FDA to review missing drug company documents

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http://bmj.bmjjournals.com/cgi/content/full/330/7481/7

BMJ 2005;330:7 (1 January), doi:10.1136/bmj.330.7481.7

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FDA to review " missing " drug company documents

Jeanne Lenzer

New York

The US Food and Drug Administration has agreed to review confidential drug

company documents that went missing during a controversial product liability

suit more than 10 years ago. The documents appear to suggest a link between the

drug fluoxetine (Prozac), made by Eli Lilly, and suicide attempts and violence.

The missing documents, which were sent to the BMJ by an anonymous source

last month, include reviews and memos indicating that Eli Lilly officials were

aware in the 1980s that fluoxetine had troubling side effects and sought to

minimise their likely negative effect on prescribing.

The documents received by the BMJ reportedly went missing during the 1994

Wesbecker case that grew out of a lawsuit filed on behalf of victims of a

work-place shooting in 1989. ph Wesbecker, armed with an AK-47, shot eight

people dead and wounded another 12. He then shot and killed himself. Mr

Wesbecker, who had a long history of depression, had been placed on fluoxetine

one month before the shootings.

One of the internal company documents, a report of 8 November 1988,

entitled " Activation and Sedation in Fluoxetine Clinical Trials, " found that in

clinical trials " 38% of fluoxetine-treated patients reported new activation but

19% of placebo-treated patients also reported new activation yielding a

difference of 19% attributable to fluoxetine. "

The FDA recently issued a warning that antidepressants can cause a cluster

of " activating " or stimulating symptoms such as agitation, panic attacks,

insomnia, and aggressiveness. Dr ph Glenmullen, a Harvard psychiatrist and

author of The Antidepressant Solution, published by Free Press, said it should

come as little surprise that fluoxetine might cause serious behavioural

disturbances, as it is similar to cocaine in its effects on serotonin.

Dr Kapit, the FDA clinical reviewer who approved fluoxetine, said

he was not given the Lilly data. " These data are very important. If this report

was done by Lilly or for Lilly, it was their responsibility to report it to us

and to publish it. "

Congressman Maurice Hinchey's office is currently reviewing the documents

to determine whether Lilly withheld data from the public and the FDA. Mr Hinchey

(Democrat, New York) said: " This is an alarming study that should have been

shared with the public and the FDA from the get-go, not 16 years later.

" This case demonstrates the need for Congress to mandate the complete

disclosure of all clinical studies for FDA-approved drugs so that patients and

their doctors, not the drug companies, decide whether the benefits of taking a

certain medicine outweigh the risks. "

The plaintiffs in the Wesbecker product liability sought to show that Eli

Lilly withheld negative study data from the FDA and that fluoxetine tipped

Wesbecker over into a homicidal rage. Lilly won a 9 to 3 jury verdict in late

1994 and subsequently claimed that it was " proven in a court of law... that

Prozac is safe and effective. "

The trial judge, Justice Potter, suspecting that a secret deal had

been struck, pursued Lilly and the plaintiffs, eventually forcing Lilly in 1997

to admit that it had made a secret settlement with the plaintiffs during the

trial. Infuriated by Lilly's actions, Judge Potter ordered the finding changed

from a verdict in Lilly's favour to one of " dismissed as settled with

prejudice, " saying, " Lilly sought to buy not just the verdict but the court's

judgment as well. "

Graham, currently associate director in the FDA's Office of Drug

Safety, criticised the analysis of post-marketing surveillance data submitted by

Lilly to the FDA. After discovering that Lilly failed to obtain systematic

assessments of violence and had excluded 76 of 97 cases of reported suicidality,

Dr Graham concluded in a memo dated 11 September 1990 that " because of apparent

large-scale underreporting, [Lilly's] analysis cannot be considered as proving

that fluoxetine and violent behavior are unrelated. "

Congressman Maurice Hinchey said that the internal Lilly data

" should have been shared with the public "

Credit: CONGRESSMAN MAURICE HINCHEY

An FDA advisory panel was convened in 1991 to review the fluoxetine data.

It concluded that fluoxetine was safe despite the concerns raised by Dr Graham

and others, leading critics to point out that several of the panellists had

financial ties to Eli Lilly.

Dr Glenmullen said the missing documents obtained by the BMJ provide " the

missing link " between the recent advisory issued by the FDA and what Lilly

scientists knew 16 years ago.

Since the 1991 FDA hearings Dr Breggin, who served as the medical

expert in the Wesbecker case, has warned that the stimulant effects of

fluoxetine can cause suicide and violence. He cautions that the 38% activation

rate reported in the missing document is probably low because " it doesn't

include other symptoms of activation such as panic attacks, hypomania, and

mania. "

Dr Kapit, the original reviewer for fluoxetine, told the BMJ, " If we have

good evidence that we were misled and data were withheld then I would change my

mind [about the safety of fluoxetine]. I do agree now that these stimulatory

side effects, especially in regards to suicidal ideation and homicidal ideation,

are worse than I thought at the time that I reviewed the drug. "

Lilly declined to be interviewed but issued a written statement saying,

" Prozac has helped to significantly improve millions of lives. It is one of the

most studied drugs in the history of medicine, and has been prescribed for more

than 50 million people worldwide. The safety and efficacy of Prozac is well

studied, well documented, and well established. "