What is compared
A generic (test) medicine contains the same active substance as the original (reference) medicine. To show that the generic is equivalent to the original, its bioavailability is tested: how quickly and in what amount the active substance reaches the bloodstream. If these figures are close enough for the two medicines, they are called bioequivalent.
How a study is designed
Most often it is a crossover study in healthy volunteers:
- Volunteers are randomly divided into two groups.
- In the first period, one group takes the original medicine and the other takes the generic.
- A break follows (the washout period), long enough that by the start of the next period the substance is no longer detectable in the blood.
- In the second period, the medicines are swapped.
- During the dosing periods, blood samples are taken at pre-set times and the concentration of the active substance is measured.
Each participant is compared with themselves, so differences between people have less effect on the result. If the protocol requires a different design (for example, parallel groups), it is explained in the informed consent.
Three parameters to know
The test results are used to plot a concentration–time curve. Three values are calculated from it:
- Cmax — the maximum concentration of the substance in the blood;
- Tmax — the time at which that concentration is reached;
- AUC — the area under the curve: the total amount of the substance that has entered the blood over the observation period.
The main parameters for comparison are Cmax and AUC: they reflect both the rate and the extent of absorption.
How the conclusion is drawn
For Cmax and AUC, the ratio of the generic to the original is calculated, together with its confidence interval. The standard criterion is that the 90 % confidence interval of the ratio lies within 80.00–125.00 % (clauses 81 and 87 of the EAEU Rules; the calculation is done on log-transformed measures, clause 88). If it does, the medicines are considered bioequivalent. For drugs with a narrow therapeutic range the limits are tighter — 90.00–111.11 % (clause 104) — and for highly variable drugs the Rules allow widened limits for Cmax under the conditions they set out (clauses 105–109).
What this means for a sponsor
A bioequivalence study is part of the registration dossier of a generic medicine. Its quality depends on the design, the accuracy of sampling times, sample handling and the analytical method. That is why, when choosing a site, sponsors look at its experience, its equipment for processing and storing samples, and its quality system — see “How to evaluate a clinical study site”.
Bessalar Clinic conducts bioequivalence studies: send us a protocol or synopsis, and we will assess feasibility and prepare a quote.
Sources
- Rules for Conducting Bioequivalence Studies of Medicinal Products within the EAEU — Decision of the Council of the Eurasian Economic Commission of 3 November 2016 No. 85 (as amended by Decisions No. 67 of 4 September 2020, No. 22 of 15 February 2023 and No. 30 of 12 April 2024): clause 15 — the standard design (a randomised two-period crossover study with a single dose); clause 26 — at least 12 subjects in the analysis; clause 27 — studies are conducted in healthy volunteers, except where the product poses an obvious threat to their health and such a study would be unethical; clause 28 — age of at least 18; clauses 81, 87 and 88 — the criterion (the 90 % confidence interval, limits of 80.00–125.00 %) and log transformation; clause 104 — the narrow limits; clauses 105–109 — highly variable drugs.
Questions and answers
How is a bioequivalence study different from a clinical study of efficacy?
A bioequivalence study does not look at how a medicine treats a disease. It compares how the active substance of two medicines enters the blood. If it behaves in the same way, the efficacy and safety data of the original medicine can be relied on for the generic.
Why are bioequivalence studies carried out in healthy volunteers?
Healthy people have fewer factors that affect how a substance enters the blood (concomitant diseases and medicines), so differences between the medicines show up more clearly. For some medicines, for example those used in serious diseases, the study is carried out in patients; this is determined by the protocol.
See also
Bioequivalence studies in Moscow
A bioequivalence study shows that a generic medicine reaches the bloodstream in the same way as the reference medicine. Bessalar Clinic conducts such studies in healthy volunteers in its in-patient unit and processes samples on site.
Learn more
Phases of clinical trials: how Phases I, II, III and IV differ
Clinical trials of a new medicine go through four phases. Phase I studies safety and dose, Phase II studies efficacy and the dosing regimen, Phase III confirms the results in a large group, and Phase IV follows the medicine after registration.
Learn more