There's been a growing understanding in the drug development world that studies boasting
of positive data on a drug tend to get published in the scientific literature with great fanfare; negative studies are often
silently allowed to sink out from sight. Now a new report in the New England Journal of Medicine concludes how that
trend has played out in the antidepressant field. Ninety-four percent of studies with positive drug
data showed up in print, compared to 14 percent of the studies with negative or inconclusive results. And that has
skewed the reported effectiveness of the drugs. If you combine the negative studies on antidepressants they were able to outperform
placebos by only a modest amount, not the 60 percent in published trials that demonstrated a positive
That's not likely to be news to practitioners in the field. Antidepressants have long
been notoriously unreliable. But it's, well, depressing, to see developers have been gaming the system with such indifference
to the scientific pursuit of the truth. Could they have been more interested in making a marketing case for a drug? Need you
Antidepressant Studies Unpublished
By Benedic Carey, Jan 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 But when the less positive, unpublished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
“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
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.
Because of an editing error, an article on Jan. 17 about a new report on publication
of drug company studies of antidepressants referred imprecisely to one of its findings. The report, in The New England Journal
of Medicine, found that Eli Lilly had presented one study of its antidepressant Prozac as positive, even though a review of
the study by the Food and Drug Administration determined that the drug did not perform as well as a placebo. None of the Prozac
studies analyzed in the report went unpublished.