Pfizer Finds Two Failed Trials Equal One Coup for Zoloft

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> Fri, 6 Aug 2004 16:51:31 -0400

> [sSRI-Research] Pfizer Finds Two Failed

> Trials Equal One Coup for Zoloft

>

> URL for this article:

>

http://online.wsj.com/article/0,,SB109173990602884222,00.html

>

> Pfizer Finds Two Failed Trials Equal One Coup for

> Zoloft

>

> By BARBARA MARTINEZ and CHRISTOPHER WINDHAM

> Staff Reporters of THE WALL STREET JOURNAL

> August 6, 2004; Page B1

>

> When Pfizer Inc. sought a six-month extension of its

> patent for its

> blockbuster antidepressant Zoloft in 1998, the U.S.

> Food and Drug

> Administration told the company to conduct two

> clinical trials on depressed

> children.

>

> Pfizer spent almost a year working with the FDA to

> design the trials. Upon

> completion of the tests, Zoloft failed to show

> better efficacy than a

> placebo, according to the standards laid out by the

> FDA. The company didn't

> seek approval to sell the drug for use in depressed

> children and doesn't

> make the individual study results available to

> doctors or patients.

>

> But a 2003 article based on those two trials,

> published in the widely read

> JAMA, the Journal of the American Medical

> Association, said that Zoloft is

> an " effective " treatment for childhood depression.

>

> How Pfizer parlayed two failed clinical trials into

> a positive article

> offers a window into the current storm over

> unpublished clinical data. In

> June, New York Attorney General Eliot Spitzer

> accused GlaxoSmithKline PLC of

> fraud for hiding unfavorable trial data about its

> antidepressant Paxil, and

> he warned that he is looking at other drug makers.

> Pfizer says it has not

> been contacted by the attorney general's office.

> Glaxo denies wrongdoing and

> has made much of its clinical trial data available

> on the Web.

>

> There is no doubt that antidepressants help millions

> of patients, including

> some children. Some doctors worry that the recent

> spotlight on unpublished

> clinical trials may cause patients to stop taking

> antidepressants that may

> be helping them. A new FDA review of clinical trials

> involving nine

> different antidepressants, including unpublished

> studies, found evidence of

> a link between the drugs and suicidal tendencies in

> children.

>

> Zoloft is the most widely prescribed antidepressant

> for children and

> adolescents, with nearly three million pediatric

> prescriptions written in

> 2002. It is approved as a treatment for

> obsessive-compulsive disorder in

> children, but doctors can prescribe it for any use.

>

> Under terms of a pediatric-study law implemented in

> 1998, Pfizer, simply by

> having conducted the two trials, won its six-month

> extension -- potentially

> worth a billion dollars in extra revenue. Zoloft,

> Pfizer's third-largest

> selling drug, now loses patent protection in 2006.

>

> Even though the pediatric-study law was intended to

> generate data to help

> doctors evaluate drugs, there wasn't any requirement

> in 1998 to make results

> from the failed studies public (a later rule now

> requires that a summary be

> made public). The FDA added to Zoloft's prescribing

> information, or label,

> some information about weight loss in children

> taking the drug, as well as a

> statement that the drug's efficacy in depressed

> pediatric patients " has not

> been established. "

>

> The FDA posted a memo in February on its Web site

> that described the studies

> as having " failed. " For the JAMA article,

> researchers combined the results

> of 376 children and adolescents in the two trials.

> Pfizer says the

> researchers did so to get more statistical power and

> reduce the likelihood

> that any result was due to chance.

>

> Based on the combined studies, the authors reported

> that 69% of the kids on

> Zoloft " responded " to the medication, which the

> researchers said is a

> statistically significant improvement over the 59%

> of kids who responded to

> a placebo. According to calculation provided to the

> Wall Street Journal,

> more patients in each of the two studies responded

> to Zoloft than did to

> placebo. But in the statistical analysis of a

> different measure considered

> by the FDA, Zoloft didn't outperform the placebo in

> one of the studies and

> did outperform in the other, but not by a

> statistically significant amount,

> according to Pfizer. While there is nothing to

> suggest Pfizer did anything

> untoward in combining the studies, Thomas P.

> Laughren, the FDA's team leader

> on psychiatric drug products in the division of the

> neuropharmacological

> drug products, says, " Relying on a secondary, pooled

> analysis is not

> acceptable " to his agency.

>

> The decision to pool the results for publication

> came before the trials were

> completed, says Cathryn M. Clary, vice president of

> Pfizer's U.S. Medical

> Psychiatry and Neurology unit.

>

> The JAMA article also didn't include remission data

> that the researchers had

> collected. Remission is considered the near-complete

> absence of symptoms, a

> better outcome than a patient who simply

> " responded. "

>

> In April, researchers who reviewed data from the two

> Pfizer studies, among

> other unpublished antidepressant studies, in the

> British journal Lancet,

> said that when the unpublished remission data and a

> possible increase in

> suicidal behavior are factored into the equation,

> there's an " unfavorable

> risk-benefit balance " for Zoloft use in children. If

> researchers collected

> data on remission, " then they should publish it, "

> said Tim Kendall, one of

> the Lancet authors and co-director of the National

> Collaborating Center for

> Mental Health in Britain.

>

> Pfizer's Dr. Clary says that at the time the two

> trials were conducted,

> remission data weren't typically included in child

> studies of

> antidepressants. A Pfizer spokeswoman says it would

> be inappropriate to

> present remission data on a short-term study of 10

> weeks. But the JAMA

> article referred to a published 2002 study on Prozac

> use in children that

> included remission data from an even shorter amount

> of time.

>

> One of the researchers of that study, Karen Dineen

> Wagner, professor of

> psychiatry at the University of Texas Medical Branch

> at Galveston, was the

> lead author of the JAMA Zoloft article. Dr. Wagner

> didn't return phone calls

> or e-mails. A spokeswoman at the university says she

> " prefers not to

> comment. "

>

> The JAMA article notes that two of the Zoloft

> patients and two of the

> placebo patients attempted suicide during the

> trials, and an additional

> three Zoloft patients had suicidal ideas. None of

> the placebo patients had

> suicidal ideas.

>

> Dr. Wagner's financial disclosure in the article

> said she had extensive ties

> to the drug industry, such as receiving " research

> support, " serving as a

> consultant, and participating in " speaker's

> bureaus. " Three of the other

> researchers also received fees from Pfizer and other

> drug makers.

>

> David Price, who leads a group that develops Kaiser

> Permanente's

> depression-treatment guidelines, questioned Pfizer's

> influence on the

> study's results in a letter to the editor published

> by JAMA in January.

> Although the principal author of the article was an

> academic researcher,

> footnotes said that Pfizer's Ruoyong Yang was the

> " principal statistician

> for the analyses. " It's more common for an

> independent statistician to do

> the statistical analysis, says Dr. Price.

>

> " This was peer reviewed by all-star people, " says

> Catherine DeAngelis, the

> editor-in-chief of JAMA. Although the combined study

> didn't mention that the

> two studies individually failed FDA standards, she

> says it would be obvious

> to anyone reading the article that either of the two

> alone lacked the

> [statistical] power " for meaningful results.

>

> The FDA says the sample sizes were not necessarily

> too small. Pfizer

> " proposed two studies that were intended to stand

> alone, and they failed

> individually to show an effect, " says the FDA's Dr.

> Laughren.

>

> Write to Barbara Martinez at

> barbara.martinez and Christopher

> Windham at christopher.windham