Wednesday, December 28, 2005

Dropout Rates Revisited

Most often, studies about study design are incredibly tedious and not very interesting.  But this one is different.  It should interest anyone who cares about the design and interpretation of psychiatric drug studies:
Dropout Rates in Placebo-Controlled and Active-Control Clinical Trials of Antipsychotic Drugs: A Meta-analysis Georg Kemmler, PhD; Martina Hummer, MD; Christian Widschwendter, MD; W. Wolfgang Fleischhacker, MD Arch Gen Psychiatry. 2005;62:1305-1312. Context  Dropout rates in randomized clinical trials of antipsychotic drugs have consistently been reported to be high, and the use of a placebo-controlled design is hypothesized to be one of the reasons for this.

Objective  To investigate this hypothesis in a meta-analysis of available data from pertinent clinical trials.

Data Sources  Comprehensive search of PubMed- and MEDLINE-listed journals.

Study Selection  Double-blind randomized controlled clinical trials of the second-generation antipsychotics risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, and aripiprazole meeting the following criteria: unselected patient population with a diagnosis of schizophrenia or schizoaffective disorder, change in psychopathologic symptoms as the primary end point, and trial duration of 12 weeks or less.

Data Extraction  Sample size, mean age, baseline disease severity, dropout rate, trial design, trial duration, and publication year.

Data Synthesis  Thirty-one trials meeting the inclusion criteria were found, comprising 10 058 subjects. Weighted mean dropout rates in the active treatment arms were significantly higher in placebo-controlled trials (PCTs) than in active-control trials: 48.1% (PCTs) vs 28.3% (active-control trials) for second-generation antipsychotics (odds ratio, 2.34; 95% confidence interval, 1.58-3.47) and 55.4% (PCTs) vs 37.2% (active-control trials) for classical antipsychotics (odds ratio, 2.10; 95% confidence interval, 1.29-3.40). Within PCTs, attrition rates were significantly higher in the placebo arms than with second-generation antipsychotics (60.2% vs 48.1%; odds ratio, 1.63; 95% confidence interval, 1.37-1.94). Within the subset of trials in which both second-generation and classical antipsychotics were used, dropout rates were significantly higher with classical antipsychotics.

Conclusions  Use of a placebo-controlled design had a major effect on the dropout rates observed. Because high dropout rates affect the generalizability of such studies, it is suggested that, in addition to the PCTs, studies with alternative designs need to be considered when evaluating an antipsychotic’s clinical profile.
It appears that patients are more likely to drop out of (withdraw from) the active arm of a placebo-controlled study, if the study medication is a second-generation ("atypical") antipsychotic, compared to similar studies that compare classical antipsychotics to placebo.  At first glance, this seems counterintuitive.  In clinical practice, patients are much more likely to stop taking classical antipsychotics than second-generation ones. 

It is not possible to be sure why this study had the outcome it did.  However, I suspect that it has to do with the fact that it is much harder for patients to be able to tell if they are getting the active drug or the placebo, if the active drug is a second-generation antipsychotic.  Pharmaceutical companies that have dropped certain investigational drugs, due to difficulty demonstrating consistent separation from placebo, might want to go back and look at their dropout rates.  It is conceivable that some promising agents might have been abandoned when the preliminary studies were limited by this effect. 

I wonder, too, if the same thing might turn out to be true for antidepressants, but I can only speculate about that. The whole business of interpreting drug studies keeps getting more complicated.