A medicinal product is bioequivalent to the reference product if bioequivalence studies show that, with the same dose, blood concentration profiles over time overlap and, therefore, such concentrations are unlikely to produce significant differences in efficacy and safety (therapeutic effects/adverse reactions).
Bioequivalence studies are pharmacokinetic studies (from the Greek kinesis, movement, and pharmakon, medicine) that aim at comparing the bioavailability of two medicinal products, i.e. the amount of medicinal product that passes into the blood circulation after administration, in relation to the speed at which this occurs.
Bioequivalence is assessed by comparing the parameters characterising bioavailability (the maximum plasma concentration of the medicine [Cmax]; the time at which this concentration is reached after administration [Tmax]; the area under the curve [AUC], which represents the trend in the medicine’s plasma concentration over time).
The ratio of the mean concentrations of AUC and Cmax, obtained after administration of the two medicines, statistically analysed, should fall within an acceptability range of 0.80-1.25, with a 90% probability (or within a ± 20% range if the difference between the parameters is used instead of their ratio). The confidence interval (0.80-1.25) has been agreed at international level, taking into account the variations in bioavailability that may occur in one person receiving that specific medicinal product at different times, and in different subjects.
Where bioequivalence between the generic medicinal product and the reference medicinal product is demonstrated, efficacy and safety are considered overlapping and medicinal products are deemed to be therapeutically equivalent.
For generic medicinal products, there is therefore a derogation from the obligation to submit pre-clinical tests (pharmacological and toxicological studies) and clinical trials, as laid down in Article 8, paragraph 3, letter l), of Legislative Decree No 219/2006, since they have already been submitted and assessed by the regulatory authority for the reference medicinal product.
The quality of a generic medicinal product is comprehensively assessed in accordance with applicable European legislation and guidelines. In addition, equivalence in terms of critical quality attributes between generic and reference medicinal products is assessed, taking into account that suppliers of raw materials, formulation, manufacturing process and manufacturers are usually different and could characterise the quality and stability of medicinal products differently.