FDA working against citizens and for Big Pharma

http://online.wsj.com/article/SB1200...googlenews_wsj

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to a review of unpublished data submitted to the Food and Drug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 MedicineAs 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are effective, doctors unaware of the unpublished data are making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.