Clinical Trials

❘❙❚■ Chapter 27 | InteractionFigure 2. Mean change in systolic blood pressure (SBP) from baseline by center for a hypotheticalmulticenter study.Mean SBP change from baseline (mm Hg)20–2–4–6–8–10Drug ADrug B12 3 4 5 6 7 8 9 10Rank of centerand center occurred (P < 0.001). If the interaction is ignored and a main effectregression analysis is performed, the overall treatment effect is estimated to be0.56 mm Hg (95% CI 0.20, 0.91; P < 0.01). However, this positive significant resultis somewhat misleading because it is not reproducible in the three centers showinga negative change. In other words, if we randomly select a center from the pool ofcenters and repeat the study with the same protocol, there is a relatively highchance that a totally opposite result will be observed. The three centers witha negative change have 300 patients who show different results. As a consequence,the reproducibility and generalizability of the targeted patient population and thetreatment setting are questionable.In other words, if there is no evidence of treatment-by-center interaction, the datacan be pooled for analysis across centers. By carrying out an analysis with combineddata, an overall estimate of the treatment effect across centers is provided. On theother hand, if an interaction effect between treatment and center is found, theoverall (or average) summary statistic can be misleading and, hence, consideredto be inadequate [5,6]. In this case, it is preferable to describe the nature of theinteraction and to indicate which centers contribute towards the interaction [5].Treatment-by-period interaction in a crossover trialIn the earlier stages of drug development, crossover trials are frequently used toinvestigate the pharmacokinetics of a study drug. In any crossover trial a so-calledtreatment-by-period interaction can be present. This means that the effect of thetreatment is influenced by the period of the trial that the patient is in. Even after314