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BIOEQUIVALENCE IMPLIES THERAPEUTIC EQUIVALENCE. I. BIOSTATISTICAL APPROACH

FLORENTINA GHERGHICEANU¹, ROXANA SANDULOVICI², IRINA PRASACU^3*, VALENTINA ANUȚA³, CONSTANTIN MIRCIOIU³

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The axiom that “if two drugs achieve same plasma levels for the active substance, they have the same therapeutic effect” is accepted in all specific legislations and it is not object of dispute. So, that bioequivalence implies therapeutically equivalence. Following economic interest or following real concern regarding the effect, but unawareness about the biopharmaceutical and pharmacokinetic component of drug actions, about methodology of bioequivalence studies, a large number of papers appeared along time, alarming about possible risks associated with generic substitution for particular drugs or for particular diseases. The aim of the paper was to present rigorous mathematical arguments for establishing that bioequivalence implies therapeutic equivalence. The confidence intervals for the difference between a tested and a reference drug are simulated starting from the intra-subjects variability and the actual difference between pharmacokinetic parameters. Performing a concrete calculus starting from the confidence interval statistical method for testing bioequivalence, it is shown that the difference between two bioequivalent drugs is most likely all the time lower than 10%. It concerns the fear of clinicians, concerning the highly variable drugs, but the problem is false since, for clinicians, variability is, in fact, inter-subjects variability and error term in the bioequivalence testing formula depend on intra-subjects variability, which is much lower than inter-subjects variability, in all cases. Finally, is shown that estimation of the number of subjects required for a statistical significant proof that two bioequivalent drugs are not therapeutic equivalent, leads to numbers of hundreds of thousands. Theoretically and practically, bioequivalence (BE) implies therapeutic equivalence and there is no scientific argument or practical example that cancels this conclusion.