OT: WSJ Article - Antidepressants Under Scrutiny Over Efficacy

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Antidepressants

Under Scrutiny

Over Efficacy

Sweeping Overview Suggests

Suppression of Negative Data

Has Distorted View of Drugs

By DAVID ARMSTRONG and KEITH J. WINSTEIN

January 17, 2008; Page D1

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to a review of unpublished data submitted to the Food and Drug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

ACCENTUATE THE POSITIVE

A review of research submitted to the FDA:

• Of 74 studies reviewed, 38 were judged to be positive by the FDA.

All but one were published, researchers said.

• Most of the studies found to have negative or questionable results

were not published, researchers found.

Source: The New England Journal of MedicineAs 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they are effective, doctors unaware of the unpublished data are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 k

, 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. GlaxoKline 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. , 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.

, 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

GlaxoKline 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 s 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

Hedaya, a professor of clinical psychiatry at town 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. . But information that

hasn't yet made it online is hard to come by. Dr. 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.

Write to Armstrong at david.armstrong@... and J.

Winstein at keith.winstein@...