Two different questions
When a generic medicine is brought to market, it must be shown to be equivalent to the reference product (most often the original). There are two ways of doing this, and they answer different questions:
- Bioequivalence: does the active substance enter the blood in the same way? It is measured by the concentration of the substance in the blood over time.
- Therapeutic equivalence: do the products act on the disease in the same way? It is assessed by clinical effect and safety in patients.
The law allows both kinds of study for generic medicines — “under the procedure established by acts forming the law of the Union” (Article 38, Part 2 of Law No. 61-FZ). Bioequivalence is defined in the EAEU Rules (clause 11) and in the Law (Article 4, items 12.4 and 45).
Comparison
| Bioequivalence | Therapeutic equivalence | |
|---|---|---|
| What is compared | The concentration of the active substance in the blood over time | Clinical effect and safety |
| Who takes part | As a rule, healthy volunteers (EAEU Rules, clause 27) | Patients with the disease the medicine is intended for |
| Main measures | Cmax and AUC: the ratio to the reference product and the 90 % confidence interval | A clinical measure set in advance in the protocol |
| Typical design | A two-sequence crossover study with a single dose (clause 15) | Set by the protocol: parallel groups or crossover, a course of treatment |
| Sample size | Calculated from variability; at least 12 in the analysis (clause 26) | Calculated from the clinical measure; usually considerably larger |
| Where it takes place | The clinic’s in-patient unit: volunteers are observed and samples are taken to a schedule | A clinic that observes patients; often several centres |
When bioequivalence is enough
If the active substance enters the blood and its concentration reflects its action, showing the same entry into the blood is normally considered sufficient: the data on the efficacy and safety of the original are then carried over to the generic. That is how most studies of immediate-release tablets and capsules work, and the EAEU Rules were written for them (clause 4). In some cases a study in people can be replaced by a laboratory comparison — see “Biowaiver”.
When therapeutic equivalence is needed
If the concentration in the blood does not reflect the action of the medicine, for example because it acts locally and is hardly absorbed, equivalence is shown by pharmacodynamic or comparative clinical studies (clause 4 of the EAEU Rules, Annexes 2 and 3). For locally acting forms the Rules have separate annexes (Nos. 11–13); Annex 9 covers topical corticosteroids and Annex 10 modified-release and transdermal forms.
How to tell which study your product needs
- Identify the dosage form. Immediate-release tablets and capsules are the main scope of the Bioequivalence Rules (clause 4); for other forms see Annexes 9–13 and EAEU acts.
- Check whether a waiver is possible. For some products a study in people is replaced by a laboratory comparison — a biowaiver.
- Check the registration requirements. Which kind of study is required for your product is determined by EAEU acts (Article 38, Part 2 of the Law); if in doubt, discuss it in advance with a regulatory specialist.
- Discuss the design. Agree the protocol with a biostatistician and a regulatory specialist before assessing a site.
What next
Once you have chosen the design, send the synopsis or protocol: we will assess feasibility at the clinic. For bioequivalence studies, the number of volunteers can be estimated in the calculator.
Sources
- Federal Law No. 61-FZ of 12 April 2010 “On the Circulation of Medicines”, Article 4 (items 12.4, 45) and Article 38 (Part 2) — text on ConsultantPlus.
- EAEU Bioequivalence Rules — clauses 4, 6, 11, 15, 26, 27; Annexes 9–13.
Questions and answers
Can a therapeutic equivalence study replace a bioequivalence study?
They are different kinds of study with different participants and measures. For generic medicines the law allows bioequivalence and (or) therapeutic equivalence studies under the procedure set by EAEU acts (Article 38, Part 2 of Law No. 61-FZ). Which kind is required for a particular medicine is determined by those acts; for borderline cases a regulatory specialist is needed.
Why is bioequivalence tested in healthy volunteers rather than patients?
Healthy people have fewer factors that affect how the substance enters the blood, so differences between products are easier to see. The EAEU Rules require such studies to be conducted in healthy volunteers, except where the product poses an obvious threat to their health and such a study would be unethical (clause 27).
This material is for information only and is not legal advice. The rules are cited as of the date of the last update; check the current versions of the documents before making decisions.
See also
What is bioequivalence? Cmax, AUC and Tmax in plain language
Bioequivalence is the similarity in how two medicines with the same active substance enter the bloodstream. It is tested in volunteers by comparing concentration–time curves using Cmax and AUC.
Learn more
Biowaiver: when a bioequivalence study may not be required
A biowaiver is an exemption from a bioequivalence study in people: equivalence is confirmed by a laboratory dissolution comparison if the product meets the conditions of the EAEU Rules. It does not apply to every product; where the conditions are not met, a study in volunteers is needed.
Learn more
EAEU rules for bioequivalence studies: a short guide
The EAEU Rules for Conducting Bioequivalence Studies (EEC Council Decision No. 85 of 3 November 2016) set the study design, the number and selection of volunteers, data analysis and the content of the report. The standard is a two-sequence crossover study, with at least 12 subjects in the analysis.
Learn more