ESTIMATING THE MINIMUM THERAPEUTICALLY EFFECTIVE DOSE OF A COMPOUND VIA REGRESSION MODELING AND PERCENTILE ESTIMATION

Estimation of the minimum effective dose (MED) of a compound from a ty pical placebo-controlled dose-response study can be carried out in sev eral ways. Current approaches compare treatment doses against a placeb o dose via selected contrasts to determine the lowest dose level at wh ich the contrast is statistically significant. Ruberg shows how this a pproach works for various choices of contrasts. Instead, the MTED (min imum therapeutically effective dose) might be defined as the lowest do se level that yields a therapeutic benefit to patients, on average, or to a given percentage of patients. One could use a lower confidence l imit for the mean approach to determine the dose yielding (on average) a therapeutic benefit via regression modelling of the continuous trea tment dose response. More importantly, a patient relevant approach wou ld be to actually estimate regression percentiles or construct regress ion tolerance intervals. Such an approach addresses the question 'What percentage of patients are receiving therapeutic (yet safe) doses',in stead of just knowing that a dose is effective 'on average', and thus would help to understand the distribution of patient responses at a gi ven treatment dose. This further enables one to better evaluate the ef ficacy versus safety trade-off as dose increases and provides better g uidelines for prescribed dose levels.