The Flawed Basis for FDA Post-Marketing Safety Decisions: The Example of Anti-Depressants and Children

Abstract

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.

The drugs don’t work? antidepressants and the current and future pharmacological management of depression

“…In addition, data was not prospectively collected to investigate suicidal attempts and limited narrative information was often only available. As such, classification of adverse events necessarily relied on inferences and often departed from standardized suicide assessment scales for children and adults, which in turn questions the strength of the conclusions reached [Klein, 2006].…”

Ten years after the FDA black box warning for antidepressant drugs: a critical narrative review

“…Furthermore, the FDA's findings appear to be based on inferences, since the evidence was obtained in a manner that is not methodologically reliable, nor fulfilling the requirements of the definitions of "suicidal tendencies" utilized by the standardized scales 22 .…”

“…Such action provoked a marked decrease in AD prescription 21 . The American Medical Association and the American Psychiatric Association subsequently warned of the potentially negative consequences that a decline in AD access could have on patients, who might otherwise be significantly benefited by their prescription 22 .…”

The ethics of psychopharmacological research in legal minors

“…Several studies on paediatric depression were hurriedly conducted in the USA under the pressure of time before the legislation ran out. As a result, these studies are methodically flawed [16]. In Europe, similar legislation has been in effect since 2007, but the impact of the 'EU Regulation on medicinal products for use in children' has yet to be seen [17].…”

“…The possibility of legislation to increase the availability of approved and safe drugs for children has been discussed in the USA and Europe [11,[14][15][16][17][45][46][47]]. An essential difference exists between the US and Europe in funding clinical trials with minors.…”