PLC, maker of Wellbutrin
and Paxil, said it has posted the results of more than 3,000 trials
involving 82 medications on its Web site, and also has filed information on
1,060 continuing trials at a federal government Web site.

Schering-Plough Corp., whose Organon Corp. unit markets Remeron, and Eli
Lilly & Co., which makes Prozac, said their study results were indeed
published
-- not individually, but as part of larger medical articles that combined
data from more than one study at a time. The New England Journal study
counted a clinical trial as published only if it was the sole subject of an
article. "Lilly has a policy that we disclose and publish all the results
from our clinical trials, regardless of the outcomes from them," a Lilly
spokeswoman said.

Pharmaceutical companies are under no obligation to publish the studies they
sponsor and submit to the FDA, nor are the researchers they hire to do the
work.
The researchers publishing in the New England Journal were able to identify
unpublished studies by obtaining and comparing documents filed by the
companies with the FDA against databases of medical publications.

"There is no effort on the part of the FDA to withhold or to not post drug
review documents," an FDA representative said. For newer drugs, information
is posted online "as soon as possible." Older documents aren't always
available online and efforts to add those files to the Web are slowed by "a
lack of resources," the agency said, acknowledging that there is a backlog
in complying with records requests.

A total of 74 studies involving a dozen
antidepressants and 12,564 patients were registered with the FDA from 1987
through 2004. The FDA considered 38 of the studies to be positive. All but
one of those studies was published, the researchers said.

The other 36 were found to have negative or questionable results by the FDA.
Most of those studies
-- 22 out of 36 -- weren't published, the researchers found. Of the 14 that
were published, the researchers said at least 11 of those studies
mischaracterized the results and presented a negative study as positive.

Five Trials
For example, Pfizer submitted five trials on its drug Zoloft to the FDA, the
study says. The drug seemed to work better than the placebo in two of them.
In three other trials, the placebo did just as well at reducing indications
of depression. Only the two favorable trials were published, researchers
found, and Pfizer discusses only the positive results in Zoloft's literature
for doctors.

One way of turning the study results upside down is to ignore a negative
finding for the "primary outcome" -- the main question the study was
designed to answer -- and highlight a positive secondary outcome. In nine of
the negative studies that were published, the authors simply omitted any
mention of the primary outcome, the researchers said.

The resulting publication bias threatens to skew the medical professional's
understanding of how effective a drug is for a particular condition, the
researchers say. This is particularly significant as the growing movement
toward "evidence-based medicine" depends on analysis of published studies to
make treatment decisions.

Colleagues' Questions
Dr. Turner, who once worked at the FDA reviewing data on psychotropic drugs,
said the idea for the study was triggered in part by colleagues who
questioned the need for further clinical drug trials looking at the
effectiveness of antidepressants. "There is a view that these drugs are
effective all the time," he said. "I would say they only work 40% to 50% of
the time," based on his reviews of the research at the FDA, "and they would
say, 'What are you talking about? I have never seen a negative study.'" Dr.
Turner, said he knew from his time with the agency that there were negative
studies that hadn't been published.

The suppression of negative studies isn't a new concern. The tobacco
industry was accused of sitting on research that showed nicotine was
addictive, for instance. The issue has come up before notably with
antidepressants: In 2004, the New York state attorney general sued
GlaxoSmithKline for alleged fraud, saying it suppressed studies showing that
the antidepressant Paxil was no better than a placebo in treating depression
in children. Glaxo denied the charge and eventually settled with the
attorney general. The company later posted on its Web site the full reports
of all of the studies of Paxil in children.

But publication of negative studies is an issue that cuts across all medical
specialties. And it has engendered some strong reactions in the
medical-research world: To make it harder to conceal negative study
findings, an association of medical journal editors began requiring in 2005
that clinical trials be publicly disclosed at the outset to be considered
for publication later. The system isn't foolproof, since manufacturers often
run exploratory studies without registering them and can selectively
disclose favorable results. The rule only applies to studies intended for
publication in a medical journal.

Some studies that don't eventually get published are registered with online
trial registries, including the federal government's www.clinicaltrials.gov.
Nonetheless, many studies still aren't being registered or reported, says
Kay Dickersin, the director of the Center for Clinical Trials at the Johns
Hopkins Bloomberg School of Public Health. "We need something more
meaningful," she said. "The average person has no idea that
www.clinicaltrials.gov is not comprehensive."

The New England Journal study also points to the need for the FDA to
disclose more information about the studies it receives, says Robert Hedaya,
a professor of clinical psychiatry at Georgetown University Hospital. He
said it was "disturbing" that the information on the negative studies wasn't
made widely available by the FDA.

The FDA does post information, including unpublished studies, for some drugs
on its Web site, says Dr.
Turner. But information that hasn't yet made it online is hard to come by.
Dr. Turner said he made public records requests for information not on the
Web site more than a year ago, but the requests have gone largely
unfulfilled. He said he was able to get some of the FDA's information on
unpublished studies from other researchers who acquired it from the agency
through their own record requests.

The 'Effect Size'

In this week's study, the researchers found that failing to publish negative
findings inflated the reported effectiveness of all 12 of the
antidepressants studied, which were approved between 1987 and 2004. The
researchers used a measurement called effect size. The larger the effect
size, the greater the impact of a treatment.

The average effect size of the antidepressant Zoloft rose 64% by the failure
to publish negative or questionable data on the drug, the researchers found.

