Clinical Trials

Clinical Trials: A Practical Guide ■❚❙❘Classification of an interaction effectInteraction effects can be classified as quantitative or qualitative [1].A quantitative interaction effect occurs when the magnitude of the treatmenteffect varies according to different levels (values) of another factor, but thedirection of the treatment effect remains the same for all levels of the factor.A qualitative interaction occurs when the direction of the treatment effect differsfor at least one level of the factor.To illustrate the two interaction effects described above, consider a hypotheticaltrial of an antihypertensive drug. Suppose that one of the objectivesof the trial is to assess whether the reduction in SBP is the same for smokers andnonsmokers. Treatment and smoking status both have two levels (for the former,the levels are placebo and active drug treatment; for the latter, the levels arenonsmoker and smoker), generating four possible combinations. Suppose that theprimary endpoint is the change in SBP from baseline. The effect of eachcombination on the outcome can be displayed graphically to allow for visualinspection of the various interactions (Figure 1).In Figure 1, mean change in SBP from baseline is on the vertical axis, while thehorizontal axis represents smoking status. The mean change from baseline SBP bytreatment can then be plotted at each level of smoking status, and a line canbe drawn between the points for each treatment level. The distance betweenthe two lines represents the treatment effect (the difference in the mean changein SBP between the active drug and the placebo).In Figure 1, panel A shows a pattern of no interaction effect; this is characterizedby two parallel lines that are equidistant at the two levels of smoking status (ie, theeffect of the study drug is to reduce SBP by the same amount in smokers andnonsmokers). Panels B and C show a possible quantitative interaction betweentreatment and smoking status; the two lines do not cross and so the treatmenteffect does not change its direction, although the distance between the lines isdifferent at each level of smoking status. In panels B and C, the results indicatethat the active treatment is more effective at reducing SBP than placebo. Whilepanel B demonstrates that the treatment leads to a greater reduction in SBPamong nonsmokers than smokers, the opposite effect is observed in panel C.In panel D, the difference in the mean reduction in SBP between the activetreatment and placebo group is positive (a larger reduction in SBP on placebothan on active treatment) among smokers, but negative (a larger reduction in SBPon active treatment than on placebo) among nonsmokers. Panel D shows apossible qualitative interaction between treatment and smoking status. Since the307