The flawed basis for FDA post-marketing safety decisions: the example of anti-depressants and children.

The FDA (February 3, 2005) issued a black box warning that all antidepressants increase the risk of suicidal thinking and behavior in children and adolescents that must be cited in all advertising as well as included in the package insert. Following this, there was a sharp decrease in antidepressant prescriptions for children with uncertain public health impact. The current black box does not claim that these medications increase the risk of completed suicides, although this is the clear implication of the term 'suicidality'. The interpretation by the press is unequivocal that lethal outcomes prompted this action. This review concludes the following: (1) Since no suicide occurred in clinical trials of approximately 4400 children, the analyses relied upon 'suicidality' as a surrogate. (2) The classification of adverse events by the Columbia group necessarily relied on inferences, because the available evidence was not prospectively collected for this purpose. (3) The data analysis relied on a composite variable labeled 'suicidality', an unvalidated, inappropriate surrogate. Specific criticisms of analytic procedures and inferences are presented. The failure of the FDA's post-marketing surveillance system is reviewed. The data necessary for objective evaluations of possible post-marketing harm cannot be gathered by the current process. Proper prospective post-marketing surveillance by linked computerized medical records is a crucial issue that deserves major public and political attention and prompt action.