FAILURE OF STATISTICAL METHODS TO PROVE BIOEQUIVALENCE OF TWO MELOXICAM BIOEQUIVALENT FORMULATIONS. II. NON-PARAMETRIC METHODS
Roxana Colette Sandulovici, Anca Vatasescu, Florin, Constantin Mircioiu, Carol Davila · 2011
Applying the “official” parametric methods to analyze the results of a clinical bioequivalence (BE) study concerning two suppository formulations containing meloxicam as active substance, the bioequivalence couldn’t be proved, tested drug appearing to have a greater bioavailability than the reference drug. Since the reference drug presented an important intervariability and the tested drug proved a greater bioavailability than the reference drug, it was considered that the products could be bioequivalent, but the official statistical test failed to prove this. Following mainly the high variability of reference drug and a distribution of plasma levels of reference drug far from normality, the failure was thought as a consequence of the application of statistical parametric tests beyond the field of their validity. Statistical models for building non-parametric confidence intervals for the ratios of means of pharmacokinetic parameters were less restrictive that in the case of parametric analysis. In a first approximation there were neglected the sequence effects and further, both sequence and period effects. The results lead to the same failure of proving BE, like parametric methods. The conclusion was that non-parametric methods lead to the same conclusion concerning BE but are more efficient in rejecting the effects of outliers. Suspicion remains that even non-parametric methods are not efficient in correcting the bias induced by partition of data in some different classes as in the case of pharmacokinetic parameters of the reference drug. Rezumat Aplicând metodele “oficiale” parametrice pentru a analiza rezultatelor unui studiu clinic de bioechivalenţa (BE) a doua formulari de supozitoare care conţin ca substanţa activa meloxicam, BE nu a putut fi demonstrata, medicamentul testat dovedind o biodisponibilitate (BD) mai mare decât medicamentul de referinţa. Deoarece medicamentul de referinţa a prezentat o intervariabilitate foarte mare, iar medicamentul testat a avut o BD mai mare decât cel de referinţa, s-a luat in considerare faptul ca produsele ar putea fi BE, dar testele statistice oficiale nu au demonstrat acest lucru. Urmarind in principal variabilitatea mare si distribuţia nivelelor plasmatice a medicamentului de referinţa, departe de normalitate, s-a considerat ca esuarea demonstrarii BE este consecinţa aplicarii testelor statistice parametrice in afara câmpului lor de aplicare.