Antidepressant safety and efficacy revisited

RxNews recently reported on issues surrounding the safety of antidepressants in pediatric patients. Although there is still no conclusive evidence that antidepressants increase the risk of suicide in this population, recent legal proceedings against GlaxoSmithKline (GSK) draw attention to both the safety and efficacy of these drugs when used to treat major depressive disorder (MDD) in children and adolescents.

It should be noted that only one selective serotonin reuptake inhibitor (SSRI), fluoxetine ( Prozac®), is currently indicated for the treatment of MDD in pediatric patients.  Despite this fact, off-label use of Paxil® for the treatment of pediatric mood disorders is not uncommon.

Is Paxil® safe and effective in children?

The basis of the lawsuit filed by New York Attorney General Eliot Spitzer against GSK is that “GSK has engaged in repeated and persistent fraud by misrepresenting, concealing and otherwise failing to disclose to physicians information in its control concerning the safety and effectiveness of its antidepressant medication paroxetine HCL (Paxil®) in treating children and adolescents with major depressive disorder.”The lawsuit specifically points to two randomized placebo-controlled studies that “failed to show that paroxetine HCL was more effective than placebo or that there was any evidence of efficacy for treating MDD in children and adolescents.”  A third study failed to demonstrate the superior efficacy of paroxetine HCL versus placebo at a level of statistical significance on either primary endpoints.

GSK continues to maintain that all pediatric study data have been made available to the Food and Drug Administration (FDA) and were disseminated to physicians through various means including medical information letters.  One such letter clearly acknowledges that paroxetine HCL is not efficacious in the treatment of MDD in children and adolescents.  This letter also reports that data from pooled analyses of pediatric patients with MDD, obsessive/compulsive disorder and social anxiety disorder found that “the incidence of adverse events possibly related to suicidal behavior while on therapy (treatment phase plus taper phase) was 2.4% (18/738) for paroxetine HCL and 1.1% (7/647) for placebo”.  This difference, however, did not reach statistical significance (p=0.07).

Antidepressant labeling changes: Warnings updated

A slew of antidepressant labeling changes have occurred since October 2003, when FDA first issued a Public Health Advisory alerting health care professionals to a possible link between antidepressant use and suicidality in children (Table 1).  As of June 28, 2004, eight out of ten antidepressant manufacturers have complied with FDA’s request to include a class warning on suicide risks in their products’ labeling. Pfizer, the maker of Zoloft®, is still negotiating labeling language with FDA. Luvox®, the remaining product specified by FDA in its March 22, 2004 Public Health Advisory, was withdrawn from the market in 2002 and has not been re-approved.

Other legal and regulatory changes may soon follow, as the Senate Finance Committee is now investigating FDA’s conduct in evaluating the potential link between antidepressants and suicidality.  Thus far, the Senate committee has found evidence of the “unequal” status of the Office of Drug Safety (ODS) and the Office of New Drugs (OND), pointing to the apparent subservience of ODS relative to OND.  Senate Finance Committee Chairman Chuck Grassley (R-Iowa) wrote in a June 16 letter to FDA that “the ODS was described by one employee as the ‘unwanted stepchild’ at FDA, rather than a watchdog for the public at large.”  These eye-opening revelations may be the impetus needed to bring about meaningful changes within FDA and could eventually lead to substantive improvements in its drug safety review process.

Publication Bias

The focus of the lawsuit levied against GSK centers on the manufacturer’s alleged suppression or selective publication of drug safety and efficacy data. This issue has long been a concern of The American Medical Association, which has called for a Health and Human Services (HHS)-administered national clinical trials registry to address the issue of publication bias and ensure the unrestricted flow of information to health care providers and patients.  GSK has responded to this request by announcing that it intends to create an electronic database to “provide summaries of trial protocols and corresponding results for GSK-sponsored trials.”  Of course, the existence of a GSK database does not preclude the development of an independently maintained registry such as the one proposed by HHS.  At the very least, it would be reasonable to expect a shift in the way drug manufacturers handle the release of clinical trial data, and the publication planning process itself.

Many questions regarding the safety and efficacy of antidepressants in pediatric patients remain unanswered.  To date, eight out of ten antidepressants have received updated suicidality warnings. FDA is continuing its review of available clinical trial data to try to determine whether there is evidence that some or all antidepressants increase the risk of suicidality in pediatric patients with depression or other psychiatric disorders. FDA plans to present the findings from this review to the Psychopharmacological Drugs Advisory Committee and the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee during the summer of 2004.