On the trough-to-peak ratio of drug effect in antihypertensive trials

Blood pressure in hypertensives (treated or untreated) varies over the course of the day, and, although animal models and human intervention studies have demonstrated that the ill effects of hypertension are mediated by the pressure itself, and not by some confounder, it remains unknown what time-related function of pressure (simple mean, root-mean-square, duration of pressure above some threshhold, and so on) might be the best predictor of hypertension-related morbidity. There is no accepted means of describing the time course of blood pressure, let alone a difference between two such descriptions, which might then be a description of the time course of a drug effect. In a document dated 1988, the US Food and Drug Administration (FDA) defined the trough-to-peak drug-effect ratio and indicated that drug approval would be granted only when values of this statistic were satisfactory. The FDAʹs belief in the importance of the time-course of drug effect has grown stronger over time, but the idea that only drugs with certain trough-to-peak ratios could be approved was discarded by the FDA within months of its appearance. In recent years, more promising means of assessing the time-course of drug effect have begun to take shape.