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Executive Summary

No reliable evidence exists to link Lilly's Prozac (fluoxetine) or other antidepressants with suicidality or violent behavior, FDA's Psychopharmacological Drugs Advisory Committee determined at its Sept. 20 meeting. By a unanimous vote, the committee concluded that the data presented from FDA's spontaneous reporting system, from Lilly's clinical trials of Prozac, and testimonals by individuals who took Prozac, did not provide solid proof that Prozac or other antidepressant drugs cause or intensify suicidal tendencies or other violent behavior. Committee member Robert Hammer, PhD, Associate Professor of Biostatistics, Medical College of Virginia, said that "these data have been analyzed very thoroughly." Observing that a statistician once said that " 'if you torture the data, they'll confess," 'Hammer said: "I think these data have been tortured thoroughly and they still haven't confessed." Commenting on the need for more data, committee member Nina Rosenberg Schooler, PhD, University of Pittsburgh, said that "we really do need to know more about these drugs generally in studies that focus fairly specifically on issues of suicidality and suicidal thoughts." Lilly research exec Robert Zerbe reported that "in collaboration with FDA and outside consultants we have just initiated a study which will better characterize patients in which suicidal ideation emerges during various forms of treatment." Zerbe also pointed out the recent publication of a paper "describing a meta-analysis of our large U.S. data base" in the Sept. 21 issue of The British Medical Journal. Written by Charles Beasley, Jr. Bruce Dornseif et al., the BMJ article reports on a "retrospective analysis of pooled data from 17 double-blind clinical trials in [a total of 3,065] patients with major depressive disorder," comparing Prozac, a tricyclic antidepressant and placebo. The authors state that "suicidal acts did not differ significantly in comparisons of fluoxetine with placebo (0.2% v. 0.2%, p = 0.494)," but "suicidal ideation emerged marginally significantly less often with fluoxetine than with placebo (0.9% v. 2.6%, p = 0.094)." In another unanimous vote the committee concluded that the evidence does not indicate that a particular drug or a drug class poses a greater risk than others. Adverse drug reaction data on Prozac was also deemed inadequate to establish a causal link between the drug and suicidal or violent behavior in patients. Bruce Stadel, MD, branch chief for FDA's Division of Epidemiology and Surveillance asserted that the data on Prozac compiled from reports to FDA's Spontaneous Reporting System "can be suggestive, but it is very difficult to achieve a judgment of causality." This claim was echoed by NIMH Chief of Clinical Pharmacology Bill Potter, MD, who said, "we have not been presented with evidence to cause alarm that this antidepressant [Prozac] or any other antidepressant is contributing to suicidal behavior." While suggesting an unusually large number of reports of adverse reactions to Prozac, the data is difficult to interpret accurately because several factors could explain the reports, Stadel and Potter indicated. Among the factors sited by Stadel were the fact that Prozac is a relatively new drug, first marketed in 1988, and "there is an upswing in reporting in the initial year or two of marketing." Observing that publicity also influences the number of reports made, Stadel pointed to a "very large increase" in reports following the 1990 release of a report by Martin Teicher MD/PhD (McLean Hospital, Belmont, Mass.) suggesting the link between Prozac and suicidal behavior. Stadel maintained that there has been a general "large increase in the rate of reporting" for all drugs of adverse reactions "in the last few years. FDA epidemiologist Charles Anello pointed out that between 1968 and 1983 the average number of annual drug experience reports was 10,000. The current reports are running about 70,000 annually. The committee's conclusion concurs with FDA's initial review of the Prozac/suicidal ideation relationship. Focusing specifically on the adverse publicity about Prozac, FDA Division of Neuropharmacological Drugs Director Paul Leber, MD, stated that the data sources used for assessments "do not, at least to date and in the judgment of agency scientists and physicians, provide support for a differential risk of Prozac related suicidal thoughts, acts or other violent behaviors." However, he noted, "that the lack of a compelling body of evidence proving Prozac responsible is not in and of itself exculpatory." During the open public hearing section of the meeting, testimony was given by 32 people, most of whom claimed that they or someone they knew had attempted suicide or exhibited other violent behavior under the influence of Prozac. Lilly representative Gary Tollefson, MD/PhD., presented data from clinical studies of Prozac involving "over 5,000 patients" in the U.S. and Europe. Citing a 3,065 patient trial for Prozac's NDA, Tollefson claimed that the rate of suicidal acts for patients receiving Prozac "was not significantly different" from those of patients treated with placebo and tricyclic antidepressants. Although the committee determined that there was no evidence to support a causal relationship between antidepressants and suicidal ideation, some committee members felt that the stories of suicide attempts and violent behavior could partly be due to inappropriate medical care by physicians prescribing antidepressants. "As we listened to the stories this morning, many of which were really heartbreaking . . . [it] certainly seemed to me like bad medical care," Hammer noted. "I think what many of us are feeling is that we'd like somehow to give advice to improve that medical care." Hammer was skeptical, however, whether FDA could convey that message through standard communications such as labeling or Dear Doctor letters. The majority of committee members voted against changing the labeling for all antidepressants, but some members felt that the labeling could be modified to convey to physicians the importance of monitoring patients for adverse events. Indicating that FDA will still consider labeling changes, Office of Drug Evaluation I Director Robert Temple, MD, said that "if people want to write into us quickly . . . particular words we can certainly consider that from the committee." Lilly representatives and others at the meeting expressed fear that a change in labeling for antidepressive drugs would make patients reluctant to use the medications and therefore not receive important therapy. Susan Dime, director of the 35,000- member Depressive and Manic Depressive Association, said that "we should not discourage" the use of antidepressives. The committee also discussed the idea of issuing a "Dear Doctor" letter to discuss the possibility that patients taking antidepressants might attempt suicide or act violently, and the importance of looking for early signs of such problems. To assure that the results of the committee meeting are not misinterpreted, Leber suggested that FDA could "write a 'Talk Paper' on behalf of the agency, which would contain our distillation of the advice given."

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