PFPC Daily - December 31, 2004

Yesterday we posted a news item which reported that documents
previously "lost" by Eli Lilly - showing Prozac risks in 1988 - had
been found and sent to the British Medical Journal by an anonymous
source. The BMJ had forwarded the papers to the FDA who is now
investigating. Below is the BMJ article as it appeared today on its
website.

BMJ 2005;330:7 (1 January)

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. Joseph 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 Joseph 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 Richard 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 John 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."

David 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."

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 Peter 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."

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