US: Antidepressants Under Scrutiny Over Efficacy

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according to a review of unpublished data submitted to the Food and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.

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drugs show they are effective, doctors unaware of the unpublished data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

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New England Journal were able to identify unpublished studies by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

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

Some studies that don't eventually get published are
registered with online trial registries, including the federal
government's 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 is not

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.

AMP Section Name:Pharmaceuticals
  • 182 Health

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