Sweeping Overview Suggests Suppression of Negative Data Has Distorted View of Drugs

By DAVID ARMSTRONG and KEITH J. WINSTEIN

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popular antidepressants has been exaggerated by selective publication of favorable results, according to a review of unpublished data submitted to the Food and Drug Administration.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Since the overwhelming amount of published data on the drugs show they are effective, doctors unaware of the unpublished data are making inappropriate prescribing decisions that aren’t in the best interest of their patients, according to researchers led by Erick Turner, a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 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 The researchers publishing in the New England Journal were able to identify unpublished studies by obtaining and comparing documents filed by the companies with the FDA against databases of medical publications.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.