Carry-over biases in clinical pharmacology.

If the effect of a treatment carries on after the treatment is withdrawn then the response to a second treatment may well be due in part to the previous treatment. This so called carry-over effect may bias any clinical trial in which subjects are tested more than once. Cross-over studies can be routinely checked for this bias. In other study designs, however, common sense and alertness for unusual patterns in the data are the only defences against it. The amount of carry-over bias in clinical trials can be somewhat minimized by the following measures. Dose-response studies, dose-titration studies, and open evaluation studies should require a sufficient washout period between the administrations of the drugs. Studies using duplicate standard deviations for the estimation of intra-individual reproducibility of a test should routinely include a statistical test for differences between the duplicate data. Self-controlled studies should not be used otherwise than as an initial orientation for a new treatment. Parallel studies should routinely be stratified for symmetry of previous treatments. Studies with subjective variables are frequently influenced by psychological carry-over effects and should, therefore, be validated together with objective variables whenever possible.