Study Says Patients, Doctors Get
Distorted View of Antidepressants

Researchers Say Unpublished Reports Have Found
Many Drugs Have Little or No Effect on Patients

DAVID ARMSTRONG / Wall Street Journal 16jan2008

Numerous unpublished studies submitted to the Food and Drug Administration by pharmaceutical companies have found that many popular antidepressants have little or no effect on patients, according to a new review of the previously hidden findings.

As a result, researchers asserted in this week's New England Journal of Medicine [abstract below], doctors and patients are getting a distorted view of the effectiveness of blockbuster anti-depressants like Wyeth's Effexor and Zoloft, made by Pfizer Inc.

Since the overwhelming amount of published data on the drugs show they are effective, doctors unaware of the unpublished data are making inappropriate prescribing decisions that are not in the best interest of their patients, according to researchers led by Erick Turner, a psychiatrist at Oregon Health and Science University. Sales of antidepressants total about $21 billion a year, according to IMS Health.

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 The researchers publishing in the New England journal were able to identify unpublished studies by obtaining and comparing documents filed by the companies with the FDA against databases of medical publications.

Pfizer and Wyeth declined to comment on the study results. Both companies said they had committed to disclose all study results, although not necessarily in medical journals.

An FDA spokesperson said, "There is no effort on the part of the FDA to withhold or to not post drug review documents." For newer drugs, information is posted online "as soon as possible," the spokesperson said. The agency said older documents are not always available online and efforts to add those files to the Web are slowed by "a lack of resources." As for the delay in fulfilling Dr. Turner's records requests, the agency said it doesn't comment on individual requests. It did acknowledge there is a backlog in complying with records requests.

A total of 74 studies involving a dozen anti-depressants and 12,564 patients were registered with the FDA from 1987 through 2004. The FDA deemed 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 — were not published. 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.

One way of turning the study results upside down is to ignore a negative finding for the primary outcome being measured 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 resulting publication bias threatens to skew the medical professional's understanding of how effective a drug is for a particular condition, the researchers say. The growing movement of evidence-based medicine depends on analysis of published studies to make treatment decisions.

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, and they would say, 'What are you talking about? I have never seen a negative study.'" Dr. Turner, from his time reviewing studies at the FDA, said he knew there were negative studies that hadn't been published.

In 2004, the New York state attorney general sued GlaxoSmithKline PLC for alleged fraud, saying it suppressed studies showing that the antidepressant Paxil was no better than 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.

In this week's study, the researchers found that failing to publish negative findings inflated the reported effectiveness of all of the anti-depressant drugs. The researchers used a measurement called effect size. The larger the effect size, the greater the impact of a treatment.

The effect size of the antidepressant Zoloft was increased 64% by the failure to publish negative or questionable data on the drug, the researchers found. Looking at it another way, the researchers found the drug was closer to having a "small" effect for people taking it when all of the data is considered. When primarily positive results are all that is published, the drug was shown to have an increased effect closer to "medium."

source: 16jan2007

Selective Publication of Antidepressant Trials and
Its Influence on Apparent Efficacy

New England Journal of Medicine v.358:252-260, n.3, 17jan2008

Erick H. Turner, M.D., Annette M. Matthews, M.D., Eftihia Linardatos, B.S., Robert A. Tell, L.C.S.W., and Robert Rosenthal, Ph.D.

ABSTRACT

Background
Evidence-based medicine is valuable to the extent that the evidence base is complete and unbiased. Selective publication of clinical trials — and the outcomes within those trials — can lead to unrealistic estimates of drug effectiveness and alter the apparent risk–benefit ratio.

Methods
We obtained reviews from the Food and Drug Administration (FDA) for studies of 12 antidepressant agents involving 12,564 patients. We conducted a systematic literature search to identify matching publications. For trials that were reported in the literature, we compared the published outcomes with the FDA outcomes. We also compared the effect size derived from the published reports with the effect size derived from the entire FDA data set.

Results
Among 74 FDA-registered studies, 31%, accounting for 3449 study participants, were not published. Whether and how the studies were published were associated with the study outcome. A total of 37 studies viewed by the FDA as having positive results were published; 1 study viewed as positive was not published. Studies viewed by the FDA as having negative or questionable results were, with 3 exceptions, either not published (22 studies) or published in a way that, in our opinion, conveyed a positive outcome (11 studies). According to the published literature, it appeared that 94% of the trials conducted were positive. By contrast, the FDA analysis showed that 51% were positive. Separate meta-analyses of the FDA and journal data sets showed that the increase in effect size ranged from 11 to 69% for individual drugs and was 32% overall.

Conclusions
We cannot determine whether the bias observed resulted from a failure to submit manuscripts on the part of authors and sponsors, from decisions by journal editors and reviewers not to publish, or both. Selective reporting of clinical trial results may have adverse consequences for researchers, study participants, health care professionals, and patients.

Source Information
From the Departments of Psychiatry (E.H.T., A.M.M.) and Pharmacology (E.H.T.), Oregon Health and Science University; and the Behavioral Health and Neurosciences Division, Portland Veterans Affairs Medical Center (E.H.T., A.M.M., R.A.T.) — both in Portland, OR; the Department of Psychology, Kent State University, Kent, OH (E.L.); the Department of Psychology, University of California–Riverside, Riverside (R.R.); and Harvard University, Cambridge, MA (R.R.).

Address reprint requests to Dr. Turner at Portland VA Medical Center, P3MHDC, 3710 SW US Veterans Hospital Rd., Portland, OR 97239, or at turnere@ohsu.edu.

source: 16jan2008