Minimally clinically relevant difference

There are a number of values of the treatment effect (delta or A) that could lead to rejection of the null hypothesis of no difference between the two means. For purposes of estimating a sample size the power of the study (that is, the probability that the null hypothesis of no difference is rejected given that the alternate hypothesis is true) is calculated for a specific value of A. in the case of a superiority trial, this specific value represents the minimally clinically relevant difference between groups that, if found to be plausible on the basis of the sample data through construction of a confidence interval, would be viewed as evidence of a definitive and clinically important treatment effect. 

PpLACEBO value that is considered the minimally clinically relevant difference (CRD). 

The definition of the minimally clinically relevant difference of interest involves clinical, medical, and regulatory experience and judgments. The appropriate sample size formula depends on the test of interest and should take into account the need for multiple comparisons (either among treatments or with respect to multiple examinations of the data). The project statistician provides critical guidance in this area. 

Cortisol and aldosterone concentrations were reduced by etomidate in adults (403,404), but the clinical relevance was minimal after a single bolus (405). A reduction in cortisol was reported 2 hours after delivery in 40 infants whose mothers received etomidate for cesarean section. There were also nine cases of severe to moderate hypoglycemia in this study, but the changes in blood glucose concentration were not significantly different from those in controls (406). 

The AUC of a single 500-mg oral dose of amoxicillin was found to be 12.17 mierograms/mL per hour in 10 healthy subjeets on a low fibre diet (7.8 g of insoluble fibre daily) but only 9.65 mierograms/mL per hour when they ate a high fibre diet (36.2 g of insoluble fibre daily) a difference of about 20%. Peak serum levels were the same and occurred at 3 hours. The clinical relevance of these changes is likely to be minimal. 

Systemic absorption of the extrapulmonary fraction through the GI tract has been reported for p -agonists. Only 7% of a nominal dose of terbutaline delivered via a pMDI reaches the systemic circulation via the GI tract (103), whereas approximately 35% of a dose of salbutamol (104) reaches the systemic circulation by GI absorption. These differences in GI absorption may well explain differences in systemic concentrations between P -agonists, but the clinical relevance of this difference is minimal, in particular since there is no clear relationship between systemic concentration of Pj-agonists and side effects... 

The clinical relevance of L/T ratio, a theoretical concept, is, however, less clear. Indeed, the L/T ratio is useful only in comparing the same drug substance in different inhaler devices. Comparisons between drugs should not be made, as different substances may differ in terms of relative activities in lungs and systemic circulation. For example, inhaled glucocorticosteroids, such as fluticasone, with minimal GI bioavailabiUty and hence a very high I/T ratio, have been shown to exert systemic effects (51). The L/T ratio should thus always be verified clini-... 

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