Clinical Trials: Design Flaws Associated with Use of a Placebo.
BACKGROUND: The placebo arm of a trial, although it controls for psychological placebo effects and natural history of a disease and facilitates effective blinding, is susceptible to bias just like the true treatment arm is. The placebo arm of a trial may even be particularly vulnerable to specific types of bias. The present article focuses on design flaws associated with the use of a placebo. RESULTS: (1) Placebo-controlled trials using mortality rather than morbidity as the end point may have both ethical and statistical problems. (2) Bias may affect placebo data to a larger extent than active treatment data. (3) Trials may provide an atmosphere of exaggerated placebo effects and, consequently, inadequate power to determine differences between placebo and active treatment groups. (4) A biased placebo period due to carryover effect is a common problem of controlled trials with a crossover or self-controlled design. (5) Adjustment for asymmetries between placebo and treatment group in a parallel-group trial is inappropriate if such asymmetries are not completely independent on the main variables of the study. (6) Samples may not be representative when a large number of patients inappreciative of a possible treatment with placebo refuse randomization. CONCLUSIONS: It is emphasized that routinely accounting for design flaws associated with use of placebo may further improve the powerful method of controlled clinical trials.
Cleophas
Ton J.M.
TJ
Departments of Medicine and Clinical Pharmacology, Merwede Hospital, Dordrecht, The Netherlands.