Placebo or active control trials of antipsychotic drugs?
The placebo-controlled trial has been the standard method to demonstrate efficacy and safety of antipsychotic drugs. We reviewed the scientific and ethical advantages and disadvantages of the placebo-controlled trial and an alternative method, the active-control trial, focusing more specifically on the active-control noninferiority trial. Recent meta-analyses indicate that a therapeutic dose of second-generation antipsychotic will very likely be statistically superior to placebo in an adequate trial, and that the average improvement of schizophrenia symptoms in a placebo arm will be small. These findings strengthen the scientific and ethical justification for the active-control noninferiority trial. New drugs in the pharmacotherapy for schizophrenia are often claimed to differ from their marketed competitors in their safety profile rather than in antipsychotic efficacy. Thus, in many cases, it appears sufficient to demonstrate mere noninferiority (rather than superiority) of antipsychotic efficacy in comparison with a standard antipsychotic. The active-control noninferiority trial is suitable for such demonstration. Sample size requirements for various equivalence margins in noninferiority trials are provided. Scientific and ethical arguments should lead to a more frequent use of the active-control noninferiority trial design.
Department of Biological Psychiatry, Innsbruck University Clinics, Austria. wolfgang.fleischhacker@uibk.ac.at
W Wolfgang
WW
Fleischhacker
Pal
P
Czobor
Martina
M
Hummer
Georg
G
Kemmler
Ralf
R
Kohnen
Jan
J
Volavka
D014150:Antipsychotic Agents / Q000627:therapeutic use*; D018849:Controlled Clinical Trials as Topic / Q000941:ethics / Q000379:methods* / Q000592:standards; D026690:Ethics, Clinical; D006801:Humans; D008433:Mathematics; D015201:Meta-Analysis as Topic; D018579:Patient Selection / Q000941:ethics; D010919:Placebos; D011569:Psychiatric Status Rating Scales; D012107:Research Design / Q000592:standards* / Q000706:statistics & numerical data; D018401:Sample Size; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D013810:Therapeutic Equivalency; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D010919:Placebos