Write to David Armstrong at david.armstr...@wsj.com and Keith J. Winstein at
keith.winst...@wsj.com

Sidebar:
Under Wraps
Estimate of the impression of how much each drug's effectiveness was
inflated by not publishing unfavorable studies

Company                                   Drug                  Estimated
change in drug efficacy

Bristol Meyers-Squibb            Serzone                         69%
Pfizer                                         Zoloft
64                
Schering Plough                      Remeron                          61
GlaxoSmithKline                     Wellbutrin SR                   55
GlaxoSmithKline                     Paxil                                40
Eli Lilly                                   Cymbalta
33
Wyeth                                       Effexor
28  
Wyeth                                       Effexor XR
27
Forest                                       Celexa
25
Forest                                       Lexapro
16
Eli Lilly                                      Prozac
14
GlaxoSmithKline                     Paxil CR                          11

~~~~~~~~~~~~~~~~~~~~

http://www.nytimes.com/2008/01/17/health/17depress.html?_r=1&oref=slogin
THE NEW YORK TIMES
Antidepressant Studies Unpublished
Eli Lilly, manufacturer of Prozac, was among those criticized.
By BENEDICT CAREY
Published: January 17, 2008

The makers of antidepressants like Prozac and Paxil never published the
results of about a third of the drug trials that they conducted to win
government approval, misleading doctors and consumers about the drugs' true
effectiveness, a new analysis has found.

In published trials, about 60 percent of people taking the drugs report
significant relief from depression, compared with roughly 40 percent of
those on placebo pills. But when the less positive, unpublished trials are
included, the advantage shrinks: the drugs outperform placebos, but by a
modest margin, concludes the new report, which appears Thursday in The New
England Journal of Medicine.

Previous research had found a similar bias toward reporting positive results
for a variety of medications; and many researchers have questioned the
reported effectiveness of antidepressants. But the new analysis, reviewing
data from 74 trials involving 12 drugs, is the most thorough to date. And it
documents a large difference: while 94 percent of the positive studies found
their way into print, just 14 percent of those with disappointing or
uncertain results did.

The finding is likely to inflame a continuing debate about how drug trial
data is reported. In 2004, after revelations that negative findings from
antidepressant trials had not been published, a group of leading journals
agreed to stop publishing clinical trials that were not registered in a
public database. Trade groups representing the world's largest drug makers
announced that members' companies would begin to release more data from
trials more quickly, on their own database, clinicalstudyresults.org.

And last year, Congress passed legislation that expanded the type of trials
and the depth of information that must be submitted to clinicaltrials.gov, a
public database operated by the National Library of Medicine. The Food and
Drug Administration's Web site provides limited access to recent reviews of
drug trials, but critics say it is very hard to navigate.

"This is a very important study for two reasons," said Dr. Jeffrey M.
Drazen, editor in chief of The New England Journal. "One is that when you
prescribe drugs, you want to make sure you're working with best data
possible; you wouldn't buy a stock if you only knew a third of the truth
about it."

Second, Dr. Drazen continued, "we need to show respect for the people who
enter a trial."
"They take some risk to be in the trial, and then the drug company hides the
data?" he asked. "That kind of thing gets us pretty passionate about this
issue."

Alan Goldhammer, deputy vice president for regulatory affairs at the
Pharmaceutical Research and Manufacturers of America, said the new study
neglected to mention that industry and government had already taken steps to
make clinical trial information more transparent. "This is all based on data
from before 2004, and since then we've put to rest the myth that companies
have anything to hide," he said.

In the study, a team of researchers identified all antidepressant trials
submitted to the Food and Drug Administration to win approval from 1987 to
2004. The studies involved 12,564 adult patients testing drugs like Prozac
from Eli Lilly, Zoloft from Pfizer and Effexor from Wyeth.

The researchers obtained unpublished data on the more recently approved
drugs from the F.D.A.'s Web site.
For older drugs, they tracked down hard copies of unpublished studies
through colleagues, or using the Freedom of Information Act. They checked
all of these studies against databases of published research, and also wrote
to the companies that conducted the studies to ask if specific trials had
been published.

They found that 37 of 38 trials that the F.D.A. viewed as having positive
results were published in journals.
The agency viewed as failed or unconvincing 36 other trials, of which 14
made it into journals.

But 11 of those 14 journal articles "conveyed a positive outcome" that was
not justified by the underlying F.D.A. review, said the new study's lead
author, Dr. Erick H. Turner, a psychiatrist and former F.D.A. reviewer who
now works at Oregon Health and Sciences University and the Portland Veterans
Affairs Medical Center. His co-authors included researchers at Kent State
University and the University of California, Riverside.

Dr. Turner said the selective reporting of favorable studies sets up
patients for disappointment. "The bottom line for people considering an
antidepressant, I think, is that they should be more circumspect about
taking it," he said, "and not be so shocked if it doesn't work the first
time and think something's wrong with them."

For doctors, he said, "They end up asking, 'How come these drugs seem to
work so well in all these studies, and I'm not getting that response?' "

Dr. Thomas P. Laughren, director of the division of psychiatry products at
the F.D.A., said the agency had long been aware that favorable studies of
drugs were more likely to be published. "It's a problem we've been
struggling with for years," he said in an interview. "I have no problem with
full access to all trial data; the question for us is how do you fit it all
on a package insert," the information that accompanies many drugs.

Dr. Donald F. Klein, an emeritus professor of psychiatry at Columbia, said
drug makers were not the only ones who can be reluctant to publish
unconvincing results. Journals, and study authors, too, may drop studies
that are underwhelming.

"If it's your private data, and you don't like how it came out, well, we
shouldn't be surprised that some doctors don't submit those studies," he
said.