FDA to review missing [Lilly] drug company documents

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[sSRI-Research] FDA to review "missing" [Lilly] drug companydocumentsNewsFDA to review "missing" drug company documentsJeanne LenzerNew Yorkhttp://bmj.bmjjournals.com/cgi/content/full/330/7481/7The US Food and Drug Administration has agreed to review confidentialdrug company documents that went missing during a controversialproduct liability suit more than 10 years ago. The documents appearto suggest a link between the drug fluoxetine (Prozac), made by EliLilly, and suicide attempts and violence.The missing documents, which were sent to the BMJ by an anonymoussource last month, include reviews and memos indicating that EliLilly officials were aware in the 1980s that fluoxetine had troublingside effects and sought to minimise their likely negative effect onprescribing.The documents received by the BMJ reportedly went missing during the1994 Wesbecker case that grew out of a lawsuit filed on behalf ofvictims of a work-place shooting in 1989. Joseph Wesbecker, armedwith an AK-47, shot eight people dead and wounded another 12. He thenshot and killed himself. Mr Wesbecker, who had a long history ofdepression, had been placed on fluoxetine one month before theshootings.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 patientsreported new activation but 19% of placebo-treated patients alsoreported new activation yielding a difference of 19% attributable tofluoxetine."The FDA recently issued a warning that antidepressants can cause acluster of "activating" or stimulating symptoms such as agitation,panic attacks, insomnia, and aggressiveness. Dr Joseph Glenmullen, aHarvard psychiatrist and author of The Antidepressant Solution,published by Free Press, said it should come as little surprise thatfluoxetine might cause serious behavioural disturbances, as it issimilar 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 theirresponsibility to report it to us and to publish it."Congressman Maurice Hinchey's office is currently reviewing thedocuments to determine whether Lilly withheld data from the publicand the FDA. Mr Hinchey (Democrat, New York) said: "This is analarming study that should have been shared with the public and theFDA from the get-go, not 16 years later."This case demonstrates the need for Congress to mandate the completedisclosure of all clinical studies for FDA-approved drugs so thatpatients and their doctors, not the drug companies, decide whetherthe benefits of taking a certain medicine outweigh the risks."The plaintiffs in the Wesbecker product liability sought to show thatEli Lilly withheld negative study data from the FDA and thatfluoxetine tipped Wesbecker over into a homicidal rage. Lilly won a 9to 3 jury verdict in late 1994 and subsequently claimed that itwas "proven in a court of law... that Prozac is safe and effective."The trial judge, Justice John Potter, suspecting that a secret dealhad been struck, pursued Lilly and the plaintiffs, eventually forcingLilly in 1997 to admit that it had made a secret settlement with theplaintiffs during the trial. Infuriated by Lilly's actions, JudgePotter ordered the finding changed from a verdict in Lilly's favourto one of "dismissed as settled with prejudice," saying, "Lillysought to buy not just the verdict but the court's judgment as well."David Graham, currently associate director in the FDA's Office ofDrug Safety, criticised the analysis of post-marketing surveillancedata submitted by Lilly to the FDA. After discovering that Lillyfailed to obtain systematic assessments of violence and had excluded76 of 97 cases of reported suicidality, Dr Graham concluded in a memodated 11 September 1990 that "because of apparent large-scaleunderreporting, [Lilly's] analysis cannot be considered as provingthat fluoxetine and violent behavior are unrelated."Congressman Maurice Hinchey said that the internal Lilly data "shouldhave been shared with the public"Credit: CONGRESSMAN MAURICE HINCHEYAn FDA advisory panel was convened in 1991 to review the fluoxetinedata. It concluded that fluoxetine was safe despite the concernsraised by Dr Graham and others, leading critics to point out thatseveral of the panellists had financial ties to Eli Lilly.Dr Glenmullen said the missing documents obtained by the BMJprovide "the missing link" between the recent advisory issued by theFDA and what Lilly scientists knew 16 years ago.Since the 1991 FDA hearings Dr Peter Breggin, who served as themedical expert in the Wesbecker case, has warned that the stimulanteffects of fluoxetine can cause suicide and violence. He cautionsthat the 38% activation rate reported in the missing document isprobably low because "it doesn't include other symptoms of activationsuch as panic attacks, hypomania, and mania."Dr Kapit, the original reviewer for fluoxetine, told the BMJ, "If wehave good evidence that we were misled and data were withheld then Iwould change my mind [about the safety of fluoxetine]. I do agree nowthat these stimulatory side effects, especially in regards tosuicidal ideation and homicidal ideation, are worse than I thought atthe time that I reviewed the drug."Lilly declined to be interviewed but issued a written statementsaying, "Prozac has helped to significantly improve millions oflives. It is one of the most studied drugs in the history ofmedicine, and has been prescribed for more than 50 million peopleworldwide. The safety and efficacy of Prozac is well studied, welldocumented, and well established."