Bioequivalence of generic medicinal products - general rules

Two medicinal products are considered therapeutically equivalent if they are bioequivalent, that is if the rate and extent at which the medicinal product enters the bloodstream in its active form, after administration in the same dose are the same, which translates into identical safety and efficacy.

Bioequivalence can be demonstrated through time curves of plasma concentration which compare the extent and the rate of absorption of active substance(s) from the test and reference medicinal product on a number of healthy test persons. This involves monitoring the following pharmacokinetic parameters:

  • the area under the plasma concentration time curve of the active substance (AUC), which is a parameter for the absorption rate;
  • the maximum plasma concentration of the active substance (Cmax);
  • the time at which the maximum plasma concentration is observed (Tmax), which is a parameter for the absorption rate of the active substance.

These data are evaluated according to scientifically proved statistical methods. The mean values of the pharmacokinetic parameters of both medicinal products are compared and the 90 % confidence intervals are calculated. Bioequivalence is demonstrated when the confidence intervals of those kinetic parameters are contained between 80 % and 125 %. In practice, bioequivalence between two products can be demonstrated in most cases only when the mean AUC and Cmax values between the test and reference product do not differ by more than 5 %. Due to the variability of bioavailability specific to each product and patient, differences in mean values of more than 5 % can lead to confidence intervals exceeding the 80-125 % limit.

In rare cases, for certain active substances and certain pharmaceutical forms, bioequivalence between the test and reference medicinal product can be demonstrated without in vivo bioequivalence studies. It can be shown for example based on in vitro data.

For some medicinal products, relatively small differences in dose or strength can lead to therapeutic failures and/or worse adverse reactions. Such medicinal products are called medicinal products with narrow therapeutic range, that means that the difference between the toxic dose and the therapeutic dose is small. Most of these medicinal products require monitoring, where the blood concentration is measured in order to control and personalise the patient's treatment. For medicinal products with a narrow therapeutic range, a small difference in the amount available in the body can have bigger consequences than other medicinal products. Therefore, strict guarantees of bioequivalence are necessary when comparing a generic medicinal product with a reference medicinal product. The experts assess reference and generic medicinal products with a narrow therapeutic range using appropriate and strict criteria to ensure that their efficacy, safety and quality would be equivalent to other medicinal products. This way the statistical evaluation of the different pharmacokinetic parameters used in bioequivalence may be stricter for those medicinal products by using even tighter limits. The strict range of 80-125 % commonly used is tightened in some cases to 90-111% .

Many active substances exist in different salt forms, for example morphine hydrochloride and morphine sulfate. In some cases, the active substance of the generic medicinal product and the reference medicinal product differ in salts or esters. The question is how much these salts differ from each other in terms of absorption, distribution and elimination in/by the body. In general, the difference in salts does not affect the behaviour of the medicinal product in the body, nor its efficacy. However, when evaluating the marketing authorisation application, experts examine the medicinal products taking into account the proposed salt and monitor the efficacy, safety and quality of the different salts of the same active substance.

More information
Official guideline of the European Medicines Agency (EMA) on the investigation of bioequivalence  

Last updated on 10/02/2023