Antidepressant Studies Unpublished

Antidepressant Studies Unpublished
Eli Lilly, manufacturer of Prozac, was among those criticized.

http://www.nytimes.com/2008/01/17/he...=1&oref=slogin

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 But when the less positive, unpublished trials are included, the advantage shrinks: the drugs outperform placebos, but by a modest margin, concludes the new report, which appears Thursday in The New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.