BMJ 2005;330:7 (1 January), doi:10.1136/bmj.330.7481.7
FDA to review "missing" drug company documents
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
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
"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."<link>
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 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
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."